Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002)

Sue S Yom, Pedro Torres-Saavedra, Jimmy J Caudell, John N Waldron, Maura L Gillison, Ping Xia, Minh T Truong, Christina Kong, Richard Jordan, Rathan M Subramaniam, Min Yao, Christine H Chung, Jessica L Geiger, Jason W Chan, Brian O'Sullivan, Dukagjin M Blakaj, Loren K Mell, Wade L Thorstad, Christopher U Jones, Robyn N Banerjee, Christopher Lominska, Quynh-Thu Le, Sue S Yom, Pedro Torres-Saavedra, Jimmy J Caudell, John N Waldron, Maura L Gillison, Ping Xia, Minh T Truong, Christina Kong, Richard Jordan, Rathan M Subramaniam, Min Yao, Christine H Chung, Jessica L Geiger, Jason W Chan, Brian O'Sullivan, Dukagjin M Blakaj, Loren K Mell, Wade L Thorstad, Christopher U Jones, Robyn N Banerjee, Christopher Lominska, Quynh-Thu Le

Abstract

Purpose: Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.

Patients and methods: In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).

Results: Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (P = .04). For IMRT, 2-year PFS was 87.6% (P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (P = .56).

Conclusion: The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

Trial registration: ClinicalTrials.gov NCT02254278.

Figures

FIG 1.
FIG 1.
CONSORT Flow Diagram for NRG-HN002. IMRT, intensity-modulated radiation therapy; MDADI, MD Anderson Dysphagia Inventory; PFS, progression-free survival.
FIG 2.
FIG 2.
NRG-HN002 progression-free (A) and overall survival (B), local-regional failure (C), and distant metastasis (D). HR, hazard ratio; IMRT, intensity-modulated radiation therapy.
FIG A1.
FIG A1.
High-grade adverse event rates over time by treatment arm.
FIG A2.
FIG A2.
Feeding tube rates over time by treatment arm.

References

    1. Chaturvedi AK Engels EA Pfeiffer RM, et al. : Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29:4294-4301, 2011
    1. D'Souza G Kreimer AR Viscidi R, et al. : Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356:1944-1956, 2007
    1. Herrero R: Human papillomavirus and oral cancer: The International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 95:1772-1783, 2003
    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 100:261-269, 2008
    1. Fakhry C Zhang Q Nguyen-Tan PF, et al. : Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 32:3365-3373, 2014
    1. Aggarwal P Zaveri JS Goepfert RP, et al. : Swallowing-related outcomes associated with late lower cranial neuropathy in long-term oropharyngeal cancer survivors: Cross-sectional survey analysis. Head Neck 41:3880-3894, 2019
    1. Adelstein DJ Li Y Adams GL, et al. : An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92-98, 2003
    1. Bourhis J Sire C Graff P, et al. : Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): An open-label phase 3 randomised trial. Lancet Oncol 13:145-153, 2012
    1. Trotti A Pajak TF Gwede CK, et al. : TAME: Development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol 8:613-624, 2007
    1. Machtay M Moughan J Trotti A, et al. : Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: An RTOG analysis. J Clin Oncol 26:3582-3589, 2008
    1. Kimple RJ Smith MA Blitzer GC, et al. : Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 73:4791-4800, 2013
    1. Rieckmann T Tribius S Grob TJ, et al. : HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 107:242-246, 2013
    1. Chen AM Felix C Wang PC, et al. : Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: A single-arm, phase 2 study. Lancet Oncol 18:803-811, 2017
    1. Chera BS Amdur RJ Tepper JE, et al. : Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer 124:2347-2354, 2018
    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 103:49-56, 2012
    1. Hall SF Liu FF O'Sullivan B, et al. : Did the addition of concurrent chemotherapy to conventional radiotherapy improve survival for patients with HPV+ve and HPV−ve oropharynx cancer? A population-based study. Br J Cancer 117:1105-1112, 2017
    1. Eisbruch A Harris J Garden AS, et al. : Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys 76:1333-1338, 2010
    1. Beitler JJ Switchenko JM Dignam JJ, et al. : Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx. Cancer 125:704-711, 2019
    1. Ang KK Harris J Wheeler R, et al. : Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24-35, 2010
    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 35:490-497, 2017
    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 36:945-954, 2012
    1. Bhide SA Gulliford S Kazi R, et al. : Correlation between dose to the pharyngeal constrictors and patient quality of life and late dysphagia following chemo-IMRT for head and neck cancer. Radiother Oncol 93:539-544, 2009
    1. Gillespie MB Brodsky MB Day TA, et al. : Swallowing-related quality of life after head and neck cancer treatment. Laryngoscope 114:1362-1367, 2004
    1. Ringash J O'Sullivan B Bezjak A, et al. : Interpreting clinically significant changes in patient-reported outcomes. Cancer 110:196-202, 2007
    1. Grossman SA Schreck KC Ballman K, et al. : Point/counterpoint: Randomized versus single-arm phase II clinical trials for patients with newly diagnosed glioblastoma. Neurooncol 19:469-474, 2017
    1. Gillison ML Trotti AM Harris J, et al. : Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): A randomised, multicentre, non-inferiority trial. Lancet 393:40-50, 2019
    1. Mehanna H Robinson M Hartley A, et al. : Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): An open-label randomised controlled phase 3 trial. Lancet 393:51-60, 2019
    1. Nichols AC Theurer J Prisman E, et al. : Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): An open-label, phase 2, randomised trial. Lancet Oncol 20:1349-1359, 2019
    1. Guo T Qualliotine JR Ha PK, et al. : Surgical salvage improves overall survival for patients with HPV-positive and HPV-negative recurrent locoregional and distant metastatic oropharyngeal cancer: Surgical salvage for recurrent OPSCC. Cancer 121:1977-1984, 2015
    1. Patel SN Cohen MA Givi B, et al. : Salvage surgery for locally recurrent oropharyngeal cancer: Salvage surgery for locally recurrent oropharyngeal cancer. Head Neck 38:E658-E664, 2016
    1. Noronha V Joshi A Patil VM, et al. : Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: A phase III randomized noninferiority trial. J Clin Oncol 36:1064-1072, 2018
    1. Bauml JM Vinnakota R Anna Park YH, et al. : Cisplatin every 3 weeks versus weekly with definitive concurrent radiotherapy for squamous cell carcinoma of the head and neck. J Natl Cancer Inst 111:490-497, 2019
    1. Liang H Xia WX Lv X, et al. : Concurrent chemoradiotherapy with 3-weekly versus weekly cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: A phase 3 multicentre randomised controlled trial (ChiCTR-TRC-12001979). J Clin Oncol 35, 2017. (suppl; abstr 6006)
    1. Szturz P Wouters K Kiyota N, et al. : Low-dose vs. High-dose cisplatin: Lessons learned from 59 chemoradiotherapy trials in head and neck cancer. Front Oncol 9:86, 2019
    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 32:2940-2950, 2014
    1. Strumberg D Brügge S Korn MW, et al. : Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 13:229-236, 2002
    1. Nonnekens J, Hoeijmakers JH: After surviving cancer, what about late life effects of the cure? EMBO Mol Med 9:4-6, 2017
    1. Forastiere AA Zhang Q Weber RS, et al. : Long-term results of RTOG 91-11: A comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31:845-852, 2013
    1. Ma DJ Price KA Moore EJ, et al. : Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiotherapy in human papillomavirus-associated oropharynx squamous cell carcinoma. J Clin Oncol 37:1909-1918, 2019
    1. Swisher-McClure S Lukens JN Aggarwal C, et al. : A phase 2 trial of alternative volumes of oropharyngeal irradiation for de-intensification (AVOID): Omission of the resected primary tumor bed after transoral robotic surgery for human papilloma virus-related squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 20:1349-1359, 2019
    1. Seiwert T Melotek JM Foster CC, et al. : OPTIMA—a phase 2 trial of induction chemotherapy response-stratified radiation therapy dose and volume de-escalation for HPV+ oropharyngeal cancer: Efficacy, toxicity, and HPV subtype Analysis. Int J Radiat Oncol Biol Phys 100:1309, 2018
    1. National Cancer Institute : NCTN/NCORP Data Archive,

Source: PubMed

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