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Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: Findings from a phase 2 trial.

ABSTRACT: BACKGROUND:The current study represents a subset analysis of quality-of-life (QOL) outcomes among patients treated on a phase 2 trial of de-escalated chemoradiation for human papillomavirus (HPV)-associated oropharyngeal cancer. METHODS:Eligibility included newly diagnosed, (American Joint Committee on Cancer, 7th edition) stage III or IV oropharyngeal squamous cell carcinoma, p16 positivity, age???18 years, and a Zubrod performance status of 0 to 1. Treatment was induction paclitaxel at a dose of 175?mg/m2 and carboplatin at an area under the curve of 6 for 2 cycles followed by response-adapted, dose-reduced radiation of 54 Gy or 60 Gy with weekly concurrent paclitaxel at a dose of 30?mg/m2 . The University of Washington Quality of Life (UW-QOL) and the Functional Assessment of Cancer Therapy-Head and Neck questionnaires were used to assess patient-reported QOL as a secondary endpoint. RESULTS:A total of 45 patients were registered, 40 of whom completed QOL surveys and were evaluable. Nadirs for overall UW-QOL and Functional Assessment of Cancer Therapy-Head and Neck scores were reached at 4 weeks after treatment but returned to baseline at 3 months. Nearly all functional indices returned to baseline levels by 6 to 9 months. The mean overall UW-QOL score was 71.6 at baseline compared with 70.8, 73.0, 83.3, and 81.1, respectively, at 3 months, 6 months, 1 year, and 2 years after therapy. The percentage of patients rating their overall QOL as "very good" or "outstanding" at 6 months, 1 year, and 2 years using the UW-QOL was 50%, 77%, and 84%, respectively. CONCLUSIONS:This de-escalation regimen achieved QOL outcomes that were favorable compared with historical controls. These results serve as powerful evidence that ongoing de-escalation efforts lead to tangible gains in function and QOL. Cancer 2018;124:521-9. © 2017 American Cancer Society.

SUBMITTER: Hegde JV

PROVIDER: S-EPMC5916816 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: Findings from a phase 2 trial.

Hegde John V JV Shaverdian Narek N Shaverdian Narek N Daly Megan E ME Felix Carol C Wong Deborah L DL Rosove Michael H MH Garst Jordan H JH Wang Pin-Chieh PC Veruttipong Darlene D Rao Shyam S Fragoso Ruben C RC Riess Jonathan W JW Steinberg Michael L ML Chen Allen M AM

Cancer 20171017 3

<h4>Background</h4>The current study represents a subset analysis of quality-of-life (QOL) outcomes among patients treated on a phase 2 trial of de-escalated chemoradiation for human papillomavirus (HPV)-associated oropharyngeal cancer.<h4>Methods</h4>Eligibility included newly diagnosed, (American Joint Committee on Cancer, 7th edition) stage III or IV oropharyngeal squamous cell carcinoma, p16 positivity, age ≥ 18 years, and a Zubrod performance status of 0 to 1. Treatment was induction paclit ...[more]

PMID: 29044458

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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:IntroductionMost patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy.MethodsPatients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors.ResultsTen patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples.ConclusionChemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.

Project description:Purpose:This study aimed to compare the swallowing function in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma treated with de-intensified chemoradiation therapy (6 weeks, 60?Gy) versus those receiving standard-of-care chemoradiation therapy (7 weeks, 70?Gy). Methods and materials:A retrospective review was conducted of 78 patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma with modified barium swallow studies pretreatment and 6 to 8 weeks posttreatment. The swallowing function was objectively scored for penetration, aspiration, and pharyngeal residue. Forty patients received de-intensified chemoradiation therapy (60?Gy image guided radiation therapy with weekly cisplatin 30?mg/m2) and 38 patients received standard-of-care chemoradiation therapy (70?Gy image guided radiation therapy with chemotherapy of the medical oncologist's choosing). Univariate and multivariate analyses were performed to detect differences between the cohorts with regard to laryngeal penetration, aspiration, and pharyngeal residue. A multivariate logistic regression was used to determine the overall effect of treatment on the swallowing function. Patient-reported swallowing outcomes in de-intensified cohort were assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Module for Head and Neck Cancer and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events questionnaires. Results:Patients treated with de-intensified chemoradiation therapy were associated with a suggestion of lower risk of developing overall swallowing dysfunction (odds ratio [OR], 0.62; P?=?.07), laryngeal penetration (OR, 0.63; P?=?.12), and pharyngeal residue (OR, 0.61; P?=?.08). The mean pre- and 2-year post-European Organisation for Research and Treatment of Cancer Quality of Life scores pertaining to swallowing (1-4 scale, higher worse) in the de-intensified cohort were 1.4 and 1.2 for liquids; 1.2 and 1.1 for purees; 1.5 and 1.7 for solids, 1.0 and 1.3 for choked when swallowing; and 9.0 and 10.8 for composite score, respectively. The mean pre- and 2-year post-Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events swallowing difficulty scores (1-5 scale, with higher scores being worse) were 1.5 and 1.8, respectively. Conclusions:Compared with 7 weeks of 70?Gy, 6 weeks of 60?Gy de-intensified chemoradiation therapy appears to better preserve the baseline swallowing function (per objective modified barium swallow assessment). Patients treated with de-intensified chemoradiation therapy reported minimal changes in swallowing function.

Project description:BackgroundThe incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.MethodsWe did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080.FindingsBetween Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007).InterpretationCompared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin.FundingCancer Research UK.

Project description:PurposeTo report the results of a phase II clinical trial of de-intensified chemoradiotherapy for patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma.Materials and methodsMajor inclusion criteria were (1) having American Joint Committee on Cancer (AJCC) 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) being p16 positive, and (3) reporting minimal or remote smoking history. Treatment was limited to 60 Gy intensity-modulated radiotherapy with concurrent intravenous cisplatin 30 mg/m2 once per week. Patients with T0-T2 N0-1 (AJCC 7th edition) did not receive chemotherapy. All patients had a 10- to 12-week post-treatment positron emission tomography/computed tomography to assess for neck dissection. The primary end point was 2-year progression-free survival. Secondary end points included 2-year local-regional control, distant metastasis-free survival and overall survival, and patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events).ResultsOne hundred fourteen patients were enrolled (median follow-up of 31.8 months), with 81% having a minimum follow-up of 2 years. Eighty percent of patients had 10 or fewer tobacco pack-years. Two-year local-regional control, distant metastasis-free survival, progression-free survival, and overall survival were as follows: 95%, 91%, 86%, and 95%, respectively. Mean pre- and 2-year post-treatment European Organisation for Research and Treatment of Cancer quality of life scores were as follows: global, 79/84 (lower worse); swallowing, 8/9 (higher worse); and dry mouth, 14/45 (higher worse). Mean pre- and 2-year post-treatment patient-reported outcomes version of the Common Terminology Criteria for Adverse Events scores (0 to 4 scale, higher worse) were as follows: swallowing, 0.5/0.7, and dry mouth, 0.4/1.3. Thirty-four percent of patients required a feeding tube (median, 10.5 weeks; none permanent). There were no grade 3 or higher late adverse events.ConclusionClinical outcomes with a de-intensified chemoradiotherapy regimen of 60 Gy intensity-modulated radiotherapy with concurrent low-dose cisplatin are favorable in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma. Neither neoadjuvant chemotherapy nor routine surgery is needed to obtain favorable results with de-escalation.

Dataset Information

Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: Findings from a phase 2 trial.

Publications

Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: Findings from a phase 2 trial.

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