Crile GW. Excision of cancer of the head and neck. With special reference to the plan of dissection based on one hundred and thirty-two operations. JAMA. 1906;47:1780-1786.

Landmark article describing the results from 132 operations for various head and neck sites, concluding that en bloc resection was the most effective approach to treatment.

Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953 Sep;6(5):963-8. doi: 10.1002/1097-0142(195309)6: 53.0.co;2-q. PMID: 13094644.

Introduced the hypothesis of independent growth of multicentric foci of cancerous cells and one of the most widely cited related to biologic behavior of oral cancer and per-cancer.

Martin H. Radical surgery in cancer of the head and neck; the changing trends in treatment. Surg Clin North Am. 1953 Apr:329-50. doi: 10.1016/s0039-6109(16)33882-8. PMID: 13056918.

For the first time, this article provided a detailed “How I Do It’ discussion based upon the author's extensive experience and had a tremendous impact on the surgical management of oral cancers.

Bocca E, Pignataro O, Oldini C, Cappa C. Functional neck dissection: an evaluation and review of 843 cases. Laryngoscope. 1984 Jul;94(7):942-5. doi: 10.1288/00005537-198407000-00015. PMID: 6738274.

ABSTRACT: After briefly reviewing the principles, indications, and merits of functional neck dissection, the results of 1200 neck dissections performed on 843 patients in the period 1961-1979 are presented. They compare very favorably with those reported for classic (radical) neck dissection by other leading authors; however, a retrospective analysis of data derived from material of different origin is hardly possible and has a disputable value. Therefore, we decided to compare our data on functional neck dissections (FND) with those of classic neck dissections (CND) performed by the same surgical team at the same clinic in the period 1948-1960. The clinical material was largely the same in both cases, and the data were collected and analyzed using the same criteria. In both series, neck dissections were divided into elective and curative. It could be demonstrated that the number of neck recurrences observed in the dissected necks is the same for FND and CND in curative dissections, while it is considerably lower for FND in elective neck dissections. This of course does not prove improved radicality in FND, but only proves that a systematic bilateral elective neck dissection in N0 cases affords improved cancerological safety. This radical bilateral approach to regional lymph nodes is made possible routinely by FND which avoids the problems of unnecessary mutilation. The figures produced speak in favor of a wider adoption of FND especially for expanding the indications to elective treatment of regional lymph nodes in cancer of the head and neck. Elective neck dissection is made practically harmless by this newer technique and averts the dreadful appearance of late metastases in N0 cases.

Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990 Oct;160(4):405-9. doi: 10.1016/s0002-9610(05)80554-9. PMID: 2221244.

A consecutive series of 1,081 previously untreated patients undergoing 1,119 radical neck dissections (RNDs) for squamous carcinoma of the head and neck was reviewed to study the patterns of nodal metastases. Primary tumors were located in the oral cavity in 501 patients, in the oropharynx in 207 patients, in the hypopharynx in 126 patients, and in the larynx in 247 patients. Lymph node metastases were confirmed histologically in 82% of 776 therapeutic neck dissections, and micrometastases were discovered in 33% of 343 elective RNDs. Lymph node groups in the neck were described by levels (I to V). Predominance of certain levels was seen for each primary site. Levels I, II, and III were at highest risk for metastasis from cancer of the oral cavity, and levels II, III, and IV were at highest risk for metastasis from carcinomas of the oropharynx, hypopharynx, and larynx. Supramohyoid neck dissection (clearing levels I, II, and III) for NO patients with primary squamous cell carcinomas of the oral cavity and anterolateral neck dissection (clearing levels II, III, and IV) for NO patients with primary squamous cell carcinomas of the oropharynx, hypopharynx, and larynx are recommended.

McGregor AD, MacDonald DG. Routes of entry of squamous cell carcinoma to the mandible. Head Neck Surg. 1988 May-Jun;10(5):294-301. doi: 10.1002/hed.2890100502. PMID: 3220769.

ABSTRACT: A recent preliminary report of a study to determine the patterns of invasion of squamous cell carcinoma to the nonirradiated edentulous mandible indicated that tumor entered mainly through the residual alveolar occlusal ridge. This study has now been extended and includes both nonirradiated and irradiated mandibles. Of a total of 46 nonirradiated mandibles (10 partially dentate and 36 edentulous) invaded by tumor, 41 were invaded through the occlusal surface. This confirms the findings of the preliminary report. These findings indicate that there is a rational basis on pathologic grounds for adopting a conservative approach to the nonirradiated mandible. In 16 irradiated mandibles, the routes of tumor entry were found to be much more variable than in the nonirradiated mandible. In 16 irradiated mandibles, the routes of tumor entry were found to be much more variable than in the nonirradiated mandible, and multiple foci of tumor invasion of the bone were often present wherever tumor in adjacent soft tissues approached the bone. This variability of tumor entry means that a conservative approach to mandibular excision cannot be pursued in the previously irradiated mandible and full-thickness segmental resection is necessary if bone involvement appears likely.

Ang KK, Trotti A, Brown BW, Garden AS, Foote RL, Morrison WH, Geara FB, Klotch DW, Goepfert H, Peters LJ. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):571-8. doi: 10.1016/s0360-3016(01)01690-x. PMID: 11597795.

ABSTRACT: Purpose: A multi-institutional, prospective, randomized trial was undertaken in patients with advanced head-and-neck squamous cell carcinoma to address (1) the validity of using pathologic risk features, established from a previous study, to determine the need for, and dose of, postoperative radiotherapy (PORT); (2) the impact of accelerating PORT using a concomitant boost schedule; and (3) the importance of the overall combined treatment duration on the treatment outcome. Methods and materials: Of 288 consecutive patients with advanced disease registered preoperatively, 213 fulfilled the trial criteria and went on to receive therapy predicated on a set of pathologic risk features: no PORT for the low-risk group (n = 31); 57.6 Gy during 6.5 weeks for the intermediate-risk group (n = 31); and, by random assignment, 63 Gy during 5 weeks (n = 76) or 7 weeks (n = 75) for the high-risk group. Patients were irradiated with standard techniques appropriate to the site of disease and likely areas of spread. The study end points were locoregional control (LRC), survival, and morbidity. Results: Patients with low or intermediate risks had significantly higher LRC and survival rates than those with high-risk features (P= .003 and p = .0001, respectively), despite receiving no PORT or lower dose PORT, respectively. For high-risk patients, a trend toward higher LRC and survival rates was noted when PORT was delivered in 5 rather than 7 weeks. A prolonged interval between surgery and PORT in the 7-week schedule was associated with significantly lower LRC (P = .03) and survival (P = .01) rates. Consequently, the cumulative duration of combined therapy had a significant impact on the LRC (p = .005) and survival (P = .03) rates. A 2-week reduction in the PORT duration by using the concomitant boost technique did not increase the late treatment toxicity. Conclusions: This Phase III trial established the power of risk assessment using pathologic features in determining the need for, and dose of, PORT in patients with advanced head-and-neck squamous cell cancer in a prospective, multi-institutional setting. It also revealed the impact of the overall treatment time in the combination of surgery and PORT on the outcome in high-risk patients and showed that PORT acceleration without a reduction in dose by a concomitant boost regimen did not increase the late complication rate. These findings emphasize the importance of coordinated interdisciplinary care in the delivery of combined surgery and RT.

Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M; 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 May 6;350(19):1945-52. doi: 10.1056/NEJMoa032641. PMID: 15128894.

ABSTRACT: Background: We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer. Methods: After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1/2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen. Results: After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P = .04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan-Meier estimates of progression-free survival of 47% and 36%, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P = .02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with 5-year Kaplan-Meier estimates of overall survival of 53% and 40%, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P = .007). The estimated 5-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31% after radiotherapy and 18% after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41%) than after radiotherapy (21%, P = .001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects. Conclusions: Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK; 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 May 6;350(19):1937-44. doi: 10.1056/NEJMoa032646. PMID: 15128893.

ABSTRACT: Background: Despite the use of resection and postoperative radiotherapy, high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed. We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control. Methods: Between September 9, 1995, and April 28, 2000, 459 patients were enrolled. After undergoing total resection of all visible and palpable disease, 231 patients were randomly assigned to receive radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks) and 228 patients to receive the identical treatment plus concurrent cisplatin (100 mg per square meter of body-surface area intravenously on days 1, 22, and 43). Results: After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95% confidence interval, 0.41 to 0.91; P = .01). The estimated 2-year rate of local and regional control was 825 in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95% confidence interval, 0.61 to 0.99; P = .04), but overall survival was not (hazard ratio for death, 0.84; 95% confidence interval, 0.65 to 1.09; P = .19). The incidence of acute adverse effects of grade 3 or greater was 34% in the radiotherapy group and 77% in the combined-therapy group (P < .001). Four patients who received combined therapy died as a direct result of the treatment. Conclusions: Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects.

Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501) Head Neck. 2005;27:843–850.

ABSTRACT: Background: In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of 2 trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy-enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease-free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment. Methods: Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these 2 trials. Results: Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis. Conclusions: Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy.

D'Cruz AK, Vaish R, Kapre N, Dandekar M, Gupta S, Hawaldar R, Agarwal JP, Pantvaidya G, Chaukar D, Deshmukh A, Kane S, Arya S, Ghosh-Laskar S, Chaturvedi P, Pai P, Nair S, Nair D, Badwe R; Head and Neck Disease Management Group. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med. 2015 Aug 6;373(6):521-9. doi: 10.1056/NEJMoa1506007. Epub 2015 May 31. PMID: 26027881.

ABSTRACT: Background: Whether patients with early-stage oral cancers should be treated with elective neck dissection at the time of the primary surgery or with therapeutic neck dissection after nodal relapse has been a matter of debate.Methods: In this prospective, randomized, controlled trial, we evaluated the effect on survival of elective node dissection (ipsilateral neck dissection at the time of the primary surgery) versus therapeutic node dissection (watchful waiting followed by neck dissection for nodal relapse) in patients with lateralized stage T1 or T2 oral squamous-cell carcinomas. Primary and secondary end points were overall survival and disease-free survival, respectively. Results: Between 2004 and 2014, a total of 596 patients were enrolled. As prespecified by the data and safety monitoring committee, this report summarizes results for the first 500 patients (245 in the elective-surgery group and 255 in the therapeutic-surgery group), with a median follow-up of 39 months. There were 81 recurrences and 50 deaths in the elective-surgery group and 146 recurrences and 79 deaths in the therapeutic-surgery group. At 3 years, elective node dissection resulted in an improved rate of overall survival (80.0%; 95% confidence interval [CI], 74.1 to 85.8), as compared with therapeutic dissection (67.5%; 95% CI, 61.0 to 73.9), for a hazard ratio for death of 0.64 in the elective-surgery group (95% CI, 0.45 to 0.92; P = .01 by the log-rank test). At that time, patients in the elective-surgery group also had a higher rate of disease-free survival than those in the therapeutic-surgery group (69.5% vs 45.9%, P < .001). Elective node dissection was superior in most subgroups without significant interactions. Rates of adverse events were 6.6% and 3.6% in the elective-surgery group and the therapeutic-surgery group, respectively.Conclusions: Among patients with early-stage oral squamous-cell cancer, elective neck dissection resulted in higher rates of overall and disease-free survival than did therapeutic neck dissection.

Schilling C, Stoeckli SJ, Haerle SK, Broglie MA, Huber GF, Sorensen JA, Bakholdt V, Krogdahl A, von Buchwald C, Bilde A, Sebbesen LR, Odell E, Gurney B, O'Doherty M, de Bree R, Bloemena E, Flach GB, Villarreal PM, Fresno Forcelledo MF, Junquera Gutiérrez LM, Amézaga JA, Barbier L, Santamaría-Zuazua J, Moreira A, Jacome M, Vigili MG, Rahimi S, Tartaglione G, Lawson G, Nollevaux MC, Grandi C, Donner D, Bragantini E, Dequanter D, Lothaire P, Poli T, Silini EM, Sesenna E, Dolivet G, Mastronicola R, Leroux A, Sassoon I, Sloan P, McGurk M. Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer. Eur J Cancer. 2015 Dec;51(18):2777-84. doi: 10.1016/j.ejca.2015.08.023. Epub 2015 Nov 18. PMID: 26597442.

ABSTRACT: Purpose: Optimum management of the N0 neck is unresolved in oral cancer. Sentinel node biopsy (SNB) can reliably detect microscopic lymph node metastasis. The object of this study was to establish whether the technique was both reliable in staging the N0 neck and a safe oncological procedure in patients with early-stage oral squamous cell carcinoma. Methods: An European Organisation for Research and Treatment of Cancer-approved prospective, observational study commenced in 2005. Fourteen European centres recruited 415 patients with radiologically staged T1-T2N0 squamous cell carcinoma. SNB was undertaken with an average of 3.2 nodes removed per patient. Patients were excluded if the sentinel node (SN) could not be identified. A positive SN led to a neck dissection within 3 weeks. Analysis was performed at 3-year follow-up. Results: An SN was found in 99.5% of cases. Positive SNs were found in 23% (94 in 415). A false-negative result occurred in 14% (15 in 109) of patients, of whom eight were subsequently rescued by salvage therapy. Recurrence after a positive SNB and subsequent neck dissection occurred in 22 patients, of which 16 (73%) were in the neck and just 6 patients were rescued. Only minor complications (3%) were reported following SNB. Disease-specific survival was 94%. The sensitivity of SNB was 86% and the negative predictive value 95%. Conclusion: These data show that SNB is a reliable and safe oncological technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer. EORTC Protocol 24021: Sentinel Node Biopsy in the Management of Oral and Oropharyngeal Squamous Cell Carcinoma.

Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252. Epub 2016 Oct 8. PMID: 27718784; PMCID: PMC5564292.

ABSTRACT: Background: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. Methods: In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. Results: The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P = .01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P = .32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. Conclusions: Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, González Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1. Erratum in: Lancet. 2020 Jan 25;395(10220):272. Erratum in: Lancet. 2020 Feb 22;395(10224):564. PMID: 31679945.

ABSTRACT: Background: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. Methods: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomization to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and noninferiority (noninferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. Findings: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n = 301), pembrolizumab with chemotherapy (n = 281), or cetuximab with chemotherapy (n = 300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45 to 0·83], P = ·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64 to 0·96], P = ·.0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71 to 1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], P = .0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45 to 0·82], P = .0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53 to 0·80], P < ·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.Interpretation: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.

Article InfoPublication History

Accepted: March 22, 2021

Received: March 22, 2021

Footnotes

Conflict of Interest Disclosures: None of the authors have any relevant financial relationship(s) with a commercial interest.

Identification

DOI: https://doi.org/10.1016/j.joms.2021.03.020

Copyright

© 2021 Published by Elsevier Inc. on behalf of The American Association of Oral and Maxillofacial Surgeons.

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