Window Studies in Squamous Cell Carcinoma of the Head and Neck: Values and Limits

  • Dan P. ZandbergEmail author
  • Robert L. Ferris
Head and Neck Cancer (L Licitra, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Head and Neck Cancer

Opinion statement

In head and neck cancer, we continue to work towards a more personalized approach to treatment of patients, where analysis of a patient’s tumor guides targeting of molecular or immunologic pathways. Critically important to this pursuit is a better understanding of the direct biologic effect of a drug or combination on the tumor microenvironment in humans, as well as biomarker discovery. These goals are consistent with the primary purpose of a “window of opportunity” trial and while conduct of these trials requires a careful balance of benefits and potential risks, to date these trials have been both feasible and safe in HNSCC in the curative intent setting. In the era of immunotherapy, with countless possible combinations and ongoing clinical trials, window trials are even more important for informing clinical trial design and appropriate combination therapy, and ultimately a more personalized approach to our patients that leads to improvement in outcomes.


Window trial HNSCC Neoadjuvant Anti-PD-1 Immunotherapy Targeted therapy Cetuximab 


Compliance with Ethical Standards

Conflict of Interest

Dan P. Zandberg has received research support for role as PI for clinical trials conducted by Merck, Bristol-Myers Squibb, and AstraZeneca.

Robert L. Ferris has received research funding for clinical trials conducted by AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck, Tesaro, and VentiRx Pharmaceuticals, and has served on advisory boards for Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, PPD, Lilly, Merck, Pfizer, and Tesaro.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefGoogle Scholar
  2. 2.
    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.CrossRefGoogle Scholar
  3. 3.
    Zandberg DP, Bhargava R, Badin S, Cullen KJ. The role of human papillomavirus in nongenital cancers. CA Cancer J Clin. 2013;63(1):57–81.CrossRefGoogle Scholar
  4. 4.
    Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28(27):4142–8.CrossRefGoogle Scholar
  5. 5.
    Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker LM, Sarlis NJ, et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol. 2011;22(5):1071–7.CrossRefGoogle Scholar
  6. 6.
    Vermorken JB, Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol. 2010;21 Suppl 7:vii252–61.PubMedGoogle Scholar
  7. 7.
    Graham PJ, Brar MS, Foster T, McCall M, Bouchard-Fortier A, Temple W, et al. Neoadjuvant chemotherapy for breast cancer, is practice changing? A population-based review of current surgical trends. Ann Surg Oncol. 2015;22(10):3376–82.CrossRefGoogle Scholar
  8. 8.
    Tsao AS. Current readings: window-of-opportunity trials for thoracic malignancies. Semin Thorac Cardiovasc Surg. 2014;26(4):323–30.CrossRefGoogle Scholar
  9. 9.
    Schmitz S, Duhoux F, Machiels JP. Window of opportunity studies: do they fulfil our expectations? Cancer Treat Rev. 2016;43:50–7.CrossRefGoogle Scholar
  10. 10.
    Sacco AG, Worden FP. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 2016;9:1927–43.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Egloff AM, Grandis JR. Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer. Semin Oncol. 2008;35(3):286–97.CrossRefGoogle Scholar
  12. 12.
    Moreira J, Tobias A, O’Brien MP, Agulnik M. Targeted therapy in head and neck cancer: an update on current clinical developments in epidermal growth factor receptor-targeted therapy and immunotherapies. Drugs. 2017;77(8):843–57.CrossRefGoogle Scholar
  13. 13.
    Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1(11):1311–8.PubMedGoogle Scholar
  14. 14.
    Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.CrossRefGoogle Scholar
  15. 15.
    Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.CrossRefGoogle Scholar
  16. 16.
    Schmitz S, Hamoir M, Reychler H, Magremanne M, Weynand B, Lhommel R, et al. Tumour response and safety of cetuximab in a window pre-operative study in patients with squamous cell carcinoma of the head and neck. Ann Oncol. 2013;24(9):2261–6.CrossRefGoogle Scholar
  17. 17.
    Gross ND, Bauman JE, Gooding WE, Denq W, Thomas SM, Wang L, et al. Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer. Clin Cancer Res. 2014;20(12):3289–98.CrossRefGoogle Scholar
  18. 18.
    Bauman JE, Duvvuri U, Gooding WE, Rath TJ, Gross ND, Song J, et al. Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. JCI Insight. 2017;2(6):e90449.CrossRefGoogle Scholar
  19. 19.
    • Machiels JP, Bossi P, Menis J, Lia M, Fortpied C, Liu Y, et al. Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN). Ann Oncol. 2018;29(4):985–91. Important, well-conducted window trial.CrossRefGoogle Scholar
  20. 20.
    Ferris RL, Goncalves A, Baxi S, UM Martins, Gauthier H, Langenberg M, et al. LBA46—an open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate 358): safety and efficacy of neoadjuvant nivolumab in squamous cell carcinoma of the head and neck. Ann Oncol. 2017;28(suppl_5):ESMO 2017 Congress.Google Scholar
  21. 21.
    R Uppaluri, Zolkind P, Lin T, Nussenbaum B, Jackson R, Rich J, et al. Neoadjuvant pembrolizumab in surgically resectable, HPV negative, locally advanced head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 35, 2017 (Suppl; abstr 6012) ASCO Annual Meeting 2017. 2017.Google Scholar
  22. 22.
    •• Bell R, Duhen R, Leidner R, Curti B, Ballesteros-Merino C, Piening B, et al. Neoadjuvant anti-OX40 (MEDI6469) prior to surgery in head and neck squamous cell carcinoma. J Clin Oncol 36, 2018 (suppl; abstr 6011). Oral abstract presentation at ASCO 2018 Annual Meeting. 2018. Important thorough window trial with a newer checkpoint inhibitor.Google Scholar
  23. 23.
    Colevas AD, Bedi K, Chang S, Nieves U, Chatterjee S, Davidzon A, et al. A study to evaluate immunological response to PD-1 inhibition in squamous cell carcinoma of the head and neck (SCCHN) using novel PET imaging with [18F]F-AraG. J Clin Oncol 36, 2018 (suppl; abstr 6050) ASCO 2018 Annual Meeting Poster Presentation. 2018.Google Scholar
  24. 24.
    Wolf GT, Fee WE Jr, Dolan RW, Moyer JS, Kaplan MJ, Spring PM, et al. Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer. Head Neck. 2011;33(12):1666–74.CrossRefGoogle Scholar
  25. 25.
    Berinstein NL, McNamara M, Nguyen A, Egan J, Wolf GT. Increased immune infiltration and chemokine receptor expression in head and neck epithelial tumors after neoadjuvant immunotherapy with the IRX-2 regimen. Oncoimmunology. 2018;7(5):e1423173.CrossRefGoogle Scholar
  26. 26.
    Ferris RL, Lenz HJ, Trotta AM, Garcia-Foncillas J, Schulten J, Audhuy F, et al. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev. 2017;63:48–60.CrossRefGoogle Scholar
  27. 27.
    Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie HB, Davidson HC, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T cell immunity in head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72.CrossRefGoogle Scholar
  28. 28.
    •• Shayan G, Kansy BA, Gibson SP, Srivastava RM, Bryan JK, Bauman JE, et al. Phase Ib study of immune biomarker modulation with neoadjuvant cetuximab and TLR8 stimulation in head and neck cancer to overcome suppressive myeloid signals. Clin Cancer Res. 2018;24(1):62–72. Important combination immunotherapy window trial.CrossRefGoogle Scholar
  29. 29.
    Jie HB, Schuler PJ, Lee SC, Srivastava RM, Argiris A, Ferrone S, et al. CTLA-4(+) regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75(11):2200–10.CrossRefGoogle Scholar
  30. 30.
    Stabile LP, He G, Lui VW, Thomas S, Henry C, Gubish CT, et al. c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met. Clin Cancer Res. 2013;19(2):380–92.CrossRefGoogle Scholar
  31. 31.
    Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biol Ther. 2011;11(9):777–92.CrossRefGoogle Scholar
  32. 32.
    Postel-Vinay S, Collette L, Paoletti X, Rizzo E, Massard C, Olmos D, et al. Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents—Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted Therapies, an European Organization for Research and Treatment of Cancer-led study. Eur J Cancer. 2014;50(12):2040–9.CrossRefGoogle Scholar
  33. 33.
    Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J Clin Oncol. 2000;18(3):684–92.CrossRefGoogle Scholar
  34. 34.
    Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(5):583–94.CrossRefGoogle Scholar
  35. 35.
    Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.UPMC Hillman Cancer CenterPittsburghUSA

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