RE: Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival

JNCI: Journal of the National Cancer Institute, Apr 2018

Overgaard, Jens

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RE: Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival

JNCI J Natl Cancer Inst ( RE: Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival Jens Overgaard 0 1 0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please 1 Affiliation of author: Department of Experimental Clinical Oncology, Aarhus University Hospital , Aarhus , Denmark - An article in the Journal by Bledsoe et al. recently reported on patterns of care and survival in patients treated with radiotherapy for early-stage glottic carcinoma ( 1 ). A similar study by Stokes et al. was also published in the International Journal of Radiation Oncology * Biology * Physics ( 2 ). Both evaluated the role of hypofractionated radiotherapy using the National Cancer Database and identified almost the same patients. The results and conclusions, not surprisingly, were the same: that hypofractionated radiotherapy yielded a small overall survival benefit. Early glottic cancer is a local disease, which rarely spreads to the regional lymph nodes and more seldom disseminates ( 3 ). The aim is therefore to control the disease locally with minimal morbidity. This can be achieved by either radiotherapy or surgery. The superior value of either treatment modality is disputed because of a lack of comparative clinical studies. Radiotherapy, however, continues to have a dominating role. For both alternatives, there exists a successful probability of being salvaged by the other modality. The therapeutic intervention must be evaluated by the local therapeutic outcome rather than the indirect end point of overall survival because early glottic carcinoma is a disease where the risk of dying from another (often tobacco-related) cancer is substantially higher than the risk from the cancer in question ( 4 ). Patients also have a high probability of tobacco-related comorbidity and consequential mortality ( 4 ). In this aspect, the recorded comorbidity in the National Cancer Database (around 15%) is much lower than in other studies, so does a comorbidity score of zero also include “unknown”? Unless local failure and survival are directly related, one may question how much guidance the latter end point will give to a fairly small variation in a radiotherapy procedure to a local disease (with substantial salvage possibilities). The key factors related to outcome after radiotherapy are T stage and tumor volume; total dose and overall treatment time, but to a lesser extent the dose per fraction; histopathological differentiation; and female sex ( 3 ). Since Withers et al. ( 5 ) demonstrated the importance of accelerated repopulation (in head and neck cancer), numerous studies have shown that reduction of the overall treatment time can improve the outcome of radiotherapy ( 6 ). This is seen in well-differentiated tumors, and the benefit is found in the T site, but to only a lesser extent in nodal disease. Because early glottic carcinomas are characterized by being well differentiated and have no nodal disease, they represent the prime indication for accelerated fractionation ( 6 ). This has been demonstrated in a recently updated large international meta-analysis ( 7 ), which was not cited in the studies ( 1,2 ). Most importantly, the vast amount of literature on the importance of overall treatment time was not focused on in the studies by Bledsoe et al. and Stokes et al. ( 1,2 ). I would strongly argue that until this parameter has been analyzed using an appropriate local control end point, the conclusion about a causal relationship between moderate hypofractionation per se (irrespective of overall treatment time) and benefit on overall survival outcome is still dubious—not least because a similar benefit has also been suggested after treatment with accelerated hyperfractionated radiotherapy (7). 1. Bledsoe TJ , Park HS , Stahl JM , et al. Hypofractionated radiotherapy for patients with early-stage glottic cancer: Patterns of care and survival . J Natl Cancer Inst . 2017 ; 109 ( 10 ): djx042 . 2. Stokes WA , Abbott D , Phan A , et al. Patterns of care for patients with earlystage glottic cancer undergoing definitive radiation therapy: A National Cancer Database analysis . Int J Radiat Oncol Biol Phys . 2017 ; 98 ( 5 ): 1014 - 1021 . 3. Lyhne NM , Johansen J , Kristensen CA , et al. Pattern of failure in 5001 patients treated for glottic squamous cell carcinoma with curative intent - a population based study from the DAHANCA group . Radiother Oncol . 2016 ; 118 ( 2 ): 257 - 266 . 4. Bøje CR . Impact of comorbidity on treatment outcome in head and neck squamous cell carcinoma - a systematic review . Radiother Oncol . 2014 ; 110 ( 1 ): 81 - 90 . 5. Withers HR , Taylor JM , Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy . Acta Oncol . 1988 ; 27 ( 2 ): 131 - 146 . 6. Lyhne NM , Primdahl H , Kristensen CA , et al. The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma . Radiother Oncol . 2015 ; 117 ( 1 ): 91 - 98 . 7. Lacas B , Bourhis J , Overgaard J , et al. Role of radiotherapy fractionation in head and neck cancers (MARCH): An updated meta-analysis . Lancet Oncol . 2017 ; 18 : 1221 - 1237 .

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Overgaard, Jens. RE: Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival, JNCI: Journal of the National Cancer Institute, 2018, 430-431, DOI: 10.1093/jnci/djx229