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Human papillomavirus (HPV)–associated oropharyngeal squamous-cell carcinoma differs from oropharyngeal cancers caused by tobacco and other factors. In this study, patients with oropharyngeal cancer were treated with cisplatin plus radiation therapy; the 3-year rate of overall survival was 82.4% among patients with HPV-positive tumors and 57.1% among patients with HPV-negative tumors. HPV status is an independent prognostic factor for survival among patients with oropharyngeal squamous-cell carcinoma. Patients with oropharyngeal cancer were treated with cisplatin plus radiation therapy; the 3-year rate of overall survival was 82.4% among patients with HPV-positive tumors and 57.1% among patients with HPV-negative tumors. HPV status is an independent prognostic factor for survival among patients with oropharyngeal squamous-cell carcinoma. The majority of patients enrolled in therapeutic trials for squamous-cell carcinoma of the head and neck have oropharyngeal squamous-cell carcinoma, which in a subgroup of these patients is caused by infection with human papillomavirus (HPV). 1 This subgroup is defined by the presence of high-risk types of HPV in tumor cells, predominantly HPV type 16 (HPV-16). Expression of viral E6 and E7 oncoproteins that inactivate the tumor-suppressor proteins p53 and the retinoblastoma protein (pRb), respectively, is necessary for malignant behavior of these tumors. 2 Several retrospective case series have shown that among patients with oropharyngeal squamous-cell carcinoma, patients with HPV-positive tumors have . . .

Background For loco-regionally advanced, but transorally resectable oropharyngeal cancer (OPSCC), the current standard of care includes surgical resection and risk-adapted adjuvant (chemo) radiotherapy, or definite chemoradiation with or without salvage surgery. While transoral surgery for OPSCC has increased over the last decade for example in the United States due to transoral robotic surgery, this treatment approach has a long history in Germany. In contrast to Anglo-Saxon countries, transoral surgical approaches have been used frequently in Germany to treat patients with oro-, hypopharyngeal and laryngeal cancer. Transoral laser microsurgery (TLM) has had a long tradition since its introduction in the early 70s. To date, the different therapeutic approaches to transorally resectable OPSCC have not been directly compared to each other in a randomized trial concerning disease control and survival. The goal of this study is to compare initial transoral surgery to definitive chemoradiation for resectable OPSCC, especially with regards to local and regional control. Methods TopROC is a prospective, two-arm, open label, multicenter, randomized, and controlled comparative effectiveness study. Eligible patients are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1–2c, M0; T3, N0-2c, M0 UICC vers. 7) which are amenable to transoral resection. Two hundred eighty patients will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be performed according to daily routine practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant therapy. Patients treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits for 3 years are planned. Primary endpoint is time to local or locoregional failure (LRF). Secondary endpoints include overall and disease free survival, toxicity, and patient reported outcomes. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a scientific support program. Discussion This study will shed light on an urgently-needed randomized comparison of the strategy of primary chemoradiation vs. primary surgical approach. As a comparative effectiveness trial, it is designed to provide data based on two established regimens in daily clinical routine. Trial registration NCT03691441 Registered 1 October 2018 - Retrospectively registered.

Background Transoral surgery (TOS) has been widely applied for early T‐stage head and neck cancer (HNC). The resection is performed with a minimum safety margin for function preservation under a limited surgical field; therefore, it is difficult to have a strong conviction about the complete resection. This study aims to evaluate the completeness of the initial TOS procedure; possibility of primary control by TOS alone; and predictive factors in patients with early T‐stage laryngeal, oropharyngeal, and hypopharyngeal cancer. Methods Patients were treated by TOS at the primary site with or without neck dissection. The patients were divided into two groups based on the pathological evaluation of their surgical specimens: the control (observation) group, in that the resection was considered complete and the intervention (second‐look procedure) group, in that incomplete tumor resection was suspected. The predictive factors for the possibility and/or limitations of complete resection by TOS were then analyzed. Results The study enrolled 26 and 25 patients in the control and intervention group, respectively. The success rate for single resection was 66% and the predictive factor was tumor depth obtained by enhanced computed tomography (CT) examination (odds ratio, 7.870, P = .0243). The success rate for definitive therapy by TOS alone was 83% and the predictive factor was poor differentiation observed on pathological examination (odds ratio, 6.800, P = .0248). Conclusions TOS has the potential for both definitive resection and function preservation with minimal invasiveness. Identification of the risk factors for TOS is advantageous for accurate treatment selection in patients with early T‐stage HNC. Transoral surgery has the potential for both definitive resection and function preservation with minimal invasiveness. Identification of the risk factors for transoral surgery, such as tumor depth obtained by enhanced CT examination and poor differentiation observed on pathological examination, is advantageous for accurate treatment selection in patients with early T‐stage head and neck cancer.

Background Weight loss is a common problem in patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) treated with radiotherapy (RT). The aims of the present study were to determine if treated volume (TV), as a measure of the radiation dose burden, can predict weight loss in patients with oropharyngeal cancer and to analyze weight loss and body mass index (BMI) in the same patient group in relation to 5-year overall survival. Methods The ARTSCAN trial is a prospective, randomized, multicenter trial in patients with SCCHN. Nutritional data from the ARTSCAN trial were analyzed retrospectively using univariate and multivariate statistical methods based on information on percentage weight loss from the start of RT up to five months after the termination of RT (study cohort 1, n = 232) and information on patients’ BMI at the start of RT (study cohort 2, n = 203). TV was defined as the volume of the patient receiving at least 95% of the prescribed dose. TV 64.6 Gy encompasses macroscopic tumor and TV 43.7 Gy elective lymph nodes of the neck. Results TV 64.6 Gy and TV 43.7 Gy were both significantly correlated with higher weight loss up to five months after the termination of RT in study cohort 1 ( p  < 0.001 for both). BMI at the start of RT was shown to be a prognostic factor for 5-year overall survival in study cohort 2 but weight loss was not. The hazard ratios and 95% confidence intervals were 3.78 (1.46–9.75) and 2.57 (1.43–4.62) in patients with underweight and normal weight, respectively. Conclusions TV can predict weight loss during RT in patients with oropharyngeal cancer regardless of clinical stage. A high BMI (>25 kg/m 2 ) at the start of RT is positively associated with survival in patients with oropharyngeal cancer.

Background Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART). Patients and methods Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400 mg/m 2 ) and then with a weekly dosage of 250 mg/m 2 during HART. HART was started with a prescribed dosage of 2.0 Gy per day for 3 weeks, followed by 1.4 Gy twice daily to a total dose of 70.6 Gy to the gross tumour volume. CIS (40 mg/m 2 ) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2‑year progression-free survival (PFS). Results Between November 2007 and November 2010, a total of 74 patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37–69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2‑ and 5‑year overall survival rates were 64 and 41%, the 2‑ and 5‑year PFS rates were 45 and 32%, and the 2‑ and 5‑year locoregional control rates were 47 and 33%, respectively. Conclusion The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.

BackgroundThe COVID-19 pandemic has required triage and delays in surgical care throughout the world. The impact of these surgical delays on survival for patients with head and neck squamous cell carcinoma (HNSCC) remains unknown.MethodsA retrospective cohort study of 37 730 patients in the National Cancer Database with HNSCC who underwent primary surgical management from 2004 to 2016 was performed. Uni- and multivariate analyses were used to identify predictors of overall survival. Bootstrapping methods were used to identify optimal time-to-surgery (TTS) thresholds at which overall survival differences were greatest. Cox proportional hazard models with or without restricted cubic splines were used to determine the association between TTS and survival.ResultsThe study identified TTS as an independent predictor of overall survival (OS). Bootstrapping the data to dichotomize the cohort identified the largest rise in hazard ratio (HR) at day 67, which was used as the optimal TTS cut-point in survival analysis. The patients who underwent surgical treatment longer than 67 days after diagnosis had a significantly increased risk of death (HR, 1.189; 95% confidence interval [CI], 1.122–1.261; P < 0.0001). For every 30-day delay in TTS, the hazard of death increased by 4.6%. Subsite analysis showed that the oropharynx subsite was most affected by surgical delays, followed by the oral cavity.ConclusionsIncreasing TTS is an independent predictor of survival for patients with HNSCC and should be performed within 67 days after diagnosis to achieve optimal survival outcomes.

Modernisation of the American Joint Committee on Cancer and Union for International Cancer Control (AJCC/UICC) staging for HPV-positive oropharyngeal carcinoma has strengthened its fundamental role to convey prognosis and guide treatment decisions. Implementation has nonetheless revealed imbalances. An AJCC committee reappraised HPV-positive oropharyngeal carcinoma pathological staging to advance prognostic accuracy and improve clinical applicability. For this analysis, US registry data from the National Cancer Database were divided into derivation and validation cohorts. Eligible cases encompassed surgically treated adult patients aged 18 years or older with HPV-positive oropharyngeal carcinoma. The primary objective was to derive and validate an optimised HPV-positive oropharyngeal carcinoma pathological staging classification based on determinants of overall survival. Multivariable Cox regression models were used to assess lymph node characteristics for overall survival. Non-linear associations between metastatic lymph node number and survival were modelled with restricted cubic splines. Adjusted hazard ratios (AHRs) and recursive partitioning analysis methods were applied to generate optimal classification groups. Performance was evaluated with Groome's criteria. Overall, 14 447 patients across 984 facilities in the USA met the criteria for inclusion, and were divided into a derivation cohort (n=7768) and validation cohort (n=6679). Patients were treated between 2010 and 2019; 12 276 (85·0%) were male, 2171 (15·0%) were female, 13 594 (94·1%) were White, and 4552 patients (31·5%) had pathological extranodal extension (pENE). Median follow-up was 52·4 months (95% CI 51·5–53·3). Mortality risk increased with each additional metastatic lymph node (HR 1·20 [95% CI 1·11–1·29], p<0·0001), up to an optimal cutoff at 4·3 lymph nodes. Multivariable analysis confirmed the association of pENE with increased mortality risk (HR 1·47 [95% CI 1·30–1·65], p<0·0001), but no significant prognostic changes were shown by the extent of pENE (minor vs major). AHR approaches derived and validated optimised pN and pTNM stage categories (N1a: 1 positive lymph node and pENE-negative; N1b: 2–4 positive lymph nodes and pENE-negative; N2: >4 positive lymph nodes and pENE-negative or 1–4 positive lymph nodes and ENE-positive; N3: >4 positive lymph nodes and ENE-positive; Stage I: T0-2N0-1M0; Stage II: T0-2N2-3M0 or T3N0-2M0; Stage III: T3N3M0 or T4N0-3MO); Stage IV: M1. AJCC9V showed superior hazard consistency, outcome prediction, and balance, but not hazard discrimination, compared to AJCC8E. The AJCC Expert Panel on HPV-positive oropharyngeal carcinoma endorsed the proposal by Delphi consensus. The AJCC9V HPV-positive oropharyngeal carcinoma staging classification confers an improved schema for guiding prognostication and management compared to AJCC8E. Incorporating ENE and correcting imbalances will enhance clinical relevance and align pathological staging in a condition whose management continues to evolve. None.

Radiotherapy is an integral component of treatment for oropharyngeal cancer. Toxicity from the current state-of-the-art photon radiotherapy, intensity-modulated radiation therapy (IMRT), has prompted the search for alternative, less toxic therapies. One such alternative that might de-intensify treatment is proton therapy. In this trial, we aimed to directly compare IMRT with intensity-modulated proton therapy (IMPT), both concurrent with systemic therapy, hypothesising comparable disease control and survival and lower toxicity. This randomised, multicentre, open-label, non-inferiority, phase 3 trial was conducted in 21 sites (cancer centres or universities) in the USA. Patients (aged ≥18 years) with stage III or stage IV oropharyngeal cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited and randomly assigned 1:1 to receive IMPT or IMRT. All patients were treated with radiotherapy to 70 Gy in 33 fractions to the primary tumour site and cervical lymphadenopathy. The type, schedule, and dose of induction or concurrent systemic therapy were chosen locally by each institution's multidisciplinary tumour board and were consistent with international guidelines. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population; safety outcomes were assessed in the per-protocol population (ie, patients who received the assigned therapy). A non-inferiority margin of 9 percentage points for progression-free survival at 3 years was used. This trial is registered with ClinicalTrials.gov (NCT01893307) and is closed to further accrual after prespecified interim analysis. From Oct 10, 2013, to May 1, 2022, 440 patients consented (median age 61 years [IQR 55–68], 399 [91%] male, 409 [93%] White); 221 were allocated to the IMPT group (with 160 [72%] receiving IMPT) and 219 to the IMRT group (136 [62%] receiving IMRT). At a median follow-up time of 3·2 years, progression-free survival rates for the IMPT group were 82·5% (95% CI 76·1–87·3) at 3 years and 81·3% (74·5–86·5) at 5 years; corresponding rates for the IMRT group were 83·0% (76·7–87·7) and 76·2% (68·0–82·6; hazard ratio [HR] 0·88 [95% CI 0·57–1·35]; p=0·005 for non-inferiority of IMPT). Overall survival rates after IMPT were 90·9% at 5 years versus 81·0% after IMRT (HR 0·58 [95% CI 0·34–0·99]; p=0·045). Treatment-related deaths occurred in nine patients; six in the IMRT group and three in the IMPT group. Deaths from disease progression occurred in 27 patients; 18 in the IMRT group and nine in the IMPT group. 5-year disease control rates for IMPT versus IMRT were similar between treatment groups (local recurrences 2·9% vs 5·6%, p=0·474; regional recurrences 3·4% vs 3·2%, p=0·860; and distant metastases 9·1% vs 8·9%, p=0·897). Severe lymphopenia was more common in the IMRT group (89% vs 76%), as were dysphagia (49% vs 31%), xerostomia (45% vs 33%), and gastrostomy tube dependence (40·2% vs 26·8%; p=0·018). IMPT showed non-inferiority to IMRT for progression-free survival, improvement in overall survival, similar disease control, and reduced high-grade toxicity relative to IMRT. Treatment-related and post-progression deaths occurred more frequently with IMRT. IMPT is a new standard-of-care treatment option for patients with oropharyngeal cancer. MD Anderson Cancer Center, Massachusetts General Hospital, National Institutes of Health, Hitachi America.

Background TNM8 staging for oropharyngeal squamous cell carcinomas (OPSCC) surrogates p16 immunohistochemistry for HPV testing. Patients with p16+ OPSCC may lack HPV aetiology. Here, we evaluate the suitability of TNM8 staging for guiding prognosis in such patients. Methods HPV status was ascertained using p16 immunohistochemistry and high-risk HPV RNA and DNA in situ hybridisation. Survival by stage in a cohort of OPSCC patients was evaluated using TNM7/TNM8 staging. Survival of p16+/HPV− patients was compared to p16 status. Results TNM8 staging was found to improve on TNM7 (log rank p  = 0·0190 for TNM8 compared with p  = 0·0530 for TNM7) in p16+ patients. Patients who tested p16+ but were HPV− ( n  = 20) had significantly reduced five-year survival (33%) compared to p16+ patients (77%) but not p16− patients (35%). Cancer stage was reduced in 95% of p16+/HPV− patients despite having a mortality rate twice (HR 2.66 [95% CI: 1.37–5.15]) that of p16+/HPV+ patients under new TNM8 staging criteria. Conclusion Given the significantly poorer survival of p16+/HPV− OPSCCs, these data provide compelling evidence for use of an HPV-specific test for staging classification. This has particular relevance in light of potential treatment de-escalation that could expose these patients to inappropriately reduced treatment intensity as treatment algorithms evolve.