Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study

Allen M Chen, Carol Felix, Pin-Chieh Wang, Sophia Hsu, Vincent Basehart, Jordan Garst, Phillip Beron, Deborah Wong, Michael H Rosove, Shyam Rao, Heather Melanson, Edward Kim, Daphne Palmer, Lihong Qi, Karen Kelly, Michael L Steinberg, Patrick A Kupelian, Megan E Daly, Allen M Chen, Carol Felix, Pin-Chieh Wang, Sophia Hsu, Vincent Basehart, Jordan Garst, Phillip Beron, Deborah Wong, Michael H Rosove, Shyam Rao, Heather Melanson, Edward Kim, Daphne Palmer, Lihong Qi, Karen Kelly, Michael L Steinberg, Patrick A Kupelian, Megan E Daly

Abstract

Background: Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma.

Methods: We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195.

Findings: Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment.

Interpretation: Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients.

Funding: University of California.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1.
Figure 1.
Trial schema/CONSORT diagram.
Figure 2.
Figure 2.
Progression-free survival. The numbers along the x-axis represent the number of patients at risk (and censured) in a cumulative fashion.
Figure 3.
Figure 3.
Overall survival. The numbers along the x-axis represent the number of patients at risk (and censured) in a cumulative fashion.

References

    1. Gillison ML, D’Souza G, Westra WH, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 2008; 100: 407–420.
    1. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006; 24: 736–747.
    1. Klussmann JP, Mooren JJ, Lehnen M, et al. Genetic signatures of HPV-related and unrelated oropharygneal carcinoma and their prognostic implications. Clin Cancer Res 2009; 15: 1179–1786.
    1. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24–35.
    1. Lassen P, Eriksen JG, Hamilton S, et al. Effect of HPV-associated p16 expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009; 27: 1992–1998.
    1. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–269.
    1. Wansom D, Light E, Worden F, et al. Correlation of cellular immunity with human papillomavirus, p16 status, and outcome in patients with advanced oropharyngeal cancer. Arch Otolaryngol Head Neck Surg 2010; 136: 1267–1273.
    1. Spanos WC, Nowicki P, Lee DW, et al. Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer. Arch Otolaryngol Head Neck Surg 2009; 135: 1137–1146.
    1. Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 2015; 21: 632–641.
    1. Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 2014; 32: 2940–2950.
    1. Cmelak AJ, Li S, Goldwasser MA, et al. Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: Results of Eastern Cooperative Oncology Group Study E2399. J Clin Oncol 2007; 25: 3971–3977.
    1. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, (editors). American Joint Committee on Cancer staging manual, 7th edition France: Springer; 2010.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.
    1. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. . Updated June 14, 2010. Accessed January 3, 2016.
    1. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11, 570–9 (1993).
    1. Hassan SJ, Weymuller EA. Assessment of quality of life in head and neck cancer patients. Head Neck 1993; 15: 485–496.
    1. Duffy DE, Santner TJ. Confidence intervals for a binomial parameter based on multistage tests. Biometrics 1987; 43: 81–93.
    1. Simon R Optimal two-stage designs for phase II clinical trials, Controlled Clinical Trials, 1989; 10: 1–10.
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 547–581.
    1. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 2013; 31: 4550–4559.
    1. Deasy JO, Moiseenko V, Marks L, et al. Radiotherapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys 2010; 76(S): 58–63.
    1. Caudell JJ, Schaner PE, Desmond RA, et al. Dosimetric factors associated with long-term dysphagia after definitive radiotherapy for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2010; 76: 403–409.
    1. Feng FY, Kim HM, Lyden, et al. Intensity-modulated radiotherapy of head and neck cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys 2007; 68: 1289–1298.
    1. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, et al. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 2008; 26: 3770–3776.
    1. O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metatasis. J Clin Oncol 2013; 31: 543–550.
    1. Dobrosotskaya IY, Bellile E, Spector ME, et al. Weekly chemotherapy with radiation versus high-dose cisplatin with radiation as organ preservation for patients with HPV-positive and HPV-negative locally advanced squamous cell carcinoma of the oropharynx. Head Neck 2014; 36: 617–623.
    1. Dok R, Kalev P, Van Limbergen EJ, et al. P16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors. Cancer Res 2014; 74: 1739–1751.
    1. Huang SH, Waldron JN, Milosevic M, et al. Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status. Cancer 2015; 121: 545–555.
    1. Ward MJ, Thirdborough SM, Mellows T, et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer 2014; 110: 489–500.
    1. Marur S, Li S, Cmelak AJ, et al. E1308: Phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol 2016; 34: 1–8.
    1. Chen AM, Li J, Beckett LA, et al. Differential response rates to irradiation among patients with human papillomavirus positive and negative oropharyngeal cancer. Laryngoscope 2013; 123: 152–157.
    1. Gupta AK, Lee JH, Wilke WW, et al. Radiation response in two infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKT. Int J Radiat Oncol Biol Phys 2009; 74: 928–933.
    1. Chera BS, Amdur RJ, Tepper J, et al. Phase 2 trial of de-intensified chemoradiation therapy for favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2015; 93: 976–985.
    1. O’Sullivan B, Huang SH, Perez-Ordonez B, et al. Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol 2012; 103: 49–56.
    1. Chen AM, Zahra T, Daly ME, et al. Definitive radiation therapy without chemotherapy for human papiilomavirus-positive head and neck cancer. Head Neck 2013; 35: 1652–1656.
    1. Won HS, Lee YS, Jeon EK, et al. Clinical outcome of induction chemotherapy for locally advanced head and neck squamous cell carcinoma. Anticancer Res 2014; 34: 5709–5714.
    1. Holmes BJ, Maleki Z, Westra WH. The fidelity of p16 staining as a surrogate marker of human papillomavirus status in fine-needle aspirates and core biopsies of neck node metastases: implications for HPV testing protocols. Acta Cytologica 2015; 59: 97–103.
    1. Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 2012; 36: 945–954.
    1. Rietbergen NM, Brakenhoff RH, Bloemena E, et al. Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment de-escalation trials. Ann Oncol 2013; 24: 2740–2745.
    1. O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol 2016; 17: 440–451.
    1. Husain ZA, Chen T, Corso CD, et al. A comparison of prognostic ability of staging systems for human papillomavirus-related oropharyngeal squamous cell carcinoma. JAMA Oncology 2016; E1–E8
    1. Dahlstrom KR, Garden AS, William WN, et al. Proposed staging system for patients with HPV-related oropharyngeal cancer based on nasopharyngeal cancer N categories. J Clin Oncol 2016; 16: 1848–1854.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa