Paul Harari, MD

Paul Harari, MD

Professor and Chairman

Department of Human Oncology

As professor and chairman of the UW Department of Human Oncology, principal investigator for the Wisconsin H&N SPORE Grant and member of the UW Carbone Cancer Center Senior Leadership Council, I facilitate the interaction of investigators involved in basic, translational and clinical cancer research activities. I am deeply committed to the leadership of multidisciplinary clinical, teaching and research teams.

The overall theme of my clinical and laboratory research is to improve treatment outcome for patients with head and neck cancer (HNC). Areas of particular research emphasis include the interaction of molecular growth inhibitors combined with radiation and the use of conformal radiation treatment techniques to limit normal tissue toxicity. I serve as PI for a recently funded SPORE Grant in HNC at the University of Wisconsin and direct one scientific project as well as the Administrative Core within the SPORE Grant. I have previously served as PI for NIH R29 and R01 laboratory research grants investigating HNC response and resistance mechanisms in combination with radiation. I have been an active RTOG HNC Committee member for more than 20 years (now NRG) and serve as PI or co-PI for a series of national and international HNC trials.

Serving currently as president of ASTRO, a major focus is to illuminate the tremendous power and precision of radiation to heal, to cure, to image, to improve human health and quality of life. We convey this message most effectively through storytelling, the passionate stories of patients and families whose lives have been saved or extended by the expert application of radiation. A unique and highly appealing aspect of radiation oncology is the opportunity for close collaboration between technology, biology and clinical medicine. Never before have the prospects for impactful advances in our field been so bright, and many of these advances involve multi-investigator teams, working together to achieve new milestones.


Resident, University of Arizona, Radiation Oncology (1990)

Intern, University of California-Davis, Internal Medicine (1985)

MD, University of Virginia, Medicine (1984)

BS, Tufts University, Biology (1980)

Academic Appointments

Jack Fowler Professor and Chairman, Human Oncology (2007)

Associate Director, University of Wisconsin Carbone Cancer Center, University of Wisconsin Carbone Cancer Center (2007)

Jack Fowler Professor (Endowed Professorship), Human Oncology (2003)

Associate Professor, Human Oncology (1999)

Assistant Professor (tenure track), Human Oncology (1993)

Selected Honors and Awards

ASTRO Presidential Track – 2016-2020 (2016)

PI, NIH H&N Cancer SPORE Grant at the University of Wisconsin (2016–pres.)

Canadian Association Radiation Oncology (CARO) Lecturer (2014)

Katie Dinshaw Annual Oration, Indian Cancer Congress (2013)

RSNA Annual Oration in Radiation Oncology (2013)

Wharton Lecturer, Princess Margaret Hospital (2011)

ASTRO Fellow Inductee (FASTRO) (2011)

Alpha Omega Alpha Alumnus Inductee, University of Virginia School of Medicine (2011)

Course Completion: Program for Chiefs of Clinical Services, Harvard School of Public Health (2009)

ESTRO Honorary Membership Award (2009)

Harold P. Rusch Award for Translational Cancer Research (2005)

Jack Fowler Endowed Professorship in Human Oncology (2003–pres.)

Academic Sabbatical, Peter MacCallum Cancer Institute, Melbourne, Australia (2001)

Wisconsin/Hilldale Faculty/Undergraduate Research Award (1998)

Teacher of the Year in Radiation Oncology, University of Wisconsin (1998)

Wisconsin/Hilldale Faculty/Undergraduate Research Award (1995)

NIH First Award, R-29 (1995)

ASTRO Resident Research Award presented to Radiation Oncology Resident (D. Petereit), for work carried out in P. Harari laboratory during ASTRO fellowship year (1993)

RSNA Scholars Program Grant (1993)

American Cancer Society Career Development Award (1992)

Teacher of the Year in Radiation Oncology, University of Wisconsin (1991)

International Cancer Research Technology Transfer (ICRETT) Fellowship to study at Mount Vernon Hospital and Gray Laboratory, London, England (1990)

Resident Essay Award, American Society for Therapeutic Radiology and Oncology (ASTRO) (1989)

American Radium Society Young Oncologist Travel Grant for Radiation Oncology (1989)

Junior Investigator Travel Award for the Sixth International Conference on Chemical Modifiers of Cancer Treatment. Paris, France (1988)

Postdoctoral NIH Fellowship Grant under E.W. Gerner, Ph.D., for Cancer Biology Research (1986)

R.H. Love Scholarship for Medical Study (1983)

Society of the Cincinnati Scholarship for Academic Achievement (1982)

Lawson Memorial Scholarship for Medical Study (1981)

Paul A. Warren Scholarship for Excellence in Genetics (1980)

Magna Cum Laude graduate, B.S. Biology, Tufts University (1980)

Phi Beta Kappa (1979)

Boards, Advisory Committees and Professional Organizations

ASTRO Board of Directors, Presidential Track (2016–pres.)

ASTRO Board of Directors, Education Council (2012–2016)

NCI Head and Neck Cancer Steering Committee (2010–pres.)

ASTRO Head and Neck Resource Panel (2010–pres.)

Chair Search Committee, UW Department of Medical Physics (2011–2013)

UW Hospital Department Chairman Leadership Group (2010–pres.)

ASTRO Strategic Planning Task Force (2010)

ASTRO Red Journal Editor Selection Task Force (2010)

ASTRO Practical Radiation Oncology Journal Editor Selection Task Force (2009)

Scientific Committee, Wolfsberg Meeting on Molecular Radiation Biology/Oncology  (2011–pres.)

UW School of Medicine Council of Chairs (2007–pres.)

ASTRO Annual Meeting Scientific Program Committee (2005–2010)

American H&N Society, Annual Meeting Program Committee (2009–2010)

ASTRO CME/MOC Committee of the Education Council (2007–2010)

Immediate Past Chair, ASTRO Education Committee of the Education Council (2009)

Program Committee, American Head and Neck Society (2007–2008)

ASTRO Research Evaluation Committee of the Research Council (2007–2011)

Associate Director, University of Wisconsin Carbone Comprehensive Cancer Center (2007–2016)

Chairman, 1st ASTRO/ASCO/AHNS Multidisciplinary H&N Cancer Symposium (2006–20007)

ASTRO Meeting Program Committee (2005–2007)

Chairman, ASTRO Education Committee (2004–2008)

ASCO Program Committee (2004–2008)

UWCCC Clinical Research Committee (2003–2008)

American Radium Society, Executive and Program Committee (2002–2006)

ASCO Education Committee, Head & Neck Track Leader (2002–2004)

ASCO Grants Selection Committee (2002–2004)

ASTRO Education Committee (2001–2004)

NCI Signal Transduction Working Group (2001–2007)

University of Wisconsin Comprehensive Cancer Center Scientific Review Committee (1999–pres.)

Residency Training Program Director, University of Wisconsin, Radiation Oncology (1997–2007)

1998–2000 University of Wisconsin Medical Foundation Long Range Planning Committee (1998–2000)

American College of Radiology, Committee on Residency Training in Radiation Oncology of the Commission on Education (1996–2007)

Medical Director, University of Wisconsin Radiation Oncology Quality Assurance Program (1995–1998)

University of Wisconsin, PI for Radiation Therapy Oncology Group (RTOG) (1994–2007)

Radiation Therapy Oncology Group (RTOG), Head and Neck Committee and Time/Dose/Volume Committee Co-Chair (1992–1996)

Eastern Cooperative Oncology Group (ECOG), Head and Neck Committee Radiotherapy Co-Chair (1992–1994)

Program Committee, 4th Research Conference on the Biology, Treatment and Prevention of Head and Neck Cancer (1992–1994)

National Cancer Institute, Head and Neck Cancer Strategy Committee (1992–2004)

University of Wisconsin Medical Foundation Compensation and Benefit Task Force (1995–1996)

Department of Human Oncology and UWCCC Cancer Registry Data Committee (1992–2004)

Associate, University of Wisconsin Center for Tobacco Research and Intervention (1992–2010)

University of Wisconsin Comprehensive Cancer Center Clinical Affairs Committee (1992–1995)

University of Wisconsin, Department of Human Oncology Research and Development Committee (1994–pres.)

Research Focus

Head and Neck Oncology, Molecular Modulation of Radiation Response, Conformal Head and Neck Radiation Treatment Techniques, Molecular Inhibition of Growth Factor Receptor Signaling

Radiation is a central cancer treatment modality often limited by normal tissue tolerance. The Harari lab investigates how molecular signaling pathways can modulate tumor response to radiation. We explore new approaches to improve radiotherapy outcomes by enhancing tumor cell radiosensitivity and by decreasing radiation toxicity to normal tissues. We focus on a series of promising molecular agents that target various cellular signaling pathways including growth factor receptor signaling and others as shown in the adjacent figure. Close coupling of the laboratory work to the clinical arena has enabled successful translation of promising laboratory findings into single institution and multi-institutional clinical trials.


Our research commenced with epidermal growth factor receptor (EGFR) targeting agents, cetuximab in the late 90s and several others (gefitinib & erlotinib) thereafter. Promising preclinical findings with cetuximab contributed to a landmark Phase III clinical trial in patients with advanced head and neck(H&N) squamous cell carcinoma that confirmed a survival advantage with the addition of cetuximab to radiation. This compelling result provides powerful stimulus to explore the combination of radiation with other receptor targeting agents explored in our lab including various IGF-1R and angiogenesis/VEGFR targeting agents.

Despite the tremendous promise of EGFR targeting agents in cancer therapy, many patients develop acquired resistance to therapy over time. Efforts to understand the underlying mechanisms of acquired resistance and improve the effectiveness of EGFR targeting strategies and radiation provide a primary research theme in recent years. These include efforts to combining EGFR inhibitors with other molecular targeting agents and the study of new generation EGFR inhibitors with unique properties based on improved molecular understanding of HER family signaling systems. The timeline below highlights many of the accomplished and current research themes in our lab along with several important milestones in the field of EGFR research related to cancer therapy.

Project: EGFR Family: Pan-HER Ab(Sym013), a mixture of monoclonal antibodies (mAb) that target EGFR, HER2 & HER3

Increasing evidence implicates that other EGFR family members, such as HER2 and HER3 provide compensatory signaling to bypass individual targeting of EGFR (see figure). Sym013 targets EGFR, HER2 and HER3 simultaneously and may prove highly valuable to advance the overall impact of EGFR therapy in cancer and help address the challenge of acquired resistance.

Project: p53: AMG232, MDM2 inhibitor that activates p53 by blocking MDM2-p53 interaction

Our previous studies revealed p53 as a critical factor in regulating acquired resistance to EGFR inhibitors and radiation. In addition, the activation of p53 results in radiation-induced cell cycle arrest, senescence or apoptosis. The combination of radiation and AMG232 which prevents MDM2-induced p53 degradation may offer a valuable treatment strategy in primary tumors or tumors with resistance to EGFR inhibitors.

Project: ALK (anaplastic lymphoma kinase): Crizotinib/Ceritinib, ALK inhibitors

ALK is a receptor tyrosine kinase (RTK) encoded by the ALK gene which is oncogenic when fused with several particular genes, including echinoderm microtubule associated protein like gene (EML4). EML4-ALK fusion occurs in 2% to 7% of patients with non-small cell lung cancer (NSCLC). Our interest is to examine the role of ALK in radiation response and the antitumor effects of Crizotinib and Ceritinib in combination with radiation in EML4-ALK positive NSCLC. We are also investigating the effect of combination of ALK inhibitor and EGFR or c-MET inhibitor on cell survival and radiosensitivity in EML4-ALK-positive NSCLC.


Project: Tumor marker: 131I-CLR1404, is a phospholipid analogue that enriches preferentially within tumors-in collaboration with Dr. Jamey Weichert

CLR1404 provides the opportunity for tumor-selective internal delivery of radiation thereby enabling combination with reduced dose external beam radiation in the treatment of H&N cancer. This agent shows selective accumulation and retention in human tumors across a broad spectrum of animal models (over 50 xenograft models to date including our H&N patient-derived xenografts), and in our first human H&N patients tested. CLR1404 is a radiolabeled phospholipid ether analog with powerful potential as an imaging agent (labeled with 124I) and as a therapy agent (labeled with 131I). This “diapeutic approach” (diagnostic and therapeutic) exploits the unique capabilities of this molecule as outlined in this proposal. CLR1404 is an alkyl phosphocholine, the lead compound emerging from over 15 years of laboratory investigation. Plasma membrane lipid rafts serve as the portal of entry for CLR1404, and the greater abundance of lipid rafts in cancer cells vs. normal cells provides therapeutic selectivity for this approach. CLR1404 has the ability to specifically target tumors while limiting dose to surrounding normal tissues; a scenario very difficult to achieve in H&N cancer patients, even with the use of highly conformal radiation techniques.


Previous Senior Scientists

Chunrong Li, PhD

Chunrong Li,  PhD

Associate Scientist

BS, Biology, Hebei Normal University (China)

MS, Anatomy and Histology, Hebei Medical University (China)

PhD,  Biochemistry and Molecular Biology, Beijing Institute of Radiation Research (China)


Shyh-Min_Huang, PhDShyhmin Huang, PhD

National Taiwan University, Agricultural Chemistry, BS

University of Wisconsin-Madison, Biomolecular Chemistry, PhD




Locations and Facilities


WIMR 3rd floor lobby


Harari lab space


Harari Lab Tissue Culture Room
Harari Lab Tissue Culture Room


WIMR 3 floor lounge area


Photo Album


Andrew Baschnagel and student at poster presentation AACR 2017
poster presentation AACR 2017


AACR 2017
AACR 2017


Welcome Dinner for Toulany Family, March 2017
Welcome Dinner for Toulany Family, March 2017



L to right: Gopol Iyer, Andrew Baschnagel, Paul Harari, Lauryn Werner, Joe, Chunrong Li, Allie Morgan,
L to right: Gopol Iyer, Andrew Baschnagel, Paul Harari, Lauryn Werner, Joe, Chunrong Li, Allie Morgan,


SMPH Ice Cream Social, May 2016
SMPH Ice Cream Social, May 2016


SMPH Ice Cream Social in May
SMPH Ice Cream Social in May

DHO dinner at 2016 AACR - New Orleans
DHO dinner at 2016 AACR – New Orleans


AACR 2016
AACR 2016
DHO dinner at AACR 2016_2
DHO dinner at AACR 2016


DHO dinner at AACR 2016
DHO dinner at AACR 2016


Harari Throws First Pitch - Mallards Game July 2016
Harari Throws First Pitch – Mallards Game July 2016


Mallards Game July 2016


SPORE meeting, September 2016
SPORE meeting, September 2016


SPORE meeting, September 2016
SPORE meeting, September 2016


SPORE meeting, September 2016
SPORE meeting, September 2016


SPORE meeting, September 2016
SPORE meeting, September 2016



Harari Lab, 2014: L-R: Shyhmin Huang, Fang, Eric Armstrong, Chunrong Li, Paul Harari, Lauryn Werner, Zach Morris, Gopal Iyer, Dave Francis
Harari Lab, 2014: L-R: Shyhmin Huang, Fang, Eric Armstrong, Chunrong Li, Paul Harari, Lauryn Werner, Zach Morris, Gopal Iyer, Dave Francis


Harari Lab -- Farewell lunch for Mahmoud Toulany 2014
Harari Lab — Farewell lunch for Mahmoud Toulany 2014


AACR annual meeting in San Diego, Chunrong Li, Lauryn Werner, Dave Francis, Shyh-min Huang
AACR annual meeting in San Diego


AACR 2014: Lauryn Werner, Shyh-min Huang at poster presentation
AACR 2014: Lauryn Werner, Shyh-min Huang at poster presentation


Dave Francis, Poster Presentation AACR 2014
Dave Francis, Poster Presentation AACR 2014


Harari Lab AACR 2014, Chunrong, Gabrielle, Shyh-Min, Lauryn
Harari Lab AACR 2014, Chunrong, Gabrielle, Shyh-Min, Lauryn


2014 Harari birthday celebration
2014 Harari birthday celebration



Harari Lab, 2013: Lauryn, Gabrielle, Eric, Dave, Zach, Paul, Noah, Aaron Wieland, Shyhmin, Chunrong
Harari Lab, 2013: Lauryn, Gabrielle, Eric, Dave, Zach, Paul, Noah, Aaron Wieland, Shyhmin, Chunrong


Harari lab 2012: Shyhmin, Jarob, Chunrong, Tim, Charlie, Eric, Grace, Paul, Randy, Bob Yang, Alex, Molly
Harari lab 2012: Shyhmin, Jarob, Chunrong, Tim, Charlie, Eric, Grace, Paul, Randy, Bob Yang, Alex, Molly


2012 AACR annual meeting in Chicago
2012 AACR annual meeting in Chicago


Chunrong, Eric, Harari Lab, 2008: Mari Iida, Tien Hoang, Tim Kruser, Chris, Meghan, Amol Ghia, Shyhmin Huang, Deric Wheeler
Chunrong, Eric, Harari Lab, 2008: Mari Iida, Tien Hoang, Tim Kruser, Chris, Meghan, Amol Ghia, Shyhmin Huang, Deric Wheeler


2006 Sergio Benavente Farewell dinner
2006 Sergio Benavente Farewell dinner


Corey, Greg, KT, Sergio, Eric, Paul, Shyhmin, Vinai_-- Sergio Farewell dinner
Corey, Greg, KT, Sergio, Eric, Paul, Shyhmin, Vinai_–
Sergio Farewell dinner


2004 Harari Lab: Sergio, Falgun, Prakash, KT, Tien, Paul, Greg, Eric, Shyhmin
2004 Harari Lab: Sergio, Falgun, Prakash, KT, Tien, Paul, Greg, Eric, Shyhmin


2002 Harari lab photo: Shyhmin Huang, Jing Li, Vinai Gondi, Eric Armstrong, Prakash Chinnaiyan
2002 Harari lab photo: Shyhmin Huang, Jing Li, Vinai Gondi, Eric Armstrong, Prakash Chinnaiyan

About Dr. Paul M. Harari

Harari at microscope

Harari when not at work

  • Life Beyond COVID: Pay Attention to Viruses. Int J Radiat Oncol Biol Phys
    Harari PM, Lambert PF
    2020 Oct 01; 108 (2): 348-350
  • Reprint of: Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: An ASTRO-ESTRO consensus statement. Radiother Oncol
    Thomson DJ, Palma D, Guckenberger M, Balermpas P, Beitler JJ, Blanchard P, Brizel D, Budach W, Caudell J, Corry J, Corvo R, Evans M, Garden AS, Giralt J, Gregoire V, Harari PM, Harrington K, Hitchcock YJ, Johansen J, Kaanders J, Koyfman S, Langendijk JA, Le QT, Lee N, Margalit D, Mierzwa M, Porceddu S, Soong YL, Sun Y, Thariat J, Waldron J, Yom SS
    2020 Jul 27; :
    • More

      PURPOSE: Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff.

      METHODS AND MATERIALS: A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases.

      RESULTS: In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care.

      CONCLUSIONS: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.

      View details for PubMedID 32730830
  • The Promise of Combining Radiation Therapy with Immunotherapy. Int J Radiat Oncol Biol Phys
    Jagodinsky JC, Harari PM, Morris ZS
    2020 Apr 23; :
    • More

      The development of immunotherapy in oncology builds upon many years of scientific investigation into the cellular mechanics underlying interactions between tumor cells and immune cell populations. The past decade has brought an accelerating pace to the clinical investigation of new immunotherapy agents, particularly in the setting of metastatic disease. The integration of immunotherapy into phase III clinical trial design has lagged in settings of advanced loco-regional disease where combination with radiotherapy may be critical. Yet such may be the settings where immunotherapies have their greatest potential to affect cancer patient survival and achieve curative outcomes. In this review, we discuss the interaction of radiation with the immune system and the potential to augment anti-tumor immunity through combined modality approaches that integrate radiation and immunotherapies. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with immunotherapy that may go unrecognized with conventional screening and monotherapy clinical testing of novel pharmaceutical agents. Using immune checkpoint blockade as a primary example, we discuss recent preclinical and clinical studies that illustrate the potential synergy of such therapies in combination with radiation and we highlight the potential clinical value of such interactions. For various immunotherapy agents, their greatest clinical impact may rest in combination with radiation and efforts to facilitate systematic investigation of this approach are highly warranted.

      View details for PubMedID 32335187
  • Practice Recommendations for Risk-Adapted Head and Neck Cancer Radiation Therapy During the COVID-19 Pandemic: An ASTRO-ESTRO Consensus Statement. Int J Radiat Oncol Biol Phys
    Thomson DJ, Palma D, Guckenberger M, Balermpas P, Beitler JJ, Blanchard P, Brizel D, Budach W, Caudell J, Corry J, Corvo R, Evans M, Garden AS, Giralt J, Gregoire V, Harari PM, Harrington K, Hitchcock YJ, Johansen J, Kaanders J, Koyfman S, Langendijk JA, Le QT, Lee N, Margalit D, Mierzwa M, Porceddu S, Soong YL, Sun Y, Thariat J, Waldron J, Yom SS
    2020 07 15; 107 (4): 618-627
    • More

      PURPOSE: Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff.

      METHODS AND MATERIALS: A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases.

      RESULTS: In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care.

      CONCLUSIONS: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.

      View details for PubMedID 32302681
  • Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas. Int J Radiat Oncol Biol Phys
    Fisher MM, SenthilKumar G, Hu R, Goldstein S, Ong I, Miller M, Brennan SR, Kaushik S, Abel L, Nickel KP, Iyer G, Harari PM, Kimple RJ, Baschnagel AM
    2020 Apr 13; :
    • More

      PURPOSE: We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.

      EXPERIMENTAL DESIGN: FGFR1, FGFR2, FGFR3 RNA in situ hybridization (ISH) expression was assessed in a cohort of HNSCC patient samples, cell lines and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle and DNA damage repair were evaluated. Reverse phase protein array (RPPA) was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell line and PDX models.

      RESULTS: FGFR1, FGFR2 and FGFR3 RNA ISH were expressed in 41%, 81% and 89%, of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appear to be multifactorial involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared to radiation or drug alone in a FGFR-expressing HNSCC cell line xenograft and PDX.

      CONCLUSIONS: These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.

      View details for PubMedID 32298810
  • Matrix density drives 3D organotypic lymphatic vessel activation in a microfluidic model of the breast tumor microenvironment. Lab Chip
    Lugo-Cintrón KM, Ayuso JM, White BR, Harari PM, Ponik SM, Beebe DJ, Gong MM, Virumbrales-Muñoz M
    2020 Apr 16; :
    • More

      Lymphatic vessels (LVs) have been suggested as a preferential conduit for metastatic progression in breast cancer, where a correlation between the occurrence of lymph node metastasis and an increased extracellular matrix (ECM) density has been reported. However, the effect of ECM density on LV function is largely unknown. To better understand these effects, we used a microfluidic device to recreate tubular LVs in a collagen type I matrix. The density of the matrix was tailored to mimic normal breast tissue using a low-density collagen (LD-3 mg mL-1) and cancerous breast tissue using a high-density collagen (HD-6 mg mL-1). We investigated the effect of ECM density on LV morphology, growth, cytokine secretion, and barrier function. LVs cultured in HD matrices showed morphological changes as compared to LVs cultured in a LD matrix. Specifically, LVs cultured in HD matrices had a 3-fold higher secretion of the pro-inflammatory cytokine, IL-6, and a leakier phenotype, suggesting LVs acquired characteristics of activated vessels. Interestingly, LV leakiness was mitigated by blocking the IL-6 receptor on the lymphatic ECs, maintaining endothelium permeability at similar levels of LV cultured in a LD matrix. To recreate a more in vivo microenvironment, we incorporated metastatic breast cancer cells (MDA-MB-231) into the LD and HD matrices. For HD matrices, co-culture with MDA-MB-231 cells exacerbated vessel leakiness and secretion of IL-6. In summary, our data suggest that (1) ECM density is an important microenvironmental cue that affects LV function in the breast tumor microenvironment (TME), (2) dense matrices condition LVs towards an activated phenotype and (3) blockade of IL-6 signaling may be a potential therapeutic target to mitigate LV dysfunction. Overall, modeling LVs and their interactions with the TME can help identify novel therapeutic targets and, in turn, advance therapeutic discovery.

      View details for PubMedID 32297896
  • Emphasize Treatment of Known Disease Rather Than Past Footprints. Int J Radiat Oncol Biol Phys
    Witek ME, Harari PM
    2020 04 01; 106 (5): 904
  • Targeting AKT/PKB to improve treatment outcomes for solid tumors. Mutat Res
    Iida M, Harari PM, Wheeler DL, Toulany M
    2020 Jan - Apr; 819-820: 111690
    • More

      The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBβ) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA, RAS, PDPK1, and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy.

      View details for PubMedID 32120136
  • Clinical outcomes for larynx patients with cancer treated with refinement of high-dose radiation treatment volumes. Head Neck
    Burr AR, Harari PM, Haasl AM, Wieland AM, Bruce JY, Kimple RJ, Hartig GK, McCulloch TM, Witek ME
    2020 Feb 14; :
    • More

      BACKGROUND: To evaluate disease control, toxicities, and dose to dysphagia/aspiration risk structures (DARS) using a direct gross tumor volume (GTV70Gy ) to planning target volume expansion (dPTV70Gy ) for patients with squamous cell carcinoma of the larynx (LSCC).

      METHODS: A retrospective review was performed on patients with LSCC treated between 2003 and 2018. Clinical outcomes, toxicities, and dosimetric data were analyzed.

      RESULTS: Seventy-three patients were identified. Overall survival at 5-years was 57.8%. Five-year local and regional control was 79.8% and 88.2%, respectively. Distant metastatic-only failure was 2.7%. Eighty percent of failures were 95% contained within the dPTV70Gy . Mean dose and the volume of DARS receiving 70 Gy was significantly lower for dPTV70Gy compared to a consensus-defined PTV70Gy .

      DISCUSSION: Judicious reduction in high-dose target volumes can preserve high tumor control rates while reducing dose to normal surrounding structures underscoring the potential benefit of this approach in enabling local therapy intensification to improve locoregional control.

      View details for PubMedID 32057151
  • Human Tumor-Lymphatic Microfluidic Model Reveals Differential Conditioning of Lymphatic Vessels by Breast Cancer Cells. Adv Healthc Mater
    Ayuso JM, Gong MM, Skala MC, Harari PM, Beebe DJ
    2020 Jan 01; : e1900925
    • More

      Breast tumor progression is a complex process involving intricate crosstalk between the primary tumor and its microenvironment. In the context of breast tumor-lymphatic interactions, it is unclear how breast cancer cells alter the gene expression of lymphatic endothelial cells and how these transcriptional changes potentiate lymphatic dysfunction. Thus, there is a need for in vitro lymphatic vessel models to study these interactions. In this work, a tumor-lymphatic microfluidic model is developed to study the differential conditioning of lymphatic vessels by estrogen receptor-positive (i.e., MCF7) and triple-negative (i.e., MDA-MB-231) breast cancer cells. The model consists of a lymphatic endothelial vessel cultured adjacently to either MCF7 or MDA-MB-231 cells. Quantitative transcriptional analysis reveals expression changes in genes related to vessel growth, permeability, metabolism, hypoxia, and apoptosis in lymphatic endothelial cells cocultured with breast cancer cells. Interestingly, these changes are different in the MCF7-lymphatic cocultures as compared to the 231-lymphatic cocultures. Importantly, these changes in gene expression correlate to functional responses, such as endothelial barrier dysfunction. These results collectively demonstrate the utility of this model for studying breast tumor-lymphatic crosstalk for multiple breast cancer subtypes.

      View details for PubMedID 31894641
  • Clinical Implications of Scleroderma in the Decision for Radiotherapy-Based Larynx Preservation. JAMA Otolaryngol Head Neck Surg
    Rydzewski NR, Harari PM, Hartig GK, Francis D, Witek ME
    2019 Dec 12; :
  • Nationwide Survey of Patients' Perspectives Regarding Their Radiation and Multidisciplinary Cancer Treatment Experiences. J Oncol Pract
    Shaverdian N, Yeboa DN, Gardner L, Harari PM, Liao K, McCloskey S, Tuli R, Vapiwala N, Jagsi R
    2019 Nov 20; : JOP1900376
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      PURPOSE: The perspectives of patients with cancer about their treatment can inform interventions to improve the approaches of treating oncologists and experiences of future patients. We sought to identify areas where current toxicity management, informed consent processes, and physician-patient communication merit improvement.

      METHODS: In a Web-based survey administered from March to May 2018 using quota-based sampling to draw a nationwide sample of US patients with cancer treated with radiotherapy within the past 5 years, we evaluated patient perceptions of adequacy of information about adverse effects, severity of actual adverse effects experienced, and experiences divergent from expectations.

      RESULTS: Among 403 respondents, 18% felt inadequately informed about what adverse effects to expect from radiotherapy, and 37% experienced radiation adverse effects that they wished they had known more about. Similar proportions of patients treated with chemotherapy (36%) and surgery (34%) experienced toxicities related to those treatments that they wished they had known more about. Patients who noted their adverse effects to be minimal versus severe were significantly more likely to feel informed about radiotherapy adverse effects (odds ratio, 13.05; 95% CI, 5.6 to 30.38; P < .001). Across all evaluated measures, a majority of patients indicated that they did not experience the potentially anticipated radiotherapy adverse effect or that it was the same as or better than expected.

      CONCLUSION: This study suggests that experiences with radiation adverse effects generally are congruent with expectations. Nevertheless, improvement of pretreatment counseling across all cancer therapy modalities seems warranted to improve informed decision making and treatment experiences.

      View details for PubMedID 31747336
  • Open the Gates for Treatment De-Intensification in Head and Neck Cancer. J Clin Oncol
    Harari PM
    2019 08 01; 37 (22): 1854-1855
  • Human organotypic lymphatic vessel model elucidates microenvironment-dependent signaling and barrier function. Biomaterials
    Gong MM, Lugo-Cintron KM, White BR, Kerr SC, Harari PM, Beebe DJ
    2019 09; 214: 119225
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      The lymphatic system is an active player in the pathogenesis of several human diseases, including lymphedema and cancer. Relevant models are needed to advance our understanding of lymphatic biology in disease progression to improve therapy and patient outcomes. Currently, there are few 3D in vitro lymphatic models that can recapitulate the physiological structure, function, and interactions of lymphatic vessels in normal and diseased microenvironments. Here, we developed a 3D microscale lymphatic vessel (μLYMPH) system for generating human lymphatic vessels with physiological tubular structure and function. Consistent with characteristics of lymphatic vessels in vivo, the endothelium of cultured vessels was leaky with an average permeability of 1.38 × 10-5 ± 0.29 × 10-5 cm/s as compared to 0.68 × 10-5 ± 0.13 × 10-5 cm/s for blood vessels. This leakiness also resulted in higher uptake of solute by the lymphatic vessels under interstitial flow, demonstrating recapitulation of their natural draining function. The vessels secreted appropriate growth factors and inflammatory mediators. Our system identified the follistatin/activin axis as a novel pathway in lymphatic vessel maintenance and inflammation. Moreover, the μLYMPH system provided a platform for examining crosstalk between lymphatic vessels and tumor microenvironmental components, such as breast cancer-associated fibroblasts (CAFs). In co-culture with CAFs, vessel barrier function was significantly impaired by CAF-secreted IL-6, a possible pro-metastatic mechanism of lymphatic metastasis. Targeted blocking of the IL-6/IL-6R signaling pathway with an IL-6 neutralizing antibody fully rescued the vessels, demonstrating the potential of our system for screening therapeutic targets. These results collectively demonstrate the μLYMPH system as a powerful model for advancing lymphatic biology in health and disease.

      View details for PubMedID 31154151
  • Reducing radiotherapy target volume expansion for patients with HPV-associated oropharyngeal cancer. Oral Oncol
    Burr AR, Harari PM, Ko HC, Bruce JY, Kimple RJ, Witek ME
    2019 05; 92: 52-56
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      PURPOSE: To evaluate clinical outcomes and patterns of failure using a direct gross tumor volume to planning target volume expansion in patients with p16-positive oropharyngeal squamous cell carcinoma.

      METHODS AND MATERIALS: We performed a retrospective review of patients with p16-positive oropharyngeal squamous cell carcinomas treated between 2002 and 2017 with primary radiotherapy with or without concurrent systemic therapy. Patient and disease characteristics associated with disease control and clinical outcomes were analyzed by Cox proportional hazards regression and Kaplan-Meier analyses. Imaging at the time of first failure was used to categorize failure patterns.

      RESULTS: We identified 134 patients with a median follow-up of 56.2 months (range 8.2-160.2 months). Local and regional control at 5 years was 91.5% (95% CI: 86.8-96.4%), and 90.8% (95% CI: 85.6-96.2%), respectively. Of the 14 locoregional failures, there were 10 in-field (Type A), 3 marginal (Type B), and 1 geographic (Type E). Age >70 years (HR 5.42; 95% CI: 1.87-15.68) and T4 versus T1-3 (HR 4.09; 95% CI: 1.01-2.65) were associated with increased rates of locoregional failure on multivariate analysis. The rate of gastrostomy tube retention at one year was 6.0% (range 2.8-12.7%).

      CONCLUSIONS: Management of patients with p16-positive oropharyngeal squamous cell carcinoma using definitive radiotherapy and a high-dose planning target volume created without a gross tumor volume to clinical tumor volume expansion resulted in high locoregional control with the vast majority of failures occurring within the high-dose field. These data warrant prospective evaluation of this technique as a therapy de-intensification approach.

      View details for PubMedID 31010623
  • Lessons Learned From Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients. Pract Radiat Oncol
    Gay HA, Santiago R, Gil B, Remedios C, Montes PJ, López-Araujo J, Chévere CM, Imbert WS, White J, Arthur DW, Horton JK, Jagsi R, Rabinovich R, Beriwal S, Viswanathan A, Erickson BA, Rengan R, Palma D, Loo BW, Kavanaugh JA, Bradley J, Yom SS, Harari PM, Lee Burnett O
    2019 Sep - Oct; 9 (5): 305-321
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      PURPOSE: Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created.

      METHODS AND MATERIALS: Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy.

      RESULTS: Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients.

      CONCLUSIONS: These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation.

      View details for PubMedID 30999000
  • Auriculotemporal Nerve Involvement in Parotid Bed Malignancy. Ann Otol Rhinol Laryngol
    Thompson JD, Avey GD, Wieland AM, Harari PM, Glazer TA, McCulloch TM, Hartig GK
    2019 Jul; 128 (7): 647-653
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      OBJECTIVE: To identify and evaluate patients with parotid bed malignancy demonstrating radiographic findings of auriculotemporal (AT) nerve involvement.

      METHODS: A retrospective review of patients with parotid bed malignancy was performed to identify patients with imaging findings of AT nerve involvement and record associated clinical findings, symptoms, and pathology information. Independent, blinded review of radiographic images by a senior neuroradiologist was performed to identify imaging characteristics and categorize patients into highly likely or possible involvement groups.

      RESULTS: Of 547 patients identified with parotid bed malignancy, 23 patients exhibited radiographic findings suggestive of AT nerve involvement. Thirteen patients met criteria for highly likely involvement, and 10 patients met criteria for possible involvement. Cutaneous malignancy with metastasis to the parotid bed accounted for 11 of 23 patients, and the most common histology was squamous cell carcinoma (9 patients). Primary parotid malignancy accounted for 12 of 23 patients, and the most common histology was salivary ductal carcinoma (3 patients). All 13 highly likely patients reported periauricular pain, and 11 of 13 demonstrated facial weakness. Features suggesting advanced disease included radiographic findings of intracranial involvement (10/23 patients), nonsurgical primary treatment (13/23 patients), and positive margins on pathology report (7/10 patients).

      CONCLUSION: AT nerve involvement is an uncommon but important phenomenon that often occurs in the setting of advanced disease and is commonly associated with periauricular pain and coexisting facial weakness. Awareness of the associated clinical features and imaging patterns can allow for appropriate identification of this pattern of spread and help to optimize treatment planning.

      View details for PubMedID 30894024
  • Personalized Treatment for Lacrimal Sac Adenoid Cystic Carcinoma: Case Report and Literature Review. Pract Radiat Oncol
    Bowen RC, Ko HC, Avey GD, Hartig GK, Hu R, Harari PM, Lucarelli MJ
    2019 May; 9 (3): 136-141
  • A Multi-Institutional Experience of MR-Guided Liver Stereotactic Body Radiation Therapy. Adv Radiat Oncol
    Rosenberg SA, Henke LE, Shaverdian N, Mittauer K, Wojcieszynski AP, Hullett CR, Kamrava M, Lamb J, Cao M, Green OL, Kashani R, Paliwal B, Bayouth J, Harari PM, Olsen JR, Lee P, Parikh PJ, Bassetti M
    2019 Jan-Mar; 4 (1): 142-149
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      Purpose: Daily magnetic resonance (MR)-guided radiation has the potential to improve stereotactic body radiation therapy (SBRT) for tumors of the liver. Magnetic resonance imaging (MRI) introduces unique variables that are untested clinically: electron return effect, MRI geometric distortion, MRI to radiation therapy isocenter uncertainty, multileaf collimator position error, and uncertainties with voxel size and tracking. All could lead to increased toxicity and/or local recurrences with SBRT. In this multi-institutional study, we hypothesized that direct visualization provided by MR guidance could allow the use of small treatment volumes to spare normal tissues while maintaining clinical outcomes despite the aforementioned uncertainties in MR-guided treatment.

      Methods and materials: Patients with primary liver tumors or metastatic lesions treated with MR-guided liver SBRT were reviewed at 3 institutions. Toxicity was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4. Freedom from local progression (FFLP) and overall survival were analyzed with the Kaplan-Meier method and χ2 test.

      Results: The study population consisted of 26 patients: 6 hepatocellular carcinomas, 2 cholangiocarcinomas, and 18 metastatic liver lesions (44% colorectal metastasis). The median follow-up was 21.2 months. The median dose delivered was 50 Gy at 10 Gy/fraction. No grade 4 or greater gastrointestinal toxicities were observed after treatment. The 1-year and 2-year overall survival in this cohort is 69% and 60%, respectively. At the median follow-up, FFLP for this cohort was 80.4%. FFLP for patients with hepatocellular carcinomas, colorectal metastasis, and all other lesions were 100%, 75%, and 83%, respectively.

      Conclusions: This study describes the first clinical outcomes of MR-guided liver SBRT. Treatment was well tolerated by patients with excellent local control. This study lays the foundation for future dose escalation and adaptive treatment for liver-based primary malignancies and/or metastatic disease.

      View details for PubMedID 30706022
  • Is HPV-Associated Oropharyngeal Cancer Becoming More Common in Older Patients? Laryngoscope Investig Otolaryngol
    Thompson JD, Harari PM, Hartig GK
    2018 Dec; 3 (6): 446-449
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      Objective: To evaluate changing age demographics over a 15-year period for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).

      Study Design: Retrospective review of patients identified with p16-positive OPSCC at our institution over a 15-year timeframe. Materials/Methods: p16-positive immunohistochemistry was used as a surrogate for HPV-associated OPSCC. Patients were categorized according to year of diagnosis (2002-2010 versus 2011-2016). Mean age and proportion of patients over age 65 were statistically evaluated and compared.

      Results: From 2002 to 2010, 100 patients were identified with p16-positive OPSCC, mean age at diagnosis was 55.2, and the proportion of patients over 65 was 10.0%. From 2011 to 2016, 188 patients were identified with p16-positive OPSCC, mean age was 58.5, and the proportion of patients over 65 was 19.6%. Both the mean age difference and the difference in proportion of patients over 65 were statistically significant (P = .001 and P = .034, respectively).

      Conclusion: The mean age at diagnosis and proportion of patients over 65 has increased over the past 15 years at our institution. This data suggests that HPV-associated OPSCC is being diagnosed more frequently in older persons and that the age demographic may be shifting. Confirmation of this trend with larger patient numbers on a national level will be valuable. This study highlights the importance of maintaining a high clinical suspicion for HPV-associated OPSCC regardless of patient age.

      Level of evidence: 4.

      View details for PubMedID 30599028
  • Randomized phase II/III confirmatory treatment selection design with a change of survival end points: Statistical design of Radiation Therapy Oncology Group 1216. Head Neck
    Zhang QE, Wu Q, Harari PM, Rosenthal DI
    2019 01; 41 (1): 37-45
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      BACKGROUND: To confirm the treatment effects of concurrent cetuximab plus docetaxel observed in Radiation Therapy Oncology Group (RTOG) 0234 and single out the effect of cetuximab, we designed RTOG 1216, a randomized phase II/III study, which uses an intermediate end point to select the best regimen for definitive testing of survival benefit.

      METHODS: In phase II, the best regimen should demonstrate statistically significant efficacy against the control with predefined advantage over the competing arm regarding disease-free survival (DFS). We evaluate operating characteristics of the randomized II/III group sequential design through simulations and numerical integrations under the null and various alternative hypotheses.

      RESULTS: Results show the randomized II/III design yields substantial savings on sample size and time with well-controlled type I and type II error rates.

      CONCLUSION: Overall, the proposed randomized II/III design has desirable properties that offer cost effectiveness, operational efficiency, and, most importantly, scientific innovation that can be considered for similar clinical research settings.

      View details for PubMedID 30549358
  • Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet
    Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Sturgis EM, Burtness B, Ridge JA, Ringash J, Galvin J, Yao M, Koyfman SA, Blakaj DM, Razaq MA, Colevas AD, Beitler JJ, Jones CU, Dunlap NE, Seaward SA, Spencer S, Galloway TJ, Phan J, Dignam JJ, Le QT
    2018 Nov 15; :
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      BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.

      METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with, number NCT01302834.

      FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.

      INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.

      FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.

      View details for PubMedID 30449625
  • HPV impacts survival of stage IVC non-oropharyngeal HNSCC cancer patients. Otorhinolaryngol Head Neck Surg
    Burr AR, Harari PM, Ko HC, Chen S, Yu M, Baschnagel AM, Kimple RJ, Witek ME
    2018; 3 (1):
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      Objectives: Human papillomavirus (HPV) status is a favorable prognostic marker for patients with oropharyngeal squamous cell carcinoma (OPSCC) and non-metastatic head and neck non-OPSCC. We evaluated the impact of HPV status on overall survival (OS) for patients with Stage IVC non-OPSCC.

      Materials and methods: Patients diagnosed with Stage IVC non-OPSCC and known HPV status between 2010-2013 were identified in the National Cancer Database. Univariate and multivariate analyses were performed to determine factors associated with OS. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in OS analyses. Multiple imputation method was used for sensitivity analysis.

      Results: We identified 708 patients with Stage IVC non-OPSCC with 30% being HPV-positive. Unadjusted median survival was 10.3 months for HPV-negative patients and 21.4 months for HPV-positive patients (p<0.0001). Age ≥ 65 and tumor diameter were associated with worse OS (p<0.05) while treatment versus no treatment and HPV-positive status were associated with improved OS on multivariate analysis (p<0.001). Adjusted median survival for patients with HPV-negative and HPV-positive disease was 11.1 months and 23.8 months, respectively (p<0.001). On unadjusted subgroup analysis, patients with HPV-positive oral cavity disease exhibited improved outcomes (p<0.0001) while HPV-positive hypopharynx (p<0.06) and larynx (p<0.12) patients exhibited a trend for improved OS compared to HPV-negative patients. The survival advantage associated with HPV positivity was maintained on sensitivity analysis (p<0.01).

      Conclusion: These data demonstrate a clinically meaningful association between HPV status and OS in patients with non-OSPCC presenting with Stage IVC disease. In the absence of randomized data, these findings support active consideration of HPV status in clinical decision making, clinical trial design, and patient counseling regarding prognosis.

      View details for PubMedID 30271885
  • Enhanced Radiosensitivity in Solid Tumors using a Tumor-selective Alkyl Phospholipid Ether Analog. Mol Cancer Ther
    Elsaid MY, Shahi A, Wang AR, Baiu DC, Li C, Werner LR, Singhal S, Hall LT, Weichert JP, Armstrong EA, Bednarz BP, Harari PM, Iyer G, Otto M
    2018 11; 17 (11): 2320-2328
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      Antitumor alkyl phospholipid (APL) analogs comprise a group of structurally related molecules with remarkable tumor selectivity. Some of these compounds have shown radiosensitizing capabilities. CLR127 is a novel, clinical-grade antitumor APL ether analog, a subtype of synthetic APL broadly targeting cancer cells with limited uptake in normal tissues. The purpose of this study was to investigate the effect of CLR127 to modulate radiation response across several adult and pediatric cancer types in vitro as well as in murine xenograft models of human prostate adenocarcinoma, neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma. In vitro, CLR127 demonstrated selective uptake in cancer cells compared to normal cells. In cancer cells, CLR127 treatment prior to radiation significantly decreased clonogenic survival in vitro, and led to increased radiation-induced double-stranded DNA (dsDNA) breakage compared with radiation alone, which was not observed in normal controls. In animal models, CLR127 effectively increased the antitumor response to fractionated radiotherapy and led to delayed tumor regrowth at potentially clinically achievable doses. In conclusion, our study highlights the ability of CLR127 to increase radiation response in several cancer types. Given almost universal uptake of CLR127 in malignant cells, future research should test whether the observed effects can be extended to other tumor types. Our data provide a strong rationale for clinical testing of CLR127 as a tumor-targeted radiosensitizing agent. Mol Cancer Ther; 17(11); 2320-8. ©2018 AACR.

      View details for PubMedID 30108133
  • MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther
    McDaniel NK, Cummings CT, Iida M, Hülse J, Pearson HE, Vasileiadi E, Parker RE, Orbuch RA, Ondracek OJ, Welke NB, Kang GH, Davies KD, Wang X, Frye SV, Earp HS, Harari PM, Kimple RJ, DeRyckere D, Graham DK, Wheeler DL
    2018 11; 17 (11): 2297-2308
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      The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.

      View details for PubMedID 30093568
  • Results From 10 Years of a Free Oral Cancer Screening Clinic at a Major Academic Health Center. Int J Radiat Oncol Biol Phys
    Blitzer GC, Rosenberg SA, Anderson BM, McCulloch TM, Wieland AM, Hartig GK, Bruce JY, Witek ME, Kimple RJ, Harari PM
    2018 09 01; 102 (1): 146-148
  • A New Era of Image Guidance with Magnetic Resonance-guided Radiation Therapy for Abdominal and Thoracic Malignancies. Cureus
    Mittauer K, Paliwal B, Hill P, Bayouth JE, Geurts MW, Baschnagel AM, Bradley KA, Harari PM, Rosenberg S, Brower JV, Wojcieszynski AP, Hullett C, Bayliss RA, Labby ZE, Bassetti MF
    2018 Apr 04; 10 (4): e2422
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      Magnetic resonance-guided radiation therapy (MRgRT) offers advantages for image guidance for radiotherapy treatments as compared to conventional computed tomography (CT)-based modalities. The superior soft tissue contrast of magnetic resonance (MR) enables an improved visualization of the gross tumor and adjacent normal tissues in the treatment of abdominal and thoracic malignancies. Online adaptive capabilities, coupled with advanced motion management of real-time tracking of the tumor, directly allow for high-precision inter-/intrafraction localization. The primary aim of this case series is to describe MR-based interventions for localizing targets not well-visualized with conventional image-guided technologies. The abdominal and thoracic sites of the lung, kidney, liver, and gastric targets are described to illustrate the technological advancement of MR-guidance in radiotherapy.

      View details for PubMedID 29872602
  • Tumor-Specific Inhibition of In Situ Vaccination by Distant Untreated Tumor Sites. Cancer Immunol Res
    Morris ZS, Guy EI, Werner LR, Carlson PM, Heinze CM, Kler JS, Busche SM, Jaquish AA, Sriramaneni RN, Carmichael LL, Loibner H, Gillies SD, Korman AJ, Erbe AK, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM
    2018 07; 6 (7): 825-834
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      In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR.

      View details for PubMedID 29748391
  • Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology. Lancet Oncol
    Bristow RG, Alexander B, Baumann M, Bratman SV, Brown JM, Camphausen K, Choyke P, Citrin D, Contessa JN, Dicker A, Kirsch DG, Krause M, Le QT, Milosevic M, Morris ZS, Sarkaria JN, Sondel PM, Tran PT, Wilson GD, Willers H, Wong RKS, Harari PM
    2018 05; 19 (5): e240-e251
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      The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents.

      View details for PubMedID 29726389
  • Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx-Reply. JAMA Otolaryngol Head Neck Surg
    Witek ME, Hartig GK, Harari PM
    2018 06 01; 144 (6): 543
  • Impact of HPV Status on the Prognostic Potential of the AJCC Staging System for Larynx Cancer. Otolaryngol Head Neck Surg
    Davidson SM, Ko HC, Harari PM, Wieland AM, Chen S, Baschnagel AM, Kimple RJ, Witek AME
    2018 Apr 01; : 194599818766035
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      Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

      View details for PubMedID 29611770
  • When Disaster Strikes: Mitigating the Adverse Impact on Head and Neck Cancer Patients. Int J Radiat Oncol Biol Phys
    Yom SS, Harari PM
    2018 03 15; 100 (4): 838-840
  • Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx. JAMA Otolaryngol Head Neck Surg
    Ko HC, Harari PM, Chen S, Wieland AM, Yu M, Baschnagel AM, Kimple RJ, Witek ME
    2017 Nov 01; 143 (11): 1126-1133
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      Importance: Radiotherapy (RT)-based organ preservation approaches for patients with advanced laryngeal cancer have been established stepwise through prospective randomized clinical trials. However, broad adoption of these approaches has stimulated discussion about long-term results challenging their applicability in a heterogeneous patient population, most recently for patients with T3 disease.

      Objective: To define outcomes in patients with clinical T3N0M0 glottic laryngeal cancer treated with definitive surgical and RT-based approaches.

      Design, Setting, and Participants: This retrospective cohort study included patients treated from January 1, 2004, through December 31, 2013, with a median follow-up time of 58 months (range, 0-126.6 months) in the National Cancer Database. Of the 4003 patients with T3N0M0 disease, 2622 received definitive therapy defined by the study protocol. Data were obtained from the clinical oncology database sourced from hospital registry data that are collected from more than 1500 Commission on Cancer-accredited facilities. Data were analyzed from September 14, 2016, through April 24, 2017.

      Interventions: Radiotherapy, chemoradiotherapy, surgery, surgery and RT, or surgery and chemoradiotherapy.

      Main Outcomes and Measures: Five-year overall survival (OS).

      Results: A total of 2622 patients (2251 men [85.9%] and 371 women [14.1%]; median age, 64 years [range, 19-90 years]) were included in the analytic cohort. In the overall patient cohort, the adjusted 5-year survival probability was 53%. No statistical differences were observed between the primary surgery (53%; 95% CI, 48%-57%) and primary RT (54%; 95% CI, 52%-57%) cohorts. In multivariate analysis, patient factors associated with decreased OS included age (hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), insurance status (HR, 1.26; 95% CI, 1.06-1.50), and increasing comorbidity (HR, 1.20; 95% CI, 1.02-1.42).

      Conclusions and Relevance: Current management of T3N0M0 glottic laryngeal cancer relies largely on RT-based organ preservation approaches. The present study substantiates randomized clinical trial data supporting the use of RT-based organ preservation approaches for patients with T3N0M0 glottic laryngeal cancer without compromising OS.

      View details for PubMedID 29049434
  • Lymph Node Yield in Therapeutic Neck Dissection: Impact of Dissection Levels and Prior Radiotherapy. Ann Otol Rhinol Laryngol
    Lippert D, Dang P, Cannon D, Harari PM, McCulloch TM, Hoffman MR, Hartig GK
    2017 Nov; 126 (11): 762-767
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      OBJECTIVE: Lymph node yield in therapeutic neck dissection is clinically significant and incompletely studied. We quantified node yield based on extent of neck dissection and presence of preoperative radiation. We also evaluated factors affecting incidence of extracapsular spread (ECS).

      METHODS: Retrospective review of 499 patients undergoing therapeutic neck dissection; 414 patients met inclusion criteria and were divided into 2 groups: neck dissection alone or before radiation (surgery first: 280 patients; 385 dissections) and primary radiation before surgery (radiation first: 134 patients; 157 dissections). Node yield relative to levels dissected and incidence of ECS were examined.

      RESULTS: Dissection-specific node yield was greater in the surgery first group for dissection of levels I-V (31.1 ± 16.7 vs 24.0 ± 14.7, P < .001) and levels II-V (26.7 ± 14.4 vs 21.1 ± 10.7). Extracapsular spread incidence was 32.1% (98/305) in the surgery first group and 15.4% (23/149) in the radiation first group ( P < .001).

      CONCLUSION: This study clarifies anticipated node yield based on number of levels dissected and presence of preoperative radiation. Node yield and incidence of ECS are lower in patients undergoing preoperative radiation.

      View details for PubMedID 28948832
  • Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma. Radiother Oncol
    Werner LR, Kler JS, Gressett MM, Riegert M, Werner LK, Heinze CM, Kern JG, Abbariki M, Erbe AK, Patel RB, Sriramaneni RN, Harari PM, Morris ZS
    2017 Sep; 124 (3): 418-426
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      BACKGROUND AND PURPOSE: We recently reported a time-sensitive, cooperative, anti-tumor effect elicited by radiation (RT) and intra-tumoral-immunocytokine injection in vivo. We hypothesized that RT triggers transcriptional-mediated changes in tumor expression of immune susceptibility markers at delayed time points, which may explain these previously observed time-dependent effects.

      MATERIALS AND METHODS: We examined the time course of changes in expression of immune susceptibility markers following in vitro or in vivo RT in B78 murine melanoma and A375 human melanoma using flow cytometry, immunoblotting, and qPCR.

      RESULTS: Flow cytometry and immunoblot revealed time-dependent increases in expression of death receptors and T cell co-stimulatory/co-inhibitory ligands following RT in murine and human melanoma. Using high-throughput qPCR, we observed comparable time courses of RT-induced transcriptional upregulation for multiple immune susceptibility markers. We confirmed analogous changes in B78 tumors irradiated in vivo. We observed upregulated expression of DNA damage response markers days prior to changes in immune markers, whereas phosphorylation of the STAT1 transcription factor occurred concurrently with changes following RT.

      CONCLUSION: This study highlights time-dependent, transcription-mediated changes in tumor immune susceptibility marker expression following RT. These findings may help in the design of strategies to optimize sequencing of RT and immunotherapy in translational and clinical studies.

      View details for PubMedID 28893414
  • Prognostic implications of human papillomavirus status for patients with non-oropharyngeal head and neck squamous cell carcinomas. J Cancer Res Clin Oncol
    Ko HC, Harari PM, Sacotte RM, Chen S, Wieland AM, Yu M, Baschnagel AM, Bruce JY, Kimple RJ, Witek ME
    2017 Nov; 143 (11): 2341-2350
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      PURPOSE: We examined overall survival in a large cohort of patients with human papillomavirus (HPV)-positive and HPV-negative non-oropharyngeal squamous cell carcinoma of the head and neck (non-OPSCC).

      METHODS: Patients diagnosed with non-OPSCC and known HPV status were identified in the National Cancer Database (NCDB). Multivariate logistic regression was applied to examine factors associated with HPV status. Multivariate analysis was utilized to determine factors correlated with overall survival. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in survival analyses. Multiple imputation method was used for sensitivity analysis.

      RESULTS: We identified 19,993 non-OPSCC patients with 5070 being positive for HPV in the NCDB. Median follow-up was 23.5 months. HPV-positive patients were more commonly male, white, with a lower comorbidity index score, presenting with T-stage <2, and N-stage ≥1. Unadjusted 3-year overall survival was 62% and 80% for HPV-negative and HPV-positive patients, respectively (p < 0.0001). On multivariate analysis, mortality was reduced for HPV-positive patients with early stage (HR = 0.68) and locally advanced disease (HR = 0.46). Adjusted 3-year overall survival was 65% for HPV-negative and 76% for HPV-positive patients (p < 0.0001). The survival advantage of HPV was maintained in all subsites and robust on sensitivity analysis.

      CONCLUSIONS: Patients with HPV-positive non-OPSCC exhibit similar characteristics as HPV-positive OPSCC. Overall survival was significantly higher for patients with HPV-positive versus HPV-negative non-OPSCC. These data reveal that HPV-positive non-OPSCC represent a favorable cohort that warrants recognition in the design of future clinical trial investigation.

      View details for PubMedID 28752235
  • Clinical outcomes for patients presenting with N3 head and neck squamous cell carcinoma: Analysis of the National Cancer Database. Head Neck
    Ko HC, Chen S, Wieland AM, Yu M, Baschnagel AM, Hartig GK, Harari PM, Witek ME
    2017 Nov; 39 (11): 2159-2170
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      BACKGROUND: There is a paucity of data regarding head and neck squamous cell carcinomas (HNSCCs) and N3 nodal disease.

      METHODS: Retrospective analysis of patients with N3 HNSCC identified in the National Cancer Database (NCDB) was performed.

      RESULTS: We identified 4867 patients with N3 HNSCC treated with primary surgery or chemoradiotherapy (CRT). Propensity-adjusted median survival was 54.2 and 44.8 months for surgery and CRT, respectively (P = .06). Oropharyngeal primary subsite demonstrated a survival advantage with surgery versus CRT with propensity-adjusted median survivals of 86.0 and 61.9 months, respectively (P < .05).

      CONCLUSION: Management of N3 HNSCC relies largely on CRT. Patients with N3 nodal disease with nonoropharyngeal primary tumors exhibit 5-year overall survival approaching 30% independent of initial treatment modality. Patients with oropharyngeal primaries exhibit improved outcomes with surgery largely influenced by the human papillomavirus (HPV)-negative subset. These data represent the most comprehensive analysis of N3 HNSCC outcomes and serves as a foundation for future research and clinical management.

      View details for PubMedID 28737019
  • Why So Challenging to Personalize Radiation Dose? Int J Radiat Oncol Biol Phys
    Harari PM
    2017 08 01; 98 (5): 1012-1013
  • Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition. Clin Cancer Res
    Prabakaran PJ, Javaid AM, Swick AD, Werner LR, Nickel KP, Sampene E, Hu R, Ong IM, Bruce JY, Hartig GK, Wieland AM, Canon J, Harari PM, Kimple RJ
    2017 Oct 15; 23 (20): 6044-6053
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      Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044-53. ©2017 AACR.

      View details for PubMedID 28659312
  • Small cell carcinoma of the head and neck: An analysis of the National Cancer Database. Oral Oncol
    Pointer KB, Ko HC, Brower JV, Witek ME, Kimple RJ, Lloyd RV, Harari PM, Baschnagel AM
    2017 Jun; 69: 92-98
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      PURPOSE/OBJECTIVE(S): To evaluate treatment trends and overall survival of patients with small cell carcinoma of the head and neck region.

      MATERIALS/METHODS: Patients from 2004 to 2012 were identified from the National Cancer Database. Patient demographics and overall survival were analyzed. Multivariable analysis was used to identify predictors of survival.

      RESULTS: Among 347,252 head and neck patients a total of 1042 (0.3%) patients with small cell carcinoma were identified. 17% of patients were diagnosed as stage I/II, 61% as stage III/IVA/IVB and 22% as stage IVC disease. The distribution by anatomic site was 9% oral cavity, 12% oropharynx, 35% larynx, 4% hypopharynx, 10% nasopharynx and 30% nasal cavity and paranasal sinuses. The median overall survival by anatomical site was 20.8months for oral cavity, 23.7months for oropharynx, 17.9months for larynx/hypopharynx, 15.1months for nasopharynx and 36.4months for nasal cavity primary tumors. On multivariable analysis across stage, patients with nasal cavity and paranasal sinuses tumors had the best survival and patients with nasopharynx primaries had the worst survival. In stage I/II patients, type of treatment delivered resulted in no overall survival difference (p=0.78). In patients with locally advanced disease, there was no difference in survival between those treated with combined surgery, radiotherapy and chemotherapy compared to those treated only with radiotherapy and chemotherapy (p=0.46). The addition of radiotherapy to chemotherapy in the metastatic setting did not result in improved survival (p=0.14).

      CONCLUSIONS: Small cell carcinoma of the head and neck is a rare malignancy with a poor prognosis. The addition of surgery to radiotherapy and chemotherapy did not improve survival in patients with locally advanced disease.

      View details for PubMedID 28559027
  • Obituary and Tribute to John "Jack" Francis Fowler, PhD, DSc (1925-2016). Int J Radiat Oncol Biol Phys
    Harari PM, Ritter MA, van der Kogel AJ
    2017 04 01; 97 (5): 886-888
  • Chondroradionecrosis of the larynx: 24-year University of Wisconsin experience. Head Neck
    Gessert TG, Britt CJ, Maas AMW, Wieland AM, Harari PM, Hartig GK
    2017 Jun; 39 (6): 1189-1194
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      BACKGROUND: Chondroradionecrosis (CRN) is an uncommon but significant complication of laryngeal radiotherapy that presents a diagnostic challenge to clinicians through its similarity in presentation to cancer recurrence.

      METHODS: Two hundred ninety-four patients underwent primary, adjuvant, or salvage radiation for laryngeal cancer from 1991 to 2015 at the University of Wisconsin. Medical records were reviewed to identify and characterize patients with a diagnosis of CRN.

      RESULTS: Of the 294 patients, 7 cases (2.4%) of CRN were identified. Development of CRN was associated with the presence of cartilage invasion by tumor (p = .038) and ongoing alcohol use postradiotherapy (p = .036). Additionally, a trend between development of CRN and ongoing smoking postradiotherapy was observed (p = .067).

      CONCLUSION: The diagnosis of CRN is challenging, and the likelihood of successful resolution is modest. A high premium should be placed on efforts directed at prevention, such as tobacco and alcohol cessation. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1189-1194, 2017.

      View details for PubMedID 28295829
  • Identification of stable housekeeping genes in response to ionizing radiation in cancer research. Sci Rep
    Iyer G, Wang AR, Brennan SR, Bourgeois S, Armstrong E, Shah P, Harari PM
    2017 03 06; 7: 43763
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      Housekeeping genes (HKGs) are essential for basic maintenance of a variety of cellular processes. They ideally maintain uniform expression independent of experimental conditions. However, the effects of ionizing radiation (IR) on HKG expression is unclear. Statistical algorithms, geNorm and Normfinder were used for estimating the stability of HKGs as raw quantification cycle (Cq) values were not a reliable factor for normalization. Head and neck, non-small lung and pancreas cells were exposed to 2, 4 and 6 Gy IR doses and expression of fourteen HKGs was measured at 5 min to 48 h post-irradiation within a given tissue. Paired and single cell line analyses under these experimental conditions identified TATA-Box Binding Protein (TBP) and Importin 8 (IPO8) to be stable in non-small cell lung cancer. In addition to these two genes, Ubiquitin C (UBC) in head and neck cancer and Transferrin receptor (TFRC) and β-Glucuronidase (GUSB) in pancreatic cancer were identified to be stable as well. In summary we present a resource for top ranked five stable HKGs and their transcriptional behavior in commonly used cancer model cell lines and suggest the use of multiple HKGs under radiation treatment conditions is a reliable metric for quantifying gene expression.

      View details for PubMedID 28262749
  • Dosimetric Comparison of Real-Time MRI-Guided Tri-Cobalt-60 Versus Linear Accelerator-Based Stereotactic Body Radiation Therapy Lung Cancer Plans. Technol Cancer Res Treat
    Wojcieszynski AP, Hill PM, Rosenberg SA, Hullett CR, Labby ZE, Paliwal B, Geurts MW, Bayliss RA, Bayouth JE, Harari PM, Bassetti MF, Baschnagel AM
    2017 Jun; 16 (3): 366-372
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      PURPOSE: Magnetic resonance imaging-guided radiation therapy has entered clinical practice at several major treatment centers. Treatment of early-stage non-small cell lung cancer with stereotactic body radiation therapy is one potential application of this modality, as some form of respiratory motion management is important to address. We hypothesize that magnetic resonance imaging-guided tri-cobalt-60 radiation therapy can be used to generate clinically acceptable stereotactic body radiation therapy treatment plans. Here, we report on a dosimetric comparison between magnetic resonance imaging-guided radiation therapy plans and internal target volume-based plans utilizing volumetric-modulated arc therapy.

      MATERIALS AND METHODS: Ten patients with early-stage non-small cell lung cancer who underwent radiation therapy planning and treatment were studied. Following 4-dimensional computed tomography, patient images were used to generate clinically deliverable plans. For volumetric-modulated arc therapy plans, the planning tumor volume was defined as an internal target volume + 0.5 cm. For magnetic resonance imaging-guided plans, a single mid-inspiratory cycle was used to define a gross tumor volume, then expanded 0.3 cm to the planning tumor volume. Treatment plan parameters were compared.

      RESULTS: Planning tumor volumes trended larger for volumetric-modulated arc therapy-based plans, with a mean planning tumor volume of 47.4 mL versus 24.8 mL for magnetic resonance imaging-guided plans ( P = .08). Clinically acceptable plans were achievable via both methods, with bilateral lung V20, 3.9% versus 4.8% ( P = .62). The volume of chest wall receiving greater than 30 Gy was also similar, 22.1 versus 19.8 mL ( P = .78), as were all other parameters commonly used for lung stereotactic body radiation therapy. The ratio of the 50% isodose volume to planning tumor volume was lower in volumetric-modulated arc therapy plans, 4.19 versus 10.0 ( P < .001). Heterogeneity index was comparable between plans, 1.25 versus 1.25 ( P = .98).

      CONCLUSION: Magnetic resonance imaging-guided tri-cobalt-60 radiation therapy is capable of delivering lung high-quality stereotactic body radiation therapy plans that are clinically acceptable as compared to volumetric-modulated arc therapy-based plans. Real-time magnetic resonance imaging provides the unique capacity to directly observe tumor motion during treatment for purposes of motion management.

      View details for PubMedID 28168936
  • Erratum to: Insulin-like growth factor 1 receptor mediated tyrosine 845 phosphorylation of epidermal growth factor receptor in the presence of monoclonal antibody cetuximab. BMC Cancer
    Iyer G, Price J, Bourgeois S, Armstrong E, Huang S, Harari PM
    2016 Dec 01; 16 (1): 928
  • Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012. Int J Radiat Oncol Biol Phys
    Brower JV, Chen S, Bassetti MF, Yu M, Harari PM, Ritter MA, Baschnagel AM
    2016 Dec 01; 96 (5): 985-993
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      PURPOSE: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy.

      METHODS AND MATERIALS: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching.

      RESULTS: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses).

      CONCLUSIONS: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.

      View details for PubMedID 27869098
  • Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study). Front Oncol
    Fayette J, Wirth L, Oprean C, Udrea A, Jimeno A, Rischin D, Nutting C, Harari PM, Csoszi T, Cernea D, O'Brien P, Hanley WD, Kapp AV, Anderson M, Penuel E, McCall B, Pirzkall A, Vermorken JB
    2016; 6: 232
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      BACKGROUND: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab.

      METHODS: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m(2) load, 250 mg/m(2) IV, q1w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) status].

      RESULTS: Patients (N = 121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 years; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression-free survival [4.2 vs. 4.0 months; HR: 1.23 (90% confidence interval (CI): 0.89-1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% CI: 0.81-1.63)], and objective response rate (12 vs. 14.5%), with no difference between patients with NRG1-high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade ≥3 adverse events (AEs) (duligotuzumab vs. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10 vs. 16%); any grade rash-related events were less with duligotuzumab (49 vs. 67%).

      CONCLUSION: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR-HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab.

      View details for PubMedID 27843803
  • Insulin growth factor 1 like receptor (IGF-1R). BMC Cancer
    Iyer G, Price J, Bourgeois S, Armstrong E, Huang S, Harari PM
    2016 Oct 06; 16 (1): 773
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      BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood.

      METHODS: In this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab. Co-immunoprecipitation, small molecule inhibitors against phospho-Src and IGF-1R, quantitative western blot of EGFR and Src phosphorylation, cell proliferation assays were used to suggest the role of IGF-1R mediated phosphorylation of specific tyrosine Y845 on EGFR via increased heterodimerization of EGFR and IGF-1R in cetuximab resistant cells.

      RESULTS: Heterodimerization of EGFR with IGF-1R was increased in cetuximab resistant HNSCC cell line UMSCC6. Basal levels of phosphorylated EGFR Y845 showed significant increase in the presence of cetuximab. Surprisingly, this activated Y845 level was not inhibited in the presence of Src inhibitor PP1. Instead, inhibition of IGF-1R by picropodophyllin (PPP) reduced the EGFR Y845 levels. Taken together, these results suggest that heterodimerization of EGFR with IGF-1R can lead to increased activity of EGFR and may be an important platform for cetuximab mediated signaling in head and neck tumors that have become resistant to anti-EGFR therapy.

      CONCLUSIONS: EGFR-IGF-1R interaction has a functional consequence of phosphorylation of EGFR Y845 in cetuximab resistant HNSCC cells and dual targeting of EGFR and IGF-1R is a promising therapeutic strategy.

      View details for PubMedID 27716204
  • Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database. Ann Oncol
    Brower JV, Amini A, Chen S, Hullett CR, Kimple RJ, Wojcieszynski AP, Bassetti M, Witek ME, Yu M, Harari PM, Baschnagel AM
    2016 Oct; 27 (10): 1887-94
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      BACKGROUND: Concurrent chemoradiation is the standard of care in non-operable stage III non-small-cell lung cancer (NSCLC). Data have suggested a benefit of dose escalation; however, results from the randomized dose-escalation trial RTOG 0617 revealed a lower survival rate with high-dose radiation. To evaluate the impact of dose escalation on overall survival (OS) in stage III NSCLC treated with chemoradiotherapy outside the controlled setting of a randomized trial, we carried out an observational, population-based investigation of the National Cancer Database (NCDB).

      PATIENTS AND METHODS: A total of 33 566 patients with stage III NSCLC treated with chemoradiation from 2004 to 2012 and radiation doses between 59.4 and 85 Gy were included. The primary end point was OS, with median survival calculated via Kaplan-Meier. Univariate, multivariable and propensity-score matching analyses were carried out.

      RESULTS: Patients were stratified by dose with median OS of: 18.8, 19.8 and 21.6 months for cohorts receiving 59.4-60, 61-69 and ≥70 Gy, respectively (P < 0.001). Granular dose analyses were carried out demonstrating increased OS with increasing radiation dose: median survival of 18.8, 21.1, 22.0 and 21.0 months for 59.4-60, 66, 70 and ≥71 Gy, respectively. While 66, 70 and ≥71 Gy resulted in increased OS in comparison with 59.4-60 Gy, no significant difference in OS was observed when comparing 66 with ≥71 Gy (P = 0.38).

      CONCLUSIONS: Dose escalation above 60 Gy was associated with improved OS in this cohort of stage III NSCLC patients treated with chemoradiotherapy. A plateau of benefit was observed, with no additional improvement in OS with increased dose (≥71 Gy) compared with 66-70 Gy. With evidence suggesting worse OS and quality of life with increased dose, these data support investigation of the role of intermediate-dose radiation, and in the absence of randomized evidence, may be leveraged to justify utilization of intermediate-dose radiation.

      View details for PubMedID 27502703
  • Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234). Cancer
    Divi V, Harris J, Harari PM, Cooper JS, McHugh J, Bell D, Sturgis EM, Cmelak AJ, Suntharalingam M, Raben D, Kim H, Spencer SA, Laramore GE, Trotti A, Foote RL, Schultz C, Thorstad WL, Zhang QE, Le QT, Holsinger FC
    2016 Jul 15; :
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      BACKGROUND: Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival.

      METHODS: The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group.

      RESULTS: Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status.

      CONCLUSIONS: The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016. © 2016 American Cancer Society.

      View details for PubMedID 27419843
  • Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg
    Bonner J, Giralt J, Harari P, Spencer S, Schulten J, Hossain A, Chang SC, Chin S, Baselga J
    2016 Sep 01; 142 (9): 842-9
    • More

      IMPORTANCE: The appropriate use of surgery or radiotherapy-based approaches for organ preservation has been the subject of much debate. Unfortunately, there has been a lack of improvement in overall survival for patients with laryngeal carcinoma in the last 30 years.

      OBJECTIVE: To assess the rates of laryngeal preservation and laryngectomy-free survival in patients receiving cetuximab and radiotherapy (CRT) and patients receiving radiotherapy alone.

      DESIGN, SETTING, AND PARTICIPANTS: Patients were enrolled in a multicenter, open-label, stratified, randomized, phase 3 study from April 1, 1999, through March 31, 2002, from 73 centers in the United States and 14 other countries. A secondary subgroup analysis of patients with hypopharyngeal and laryngeal carcinoma was undertaken. Rates of laryngeal preservation and laryngectomy-free survival were estimated by the Kaplan-Meier method. The hazard ratios (HRs) were calculated using a Cox proportional hazards regression model. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer core questionnaire and head and neck module.

      MAIN OUTCOMES AND MEASURES: Laryngeal preservation and laryngectomy-free survival.

      RESULTS: Of the 424 patients included in the trial, 168 treated patients with cancer of the larynx or hypopharynx were included in this analysis (90 in the CRT group and 78 in the radiotherapy alone group). The median (range) age of the patients was 59 (40-80) years in the CRT group and 61 (35-81) years in the radiotherapy alone group. In the CRT group, 72 patients (80.0%) were male and 18 (20.0%) were female. In the radiotherapy alone group, 62 (79.5%) were male and 16 (20.5%) were female. The rates of laryngeal preservation at 2 years were 87.9% for CRT vs 85.7% for radiotherapy alone, with an HR of 0.57 (95% CI, 0.23-1.42; P = .22). Similarly, the HR for laryngectomy-free survival comparing CRT vs radiotherapy alone was 0.78 (95% CI, 0.54-1.11; P = .17). This study was not powered to assess organ preservation. Median overall survival was 27 (95% CI, 20-45) vs 21 (95% CI, 17-35) months for the CRT and radiotherapy alone groups, respectively, with an HR of 0.87 (95% CI, 0.60-1.27). No differences between treatments were reported regarding overall quality of life, need for a feeding tube, or speech.

      CONCLUSIONS AND RELEVANCE: The results of a possible cetuximab-related laryngeal preservation benefit for patients with hypopharyngeal or laryngeal cancer are intriguing; these results need to be interpreted in the context of a retrospective subset analysis with limited sample size.

      TRIAL REGISTRATION: Identifier: NCT00004227.

      View details for PubMedID 27389475
  • Association of human papillomavirus and p16 status with mucositis and dysphagia for head and neck cancer patients treated with radiotherapy with or without cetuximab: Assessment from a phase 3 registration trial. Eur J Cancer
    Bonner JA, Giralt J, Harari PM, Baselga J, Spencer S, Bell D, Raben D, Liu J, Schulten J, Ang KK, Rosenthal DI
    2016 Sep; 64: 1-11
    • More

      BACKGROUND: Mucositis and dysphagia are common adverse effects of radiotherapy (RT) treatment of locally advanced squamous cell cancer of the head and neck (LA-SCCHN). Chemotherapy added to RT increases survival rates but causes worse mucositis and dysphagia. The aim of this analysis was to assess the impact of p16 status on mucositis, dysphagia, and feeding tube use in LA-SCCHN among patients treated with RT±cetuximab in the phase 3 IMCL-9815 trial.

      METHODS: Patients received RT plus weekly cetuximab or RT alone. Subgroup analyses were conducted on patients with p16-positive (n=75) or p16-negative (n=106) oropharyngeal cancer (OPC), as determined by immunohistochemical analysis. The onset and duration of mucositis and dysphagia by treatment arm and p16 status were displayed using Kaplan-Meier curves and the log-rank test. P values for the incidence of mucositis and dysphagia were calculated using the Fisher exact test. Feeding tube use was assessed as the percent of patients reporting use.

      RESULTS: The baseline characteristics of patients treated with RT±cetuximab were similar in both the p16-positive and p16-negative OPC subgroups. Patients within the p16-positive OPC subgroup had higher Karnofsky scores and were more likely to have stage T1-T3 cancer and be from the United States. Regardless of p16 status, there was no difference in the onset or duration of grade 3/4 mucositis or dysphagia in patients receiving RT plus cetuximab compared with those receiving RT alone. In the overall population, and the p16-positive and p16-negative OPC subpopulations, feeding tube use was not different for patients receiving RT plus cetuximab compared with RT alone.

      CONCLUSION: Regardless of p16 status, the addition of cetuximab to RT did not alter the incidence, time to onset, severity, or duration of mucositis and dysphagia and did not impact the frequency of feeding tube use.

      View details for PubMedID 27323346
  • Molecular Targeting of Growth Factor Receptor Signaling in Radiation Oncology. Recent Results Cancer Res
    Huang S, Peter Rodemann H, Harari PM
    2016; 198: 45-87
    • More

      Ionizing radiation has been shown to activate and interact with multiple growth factor receptor pathways that can influence tumor response to therapy. Among these receptor interactions, the epidermal growth factor receptor (EGFR) has been the most extensively studied with mature clinical applications during the last decade. The combination of radiation and EGFR-targeting agents using either monoclonal antibody (mAb) or small-molecule tyrosine kinase inhibitor (TKI) offers a promising approach to improve tumor control compared to radiation alone. Several underlying mechanisms have been identified that contribute to improved anti-tumor capacity after combined treatment. These include effects on cell cycle distribution, apoptosis, tumor cell repopulation, DNA damage/repair, and impact on tumor vasculature. However, as with virtually all cancer drugs, patients who initially respond to EGFR-targeted agents may eventually develop resistance and manifest cancer progression. Several potential mechanisms of resistance have been identified including mutations in EGFR and downstream signaling molecules, and activation of alternative member-bound tyrosine kinase receptors that bypass the inhibition of EGFR signaling. Several strategies to overcome the resistance are currently being explored in preclinical and clinical models, including agents that target the EGFR T790 M resistance mutation or target multiple EGFR family members, as well as agents that target other receptor tyrosine kinase and downstream signaling sites. In this chapter, we focus primarily on the interaction of radiation with anti-EGFR therapies to summarize this promising approach and highlight newly developing opportunities.

      View details for PubMedID 27318681
  • Dosimetric differences in flattened and flattening filter-free beam treatment plans. J Med Phys
    Yan Y, Yadav P, Bassetti M, Du K, Saenz D, Harari P, Paliwal BR
    2016 Apr-Jun; 41 (2): 92-9
    • More

      This study investigated the dosimetric differences in treatment plans from flattened and flattening filter-free (FFF) beams from the TrueBeam System. A total of 104 treatment plans with static (sliding window) intensity-modulated radiotherapy beams and volumetric-modulated arc therapy (VMAT) beams were generated for 15 patients involving three cancer sites. In general, the FFF beam provides similar target coverage as the flattened beam with improved dose sparing to organ-at-risk (OAR). Among all three cancer sites, the head and neck showed more important differences between the flattened beam and FFF beam. The maximum reduction of the FFF beam in the mean dose reached up to 2.82 Gy for larynx in head and neck case. Compared to the 6 MV flattened beam, the 10 MV FFF beam provided improved dose sparing to certain OARs, especially for VMAT cases. Thus, 10 MV FFF beam could be used to improve the treatment plan.

      View details for PubMedID 27217620
  • Correlation Between the Severity of Cetuximab-Induced Skin Rash and Clinical Outcome for Head and Neck Cancer Patients: The RTOG Experience. Int J Radiat Oncol Biol Phys
    Bar-Ad V, Zhang QE, Harari PM, Axelrod R, Rosenthal DI, Trotti A, Jones CU, Garden AS, Song G, Foote RL, Raben D, Shenouda G, Spencer SA, Harris J, Le QT
    2016 Aug 01; 95 (5): 1346-1354
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      PURPOSE: To evaluate the severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients with head and neck squamous cell carcinoma treated with chemoradiation therapy and cetuximab.

      METHODS AND MATERIALS: Analysis included patients who received loading dose and ≥1 cetuximab dose concurrent with definitive chemoradiation therapy (70 Gy + cisplatin) or postoperative chemoradiation therapy (60-66 Gy + docetaxel or cisplatin).

      RESULTS: Six hundred two patients were analyzed; 383 (63.6%) developed grade 2 to 4 cetuximab rash. Patients manifesting grade 2 to 4 rash had younger age (P<.001), fewer pack-years smoking history (P<.001), were more likely to be males (P=.04), and had p16-negative (P=.04) oropharyngeal tumors (P=.003). In univariate analysis, grade 2 to 4 rash was associated with better overall survival (hazard ratio [HR] 0.58, P<.001) and progression-free survival (HR 0.75, P=.02), and reduced distant metastasis rate (HR 0.61, P=.03), but not local-regional failure (HR 0.79, P=.16) relative to grade 0 to 1 rash. In multivariable analysis, HRs for overall survival, progression-free survival, distant metastasis, and local-regional failure were, respectively, 0.68 (P=.008), 0.85 (P=.21), 0.64 (P=.06), and 0.89 (P=.48). Grade ≥2 rash was associated with improved survival in p16-negative patients (HR 0.28 [95% confidence interval 0.11-0.74]) but not in p16-positive patients (HR 1.10 [0.42-2.89]) (P=.05 for interaction). Twenty-five percent of patients with grade 2 to 4 acute in-field radiation dermatitis experienced grade 2 to 4 late skin fibrosis, versus 14% of patients with grade 0 to 1 acute in-field radiation dermatitis (P=.002).

      CONCLUSION: Grade 2 to 4 cetuximab rash was associated with better survival, possibly due to reduction of distant metastasis. This observation was noted mainly in p16-negative patients. Grade 2 to 4 acute in-field radiation dermatitis was associated with higher rate of late grade 2 to 4 skin fibrosis.

      View details for PubMedID 27212198
  • Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Cancer
    Morris ZS, Saha S, Magnuson WJ, Morris BA, Borkenhagen JF, Ching A, Hirose G, McMurry V, Francis DM, Harari PM, Chappell R, Tsuji S, Ritter MA
    2016 Aug 15; 122 (16): 2487-95
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      BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer.

      METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data.

      RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001).

      CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

      View details for PubMedID 27203227
  • In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. Cancer Res
    Morris ZS, Guy EI, Francis DM, Gressett MM, Werner LR, Carmichael LL, Yang RK, Armstrong EA, Huang S, Navid F, Gillies SD, Korman A, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM
    2016 Jul 01; 76 (13): 3929-41
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      Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929-41. ©2016 AACR.

      View details for PubMedID 27197149
  • Assessing p16 Status of Oropharyngeal Squamous Cell Carcinoma by Combined Assessment of the Number of Cells Stained and the Confluence of p16 Staining: A Validation by Clinical Outcomes. Am J Surg Pathol
    Barasch S, Mohindra P, Hennrick K, Hartig GK, Harari PM, Yang DT
    2016 Sep; 40 (9): 1261-9
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      Human papillomavirus-related oropharyngeal squamous cell carcinoma (OPSCC) has favorable prognosis relative to other head and neck squamous cell carcinomas. Criteria for predicting human papillomavirus status based upon p16 staining, including difficult cases with partial staining patterns, have been developed; however, clinical validation of these criteria and the clinical significance of partial p16 staining have not been reported. Eighty-one archival OPSCC cases were initially stained for p16 by immunohistochemistry with clone G175-405. The percentage of p16 cells and percentage of confluence of p16 cells were categorized as 25%, 26% to 75%, or >75%. Of all cases, 16 (20%) had partial p16 expression, with 26% to 75% p16 cells. Applying previously developed criteria of >75% p16 cells or >50% positive cells with >25% confluence, 48 (59%) patients were categorized p16 and demonstrated expected clinical characteristics and superior disease-free survival and overall survival (P<0.001) compared with p16 patients. By themselves, the partial staining patients had intermediate outcomes; however, separating the partial staining cases by degree of confluence showed that those with >75% confluence had superior disease-free survival (P=0.042). When the 16 original partial staining cases were re-stained with the alternative anti-p16 E6H4 clone, p16 status remained concordant for all cases, but only 3 of the 16 were interpreted as demonstrating partial staining. This report shows that the prevalence of partial p16 staining varies with the antibody utilized and clinically validates the application of a graded evaluation of both the number as well as confluence of positive cells for risk stratification of patients with OPSCC.

      View details for PubMedID 27186851
  • Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab. J Clin Oncol
    Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA
    2016 Apr 20; 34 (12): 1300-8
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      PURPOSE: We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone.

      PATIENTS AND METHODS: In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA.

      RESULTS: Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared.

      CONCLUSION: p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone.

      View details for PubMedID 26712222
  • Gadoxetate for direct tumor therapy and tracking with real-time MRI-guided stereotactic body radiation therapy of the liver. Radiother Oncol
    Wojcieszynski AP, Rosenberg SA, Brower JV, Hullett CR, Geurts MW, Labby ZE, Hill PM, Bayliss RA, Paliwal B, Bayouth JE, Harari PM, Bassetti MF
    2016 Feb; 118 (2): 416-8
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      SBRT is increasingly utilized in liver tumor treatment. MRI-guided RT allows for real-time MRI tracking during therapy. Liver tumors are often poorly visualized and most contrast agents are transient. Gadoxetate may allow for sustained tumor visualization. Here, we report on the first use of gadoxetate during real-time MRI-guided SBRT.

      View details for PubMedID 26627702
  • Simulation study of high-dose-rate brachytherapy for early glottic cancer. Brachytherapy
    Hoffman MR, McCulloch TM, Mohindra P, Das R, Geurts M, Harari PM
    2016 Jan-Feb; 15 (1): 94-101
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      PURPOSE: External beam radiation therapy (EBRT) is effective for early glottic cancers, with cure rates of ∼90% for T1 tumors. EBRT has strengths but also disadvantages including radiation to healthy tissues and duration of 5-7 weeks. With advances in laryngeal framework surgery, new devices can provide reliable, minimally invasive access to the larynx. Such devices could be modified to insert brachytherapy catheters. Brachytherapy could provide focused radiation while limiting dose to normal structures in the larynx and neck. As a preliminary step, we performed simulations comparing EBRT to high-dose-rate brachytherapy to assess if this approach could provide dosimetric advantage.

      METHODS AND MATERIALS: One- and 2-catheter brachytherapy simulations were performed for 3 patients with T1 glottic carcinoma. Percentage of dose delivered to the target and adjacent structures was compared with conventional EBRT using 3D and intensity-modulated radiation therapy approaches.

      RESULTS: Percentage of structures exposed to 50% of the dose was lower for brachytherapy compared with 3D EBRT and intensity-modulated radiation therapy, particularly for the cricoid and contralateral arytenoid. Dose was also lower for the carotid-internal jugular vein complexes compared with 3D EBRT. Dose profiles did not differ significantly between 1- and 2-catheter simulations.

      CONCLUSION: Brachytherapy can decrease radiation to normal tissues including laryngeal cartilages and carotid-internal jugular vein complexes. Recent advancements allowing catheter placement may afford the potential to decrease radiation to healthy tissues with decreased treatment time. However, careful, stepwise evaluation of feasibility and outcomes in model systems is required before recommending this approach for such high cure rate cancers in humans.

      View details for PubMedID 26614234
  • Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models. Clin Cancer Res
    Francis DM, Huang S, Armstrong EA, Werner LR, Hullett C, Li C, Morris ZS, Swick AD, Kragh M, Lantto J, Kimple RJ, Harari PM
    2016 Feb 01; 22 (3): 633-43
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      PURPOSE: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3.

      EXPERIMENTAL DESIGN: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor-resistant cell lines and xenografts.

      RESULTS: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone.

      CONCLUSIONS: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan-HER combined with radiation as a promising clinical therapeutic strategy.

      View details for PubMedID 26420857
  • Small Molecule Inhibition of MDM2-p53 Interaction Augments Radiation Response in Human Tumors. Mol Cancer Ther
    Werner LR, Huang S, Francis DM, Armstrong EA, Ma F, Li C, Iyer G, Canon J, Harari PM
    2015 Sep; 14 (9): 1994-2003
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      MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.

      View details for PubMedID 26162687
  • Antitumor Effects of MEHD7945A, a Dual-Specific Antibody against EGFR and HER3, in Combination with Radiation in Lung and Head and Neck Cancers. Mol Cancer Ther
    Li C, Huang S, Armstrong EA, Francis DM, Werner LR, Sliwkowski MX, van der Kogel A, Harari PM
    2015 Sep; 14 (9): 2049-59
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      Human epidermal growth factor receptor family members (EGFR, HER2, HER3, and HER4) play important roles in tumorigenesis and response to cancer therapeutics. In this study, we evaluated the capacity of the dual-target antibody MEHD7945A that simultaneously targets EGFR and HER3 to modulate radiation response in lung and head and neck cancer models. Antitumor effects of MEHD7945A in combination with radiation were evaluated in cell culture and tumor xenograft models. Mechanisms that may contribute to increased radiation killing by MEHD7945A, including DNA damage and inhibition of EGFR-HER signaling pathways, were analyzed. Immunohistochemical analysis of tumor xenografts was conducted to evaluate the effect of MEHD7945A in combination with radiation on tumor growth and microenvironment. MEHD7945A inhibited basal and radiation-induced EGFR and HER3 activation resulting in the inhibition of tumor cell growth and enhanced radiosensitivity. MEHD7945A was more effective in augmenting radiation response than treatment with individual anti-EGFR or anti-HER3 antibodies. An increase in DNA double-strand breaks associated γ-H2AX was observed in cells receiving combined treatment with MEHD7945A and radiation. Immunohistochemical staining evaluation in human tumor xenografts showed that MEHD7945A combined with radiation significantly reduced the expression of markers of tumor proliferation and tumor vasculature. These findings reveal the capacity of MEHD7945A to augment radiation response in lung and head and neck cancers. The dual EGFR/HER3-targeting action of MEHD7945A merits further investigation and clinical trial evaluation as a radiation sensitizer in cancer therapy.

      View details for PubMedID 26141946
  • Quantitative evaluation of image segmentation incorporating medical consideration functions. Med Phys
    Kim H, Monroe JI, Lo S, Yao M, Harari PM, Machtay M, Sohn JW
    2015 Jun; 42 (6): 3013-23
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      PURPOSE: A quantitative and objective metric, the medical similarity index (MSI), has been developed for evaluating the accuracy of a medical image segmentation relative to a reference segmentation. The MSI uses the medical consideration function (MCF) as its basis.

      METHODS: Currently, no indices provide quantitative evaluations of segmentation accuracy with medical considerations. Variations in segmentation can occur due to individual skill levels and medical relevance--curable or palliative intent, boundary uncertainty due to volume averaging, contrast levels, spatial resolution, and unresolved motion all affect the accuracy of a patient segmentation. Current accuracy measuring indices are not medically relevant. For example, undercontouring the tumor volume is not differentiated from overcontouring tumor. Dice similarity coefficient (DSC) and Hausdorff distance (HD) are two similarity measures often used. However, these metrics consider only geometric difference without considering medical implications. Two segments (under- vs overcontouring tumor) with similar DSC and HD measures could produce significantly different medical treatment results. The authors are proposing a MSI involving a user-defined MCF derived from an asymmetric Gaussian function. The shape of the MCF can be determined by a user, reflecting the anatomical location and characteristics of a particular tissue, organ, or tumor type. The peak of MCF is set along the reference contour; the inner and outer slopes are selected by the user. The discrepancy between the test and reference contours is calculated at each pixel by using a bidirectional local distance measure. The MCF value corresponding to that distance is summed and averaged to produce the MSI. Synthetic segmentations and clinical data from a 15 multi-institutional trial for a head-and-neck case are scored and compared by using MSI, DSC, and Hausdorff distance.

      RESULTS: The MSI was shown to reflect medical considerations through the choice of MCF penalties for under- and overcontouring. Existing similarity scores were either insensitive to medical realities or simply inaccurate.

      CONCLUSIONS: The medical similarity index, a segmentation evaluation metric based on medical considerations, has been proposed, developed, and tested to incorporate clinically relevant considerations beyond geometric parameters alone.

      View details for PubMedID 26127054
  • Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems. Radiother Oncol
    Morris ZS, Weichert JP, Saker J, Armstrong EA, Besemer A, Bednarz B, Kimple RJ, Harari PM
    2015 Sep; 116 (3): 504-9
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      BACKGROUND AND PURPOSE: CLR1404 is a phospholipid ether that exhibits selective uptake and retention in malignant tissues. Radiolabeled CLR1404 enables tumor-specific positron-emission tomography (PET) imaging ((124)I) and targeted delivery of ionizing radiation ((131)I). Here we describe the first preclinical studies of this diapeutic molecule in head and neck cancer (HNC) models.

      MATERIAL AND METHODS: Tumor-selective distribution of (124)I-CLR1404 and therapeutic efficacy of (131)I-CLR1404 were tested in HNC cell lines and patient-derived xenograft tumor models. Monte Carlo dose calculations and (124)I-CLR1404 PET/CT imaging were used to examine (131)I-CLR1404 dosimetry in preclinical HNC tumor models.

      RESULTS: HNC tumor xenograft studies including patient-derived xenografts demonstrate tumor-selective uptake and retention of (124)I-CLR1404 resulting in a model of highly conformal dose distribution for (131)I-CLR1404. We observe dose-dependent response to (131)I-CLR1404 with respect to HNC tumor xenograft growth inhibition and this effect is maintained together with external beam radiation.

      CONCLUSIONS: We confirm the utility of CLR1404 for tumor imaging and treatment of HNC. This promising agent warrants further investigation in a developing phase I trial combining (131)I-CLR1404 with reduced-dose external beam radiation in patients with loco-regionally recurrent HNC.

      View details for PubMedID 26123834
  • The prognostic value of HPV in head and neck cancer patients undergoing postoperative chemoradiotherapy. Ann Transl Med
    Kimple RJ, Harari PM
    2015 May; 3 (Suppl 1): S14
  • Incidental Parotid Neoplasms: Pathology and Prevalence. Otolaryngol Head Neck Surg
    Britt CJ, Stein AP, Patel PN, Harari PM, Hartig GK
    2015 Oct; 153 (4): 566-8
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      OBJECTIVE: To better characterize parotid masses incidentally identified on imaging.

      STUDY DESIGN: Case series with chart review.

      SETTING: Academic medical center.

      SUBJECTS AND METHODS: Medical records were reviewed for 771 patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients were stratified into 2 groups: those with tumors identified solely on imaging (parotid incidentalomas [PIs]) and those with palpable masses, pain, facial nerve dysfunction, or other reasons their mass was identified (nonincidentals [NIs]). A χ(2) test was employed to compare the prevalence of malignancy in PIs compared with NIs. Trend analysis was performed to determine the prevalence of PIs over the 20-year period.

      RESULTS: Of the 771 patients, 67 (8.7%) had their mass discovered incidentally on imaging (PIs). There was a significant difference in the rate of malignancy in the NI (32.7%) compared with the PI group (6.0%) (P < .01). During the 1994 to 2003 time period, 4.0% of all parotoidectomies performed were for PIs, while during the second decade (2004-2013), this proportion increased to 10.2%. This represents a 155.0% increase in the percentage of parotidectomies carried out for PIs between these 2 periods.

      CONCLUSION: In this study, the rate of malignancy in PIs was significantly lower than the rate of malignancy in patients with NIs. The occurrence of PIs has increased over time and now represents greater than 10.0% of all parotidectomies performed at the University of Wisconsin. This information is important to consider when consenting a patient for resection of a PI.

      View details for PubMedID 26019135
  • Impact of Node Negative Target Volume Delineation on Contralateral Parotid Gland Dose Sparing Using IMRT in Head and Neck Cancer. Technol Cancer Res Treat
    Magnuson WJ, Urban E, Bayliss RA, Harari PM
    2015 Jun; 14 (3): 315-9
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      There is considerable practice variation in treatment of the node negative (N0) contralateral neck in patients with head and neck cancer. In this study, we examined the impact of N0 neck target delineation volume on radiation dose to the contralateral parotid gland. Following institutional review board approval, 12 patients with head and neck cancer were studied. All had indications for treatment of the N0 neck, such as midline base of tongue or soft palate extension or advanced ipsilateral nodal disease. The N0 neck volumes were created using the Radiation Therapy Oncology Group head and neck contouring atlas. The physician-drawn N0 neck clinical target volume (CTV) was expanded by 25% to 200% to generate volume variation, followed by a 3-mm planning target volume (PTV) expansion. Surrounding organs at risk were contoured and complete intensity-modulated radiation therapy plans were generated for each N0 volume expansion. The median N0 target volume drawn by the radiation oncologist measured 93 cm(3) (range 71-145). Volumetric expansion of the N0 CTV by 25% to 200% increased the resultant mean dose to the contralateral parotid gland by 1.4 to 8.5 Gray (Gy). For example, a 4.1-mm increase in the N0 neck CTV translated to a 2.0-Gy dose increase to the parotid, 7.4 mm to a 4.5 Gy dose increase, and 12.5 mm to an 8.5 Gy dose increase, respectively. The treatment volume designated for the N0 neck has profound impact on resultant dose to the contralateral parotid gland. Variations of up to 15 mm are routine across physicians in target contouring, reflecting individual preference and training expertise. Depending on the availability of immobilization and image guidance techniques, experts commonly recommend 3 to 10 mm margin expansions to generate the PTV. Careful attention to the original volume of the N0 neck CTV, as well as expansion margins, is important in achieving effective contralateral gland sparing to reduce the resultant xerostomia and dysguesia that may ensue after radiotherapy.

      View details for PubMedID 25782188
  • Patient and tumor characteristics predictive of primary parotid gland malignancy: A 20-year experience at the University of Wisconsin. Am J Otolaryngol
    Stein AP, Britt CJ, Saha S, McCulloch TM, Wieland AM, Harari PM, Hartig GK
    2015 May-Jun; 36 (3): 429-34
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      PURPOSE: To identify patient and tumor characteristics predictive of primary parotid malignancy.

      MATERIALS AND METHODS: Records were reviewed for patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients with primary parotid neoplasms were separated into benign or malignant subgroups. A multivariate logistic regression model was employed to compare categorical (gender, lesion side, nature of presentation, recurrence) and numerical variables (age, tumor size) between the benign and malignant groups. Mean BMI was compared between the groups by univariate analysis.

      RESULTS: 771 patients underwent parotidectomy from 1994 to 2013, and 474 had a primary parotid neoplasm. No relationship existed between malignancy and gender (p=0.610), lesion side (p=0.110), or BMI (p=0.196). Mean age (p=0.015) and tumor size (p=0.011) were significantly different between the benign and malignant groups. Patient presentation was classified into three categories: symptomatic (n=109), palpable and asymptomatic (n=303), and incidentally noted on imaging (n=57). From all patients with symptomatic, asymptomatic or incidentally noted masses, 41.3%, 10.6% and 5.3%, respectively, were diagnosed with malignant disease. There was a significant relationship between the patient's initial presentation and malignancy (p<0.001), and patients with facial nerve dysfunction or skin involvement had the greatest likelihood of malignancy. Finally, there was a significant association between malignancy and recurrence (p=0.001).

      CONCLUSIONS: In this study, age, tumor size, and nature of presentation were all associated with primary parotid malignancy. Understanding the impact of these features on the probability of malignancy is valuable in decision making and counseling of patients presenting with a newly diagnosed parotid neoplasm.

      View details for PubMedID 25766621
  • Metabolic tumor volume as a prognostic imaging-based biomarker for head-and-neck cancer: pilot results from Radiation Therapy Oncology Group protocol 0522. Int J Radiat Oncol Biol Phys
    Schwartz DL, Harris J, Yao M, Rosenthal DI, Opanowski A, Levering A, Ang KK, Trotti AM, Garden AS, Jones CU, Harari P, Foote R, Holland J, Zhang Q, Le QT
    2015 Mar 15; 91 (4): 721-9
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      PURPOSE: To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial setting.

      METHODS AND MATERIALS: Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes.

      RESULTS: Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited.

      CONCLUSION: High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.

      View details for PubMedID 25752384
  • Phase 1 trial of bevacizumab with concurrent chemoradiation therapy for squamous cell carcinoma of the head and neck with exploratory functional imaging of tumor hypoxia, proliferation, and perfusion. Int J Radiat Oncol Biol Phys
    Nyflot MJ, Kruser TJ, Traynor AM, Khuntia D, Yang DT, Hartig GK, McCulloch TM, Wiederholt PA, Gentry LR, Hoang T, Jeraj R, Harari PM
    2015 Apr 01; 91 (5): 942-51
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      PURPOSE: A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies.

      METHODS AND MATERIALS: All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m(2) and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [(18)F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [(61)Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course.

      RESULTS: Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course.

      CONCLUSIONS: The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.

      View details for PubMedID 25659884
  • Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies. Cancer Med
    Stein AP, Swick AD, Smith MA, Blitzer GC, Yang RZ, Saha S, Harari PM, Lambert PF, Liu CZ, Kimple RJ
    2015 May; 4 (5): 699-712
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      Head and neck squamous cell carcinoma (HNSCC) remains a challenging cancer to treat with overall 5-year survival on the order of 50-60%. Therefore, predictive biomarkers for this disease would be valuable to provide more effective and individualized therapeutic approaches for these patients. While prognostic biomarkers such as p16 expression correlate with outcome; to date, no predictive biomarkers have been clinically validated for HNSCC. We generated xenografts in immunocompromised mice from six established HNSCC cell lines and evaluated response to cisplatin, cetuximab, and radiation. Tissue microarrays were constructed from pre- and posttreatment tumor samples derived from each xenograft experiment. Quantitative immunohistochemistry was performed using a semiautomated imaging and analysis platform to determine the relative expression of five potential predictive biomarkers: epidermal growth factor receptor (EGFR), phospho-EGFR, phospho-Akt, phospho-ERK, and excision repair cross-complementation group 1 (ERCC1). Biomarker levels were compared between xenografts that were sensitive versus resistant to a specific therapy utilizing a two-sample t-test with equal standard deviations. Indeed the xenografts displayed heterogeneous responses to each treatment, and we linked a number of baseline biomarker levels to response. This included low ERCC1 being associated with cisplatin sensitivity, low phospho-Akt correlated with cetuximab sensitivity, and high total EGFR was related to radiation resistance. Overall, we developed a systematic approach to identifying predictive biomarkers and demonstrated several connections between biomarker levels and treatment response. Despite these promising initial results, this work requires additional preclinical validation, likely involving the use of patient-derived xenografts, prior to moving into the clinical realm for confirmation among patients with HNSCC.

      View details for PubMedID 25619980
  • Selective omission of level V nodal coverage for patients with oropharyngeal cancer: Clinical validation of intensity-modulated radiotherapy experience and dosimetric significance. Head Neck
    Mohindra P, Urban E, Pagan JD, Geye HM, Patel VB, Bayliss RA, Bender ET, Harari PM
    2016 Apr; 38 (4): 499-505
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      BACKGROUND: We sought to validate the consensus recommendation and assess dosimetric significance of selective omission of nodal level V from intensity-modulated radiotherapy (IMRT) clinical target volume (CTV) for oropharyngeal cancer.

      METHODS: IMRT plans and clinical outcomes for 112 patients with oropharyngeal cancer (nodal classification N0-N2b) were analyzed for coverage of ipsilateral and contralateral nodal level V. Additionally, new IMRT plans were generated in 6 randomly selected patients to assess its dosimetric impact.

      RESULTS: With median follow-up of 3.4 years, there were no failures identified in nodal level V with or without nodal level V omission. Upon dosimetric evaluation, significant reduction in integral dose, V10 Gy , V20 Gy , V30 Gy , V40 Gy , and V50 Gy was observed by excluding unilateral and bilateral level V from the CTV.

      CONCLUSION: We clinically validate the consensus recommendation for selective omission of level V nodal coverage in IMRT planning of patients with oropharyngeal cancer and demonstrate significant dosimetric advantages.

      View details for PubMedID 25445257
  • p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol
    Chung CH, Zhang Q, Kong CS, Harris J, Fertig EJ, Harari PM, Wang D, Redmond KP, Shenouda G, Trotti A, Raben D, Gillison ML, Jordan RC, Le QT
    2014 Dec 10; 32 (35): 3930-8
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      PURPOSE: Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx.

      PATIENTS AND METHODS: p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics.

      RESULTS: p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes.

      CONCLUSION: Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

      View details for PubMedID 25267748
  • Interaction of radiation therapy with molecular targeted agents. J Clin Oncol
    Morris ZS, Harari PM
    2014 Sep 10; 32 (26): 2886-93
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      The development of molecular targeted therapeutics in oncology builds on many years of scientific investigation into the cellular mechanics of malignant transformation and progression. The past two decades have brought an accelerating pace to the clinical investigation of new molecular targeted agents, particularly in the setting of metastatic disease. The integration of molecular targeted agents into phase III clinical trial design has lagged in the curative treatment setting, particularly in combination with established therapeutic modalities such as radiation. In this review, we discuss the interaction of radiation and molecular targeted therapeutics. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with molecular targeted agents that may go unrecognized with conventional screening and monotherapy clinical testing of novel agents. By using epidermal growth factor receptor (EGFR) as a primary example, we discuss recent clinical studies that illustrate the potential synergy of molecular targeted agents with radiation and highlight the clinical value of such interactions. For various molecular targeted agents, their greatest clinical impact may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach appear highly warranted.

      View details for PubMedID 25113770
  • Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol
    Harari PM, Harris J, Kies MS, Myers JN, Jordan RC, Gillison ML, Foote RL, Machtay M, Rotman M, Khuntia D, Straube W, Zhang Q, Ang K
    2014 Aug 10; 32 (23): 2486-95
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      PURPOSE: To report results of a randomized phase II trial (Radiation Therapy Oncology Group RTOG-0234) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) with high-risk pathologic features.

      PATIENTS AND METHODS: Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and/or extracapsular nodal extension and/or two or more nodal metastases. Patients were randomly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m(2) or docetaxel 15 mg/m(2) once per week.

      RESULTS: Between April 2004 and December 2006, 238 patients were enrolled. With a median follow-up of 4.4 years, 2-year overall survival (OS) was 69% for the cisplatin arm and 79% for the docetaxel arm; 2-year disease-free survival (DFS) was 57% and 66%, respectively. Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors. Grade 3 to 4 myelosuppression was observed in 28% of patients in the cisplatin arm and 14% in the docetaxel arm; mucositis was observed in 56% and 54%, respectively. DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial (Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck), which had a hazard ratio of 0.76 for the cisplatin arm versus control (P = .05) and 0.69 for the docetaxel arm versus control (P = .01), reflecting absolute improvement in 2-year DFS of 2.5% and 11.1%, respectively.

      CONCLUSION: The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity. The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial.

      View details for PubMedID 25002723
  • Is radiation dose reduction the right answer for HPV-positive head and neck cancer? Oral Oncol
    Kimple RJ, Harari PM
    2014 Jun; 50 (6): 560-4
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      Patients with head and neck squamous cell carcinoma (HNC) related to human papillomavirus (HPV) represent a growing and distinct patient cohort with unique molecular and epidemiologic characteristics. These patients have markedly improved survival outcomes compared to those with traditional HNC, leading some to advocate for treatment dose reduction. In this article, we review ongoing clinical trials investigating several ways to reduce therapeutic intensity for patients with HPV-positive HNC, discuss the risks and benefits associated with these trials, and summarize the data underlying the advancement of dose reduction trials for patients with HPV-positive HNC.

      View details for PubMedID 24134946
  • Sym004, a novel anti-EGFR antibody mixture, augments radiation response in human lung and head and neck cancers. Mol Cancer Ther
    Huang S, Peet CR, Saker J, Li C, Armstrong EA, Kragh M, Pedersen MW, Harari PM
    2013 Dec; 12 (12): 2772-81
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      Sym004 represents a novel EGF receptor (EGFR)-targeting approach comprising a mixture of two anti-EGFR antibodies directed against distinct epitopes of EGFR. In contrast with single anti-EGFR antibodies, Sym004 induces rapid and highly efficient degradation of EGFR. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck cancer model systems. We first examined the antiproliferative effect of Sym004 and confirmed 40% to 60% growth inhibition by Sym004. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following radiation exposure. A significant increase of γH2AX foci resulting from DNA double-strand breaks was observed in Sym004-treated cells following exposure to radiation. Mechanistic studies further showed that Sym004 enhanced radiation response via induction of cell-cycle arrest followed by induction of apoptosis and cell death, reflecting inhibitory effects on DNA damage repair. The expression of several critical molecules involved in radiation-induced DNA damage repair was significantly inhibited by Sym004, including DNAPK, NBS1, RAD50, and BRCA1. Using single and fractionated radiation in human tumor xenograft models, we confirmed that the combination of Sym004 and radiation resulted in significant tumor regrowth delay and superior antitumor effects compared with treatment with Sym004 or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and head and neck cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy.

      View details for PubMedID 24130052
  • The relative expression of Mig6 and EGFR is associated with resistance to EGFR kinase inhibitors. PLoS One
    Chang X, Izumchenko E, Solis LM, Kim MS, Chatterjee A, Ling S, Monitto CL, Harari PM, Hidalgo M, Goodman SN, Wistuba II, Bedi A, Sidransky D
    2013; 8 (7): e68966
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      The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).

      View details for PubMedID 23935914
  • Risk of cerebrovascular events in elderly patients after radiation therapy versus surgery for early-stage glottic cancer. Int J Radiat Oncol Biol Phys
    Hong JC, Kruser TJ, Gondi V, Mohindra P, Cannon DM, Harari PM, Bentzen SM
    2013 Oct 01; 87 (2): 290-6
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      PURPOSE: Comprehensive neck radiation therapy (RT) has been shown to increase cerebrovascular disease (CVD) risk in advanced-stage head-and-neck cancer. We assessed whether more limited neck RT used for early-stage (T1-T2 N0) glottic cancer is associated with increased CVD risk, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database.

      METHODS AND MATERIALS: We identified patients ≥66 years of age with early-stage glottic laryngeal cancer from SEER diagnosed from 1992 to 2007. Patients treated with combined surgery and RT were excluded. Medicare CPT codes for carotid interventions, Medicare ICD-9 codes for cerebrovascular events, and SEER data for stroke as the cause of death were collected. Similarly, Medicare CPT and ICD-9 codes for peripheral vascular disease (PVD) were assessed to serve as an internal control between treatment groups.

      RESULTS: A total of 1413 assessable patients (RT, n=1055; surgery, n=358) were analyzed. The actuarial 10-year risk of CVD was 56.5% (95% confidence interval 51.5%-61.5%) for the RT cohort versus 48.7% (41.1%-56.3%) in the surgery cohort (P=.27). The actuarial 10-year risk of PVD did not differ between the RT (52.7% [48.1%-57.3%]) and surgery cohorts (52.6% [45.2%-60.0%]) (P=.89). Univariate analysis showed an increased association of CVD with more recent diagnosis (P=.001) and increasing age (P=.001). On multivariate Cox analysis, increasing age (P<.001) and recent diagnosis (P=.002) remained significantly associated with a higher CVD risk, whereas the association of RT and CVD remained not statistically significant (HR=1.11 [0.91-1.37,] P=.31).

      CONCLUSIONS: Elderly patients with early-stage laryngeal cancer have a high burden of cerebrovascular events after surgical management or RT. RT and surgery are associated with comparable risk for subsequent CVD development after treatment in elderly patients.

      View details for PubMedID 23906930
  • Increased local failure risk with prolonged radiation treatment time in head and neck cancer treated with concurrent chemotherapy. Head Neck
    Cannon DM, Geye HM, Hartig GK, Traynor AM, Hoang T, McCulloch TM, Wiederholt PA, Chappell RJ, Harari PM
    2014 Aug; 36 (8): 1120-5
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      BACKGROUND: Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation therapy (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear.

      METHODS: We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001 to 2009. The effects of RTT and other variables on local control and survival were analyzed.

      RESULTS: Patients with RTT >7 weeks had a significantly increased risk of local failure (hazard ratio [HR], 2.6; p = .018) and death (HR, 1.9 p = .035). These results retained significance even after adjustment for tumor stage (age was not significant).

      CONCLUSION: For patients treated with concurrent chemoradiotherapy (chemoRT), prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of patients with HNSCC undergoing definitive chemoRT should be managed aggressively to limit treatment interruptions.

      View details for PubMedID 23804248
  • Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res
    Kimple RJ, Smith MA, Blitzer GC, Torres AD, Martin JA, Yang RZ, Peet CR, Lorenz LD, Nickel KP, Klingelhutz AJ, Lambert PF, Harari PM
    2013 Aug 01; 73 (15): 4791-800
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      Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2-M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.

      View details for PubMedID 23749640
  • Acute hematologic and mucosal toxicities in head and neck cancer patients undergoing chemoradiotherapy: a comparison of 3D-CRT, IMRT, and helical tomotherapy. Technol Cancer Res Treat
    Kruser TJ, Rice SR, Cleary KP, Geye HM, Tome WA, Harari PM, Kozak KR
    2013 Oct; 12 (5): 383-9
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      IMRT and helical tomotherapy for head and neck cancer (HNC) treatment are associated with higher doses to certain non-target tissues than traditional static beam techniques. We hypothesized that this may lead to higher acute mucosal and hematologic toxicities. This analysis was limited to 178 patients receiving ≥60 Gy with concurrent weekly cisplatin. Radiation delivery used 3D-CRT in 41 patients (23%), conventional IMRT in 56 patients (31%), and helical tomotherapy in 81 patients (46%). Acute mucositis rates, weekly hematologic parameters, and ability to deliver planned chemotherapy cycles were examined for each patient during their course of chemoradiotherapy. Analysis showed patients were well balanced with regard to sex, age, and stage. Treatment time, as assessed by delivered monitor units, varied significantly between the 3D-CRT (median = 502), IMRT (median = 1087), and tomotherapy (median = 6757) cohorts. Acute mucositis grades did not significantly differ between the three subsets. Through six weeks of chemoradiotherapy, the median decline in hemoglobin was 15.6%, the median decline in platelets was 30.6%, and the median decline in leukocytes was 51.5%, but these drops were not significantly different between treatment cohorts. Chemotherapy was discontinued or held secondary to hematologic toxicity in 12% of 3D-CRT patients, 5% of IMRT patients and 15% of tomotherapy patients (p = 0.14). In conclusion, HNC patients undergoing high dose radiation with concurrent weekly cisplatin chemotherapy, the longer beam-on times and larger volumes of low-to-moderate radiation doses to non-target tissues associated with modern IMRT delivery techniques do not appear to result in increased acute hematologic or mucosal toxicities.

      View details for PubMedID 23547974
  • Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts. Clin Cancer Res
    Kimple RJ, Harari PM, Torres AD, Yang RZ, Soriano BJ, Yu M, Armstrong EA, Blitzer GC, Smith MA, Lorenz LD, Lee D, Yang DT, McCulloch TM, Hartig GK, Lambert PF
    2013 Feb 15; 19 (4): 855-64
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      PURPOSE: To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient tumorgraft model of human papillomavirus (HPV)-positive and HPV-negative cancers.

      EXPERIMENTAL DESIGN: Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. During subsequent passages, both formalin-fixed/paraffin-embedded as well as flash-frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity.

      RESULTS: Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0.72). Six tumorgrafts were HPV-positive on the basis of p16 staining. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations P = 0.085 and P = 0.002, respectively). Significant growth inhibition of representative tumorgrafts was shown with cisplatin, cetuximab, or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain.

      CONCLUSIONS: We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing.

      View details for PubMedID 23251001
  • Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res
    Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, Sliwkowski MX, Harari PM
    2013 Jan 15; 73 (2): 824-33
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      EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor-resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance.

      View details for PubMedID 23172311
  • Correlation of PET images of metabolism, proliferation and hypoxia to characterize tumor phenotype in patients with cancer of the oropharynx. Radiother Oncol
    Nyflot MJ, Harari PM, Yip S, Perlman SB, Jeraj R
    2012 Oct; 105 (1): 36-40
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      UNLABELLED: Spatial organization of tumor phenotype is of great interest to radiotherapy target definition and outcome prediction. We characterized tumor phenotype in patients with cancers of the oropharynx through voxel-based correlation of PET images of metabolism, proliferation, and hypoxia.

      METHODS: Patients with oropharyngeal cancer received (18)F-fluorodeoxyglucose (FDG) PET/CT, (18)F-fluorothymidine (FLT) PET/CT, and (61)Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) PET/CT. Images were co-registered and standardized uptake values (SUV) were calculated for all modalities. Voxel-based correlation was evaluated with Pearson's correlation coefficient in tumor regions. Additionally, sensitivity studies were performed to quantify the effects of image segmentation, registration, noise, and segmentation on R.

      RESULTS: On average, FDG PET and FLT PET images were most highly correlated (R(FDG:FLT) = 0.76, range 0.53-0.85), while Cu-ATSM PET showed greater heterogeneity in correlation to other tracers (R(FDG:Cu-ATSM) = 0.64, range 0.51-0.79; R(FLT:Cu-ATSM) = 0.61, range 0.21-0.80). Of the tested parameters, correlation was most sensitive to image registration. Misregistration of one voxel lead to ΔR(FDG) = 0.25, ΔR(FLT) = 0.39, and ΔR(Cu-ATSM) = 0.27. Image noise and reconstruction also had quantitative effects on correlation. No significant quantitative differences were found between GTV, expanded GTV, or CTV regions.

      CONCLUSIONS: Voxel-based correlation represents a first step into understanding spatial organization of tumor phenotype. These results have implications for radiotherapy target definition and provide a framework to test outcome prediction based on pretherapy distribution of phenotype.

      View details for PubMedID 23068711
  • Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol
    Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, Gyanchandani R, Blumenschein GR, Chen HX, Grandis JR, Harari PM, Kies MS, Kim S
    2013 Jan; 24 (1): 220-5
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      BACKGROUND: We evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN).

      PATIENTS AND METHODS: The combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed.

      RESULTS: Cetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3-4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy.

      CONCLUSIONS: Cetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.

      View details for PubMedID 22898037
  • Head and neck carcinoma in the United States: first comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN). Cancer
    Ang KK, Chen A, Curran WJ, Garden AS, Harari PM, Murphy BA, Wong SJ, Bellm LA, Schwartz M, Newman J, Adkins D, Hayes DN, Parvathaneni U, Brachman D, Ghabach B, Schneider CJ, Greenberg M, Anné PR
    2012 Dec 01; 118 (23): 5783-92
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      BACKGROUND: Detailed information about how patients with head and neck carcinoma (HNC) are treated across practice settings does not exist. The authors conducted a prospective, observational study to examine the patterns of care for a series of patients with newly diagnosed HNC in the United States and to test 2 hypotheses: 1) There is no difference in the pattern of care between community and academic settings; and 2) the results of major randomized clinical trials will change the pattern of care in both practice settings within 1 year of publication in peer-reviewed journals.

      METHODS: Patients aged ≥ 18 years were enrolled in the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN) after providing written informed consent if they had a confirmed diagnosis of new HNC and were scheduled to receive treatment other than surgery alone.

      RESULTS: Between 2005 and 2010, 100 centers enrolled 4243 patients, including 2612 patients (62%) from academic investigators and 1631 patients (38%) from community centers. Initial treatments were radiation with concurrent chemotherapy (30%) or cetuximab (9%), adjuvant radiotherapy (21%), induction chemotherapy (16%), and other (24%). Intensity modulated radiation therapy was the dominant radiation technique (84%). Single-agent cisplatin was prescribed in nearly half of patients and more often in academic centers (53% vs 43% of patients; P < .0001). Single-agent cetuximab was the next most common drug used (19%) and was prescribed more frequently in community settings (24% vs 17%; P = .0001). The data rejected the 2 prospective hypotheses.

      CONCLUSIONS: LORHAN documented differences in patient characteristics and treatments between community and academic settings for a large series of patients in the United States.

      View details for PubMedID 22569917
  • Enhancement of radiation response with bevacizumab. J Exp Clin Cancer Res
    Hoang T, Huang S, Armstrong E, Eickhoff JC, Harari PM
    2012 Apr 26; 31: 37
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      BACKGROUND: Vascular endothelial growth factor (VEGF) plays a critical role in tumor angiogenesis. Bevacizumab is a humanized monoclonal antibody that neutralizes VEGF. We examined the impact on radiation response by blocking VEGF signaling with bevacizumab.

      METHODS: Human umbilical vein endothelial cell (HUVEC) growth inhibition and apoptosis were examined by crystal violet assay and flow cytometry, respectively. In vitro HUVEC tube formation and in vivo Matrigel assays were performed to assess the anti-angiogenic effect. Finally, a series of experiments of growth inhibition on head and neck (H&N) SCC1 and lung H226 tumor xenograft models were conducted to evaluate the impact of bevacizumab on radiation response in concurrent as well as sequential therapy.

      RESULTS: The anti-angiogenic effect of bevacizumab appeared to derive not only from inhibition of endothelial cell growth (40%) but also by interfering with endothelial cell function including mobility, cell-to-cell interaction and the ability to form capillaries as reflected by tube formation. In cell culture, bevacizumab induced a 2 ~ 3 fold increase in endothelial cell apoptosis following radiation. In both SCC1 and H226 xenograft models, the concurrent administration of bevacizumab and radiation reduced tumor blood vessel formation and inhibited tumor growth compared to either modality alone. We observed a siginificant tumor reduction in mice receiving the combination of bevacizumab and radiation in comparison to mice treated with bevacizumab or radiation alone. We investigated the impact of bevacizumab and radiation treatment sequence on tumor response. In the SCC1 model, tumor response was strongest with radiation followed by bevacizumab with less sequence impact observed in the H226 model.

      CONCLUSIONS: Overall, these data demonstrate enhanced tumor response when bevacizumab is combined with radiation, supporting the emerging clinical investigations that are combining anti-angiogenic therapies with radiation.

      View details for PubMedID 22538017
  • Heterogeneity in head and neck IMRT target design and clinical practice. Radiother Oncol
    Hong TS, Tomé WA, Harari PM
    2012 Apr; 103 (1): 92-8
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      PURPOSE: To assess patterns of H&N IMRT practice with particular emphasis on elective target delineation.

      MATERIALS AND METHODS: Twenty institutions with established H&N IMRT expertise were solicited to design clinical target volumes for the identical H&N cancer case. To limit contouring variability, a primary tonsil GTV and ipsilateral level II node were pre-contoured. Participants were asked to accept this GTV, and contour their recommended CTV and PTV. Dose prescriptions, contouring time, and recommendations regarding chemotherapy were solicited.

      RESULTS: All 20 institutions responded. Remarkable heterogeneity in H&N IMRT design and practice was identified. Seventeen of 20 centers recommended treatment of bilateral necks whereas 3/20 recommended treatment of the ipsilateral neck only. The average CTV volume was 250 cm(3) (range 37-676 cm(3)). Although there was high concordance in coverage of ipsilateral neck levels II and III, substantial variation was identified for levels I, V, and the contralateral neck. Average CTV expansion was 4.1mm (range 0-15 mm). Eight of 20 centers recommended chemotherapy (cisplatin), whereas 12/20 recommended radiation alone. Responders prescribed on average 69 and 68 Gy to the tumor and metastatic node GTV, respectively. Average H&N target volume contouring time was 102.5 min (range 60-210 min).

      CONCLUSION: This study identifies substantial heterogeneity in H&N IMRT target definition, prescription, neck treatment, and use of chemotherapy among practitioners with established H&N IMRT expertise. These data suggest that continued efforts to standardize and simplify the H&N IMRT process are desirable for the safe and effective global advancement of H&N IMRT practice.

      View details for PubMedID 22405806
  • p53 modulates acquired resistance to EGFR inhibitors and radiation. Cancer Res
    Huang S, Benavente S, Armstrong EA, Li C, Wheeler DL, Harari PM
    2011 Nov 15; 71 (22): 7071-9
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      There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.

      View details for PubMedID 22068033
  • Wound healing following combined radiation and cetuximab therapy in head and neck cancer patients. J Wound Care
    Dean NR, Sweeny L, Harari PM, Bonner JA, Jones V, Clemons L, Geye H, Rosenthal EL
    2011 Apr; 20 (4): 166-70
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      OBJECTIVE: This study set out to determine if cetuximab treatment increases the risk of wound healing complications when combined with radiation therapy.

      METHOD: We performed a retrospective chart review of head and neck cancer patients who received salvage neck dissections between 1999 and 2007, at two academic tertiary care centres. Complications from wound healing were compared between radiation and combined therapy groups.

      RESULTS: A total of 35 patients received radiation (n=20) or combined radiation and cetuximab therapy (n=15) prior to neck dissection. The treatment groups were similar in regard to demographic and primary tumour-related characteristics. The time between treatment and salvage neck dissection did not differ between the radiation (3.9 months) and combination treatment (3.0 months) groups (p=0.15). Wound healing complications occurred in 13% (2/15) of the patients treated with radiation and cetuximab and there were no complications in patients who received radiation alone (p=0.20).

      CONCLUSION: Cetuximab did not significantly increase the risk of post-surgical wound complications, although a higher absolute number of wound complications was observed in the group treated with cetuximab and radiation therapy, compared with the group treated with radiation alone.

      CONFLICT OF INTEREST: This work was supported by a grant from the National Institute of Health (2T32 CA091078-06). One of the authors, JAB, is an occasional consultant and honoraria for ImClone and Bristol-Meyers Squibb.

      View details for PubMedID 21537303
  • Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): analysis of chemoradiation treatment approaches in the United States. Cancer
    Wong SJ, Harari PM, Garden AS, Schwartz M, Bellm L, Chen A, Curran WJ, Murphy BA, Ang KK
    2011 Apr 15; 117 (8): 1679-86
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      BACKGROUND: A study was undertaken to examine the patterns of systemic therapy use in conjunction with radiation therapy for patients with locally advanced head and neck squamous cell cancer.

      METHODS: Between December 1, 2005 and May 11, 2009, 2874 patients with newly diagnosed head and neck squamous cell cancer who were scheduled to receive radiotherapy and/or drug therapy were registered in a prospective national database. The database was specifically analyzed to examine patients who received chemotherapy in conjunction with definitive radiotherapy.

      RESULTS: A total of 1144 patients received systemic therapy in conjunction with radiotherapy; 645 (56%) patients received agents concurrent with radiation therapy, 49 (4%) patients received chemotherapy before radiotherapy (induction), 224 (20%) patients received chemotherapy before and during radiotherapy (sequential), and 226 (20%) patients received chemoradiation after surgery. Single-agent cisplatin, single-agent cetuximab, and carboplatin plus paclitaxel were, in order, the 3 most commonly prescribed concurrent regimens. Concurrent cisplatin was more frequently used in the academic setting compared with the community setting (P = .0015). Postoperative chemoradiation, rather than radiation alone, was more commonly used in academic centers compared with community practice centers (P = <.0001).

      CONCLUSIONS: The LORHAN (Longitudinal Oncology Registry of Head and Neck Carcinoma) database is a useful barometer of current US practice patterns and can be applied to analyze future trends in the combined modality management of head and neck cancer. Sequential chemotherapy is used frequently, but cisplatin-based concurrent chemoradiation remains the most commonly used regimen for locally advanced head and neck cancer.

      View details for PubMedID 21472715
  • Robotics in head and neck cancer: future opportunities. Oncology (Williston Park)
    Harari PM, Hartig GK
    2010 Oct; 24 (11): 1015, 1020, 1022
  • Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One
    Hatakeyama H, Cheng H, Wirth P, Counsell A, Marcrom SR, Wood CB, Pohlmann PR, Gilbert J, Murphy B, Yarbrough WG, Wheeler DL, Harari PM, Guo Y, Shyr Y, Slebos RJ, Chung CH
    2010 Sep 13; 5 (9): e12702
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      BACKGROUND: We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC).

      METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease.

      CONCLUSIONS/SIGNIFICANCE: Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.

      View details for PubMedID 20856931
  • Head and neck squamous cell carcinoma from an unknown primary site. Am J Otolaryngol
    Wallace A, Richards GM, Harari PM, Kirwan JM, Morris CG, Katakam H, Mendenhall WM
    2011 Jul-Aug; 32 (4): 286-90
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      BACKGROUND: The purpose of this study is to present our experience treating patients with squamous cell carcinoma (SCC) from an unknown head and neck primary site and to determine whether a policy change eliminating the larynx and hypopharynx from the radiotherapy (RT) portals has impacted outcome.

      METHODS: One hundred seventy-nine patients received definitive RT with or without a neck dissection for SCC from an unknown head and neck primary site. RT was delivered to the ipsilateral neck alone or both sides of the neck and, usually, the potential mucosal primary sites. The median mucosal dose was 5670 cGy. The median neck dose was 6500 cGy. One hundred nine patients (61%) received a planned neck dissection.

      RESULTS: Mucosal control at 5 years was 92%. The mucosal control rate in patients with RT limited to the nasopharynx and oropharynx was 100%. The 5-year neck-control rates were as follows: N(1), 94%; N(2a), 98%; N(2b), 86%; N(2c), 86%; N(3), 57%; and overall, 81%. The 5-year cause-specific survival rates were as follows: N(1), 94%; N(2a), 88%; N(2b), 82%; N(2c), 71%; N(3), 48%; and overall, 73%. The 5-year overall survival rates were as follows: N(1), 50%; N(2a), 70%; N(2b), 59%; N(2c), 45%; N(3), 34%; and overall, 52%. Eleven patients (7%) developed severe complications.

      CONCLUSION: RT alone or combined with neck dissection results in a high probability of cure with a low risk of severe complications. Eliminating the larynx and hypopharynx from the RT portals did not compromise outcome and likely reduces treatment toxicity.

      View details for PubMedID 20719404
  • Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol
    Wheeler DL, Dunn EF, Harari PM
    2010 Sep; 7 (9): 493-507
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      EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

      View details for PubMedID 20551942
  • Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors. Clin Cancer Res
    Kruser TJ, Wheeler DL, Armstrong EA, Iida M, Kozak KR, van der Kogel AJ, Bussink J, Coxon A, Polverino A, Harari PM
    2010 Jul 15; 16 (14): 3639-47
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      BACKGROUND: Motesanib is a potent inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit receptors. In this report we examine the interaction between motesanib and radiation in vitro and in head and neck squamous cell carcinoma (HNSCC) xenograft models.

      EXPERIMENTAL DESIGN: In vitro assays were done to assess the impact of motesanib on VEGFR2 signaling pathways in human umbilical vein endothelial cells (HUVEC). HNSCC lines grown as tumor xenografts in athymic nude mice were utilized to assess the in vivo activity of motesanib alone and in combination with radiation.

      RESULTS: Motesanib inhibited VEGF-stimulated HUVEC proliferation in vitro, as well as VEGFR2 kinase activity. Additionally, motesanib and fractionated radiation showed additive inhibitory effects on HUVEC proliferation. In vivo combination therapy with motesanib and radiation showed increased response compared with drug or radiation alone in UM-SCC1 (P < 0.002) and SCC-1483 xenografts (P = 0.001); however, the combination was not significantly more efficacious than radiation alone in UM-SCC6 xenografts. Xenografts treated with motesanib showed a reduction of vessel penetration into tumor parenchyma, compared with control tumors. Furthermore, triple immunohistochemical staining for vasculature, proliferation, and hypoxia showed well-defined spatial relationships among these parameters in HNSCC xenografts. Motesanib significantly enhanced intratumoral hypoxia in the presence and absence of fractionated radiation.

      CONCLUSIONS: These studies identify a favorable interaction when combining radiation and motesanib in HNSCC models. The data presented suggest that motesanib reduces blood vessel penetration into tumors and thereby increases intratumoral hypoxia. These findings suggest that clinical investigations examining combinations of radiation and motesanib are warranted in HNSCC.

      View details for PubMedID 20507929
  • Therapeutic selective neck dissection outcomes. Otolaryngol Head Neck Surg
    Shepard PM, Olson J, Harari PM, Leverson G, Hartig GK
    2010 May; 142 (5): 741-6
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      OBJECTIVE: To evaluate the effectiveness of selective neck dissection in patients with nodal metastases from head and neck squamous cell carcinoma.

      STUDY DESIGN: Historical cohort study.

      SETTING: Academic medical center.

      SUBJECTS AND METHODS: A chart review was performed on 156 subjects with clinically positive regional nodal metastases managed initially with surgery, including neck dissection. Sixty-nine subjects underwent selective neck dissection (less than 5 levels), and the majority received postoperative radiotherapy (80%). Primary outcomes included Kaplan-Meier three-year ipsilateral regional control and five-year overall survival. Cox proportional univariate and multivariate analyses were performed to determine those factors associated with outcome.

      RESULTS: There were two ipsilateral regional recurrences among those undergoing selective neck dissection, yielding a regional control rate of 95.9 percent. Among those undergoing comprehensive neck dissection, nine ipsilateral regional recurrences occurred, yielding a control rate of 86.0 percent (P = 0.053). No selective neck dissection recurrences occurred in a preserved level. Selective neck dissection, as compared to comprehensive neck dissection, was not adversely associated with regional recurrence, survival, or distant metastasis, even after adjusting for possible confounders (hazard ratio 0.21, P = 0.055).

      CONCLUSION: These results demonstrate high rates of regional disease control (96%) following selective neck dissection and radiotherapy in patients with positive neck node metastases. In this population, performing selective neck dissection with adjuvant radiotherapy for the majority of patients is supported as an effective treatment approach.

      View details for PubMedID 20416466
  • Emphasizing conformal avoidance versus target definition for IMRT planning in head-and-neck cancer. Int J Radiat Oncol Biol Phys
    Harari PM, Song S, Tomé WA
    2010 Jul 01; 77 (3): 950-8
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      PURPOSE: To describe a method for streamlining the process of elective nodal volume definition for head-and-neck (H&N) intensity-modulated radiotherapy (IMRT) planning.

      METHODS AND MATERIALS: A total of 20 patients who had undergone curative-intent RT for H&N cancer underwent comprehensive treatment planning using three distinct, plan design techniques: conventional three-field design, target-defined IMRT (TD-IMRT), and conformal avoidance IMRT (CA-IMRT). For each patient, the conventional three-field design was created first, thereby providing the "outermost boundaries" for subsequent IMRT design. In brief, TD-IMRT involved physician contouring of the gross tumor volume, high- and low-risk clinical target volume, and normal tissue avoidance structures on consecutive 1.25-mm computed tomography images. CA-IMRT involved physician contouring of the gross tumor volume and normal tissue avoidance structures only. The overall physician time for each approach was monitored, and the resultant plans were rigorously compared.

      RESULTS: The average physician working time for the design of the respective H&N treatment contours was 0.3 hour for the conventional three-field design plan, 2.7 hours for TD-IMRT, and 0.9 hour for CA-IMRT. Dosimetric analysis confirmed that the largest volume of tissue treated to an intermediate (50 Gy) and high (70 Gy) dose occurred with the conventional three-field design followed by CA-IMRT and then TD-IMRT. However, for the two IMRT approaches, comparable results were found in terms of salivary gland and spinal cord protection.

      CONCLUSION: CA-IMRT for H&N treatment offers an alternative to TD-IMRT. The overall time for physician contouring was substantially reduced (approximately threefold), yielding a more standardized elective nodal volume. Because of the complexity of H&N IMRT target design, CA-IMRT might ultimately prove a safer and more reliable method to export to general radiation oncology practitioners, particularly those with limited H&N caseload experience.

      View details for PubMedID 20378266
  • Head and neck cancer. J Oncol
    Psyrri A, Burtness B, Harari PM, Vermorken JB, Licitra L, Sasaki CT
    2009; 2009: 358098
  • Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol
    Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK
    2010 Jan; 11 (1): 21-8
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      BACKGROUND: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival.

      METHODS: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at, number NCT00004227.

      FINDINGS: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002).

      INTERPRETATION: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash.

      FUNDING: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

      View details for PubMedID 19897418
  • Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: the University of Wisconsin experience. Head Neck
    Traynor AM, Richards GM, Hartig GK, Khuntia D, Cleary JF, Wiederholt PA, Bentzen SM, Harari PM
    2010 May; 32 (5): 599-606
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      BACKGROUND: We retrospectively examined the treatment efficacy and toxicity profile of intensity-modulated radiotherapy (IMRT) plus concurrent weekly cisplatin chemotherapy in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC).

      METHODS: A total of 57 patients with stage III or IV HNSCC were treated with IMRT and concurrent weekly cisplatin (dosed at 30 mg/m(2)) between November 2001 and May 2007. The median prescription dose to the gross tumor volume was 70 Gy (using 2.0-2.2 Gy daily fractions).

      RESULTS: In-field tumor control at 2 years was 89.1%, locoregional control was 85.5%, and overall survival was 86.9%. The median radiation dose delivered was 70 Gy. The mean dose intensity of cisplatin administered was 25.7 mg/m(2)/week.

      CONCLUSION: Comprehensive head and neck IMRT to 70 Gy delivered with weekly cisplatin chemotherapy (30 mg/m(2)) is feasible and generally well tolerated.

      View details for PubMedID 19757422
  • Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys
    Eisbruch A, Harris J, Garden AS, Chao CK, Straube W, Harari PM, Sanguineti G, Jones CU, Bosch WR, Ang KK
    2010 Apr; 76 (5): 1333-8
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      PURPOSE: To assess the results of a multi-institutional study of intensity-modulated radiation therapy (IMRT) for early oropharyngeal cancer.

      PATIENTS AND METHODS: Patients with oropharyngeal carcinoma Stage T1-2, N0-1, M0 requiring treatment of the bilateral neck were eligible. Chemotherapy was not permitted. Prescribed planning target volumes (PTVs) doses to primary tumor and involved nodes was 66 Gy at 2.2 Gy/fraction over 6 weeks. Subclinical PTVs received simultaneously 54-60 Gy at 1.8-2.0 Gy/fraction. Participating institutions were preapproved for IMRT, and quality assurance review was performed by the Image-Guided Therapy Center.

      RESULTS: 69 patients were accrued from 14 institutions. At median follow-up for surviving patients (2.8 years), the 2-year estimated local-regional failure (LRF) rate was 9%. 2/4 patients (50%) with major underdose deviations had LRF compared with 3/49 (6%) without such deviations (p = 0.04). All cases of LRF, metastasis, or second primary cancer occurred among patients who were current/former smokers, and none among patients who never smoked. Maximal late toxicities Grade >or=2 were skin 12%, mucosa 24%, salivary 67%, esophagus 19%, osteoradionecrosis 6%. Longer follow-up revealed reduced late toxicity in all categories. Xerostomia Grade >or=2 was observed in 55% of patients at 6 months but reduced to 25% and 16% at 12 and 24 months, respectively. In contrast, salivary output did not recover over time.

      CONCLUSIONS: Moderately accelerated hypofractionatd IMRT without chemotherapy for early oropharyngeal cancer is feasible, achieving high tumor control rates and reduced salivary toxicity compared with similar patients in previous Radiation Therapy Oncology Group studies. Major target underdose deviations were associated with higher LRF rate.

      View details for PubMedID 19540060
  • Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol
    Le Péchoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, Ciuleanu T, Arriagada R, Jones R, Wanders R, Lerouge D, Laplanche A, Prophylactic Cranial Irradiation (PCI) Collaborative Group
    2009 May; 10 (5): 467-74
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      BACKGROUND: The optimum dose of prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC) is unknown. A meta-analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses. This randomised clinical trial compared the effect of standard versus higher PCI doses on the incidence of brain metastases.

      METHODS: Between September, 1999, and December, 2005, 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were randomly assigned to a standard (n=360, 25 Gy in 10 daily fractions of 2.5 Gy) or higher PCI total dose (n=360, 36 Gy) delivered using either conventional (18 daily fractions of 2 Gy) or accelerated hyperfractionated (24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h) radiotherapy. All of the treatment schedules excluded weekends. Randomisation was stratified according to medical centre, age (</=60 and >60 years), and interval between the start of induction treatment and the date of randomisation (</=90, 91-180, and >180 days). Eligible patients were randomised blindly by the data centre of the Institut Gustave Roussy (PCI99-01 and IFCT) using minimisation, and by the data centres of EORTC (EORTC ROG and LG) and RTOG (for CALGB, ECOG, RTOG, and SWOG), both using block stratification. The primary endpoint was the incidence of brain metastases at 2 years. Analysis was by intention-to-treat. This study is registered with number NCT00005062.

      FINDINGS: Five patients in the standard-dose group and four in the higher-dose group did not receive PCI; nonetheless, all randomised patients were included in the effectiveness anlysis. After a median follow-up of 39 months (range 0-89 months), 145 patients had brain metastases; 82 in the standard-dose group and 63 in the higher-dose group. There was no significant difference in the 2-year incidence of brain metastases between the standard PCI dose group and the higher-dose group, at 29% (95% CI 24-35) and 23% (18-29), respectively (hazard ratio [HR] 0.80 [95% CI 0.57-1.11], p=0.18). 226 patients in the standard-dose group and 252 in the higher-dose group died; 2-year overall survival was 42% (95% CI 37-48) in the standard-dose group and 37% (32-42) in the higher-dose group (HR 1.20 [1.00-1.44]; p=0.05). The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality: 189 patients in the standard group versus 218 in the higher-dose group died of progressive disease. Five serious adverse events occurred in the standard-dose group versus zero in the higher-dose group. The most common acute toxic events were fatigue (106 [30%] patients in the standard-dose group vs 121 [34%] in the higher-dose group), headache (85 [24%] vs 99 [28%]), and nausea or vomiting (80 [23%] vs 101 [28%]).

      INTERPRETATION: No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI, but there was a significant increase in mortality. PCI at 25 Gy should remain the standard of care in limited-stage SCLC.

      FUNDING: Institut Gustave-Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The European Organisation for Research and Treatment of Cancer (EORTC) contribution to this trial was supported by grants 5U10 CA11488-30 through 5U10 CA011488-38 from the US National Cancer Institute.

      View details for PubMedID 19386548
  • Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. Cancer Biol Ther
    Wheeler DL, Iida M, Kruser TJ, Nechrebecki MM, Dunn EF, Armstrong EA, Huang S, Harari PM
    2009 Apr; 8 (8): 696-703
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      The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.

      View details for PubMedID 19276677
  • Longitudinal oncology registry of head and neck carcinoma (LORHAN): initial supportive care findings. Support Care Cancer
    Murphy BA, Chen A, Curran WJ, Garden AS, Harari PM, Wong SJ, Ang KK
    2009 Nov; 17 (11): 1393-401
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      GOALS OF WORK: We report the first analysis of demographic, socioeconomic, and toxicity data from the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN).

      MATERIALS AND METHODS: Eligible patients include newly diagnosed Head and Neck Cancer (HNC) patients, scheduled to receive radiotherapy or drug therapy, > or =18 years of age, and able to provide informed consent. Assessments are completed at baseline, at the completion of therapy, and yearly thereafter. Patient data are entered in the registry electronically and transferred via Secure HTTP protocols.

      RESULTS: Reported use of supportive care differed by treatment setting. When compared to community sites, patients at academic centers received more supportive interventions: feeding tube (59% vs. 48%; p = 0.001), tracheotomy tube (16% vs. 9%; p = 0.002), opioid analgesics (89% vs. 59%; p < 0.0001), anti-emetics (83% vs. 68%; p < 0.0001), and amifostine (17% vs. 12%; p = 0.02). Reported grades 3-4 mucositis/stomatitis was also higher in patients treated at academic centers (38% vs. 28%; p = 0.001).

      CONCLUSION: There was a marked decrease in the documented use of supportive care measures in the community setting. This may be due to (1) lower rates of toxicity requiring less supportive care, (2) less stringent documentation, or (3) less aggressive use of supportive care measures. The documented rate of mucositis was less than expected. This is likely due to inadequate assessment or documentation. Further exploration of these findings is warranted as they may indicate an under appreciation and undertreatment of clinically significant acute tumor and treatment-related toxicities.

      View details for PubMedID 19263090
  • A comprehensive assessment by tumor site of patient setup using daily MVCT imaging from more than 3,800 helical tomotherapy treatments. Int J Radiat Oncol Biol Phys
    Schubert LK, Westerly DC, Tomé WA, Mehta MP, Soisson ET, Mackie TR, Ritter MA, Khuntia D, Harari PM, Paliwal BR
    2009 Mar 15; 73 (4): 1260-9
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      PURPOSE: To assess patient setup corrections based on daily megavoltage CT (MVCT) imaging for four anatomic treatment sites treated on tomotherapy.

      METHOD AND MATERIALS: Translational and rotational setup corrections, based on registration of daily MVCT to planning CT images, were analyzed for 1,179 brain and head and neck (H&N), 1,414 lung, and 1,274 prostate treatment fractions. Frequencies of three-dimensional vector lengths, overall distributions of setup corrections, and patient-specific distributions of random and systematic setup errors were analyzed.

      RESULTS: Brain and H&N had lower magnitude positioning corrections and smaller variations in translational setup errors but were comparable in roll rotations. Three-dimensional vector translational shifts of larger magnitudes occurred more frequently for lung and prostate than for brain and H&N treatments, yet this was not observed for roll rotations. The global systematic error for prostate was 4.7 mm in the vertical direction, most likely due to couch sag caused by large couch extension distances. Variations in systematic errors and magnitudes of random translational errors ranged from 1.6 to 2.6 mm for brain and H&N and 3.2 to 7.2 mm for lung and prostate, whereas roll rotational errors ranged from 0.8 degrees to 1.2 degrees for brain and H&N and 0.5 degrees to 1.0 degrees for lung and prostate.

      CONCLUSIONS: Differences in setup were observed between brain, H&N, lung, and prostate treatments. Patient setup can be improved if daily imaging is performed. This analysis can assess the utilization of daily image guidance and allows for further investigation into improved anatomic site-specific and patient-specific treatments.

      View details for PubMedID 19251098
  • Hidradenomas and a hidradenocarcinoma of the scalp managed using Mohs micrographic surgery and a multidisciplinary approach: case reports and review of the literature. Dermatol Surg
    Yavel R, Hinshaw M, Rao V, Hartig GK, Harari PM, Stewart D, Snow SN
    2009 Feb; 35 (2): 273-81
  • Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells. Clin Cancer Res
    Benavente S, Huang S, Armstrong EA, Chi A, Hsu KT, Wheeler DL, Harari PM
    2009 Mar 01; 15 (5): 1585-92
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      PURPOSE: The epidermal growth factor receptor (EGFR) is recognized as a key mediator of proliferation and progression in many human tumors. A series of EGFR-specific inhibitors have recently gained Food and Drug Administration approval in oncology. These strategies of EGFR inhibition have shown major tumor regressions in approximately 10% to 20% of advanced cancer patients. Many tumors, however, eventually manifest resistance to treatment. Efforts to better understand the underlying mechanisms of acquired resistance to EGFR inhibitors, and potential strategies to overcome resistance, are greatly needed.

      EXPERIMENTAL DESIGN: To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma tumor cell line SCC-1. Cells were treated with increasing concentrations of cetuximab, gefitinib, or erlotinib, and characterized for the molecular changes in the EGFR inhibitor-resistant lines relative to the EGFR inhibitor-sensitive lines.

      RESULTS: EGFR inhibitor-resistant lines were able to maintain their resistant phenotype in both drug-free medium and in athymic nude mouse xenografts. In addition, EGFR inhibitor-resistant lines showed a markedly increased proliferation rate. EGFR inhibitor-resistant lines had elevated levels of phosphorylated EGFR, mitogen-activated protein kinase, AKT, and signal transducer and activator of transcription 3, which were associated with reduced apoptotic capacity. Subsequent in vivo experiments indicated enhanced angiogenic potential in EGFR inhibitor-resistant lines. Finally, EGFR inhibitor-resistant lines showed cross-resistance to ionizing radiation.

      CONCLUSIONS: We have developed EGFR inhibitor-resistant human head and neck squamous cell carcinoma cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.

      View details for PubMedID 19190133
  • Molecular target approaches in head and neck cancer: epidermal growth factor receptor and beyond. Semin Radiat Oncol
    Harari PM, Wheeler DL, Grandis JR
    2009 Jan; 19 (1): 63-8
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      Approximately 50,000 new cases of head and neck squamous cell carcinoma (HNSCC) will be diagnosed in the United States in 2009. Although the gradual decline in smoking rates in the United States is a highly favorable trend, the future global HNSCC incidence will likely reflect the increased marketing and penetration of tobacco products across several of our most populous countries. Although modern surgery, radiation, and conventional chemotherapy strategies for HNSCC continue to provide gradual improvement in outcome, the first molecular targeting approach to show a survival advantage for HNSCC patients has recently emerged in the context of epidermal growth factor receptor biology. The scientific background and current challenges accompanying this recent advance are described in this article as are several additional promising molecular targets for HNSCC. There is cautious anticipation that the logical advancement of molecular targeting agents in conjunction with radiation may afford increased cure rates and diminished normal tissue toxicity profiles for HNSCC patients over the years to come.

      View details for PubMedID 19028347
  • Augmentation of radiation response by panitumumab in models of upper aerodigestive tract cancer. Int J Radiat Oncol Biol Phys
    Kruser TJ, Armstrong EA, Ghia AJ, Huang S, Wheeler DL, Radinsky R, Freeman DJ, Harari PM
    2008 Oct 01; 72 (2): 534-42
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      PURPOSE: To examine the interaction between panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, and radiation in head-and-neck squamous cell carcinoma and non-small-cell lung cancer cell lines and xenografts.

      METHODS AND MATERIALS: The head-and-neck squamous cell carcinoma lines UM-SCC1 and SCC-1483, as well as the non-small-cell lung cancer line H226, were studied. Tumor xenografts in athymic nude mice were used to assess the in vivo activity of panitumumab alone and combined with radiation. In vitro assays were performed to assess the effect of panitumumab on radiation-induced cell signaling, apoptosis, and DNA damage.

      RESULTS: Panitumumab increased the radiosensitivity as measured by the clonogenic survival assay. Radiation-induced epidermal growth factor receptor phosphorylation and downstream signaling through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was inhibited by panitumumab. Panitumumab augmented radiation-induced DNA damage by 1.2-1.6-fold in each of the cell lines studied as assessed by residual gamma-H(2)AX foci after radiation. Radiation-induced apoptosis was increased 1.4-1.9-fold by panitumumab, as evidenced by Annexin V-fluorescein isothiocyanate staining and flow cytometry. In vivo, the combination therapy of panitumumab and radiation was superior to panitumumab or radiation alone in the H226 xenografts (p = 0.01) and showed a similar trend in the SCC-1483 xenografts (p = 0.08). In vivo, immunohistochemistry demonstrated the ability of panitumumab to augment the antiproliferative and antiangiogenic effects of radiation.

      CONCLUSION: These studies have identified a favorable interaction in the combination of radiation and panitumumab in upper aerodigestive tract tumor models, both in vitro and in vivo. These data suggest that clinical investigations examining the combination of radiation and panitumumab in the treatment of epithelial tumors warrant additional pursuit.

      View details for PubMedID 18793955
  • Tumor volume as a prognostic factor in oropharyngeal squamous cell carcinoma treated with primary radiotherapy. Laryngoscope
    Been MJ, Watkins J, Manz RM, Gentry LR, Leverson GE, Harari PM, Hartig GK
    2008 Aug; 118 (8): 1377-82
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      OBJECTIVES/HYPOTHESIS: Tumor volume has been demonstrated to play a prognostic role in many head and neck cancers. The purpose of this study was to conduct an institutional review analyzing the correlation between tumor volume and locoregional control of oropharyngeal squamous cell cancer treated with primary radiotherapy.

      STUDY DESIGN: Retrospective institutional chart analysis.

      METHODS: Seventy-nine patients from 1991 to 2005 with primary T1 to T4 oropharyngeal squamous cell carcinoma (base of tongue, n = 31; soft palate, n = 1; tonsils, n = 47) were treated with primary radiotherapy. Tumor volumes were measured from pretreatment computerized tomography scans by two observers. Three-dimensional tumor volumes were calculated using a computer digitizer for each computed tomography slice showing the primary lesion. Survival analysis, using the methods of Kaplan and Meier, was performed to assess whether tumor volume, Tumor, Node, Metastasis classification, tumor stage, or location were associated with locoregional failure.

      RESULTS: Tumor volume did not significantly correlate with locoregional failure (observer 1, P = .6244; observer 2, P = .5612). There was a high interobserver correlation (r = 0.98970). Univariate analysis did, however, demonstrate a significant difference in locoregional failure between T4 tumors and all other T stages (T1 vs. T4, P = .0107; T2 vs. T4, P = .0004; T3 vs. T4, P = .0155). Nodal status, tumor stage, and location did not significantly correlate with locoregional failure rate.

      CONCLUSIONS: Tumor volume does not appear to play a significant role in predicting locoregional recurrence for patients with primary squamous cell cancer of the oropharynx treated with primary radiotherapy. However, T4 status was predictive of poor locoregional control.

      View details for PubMedID 18418275
  • EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck. Curr Oncol Rep
    Mehra R, Cohen RB, Harari PM
    2008 Mar; 10 (2): 176-84
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      Squamous cell carcinoma of the head and neck (SCCHN) continues to be a source of significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR), including monoclonal antibodies and small molecule tyrosine kinase inhibitors, have demonstrated activity in this disease. The US Food and Drug Administration has approved the monoclonal antibody cetuximab in conjunction with radiation for locally advanced disease, and as a single agent for recurrent/metastatic disease. In addition, recent data have shown a survival benefit for patients with recurrent/metastatic disease who are treated with platinum, fluorouracil, and cetuximab. These promising results have prompted further study of EGFR inhibitors with radiation and cytotoxic chemotherapy to further increase the benefit of treatment for SCCHN.

      View details for PubMedID 18377832
  • Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene
    Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, Hsu KT, Harari PM
    2008 Jun 26; 27 (28): 3944-56
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      The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10-20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to cetuximab. Cells developing acquired resistance to cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, cetuximab-resistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to cetuximab.

      View details for PubMedID 18297114
  • Beware the swing and a miss: baseball precautions for conformal radiotherapy. Int J Radiat Oncol Biol Phys
    Harari PM
    2008 Mar 01; 70 (3): 657-9
  • Clinical application of EGFR inhibitors in head and neck squamous cell cancer. Cancer Treat Res
    Astsaturov I, Cohen RB, Harari PM
    2008; 139: 135-52
  • Radiation oncology advances: an introduction. Cancer Treat Res
    Bentzen SM, Harari PM, Tomé WA, Mehta MP
    2008; 139: 1-4
  • Megavoltage computed tomography: an emerging tool for image-guided radiotherapy. Am J Clin Oncol
    Hong TS, Welsh JS, Ritter MA, Harari PM, Jaradat H, Mackie TR, Mehta MP
    2007 Dec; 30 (6): 617-23
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      BACKGROUND: Helical tomotherapy is a unique approach to image-guided IMRT that combines features of a linear accelerator and a CT scanner. This design allows generation of megavoltage CT (MVCT) images, which among other uses, are used to verify daily setup. In this study, we assessed the image-quality, absorbed radiation doses, and clinical practicality of MVCT from our helical tomotherapy prototype unit.

      MATERIALS AND METHODS: Phantom studies were first performed to assess the capabilities of MVCT. Next, MVCT images from human patients prospectively enrolled on institutional review board-approved imaging and treatment protocols were analyzed. MVCT was obtained using a 4-MV beam from the University of Wisconsin helical tomotherapy prototype device. These scans were compared with conventional kilovoltage (kVCT) images from a diagnostic CT scanner.

      RESULTS: MVCT images in phantoms demonstrate an ability to detect contrast differences as small as 3%. Small objects, 1.2 to 1.6 mm, were seen with good resolution. In human subjects, MVCT imaging of tumor targets and normal anatomy revealed sufficient detail for patient repositioning. MVCT imaging of metallic objects showed minimal artifact in comparison with kVCT. Patient scans were obtained in about 1 to 5 minutes and resulted in absorbed radiation doses of 1.5 to 3 cGy.

      CONCLUSIONS: MVCT is an elegant pretreatment position and setup verification tool. MVCT images of human subjects obtained from the helical tomotherapy unit showed good resolution and contrast. The high-quality three-dimensional information permits its use in day-to-day setup verification. The unique properties of MVCT also provide the potential for primary imaging of anatomic regions near metal prostheses as well as nonmedical applications. Additional investigations are underway to improve image quality, further reduce patient dose, and aid adaptive radiotherapy and dose reconstruction.

      View details for PubMedID 18091057
  • EGFR-targeting monoclonal antibodies in head and neck cancer. Curr Cancer Drug Targets
    Astsaturov I, Cohen RB, Harari P
    2007 Nov; 7 (7): 650-65
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      The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.

      View details for PubMedID 18045070
  • Are we influencing outcome in oropharynx cancer with intensity-modulated radiotherapy? An inter-era comparison. Int J Radiat Oncol Biol Phys
    Hodge CW, Bentzen SM, Wong G, Palazzi-Churas KL, Wiederholt PA, Gondi V, Richards GM, Hartig GK, Harari PM
    2007 Nov 15; 69 (4): 1032-41
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      PURPOSE: To analyze the outcome in all oropharynx cancer patients treated at the University of Wisconsin during 1995-2005 and highlight the methodologic challenge in comparing outcome after intensity-modulated radiotherapy (IMRT) with that of historical controls.

      METHODS AND MATERIALS: Outcomes were compared in 195 oropharynx cancer patients after definitive radiotherapy with curative intent in the pre-IMRT era (pre-IMRT, n = 105), after IMRT (IMRT+, n = 52) or after non-IMRT techniques during the IMRT era (IMRT-, n = 38).

      RESULTS: With a median follow-up of 30.4 months, the 3-year overall survival rate in IMRT+, IMRT-, and pre-IMRT patients was 88.2%, 81.1%, and 67.7%, respectively; and for locoregional control was 96.1%, 78.1%, and 81.1%. Patients from the IMRT era more frequently received concurrent chemotherapy (67% vs. 6%, p < 0.001) and underwent adjuvant neck dissection (52% vs. 29%, p = 0.002). Patients with T3-4 disease and bilateral neck disease were significantly less likely to receive IMRT. Cox regression analysis identified IMRT as a significant prognostic factor (p = 0.04); however, after including T stage in the model, IMRT lost independent significance (p = 0.2). Analysis of a potential effect of IMRT on Grade 3+ mucositis or skin reaction was also hampered by the change in other treatment characteristics.

      CONCLUSIONS: Outcomes in oropharynx cancer have improved at our institution since the introduction of IMRT. However, multiple factors have contributed to this improvement, and presentation of IMRT outcomes without the full context of historical and contemporary controls may yield data that overstate outcome after IMRT.

      View details for PubMedID 17967300
  • Bridging gaps in multidisciplinary head and neck cancer care: nursing coordination and case management. Int J Radiat Oncol Biol Phys
    Wiederholt PA, Connor NP, Hartig GK, Harari PM
    2007; 69 (2 Suppl): S88-91
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      Patients with advanced head and neck cancer face not only a life-threatening malignancy, but also a remarkably complex treatment regimen that can affect their cosmetic appearance and ability to speak, breathe, and swallow. These patients benefit from the coordinated interaction of a multidisciplinary team of specialists and a comprehensive plan of care to address their physical and psychosocial concerns, manage treatment-related toxicities, and prevent or limit long-term morbidities affecting health-related quality of life. Although little has been published on patient-provider communication with a multidisciplinary team, evidence has suggested that gaps often occur in communication between patients and providers, as well as between specialists. These communication gaps can hinder the multidisciplinary group from working toward common patient-centered goals in a coordinated "interdisciplinary" manner. We discuss the role of a head-and-neck oncology nurse coordinator at a single institution in bridging gaps across the continuum of care, promoting an interdisciplinary team approach, and enhancing the overall quality of patient-centered head-and-neck cancer care.

      View details for PubMedID 17848305
  • Strategic plans to promote head and neck cancer translational research within the radiation therapy oncology group: a report from the translational research program. Int J Radiat Oncol Biol Phys
    Chung CH, Wong S, Ang KK, Hammond EH, Dicker AP, Harari PM, Le QT
    2007; 69 (2 Suppl): S67-78
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      Head and neck cancer is the fifth most common cancer in the United States, with an overall survival rate of approximately 40-50%. In an effort to improve patient outcomes, research efforts designed to maximize benefit and reduce toxicities of therapy are in progress. Basic research in cancer biology has accelerated this endeavor and provided preclinical data and technology to support clinically relevant advances in early detection, prognostic and predictive biomarkers. Recent completion of the Human Genome Project has promoted the rapid development of novel "omics" technologies that allow more broad based study from a systems biology perspective. However, clinically relevant application of resultant gene signatures to clinical trials within cooperative groups has advanced slowly. In light of the large numbers of variables intrinsic to biomarker studies, validation of preliminary data for clinical implementation presents a significant challenge and may only be realized with large trials that involve significant patient numbers. The Radiation Therapy Oncology Group (RTOG) Head and Neck Cancer Translational Research Program recognizes this problem and brings together three unique features to facilitate this research: (1) availability of large numbers of clinical specimens from homogeneously treated patients through multi-institutional clinical trials; (2) a team of physicians, scientists, and staff focused on patient-oriented head-and-neck cancer research with the common goal of improving cancer care; and (3) a funding mechanism through the RTOG Seed Grant Program. In this position paper we outline strategic plans to further promote translational research within the framework of the RTOG.

      View details for PubMedID 17848300
  • Stepwise progress in epidermal growth factor receptor/radiation studies for head and neck cancer. Int J Radiat Oncol Biol Phys
    Harari PM
    2007; 69 (2 Suppl): S25-7
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      The U.S. Food and Drug Administration approval of four new epidermal growth factor receptor (EGFR) inhibitors for cancer therapy (cetuximab, panitumumab, gefitinib, and erlotinib) over the last 3 years is a remarkable milestone in oncology. Indeed, molecular inhibition of EGFR signaling represents one of the most promising current arenas for the development of molecular-targeted cancer therapies. Epidermal growth factor receptor inhibitors from both the monoclonal antibody and tyrosine kinase inhibitor class have demonstrated clinical activity in the treatment of a broad spectrum of common human malignancies. For the discipline of radiation oncology, the 2006 report of a phase III trial demonstrating a survival advantage for advanced head and neck cancer patients with the addition of weekly cetuximab during a 7-week course of radiation is particularly gratifying. Indeed, this is the first phase III trial to confirm a survival advantage with the addition of a molecular-targeted agent to radiation. Furthermore, this result seems to have been achieved with only a modest increment in overall treatment toxicity and with very high compliance to the prescribed treatment regimen. Nevertheless, much remains to be learned regarding the rational integration of EGFR inhibitors into cancer treatment regimens, as well as methods to optimize the selection of patients most likely to benefit from EGFR inhibitor strategies.

      View details for PubMedID 17848286
  • The 2007 Inaugural ASTRO/ASCO/AHNS Multidisciplinary Head and Neck Cancer Symposium. Int J Radiat Oncol Biol Phys
    Harari PM, Cohen RB, Raben D, Myers JN, Vokes EE, Weber RS, Ang KK
    2007; 69 (2 Suppl): S1-3
  • Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol
    Harari PM, Allen GW, Bonner JA
    2007 Sep 10; 25 (26): 4057-65
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      Epidermal growth factor receptor (EGFR) signaling inhibition represents a highly promising arena for the application of molecularly targeted cancer therapies. Evolving from several decades of systematic research in cancer cell biology, a series of EGFR inhibitors from both the monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI) class have been developed and promoted into clinical application. Several EGFR inhibitors have recently gained US Food and Drug Administration approval for cancer therapy in the United States (and many other countries), including the mAbs cetuximab and panitumumab, and the small molecule TKIs gefitinib, erlotinib, and lapatinib. The rapidly expanding preclinical and clinical data contributing to these US Food and Drug Administration drug registrations validates a central role of the EGFR as an important molecular target in epithelial malignancies. In this review, we focus primarily on the biology of EGFR interactions. Through improved understanding of EGFR biology in human cancers, there is anticipation that more tumor-selective therapy approaches with diminished collateral normal tissue toxicity can be advanced. Many questions remain to be answered, particularly with regard to how best combine EGFR inhibitors with conventional cancer therapies, and how to select those patients (tumors) most likely to benefit from EGFR inhibition strategies.

      View details for PubMedID 17827454
  • Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol
    Curran D, Giralt J, Harari PM, Ang KK, Cohen RB, Kies MS, Jassem J, Baselga J, Rowinsky EK, Amellal N, Comte S, Bonner JA
    2007 Jun 01; 25 (16): 2191-7
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      PURPOSE: In this randomized, phase III study, quality of life (QoL) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) after high-dose radiotherapy alone or in combination with cetuximab.

      PATIENTS AND METHODS: Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were eligible. QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline, week 4, and at months 4, 8, and 12 postbaseline.

      RESULTS: In this study, one of the largest conducted in a population of patients with locoregionally advanced SCCHN, 424 patients received radiotherapy alone (213 patients) or radiotherapy plus cetuximab (211 patients). Radiotherapy/cetuximab significantly improved locoregional control (P = .005) and overall survival (P = .03) compared with radiotherapy alone, without significantly increasing radiotherapy-associated adverse events. The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL questionnaires was high in both arms. QoL worsened during treatment and improved after cessation of treatment, reaching baseline levels at 12 months. There were no significant differences in QoL scores between the treatment arms. This was particularly notable for global health status/QoL, social functioning, social eating, and social contact. Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients.

      CONCLUSION: The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting QoL.

      View details for PubMedID 17538164
  • Parotidectomy: ten-year review of 237 cases at a single institution. Otolaryngol Head Neck Surg
    Upton DC, McNamar JP, Connor NP, Harari PM, Hartig GK
    2007 May; 136 (5): 788-92
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      OBJECTIVE: To review a single surgeon's experience with parotidectomy with an emphasis on examining the appropriate use of partial superficial parotidectomy and the differences in early outcomes observed with the various types and extent of parotidectomy used.

      STUDY DESIGN AND SETTING: A series of 237 patients who underwent parotidectomy over a 10-year period was reviewed.

      RESULTS: Postoperative complications included facial nerve weakness (18%), sialocele (6.3%), wound infection (3.8%), hematoma (3.8%), and symptomatic Frey's syndrome (1.7%). More extensive surgical procedures, including complete superficial or total parotidectomy, were associated with a 2.7 times greater incidence of immediate postoperative facial nerve weakness compared with partial superficial parotidectomy.

      CONCLUSION: Partial superficial parotidectomy is associated with a decreased incidence of transient postoperative facial nerve weakness compared with more extensive procedures such as complete superficial or total parotidectomy. Intraoperative frozen section was an accurate means of selecting patients for the partial superficial parotidectomy procedure.

      SIGNIFICANCE: Partial superficial parotidectomy is an effective method for treating benign tumors confined to the superficial lobe.

      View details for PubMedID 17478217
  • Exploitable mechanisms for combining drugs with radiation: concepts, achievements and future directions. Nat Clin Pract Oncol
    Bentzen SM, Harari PM, Bernier J
    2007 Mar; 4 (3): 172-80
    • More

      Widening indications for combining radiation therapy with cytotoxic or molecular-targeted drugs have mainly been driven by pragmatic clinical trials. With a flurry of novel drugs in various stages of preclinical and clinical development there is a need to revise the framework that has traditionally been used for discussing possible drug-radiation interactions, especially because many of the new drugs are directed at a specific molecular target. Spatial cooperation, cytotoxic enhancement, biological cooperation, temporal modulation and normal tissue protection are proposed as five primary exploitable mechanisms for the rational combination of drugs with radiation for cancer therapy. These five mechanisms produce different clinical outcomes and, therefore, the optimum clinical end point for assessing therapeutic benefit will depend on the mechanism tested. The dependence of outcome on these mechanisms also affects the selection of preclinical models and the optimum scheduling of the two modalities, i.e. the timing and dosing of the drug relative to the radiation dose fractions. These considerations are discussed in some detail for each mechanism and illustrated with specific clinical examples. Multi-modality therapy for head and neck squamous-cell carcinoma is used to illustrate these concepts. Further clinical progress in this field will require hypothesis-driven trials to ensure efficient identification of treatments with the most favorable risk:benefit ratio.

      View details for PubMedID 17327857
  • Insulin-like growth factor-I receptor signaling blockade combined with radiation. Cancer Res
    Allen GW, Saba C, Armstrong EA, Huang SM, Benavente S, Ludwig DL, Hicklin DJ, Harari PM
    2007 Feb 01; 67 (3): 1155-62
    • More

      Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.

      View details for PubMedID 17283150
  • Planned postradiotherapy neck dissection: Rationale and clinical outcomes. Laryngoscope
    Sewall GK, Palazzi-Churas KL, Richards GM, Hartig GK, Harari PM
    2007 Jan; 117 (1): 121-8
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      OBJECTIVES: In this study, we examine pathology results and clinical outcome for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) who present with advanced neck disease and undergo planned postradiotherapy neck dissection.

      STUDY DESIGN: Review of all patients with SCCHN treated with primary radiation (or chemoradiation) and postradiotherapy neck dissection at the University of Wisconsin between 1992 to 2005 was performed. One hundred seven neck dissections were identified in 93 patients, 79 unilateral and 14 bilateral. All major treatment and outcome parameters were examined with particular emphasis on the postradiotherapy neck dissection.

      RESULTS: Thirty of 107 neck dissection specimens (28%) showed evidence of residual carcinoma on pathologic review. The mean number of lymph nodes identified at neck dissection for the entire cohort was 21 per specimen (range, 1-60) with 1.3 nodes per positive neck dissection demonstrating residual carcinoma. No correlation was found between the type of neck dissection performed and the presence of residual nodal disease. Eighty-two evaluated patients (93%) remain free of regional disease recurrence, whereas six patients have subsequently manifested neck recurrence. Four of the six patients who developed regional recurrence showed residual carcinoma in their neck dissection specimen. Five of these patients underwent comprehensive neck dissection (levels I-V); one underwent selective neck dissection (<levels I-V).

      CONCLUSION: Approximately one-fourth of the patients in this series showed pathologic evidence of residual carcinoma in the neck at the time of postradiotherapy neck dissection. The majority of these cases showed microscopic residual carcinoma in a single lymph node. Although in the early postradiotherapy setting, we cannot accurately predict the viability and growth potential of microscopic residual carcinoma in lymph nodes, these findings, combined with the modest overall morbidity of selective neck dissection, suggest that planned postradiotherapy neck dissection should be strongly considered for patients presenting with advanced neck disease. This remains a prevailing clinical practice at our institution.

      View details for PubMedID 17202940

Contact Information

Paul Harari, MD

Administrative Assistant: Julie Thomas,
600 Highland Avenue, Box 3684 Clinical Science Center
Madison, WI 53792