Evaluating Adjuvant Therapy With Chemoradiation vs Radiation Alone for Patients With HPV-Negative N2a Head and Neck Cancer | Allergy and Clinical Immunology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Evaluating Adjuvant Therapy With Chemoradiation vs Radiation Alone for Patients With HPV-Negative N2a Head and Neck Cancer

Educational Objective
To evaluate whether adding chemotherapy concurrent with adjuvant radiation therapy is associated with improved overall survival relative to adjuvant radiation therapy for patients with pN2a human papillomavirus (HPV)-negative head and neck squamous cell carcinoma with extranodal extension.
1 Credit CME
Key Points

Question  Is the addition of chemotherapy to adjuvant radiation therapy associated with improved survival among patients with human papillomavirus–negative head and neck squamous cell carcinoma with extranodal extension in a single lymph node smaller than 3 cm (American Joint Committee on Cancer Staging Manual, 8th Edition, category pN2a)?

Findings  In this cohort study of 504 patients from the National Cancer Database with pN2a human papillomavirus–negative head and neck squamous cell carcinoma who underwent margin-negative resection, adjuvant chemoradiation therapy was not associated with improved overall survival relative to adjuvant radiation therapy alone.

Meaning  Adding chemotherapy to adjuvant radiation therapy was not associated with improved survival in this study, suggesting the need for additional research to identify optimal treatment paradigms for these patients.

Abstract

Importance  The American Joint Committee on Cancer staging system (Cancer Staging Manual, 8th Edition) for head and neck squamous cell carcinoma (HNSCC) now categorizes human papillomavirus (HPV)–negative HNSCC in a single positive lymph node smaller than 3 cm with pathologic extranodal extension (ENE) as N2a. The standard of care for pathologic ENE is adjuvant chemoradiation therapy (CRT). Whether adding chemotherapy concurrent with adjuvant radiation therapy improves survival in this clinical scenario is unknown.

Objective  To assess whether adjuvant CRT relative to radiation therapy alone is associated with improved survival among patients with pN2a HPV-negative HNSCC with ENE.

Design, Setting, and Participants  This retrospective cohort study included 504 patients with pN2a HPV-negative HNSCC with ENE who had undergone margin-negative surgery and adjuvant therapy. The patients were identified from the National Cancer Database from January 1, 2004, to December 31, 2015. Statistical analyses were conducted from September 1, 2019, to April 16, 2020.

Main Outcomes and Measures  The primary end point was overall survival. The association of adjuvant CRT with overall survival was analyzed using univariate and multivariate Cox proportional hazards regression analyses. Planned subset analyses were conducted in patients younger than 70 years with no comorbidities (the subset most likely to be eligible for a clinical trial of cisplatin-based chemoradiation) and in patients with pT3/T4 disease classification.

Results  Of 504 patients (mean [SD] age, 60.5 [12.7] years; 319 [63.3%] men; 434 [86.1%] White) with pN2a HPV-negative HNSCC with ENE who had undergone margin-negative surgery and adjuvant therapy, 298 patients (59.1%) received adjuvant CRT. For the overall cohort of patients with pN2a ENE, adjuvant CRT was not associated with improved overall survival relative to adjuvant radiation therapy alone in a multivariate analysis (adjusted hazard ratio, 0.98; 95% CI, 0.74-1.30). Adjuvant CRT was still not associated with improved overall survival in a subset analysis of 304 patients younger than 70 years with no comorbidities (adjusted hazard ratio, 0.98; 95% CI, 0.66-1.45) nor in a subset of 220 patients with pT3/T4 disease classification (adjusted hazard ratio, 1.03; 95% CI, 0.70-1.54).

Conclusions and Relevance  This study found that for patients with pN2a HPV-negative HNSCC with ENE who underwent margin-negative surgery and adjuvant therapy, adding chemotherapy concurrent with adjuvant radiation therapy was not associated with improved overall survival. Additional research is necessary to identify the optimal treatment paradigm for this clinical scenario.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: June 11, 2020.

Corresponding Author: Evan M. Graboyes, MD, MPH, Department of Otolaryngology–Head & Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, MSC 550, Charleston, SC 29425 (graboyes@musc.edu).

Published Online: August 13, 2020. doi:10.1001/jamaoto.2020.2107

Author Contributions: Ms Yan and Dr Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Yan, Sharma, Day, Neskey, Pipkorn, Graboyes.

Acquisition, analysis, or interpretation of data: Yan, Li, Kaczmar, Day, Zenga, Graboyes.

Drafting of the manuscript: Yan.

Critical revision of the manuscript for important intellectual content: Li, Kaczmar, Sharma, Day, Neskey, Pipkorn, Zenga, Graboyes.

Statistical analysis: Yan, Li.

Administrative, technical, or material support: Zenga.

Supervision: Day, Neskey, Pipkorn, Graboyes.

Conflict of Interest Disclosures: Dr Kaczmar reported receiving personal fees from Regeneron outside the submitted work. Dr Graboyes reported receiving grants from the National Cancer Institute and from the Doris Duke Charitable Foundation outside the submitted work; and being an editorial board member for JAMA Otolaryngology–Head & Neck Surgery. No other disclosures were reported.

Funding/Support: This work was supported by grant P30CA138313 from the National Cancer Institute to the Biostatistics Shared Resource of the Hollings Cancer Center.

Role of the Funder/Sponsor: The funding organization had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The National Cancer Database is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methods used or for the conclusions drawn from these data by the investigators.

References
1.
Chow  LQM .  Head and neck cancer.   N Engl J Med. 2020;382(1):60-72. doi:10.1056/NEJMra1715715 PubMedGoogle ScholarCrossref
2.
National Comprehensive Cancer Network.  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Head and Neck Cancers. National Comprehensive Cancer Network; 2019.
3.
Bernier  J , Domenge  C , Ozsahin  M ,  et al; European Organization for Research and Treatment of Cancer Trial 22931.  Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer.   N Engl J Med. 2004;350(19):1945-1952. doi:10.1056/NEJMoa032641 PubMedGoogle ScholarCrossref
4.
Cooper  JS , Pajak  TF , Forastiere  AA ,  et al; Radiation Therapy Oncology Group 9501/Intergroup.  Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.   N Engl J Med. 2004;350(19):1937-1944. doi:10.1056/NEJMoa032646 PubMedGoogle ScholarCrossref
5.
Kearney  A , Cavanagh  PW . Acute and long-term effects of chemoradiation therapy in head and neck cancer. In: Doyle  PC , ed.  Clinical Care and Rehabilitation in Head and Neck Cancer. Springer International Publishing; 2019:331-349. doi:10.1007/978-3-030-04702-3_20
6.
American Joint Committee on Cancer. AJCC Cancer Staging Manual, Eighth Edition. Published 2018. Accessed July 7, 2019. https://cancerstaging.org/references-tools/deskreferences/Pages/default.aspx
7.
Dünne  AA , Müller  HH , Eisele  DW , Kessel  K , Moll  R , Werner  JA .  Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients.   Eur J Cancer. 2006;42(12):1863-1868. doi:10.1016/j.ejca.2006.01.062 PubMedGoogle ScholarCrossref
8.
American College of Surgeons. National cancer database. Published 2020. Accessed July 7, 2020. https://www.facs.org/quality-programs/cancer/ncdb
9.
Janz  TA , Graboyes  EM , Nguyen  SA ,  et al.  A comparison of the NCDB and SEER database for research involving head and neck cancer.   Otolaryngol Head Neck Surg. 2019;160(2):284-294. doi:10.1177/0194599818792205 PubMedGoogle ScholarCrossref
10.
World Health Organization. International Classification of Diseases for Oncology, 3rd edition (ICD-O-3). Accessed July 6, 2020. https://www.who.int/classifications/icd/adaptations/oncology/en/
11.
An  Y , Park  HS , Kelly  JR ,  et al.  The prognostic value of extranodal extension in human papillomavirus-associated oropharyngeal squamous cell carcinoma.   Cancer. 2017;123(14):2762-2772. doi:10.1002/cncr.30598 PubMedGoogle ScholarCrossref
12.
Sinha  P , Kallogjeri  D , Gay  H ,  et al.  High metastatic node number, not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive oropharynx cancer.   Oral Oncol. 2015;51(5):514-520. doi:10.1016/j.oraloncology.2015.02.098 PubMedGoogle ScholarCrossref
13.
American College of Surgeons. Participant User Files. NCDB PUF data dictionary. Published 2016. Accessed July 13, 2020. https://www.facs.org/quality-programs/cancer/ncdb/puf
14.
Collaborative Stage Data Collection System. Schema. Published 2020. Accessed July 6, 2020. https://cancerstaging.org/cstage/schema/Pages/version0205.aspx.
15.
Amini  A , Jones  BL , McDermott  JD ,  et al.  Survival outcomes with concurrent chemoradiation for elderly patients with locally advanced head and neck cancer according to the National Cancer Data Base.   Cancer. 2016;122(10):1533-1543. doi:10.1002/cncr.29956 PubMedGoogle ScholarCrossref
16.
Greenberg  JS , Fowler  R , Gomez  J ,  et al.  Extent of extracapsular spread: a critical prognosticator in oral tongue cancer.   Cancer. 2003;97(6):1464-1470. doi:10.1002/cncr.11202 PubMedGoogle ScholarCrossref
17.
García  J , López  M , López  L ,  et al.  Validation of the pathological classification of lymph node metastasis for head and neck tumors according to the 8th edition of the TNM Classification of Malignant Tumors.   Oral Oncol. 2017;70:29-33. doi:10.1016/j.oraloncology.2017.05.003PubMedGoogle ScholarCrossref
18.
de Juan  J , García  J , López  M ,  et al.  Inclusion of extracapsular spread in the pTNM classification system: a proposal for patients with head and neck carcinoma.   JAMA Otolaryngol Head Neck Surg. 2013;139(5):483-488. doi:10.1001/jamaoto.2013.2666 PubMedGoogle ScholarCrossref
19.
Matsumoto  F , Mori  T , Matsumura  S ,  et al.  Prognostic significance of surgical extranodal extension in head and neck squamous cell carcinoma patients.   Jpn J Clin Oncol. 2017;47(8):699-704. doi:10.1093/jjco/hyx055 PubMedGoogle ScholarCrossref
20.
Wreesmann  VB , Katabi  N , Palmer  FL ,  et al.  Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma.   Head Neck. 2016;38(suppl 1):E1192-E1199. doi:10.1002/hed.24190PubMedGoogle ScholarCrossref
21.
Shaw  RJ , Lowe  D , Woolgar  JA ,  et al.  Extracapsular spread in oral squamous cell carcinoma.   Head Neck. 2010;32(6):714-722. doi:10.1002/hed.21244PubMedGoogle Scholar
22.
Brasilino de Carvalho  M .  Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx.   Head Neck. 1998;20(1):16-21. doi:10.1002/(SICI)1097-0347(199801)20:1<16::AID-HED3>3.0.CO;2-6 PubMedGoogle ScholarCrossref
23.
Woolgar  JA , Rogers  SN , Lowe  D , Brown  JS , Vaughan  ED .  Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread.   Oral Oncol. 2003;39(2):130-137. doi:10.1016/S1368-8375(02)00030-1 PubMedGoogle ScholarCrossref
24.
Freitag  J , Wald  T , Kuhnt  T ,  et al.  Extracapsular extension of neck nodes and absence of human papillomavirus 16-DNA are predictors of impaired survival in p16-positive oropharyngeal squamous cell carcinoma.   Cancer. 2020;126(9):1856-1872. doi:10.1002/cncr.32667 PubMedGoogle ScholarCrossref
25.
Shevach  J , Bossert  A , Bakst  RL ,  et al.  Extracapsular extension is associated with worse distant control and progression-free survival in patients with lymph node-positive human papillomavirus-related oropharyngeal carcinoma.   Oral Oncol. 2017;74:56-61. doi:10.1016/j.oraloncology.2017.09.014 PubMedGoogle ScholarCrossref
26.
Kompelli  AR , Morgan  P , Li  H , Harris  W , Day  TA , Neskey  DM .  Prognostic impact of high-risk pathologic features in HPV-related oropharyngeal squamous cell carcinoma and tobacco use.   Otolaryngol Head Neck Surg. 2019;160(5):855-861. doi:10.1177/0194599818818446 PubMedGoogle ScholarCrossref
27.
College of American Pathologists. Protocol for the examination of specimens from patients with cancers of the lip and oral cavity, version 4.0.0.1. Published 2017. Accessed March 25, 2020. https://documents.cap.org/protocols/cp-headandneck-lip-oralcavity-17protocol-4001.pdf
28.
Cramer  JD , Ferris  RL , Kim  S , Duvvuri  U .  Primary surgery for human papillomavirus-associated oropharyngeal cancer: survival outcomes with or without adjuvant treatment.   Oral Oncol. 2018;87:170-176. doi:10.1016/j.oraloncology.2018.10.039 PubMedGoogle ScholarCrossref
29.
VanderWalde  NA , Fleming  M , Weiss  J , Chera  BS .  Treatment of older patients with head and neck cancer: a review.   Oncologist. 2013;18(5):568-578. doi:10.1634/theoncologist.2012-0427 PubMedGoogle ScholarCrossref
30.
Machtay  M , Moughan  J , Trotti  A ,  et al.  Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis.   J Clin Oncol. 2008;26(21):3582-3589. doi:10.1200/JCO.2007.14.8841 PubMedGoogle ScholarCrossref
31.
Pignon  JP , le Maître  A , Maillard  E , Bourhis  J ; MACH-NC Collaborative Group.  Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.   Radiother Oncol. 2009;92(1):4-14. doi:10.1016/j.radonc.2009.04.014 PubMedGoogle ScholarCrossref
32.
Sinha  P , Haughey  BH , Kallogjeri  D , Spitznagel  EL , Piccirillo  JF .  The role of postoperative chemoradiation for oropharyngeal carcinoma: a critical appraisal revisited.   Cancer. 2017;123(5):887-888. doi:10.1002/cncr.30480 PubMedGoogle ScholarCrossref
33.
Wirth  LJ , Burtness  B , Nathan  CO , Grégoire  V , Richmon  J .  Point/counterpoint: do we de-escalate treatment of HPV-associated oropharynx cancer now? and how?   Am Soc Clin Oncol Educ Book. 2019;39(39):364-372. doi:10.1200/EDBK_238315 PubMedGoogle ScholarCrossref
34.
Gillison  ML , Trotti  AM , Harris  J ,  et al.  Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.   Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X PubMedGoogle ScholarCrossref
35.
Mehanna  H , Robinson  M , Hartley  A ,  et al; De-ESCALaTE HPV Trial Group.  Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.   Lancet. 2019;393(10166):51-60. doi:10.1016/S0140-6736(18)32752-1 PubMedGoogle ScholarCrossref
36.
Chemoradiation vs immunotherapy and radiation for head and neck cancer. ClinicalTrials.gov identifier: NCT03383094. Published 2019. Accessed July 6, 2020. https://clinicaltrials.gov/ct2/show/NCT03383094
37.
Study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy (IMSTAR-HN). ClinicalTrials.gov identifier: NCT03700905. Updated January 28, 2019. Accessed July 6, 2020. https://clinicaltrials.gov/ct2/show/NCT03700905
38.
Boffa  DJ .  What’s lost in what’s missing: a thoughtful approach to missing data in the National Cancer Database.   Ann Surg Oncol. 2019;26(3):709-710. doi:10.1245/s10434-018-07130-9 PubMedGoogle ScholarCrossref
39.
Sterne  JAC , White  IR , Carlin  JB ,  et al.  Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls.   BMJ. 2009;338:b2393. doi:10.1136/bmj.b2393 PubMedGoogle ScholarCrossref
40.
Jones  EA , Shuman  AG , Egleston  BL , Liu  JC .  Common pitfalls of head and neck research using cancer registries.   Otolaryngol Head Neck Surg. 2019;161(2):245-250. doi:10.1177/0194599819838823 PubMedGoogle ScholarCrossref
41.
Saraswathula  A , Chen  MM , Colevas  AD , Divi  V .  Assessing care value for older patients receiving radiotherapy with or without cisplatin or cetuximab for locoregionally advanced head and neck cancer.   JAMA Otolaryngol Head Neck Surg. 2019. doi:10.1001/jamaoto.2019.2381 PubMedGoogle Scholar
42.
Galloway  TJ , Ridge  JA .  Treatment of head and neck cancer—sometimes, less is more.   JAMA Otolaryngol Head Neck Surg. 2019;145(12):1167-1169. doi:10.1001/jamaoto.2019.3078 PubMedGoogle ScholarCrossref
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close