Hypopharyngeal dose is associated with severe late toxicity in locally advanced head-and-neck cancer: an RTOG analysis.
OBJECTIVE
Concurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity.


METHODS
This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube≥2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors.


RESULTS
A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P=.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P=.016). The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome.


CONCLUSIONS
Severe late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.
University Hospitals Seidman Cancer Center and Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. mitchell.machtay@uhhospitals.org
Mitchell
M
Machtay
Jennifer
J
Moughan
Andrew
A
Farach
Elizabeth
E
Martin-O'Meara
James
J
Galvin
Adam S
AS
Garden
Randal S
RS
Weber
Jay S
JS
Cooper
Arlene
A
Forastiere
K Kian
KK
Ang
D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007013:Hypopharynx / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D058958:Organs at Risk / Q000528:radiation effects; D018579:Patient Selection; D011832:Radiation Injuries / Q000209:etiology*; D011879:Radiotherapy Dosage; D012044:Regression Analysis; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D017741:Survivors