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Primary surgery for human papillomavirus-associated oropharyngeal cancer: Survival outcomes with or without adjuvant treatment.

ABSTRACT: OBJECTIVES:Human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a unique form of head and neck cancer with improved prognosis. We assessed survival for stage I patients with low- or intermediate-risk pathologic features with surgery alone compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT). MATERIALS AND METHODS:We identified patients with stage I HPV+ OPSCC (after restaging with 8th edition staging system) treated with surgery alone, adjuvant RT or CRT in the National Cancer Data Base from 2010 to 2013. We compared survival for low-risk patients (?1 metastatic lymph nodes with no adverse features) and intermediate-risk patients (2-4 metastatic lymph nodes, microscopic extranodal extension (ENE) or lymphovascular invasion). RESULTS:We examined 1677 patients with median follow-up of 43.9?months. In the intermediate-risk group, 4-year overall survival was 94.0% with surgery alone, 91.5% with adjuvant RT and 92.0% with adjuvant CRT (p?=?0.72). There were similar rates of overall survival in the low-risk group. In multivariable models accounting for clinicopathologic differences the dose of adjuvant RT was not associated with mortality. On Cox proportional hazard modeling, adjuvant RT (HR 0.94; CI 0.43-2.08) or CRT (HR 0.96; CI 0.45-2.11) did not significantly improved survival compared with surgery alone in the intermediate-risk group (reference). Similar results were seen in the low-risk group. The composite number of pathologic risk features significantly improved risk stratification. CONCLUSION:We provide observational evidence that adjuvant RT or CRT does not provide a survival benefit for stage I HPV+ OPSCC with low- or intermediate-risk pathologic features.

SUBMITTER: Cramer JD

PROVIDER: S-EPMC6533632 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Primary surgery for human papillomavirus-associated oropharyngeal cancer: Survival outcomes with or without adjuvant treatment.

Cramer John D JD Ferris Robert L RL Kim Seungwon S Duvvuri Umamaheswar U

Oral oncology 20181113

<h4>Objectives</h4>Human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a unique form of head and neck cancer with improved prognosis. We assessed survival for stage I patients with low- or intermediate-risk pathologic features with surgery alone compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT).<h4>Materials and methods</h4>We identified patients with stage I HPV+ OPSCC (after restaging with 8th edition staging system) treated with sur ...[more]

PMID: 30527235

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Project description:BackgroundNew ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC).MethodsTo determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45.ResultsIn patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection.ConclusionsPOD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future.Lay summaryHuman papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Project description:BackgroundTreatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced-dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression-free survival (PFS) and overall survival while reducing toxicity.MethodsThis study was a nonrandomized phase II trial for early-stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced-dose radiotherapy. Patients with previously untreated p16-positive HPVOPC and <20 pack years' smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50-Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56-Gy chemoradiotherapy with weekly cisplatin).ResultsFifty-four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow-up was 43.9 months (9.6-75.8). Disease-specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan-Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6-59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0-42.7 months); one subject remains alive with disease.ConclusionThe results indicate that upfront surgery with neck dissection with reduced-dose radiation for T1-2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de-escalation strategy in HPVOPC.Implications for practiceTransoral robotic surgery can provide a safe platform for de-escalation in carefully selected patients with early-stage human papillomavirus-related oropharyngeal cancer. In this clinical trial, disease-specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged.

Project description:ImportanceDefinitive chemoradiotherapy and upfront surgical treatment are both accepted as the standard of care for advanced-stage oropharyngeal squamous cell carcinoma. However, the optimal primary treatment modality remains unclear.ObjectiveTo evaluate the comparative effectiveness of definitive chemoradiotherapy and upfront surgical treatment for advanced-stage oropharyngeal cancer.Design, setting, and participantsThis retrospective comparative effectiveness analysis used data from the population-based Taiwan Cancer Registry. Included patients were diagnosed with clinical stage III or IV oropharyngeal squamous cell carcinoma from 2007 to 2015 and were identified from the registry. Patients with T4b or N3 disease were excluded. Data were analyzed from June 2019 through December 2020.InterventionsDefinitive chemoradiotherapy or upfront surgical treatment.Main outcomes and measuresThe primary outcome was overall survival, for which data were available through December 31, 2018. Secondary outcomes were progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival.ResultsAmong 1180 patients, 694 patients (58.8%) were in the definitive chemoradiotherapy group and 486 patients (41.2%) were in the upfront surgical treatment group. The median (interquartile range) follow-up was 3.62 (1.63-5.47) years, and most patients were men (1052 [89.1%] men) with a primary tumor in the tonsils (712 patients [60.3%]), moderately differentiated histology (604 patients [51.2%]), clinical N2 disease (858 patients [72.7%]), and clinical stage IVA disease (938 patients [79.5%]). The mean (SD) age was 54.59 (10.35) years. Primary treatment with an upfront surgical procedure was associated with a decreased risk of death during the study period (hazard ratio [HR], 0.81; 95% CI, 0.69-0.97; P = .02). However, when adjusted for age, subsite, histological grade, and T and N classification, upfront surgical treatment was no longer associated with an increased risk of death during the study period (HR, 0.96; 95% CI, 0.80-1.16; P = .70). Progression-free survival was worse in the group receiving upfront surgical treatment than in the group receiving chemoradiotherapy (HR, 1.64; 95% CI, 1.09-2.46; P = .02), and this difference persisted after adjusting for other factors associated with prognosis (ie, age, tumor subsite, histological grade, and T and N classification) (HR, 1.72; 95% CI, 1.12-2.66; P = .01).Conclusions and relevanceThis study found that definitive chemoradiotherapy was associated with effectiveness that was comparable with that of upfront surgical treatment when adjusted for baseline factors associated with prognosis. These findings suggest that definitive chemoradiotherapy should be considered to avoid accumulating toxic effects associated with surgical treatment and chemoradiotherapy.

Project description:BackgroundHuman papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes.Methods/designThe study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint.DiscussionPATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment.Trial registrationThis study is registered with ClinicalTrials.gov identifier NCT02215265 .

Project description:BackgroundOropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.MethodsWe performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer.ResultsThe median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage.ConclusionsTumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)

Dataset Information

Primary surgery for human papillomavirus-associated oropharyngeal cancer: Survival outcomes with or without adjuvant treatment.

Publications

Primary surgery for human papillomavirus-associated oropharyngeal cancer: Survival outcomes with or without adjuvant treatment.

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