Correspondence

Treatment Deintensification and Symptom Burden in Patients With Human PapillomavirusAssociated Head and Neck Cancer We read with interest the article by Rosenthal et al regarding patterns of symptom burden during radiotherapy (RT) or concurrent chemoradiotherapy (CRT) for patients with head and neck cancer (HNC).1 Patient-reported, robust symptom-related data collection is warranted for statistical assumptions in future HNC trials in which symptom distress takes part of the endpoints. This is an important issue because recent prospective trials of cancer treatment deintensification in patients with human papillomavirus (HPV)-associated HNC have attempted to reduce treatment-related toxicity and patient symptoms while maintaining or improving established cure rates. This goal is investigated by either using upfront transoral robotic surgery (Eastern Cooperative Oncology Group 3311 trial; ClinicalTrials.gov identifier NCT01898494) or upfront induction chemotherapy followed by response-adapted (low vs standard-dose) RT (Eastern Cooperative Oncology Group E1308 trial; ClinicalTrials.gov identifier NCT01084083), or by replacing standard cisplatin chemotherapy with treatment with antiepidermal growth factor receptor (cetuximab) (Radiation Therapy Oncology Group-1016 trial, ClinicalTrials.gov identifier NCT01302834). HPV-associated HNC is a distinct disease entity with an increasing frequency, and is observed mainly in nonsmoking, nondrinking younger patients diagnosed with oropharyngeal cancer with a favorable prognosis.2,3 Since 2000, the worldwide standard treatment for patients with locally advanced HNC has been CRT.4,5 However, this treatment has not been uniformly adopted for patients with low-volume TNM stage III or IV oropharyngeal cancer, does not take into consideration the existence of HPV-driven cancers, and is associated with significant long-term toxicity.6 Toxicity has largely been ignored because of an evolved focus on survival as a priority. Given the very good prognosis of patients with HPVpositive HNC, one of the first questions is the possibility of omitting chemotherapy (or replacing it with cetuximab). The MARCH (Meta-Analysis of Radiotherapy in Cancer

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Carcinomas of Head and Neck) meta-analysis, which included 6515 patients, demonstrated a similar absolute benefit of survival (8%) using accelerated RT alone compared with CRT as in the MACH-NC (Meta-Analysis of Chemotherapy in Head and Neck Cancer) meta-analysis, which included >10,000 patients.4,7,8 In both metaanalyses, the absolute survival benefit for oropharyngeal cancer was similar. In patients with HPV-positive HNC, the better prognosis noted compared with patients with HPVnegative disease is related to increased locoregional control rather than the incidence of distant metastases.3,9 The majority of patients with HPV-positive oropharyngeal cancer present with N2bN3 disease, and therefore have a risk of developing distant metastases if chemotherapy is omitted.10,11 Moreover, in a recent meta-analysis, taxane-containing induction chemotherapy demonstrated an absolute benefit of 8% in patients with N2N3 HNC.12 Given the good locoregional control but similar incidence of distant metastases compared with patients with HPV-negative HNC, a reduction in elective neck irradiation (total radiation dose or irradiated volume) can be a solution for deintensification in patients with HPVpositive HNC. The current regimen is to deliver 45 to 50 grays to the uninvolved neck. In the modern RT era, using positron emission tomography, magnetic resonance imaging, or high-quality computed tomography, elective neck dissection or irradiation can be omitted. A recent metaanalysis assessing the detection of cervical lymph node metastases using modern imaging techniques in patients with HNC with clinically N0 disease demonstrated that minimizing morbidity by avoiding elective neck treatment is acceptable in selected cases.13 In conclusion, we are convinced that treatmentrelated long-term toxicity among patients with HNC is high, and the analysis of patterns of symptom burden as proposed by Rosenthal et al1 should be used as a benchmark for future symptom intervention clinical trials. FUNDING SUPPORT No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.

REFERENCES 1. Rosenthal DI, Mendoza TR, Fuller CD, et al. Patterns of symptom burden during radiotherapy or concurrent chemoradiotherapy for head and neck cancer: a prospective analysis using the University of

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Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module. Cancer. 2014;120:1975-1984. Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11:9-22. 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. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet. 2000;355:949-955. Pignon JP, le Maitre A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92:4-14. 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. 2008;26:3582-3589. Bourhis J, Overgaard J, Audry H, et al; Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) Collaborative Group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet. 2006;368:843-854. Blanchard P, Hill C, Guihenneuc-Jouyaux C, Baey C, Bourhis J, Pignon JP; MACH-NC and MARCH Collaborative Groups. Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer. J Clin Epidemiol. 2011;64:985-992. Petrelli F, Sarti E, Barni S. Predictive value of human papillomavirus in oropharyngeal carcinoma treated with radiotherapy: an updated

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systematic review and meta-analysis of 30 trials. Head Neck. 2014; 36:750-759. Huang SH, Perez-Ordonez B, Weinreb I, et al. Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. Oral Oncol. 2013;49:79-85. O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol. 2013; 31:543-550. Blanchard P, Bourhis J, Lacas B, et al; Meta-Analysis of Chemotherapy in Head and Neck Cancer, Induction Project, Collaborative Group. Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol. 2013;31:2854-2860. Liao LJ, Lo WC, Hsu WL, Wang CT, Lai MS. Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck-a meta-analysis comparing different imaging modalities. BMC Cancer. 2012;12:236.

Mahmut Ozsahin, MD, PhD Jean Bourhis, MD, PhD Department of Radiation Oncology Lausanne University Medical Center Lausanne, Switzerland The authors were invited to reply but did not respond. DOI: 10.1002/cncr.29152, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)

Cancer

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Treatment deintensification and symptom burden in patients with human papillomavirus-associated head and neck cancer.

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