Association of Body Mass Index With Outcomes Among Patients With Head and Neck Cancer Treated With Chemoradiotherapy

Key Points Question What is the association of overweight and obese body mass index (BMI) with posttreatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer who underwent chemoradiotherapy? Findings In this cohort study involving 445 patients, both overweight and obese BMI were associated with complete metabolic response after chemoradiotherapy. Only overweight BMI was associated with improved overall survival, progression-free survival, and reduction in locoregional failure. Meaning This study suggests that overweight BMI is an independent factor favorably associated with complete metabolic response after chemoradiotherapy, survival, and locoregional failure.


Introduction
The prevalence of obesity is anticipated to increase, with nearly 1 in 2 adults having obesity by 2030. 1 The prognostic role of body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) may vary based on cancer subtypes. 2evious meta-analysis and prospective studies showed that both obesity and overweight were associated with worse all-cause mortality, 3 cancer-related mortality, 4 and the incidence of multiple types of cancer. 5However, while similar findings were noted for breast, ovarian, and colorectal cancer, [6][7][8] obesity was a favorable prognostic factor for survival in lung cancer 2,9,10 and renal cell carcinoma. 2,113][14][15] The role of BMI in this setting remains unclear.To address these knowledge gaps, we performed an observational cohort study to evaluate the association between BMI and survival outcomes.

Methods
Our study was performed under a protocol approved by the Roswell Park Comprehensive Cancer Center institutional review board.The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline was reviewed, and our study follows the guideline.The study was conducted in accordance with the Declaration of Helsinki. 16A waiver of consent was obtained from the institutional review board of the Roswell Park Comprehensive Cancer Center due to the retrospective nature of the study making consent impractical and because contacting patients to obtain consent would pose a greater risk than the waiver.
Our retrospective database was queried for patients with head and neck cancer who underwent curative-intent definitive chemoradiotherapy at the Roswell Park Comprehensive Cancer Center between January 1, 2005, and January 31, 2021.Patients were excluded if they underwent surgery or radiotherapy alone, received a diagnosis of metastatic cancer, or had unknown BMI.Patients with low BMI (underweight, <18.5) were also excluded due to a small sample size (n <15).
Body mass index is stratified by normal weight (18.5-24.9),overweight (25.0-29.9),and obese (Ն30).Other variables of interest were extracted, including age, self-reported gender, smoking history, Karnofsky performance status, race and ethnicity, number of comorbidities, primary disease site, cancer staging based on the American Joint Committee on Cancer Staging Manual, 7th edition, 17 human papillomavirus (HPV) status, and chemotherapy.All missing values were coded as unknown for analysis.Other clinically pertinent variables were not captured in the database, such as treatment-related toxic effects.Race and ethnicity were self-reported, and this information was extracted from the electronic health record.Among patients who self-reported other racial and ethnic backgrounds, they included African American, American Indian or Alaska Native, Asian, Hispanic, and those who were unknown or declined to answer.Such categories were combined as a single group prior to performing our analyses because it would be challenging to show meaningful differences in outcomes due to their small subgroup sample sizes.
The primary end points of our study were overall survival (OS) and progression-free survival (PFS).These outcomes were defined as the time intervals from diagnosis to any death or last follow-up and from diagnosis to tumor progression or any death or last follow-up, respectively.[20]

Statistical Analysis
Comparison of baseline characteristics was performed using the Fisher exact test and the Mann-Whitney test as appropriate.Evaluation of survival outcomes was performed using the Kaplan-Meier method, log-rank tests, and Cox proportional hazards regression multivariable analyses.Logistic multivariable analysis was performed to identify variables associated with posttreatment responses and treatment interruptions.Fine-Gray multivariable analysis was performed to evaluate LRF and DF outcomes with death as a competing event.All multivariable analysis models were constructed using all patient and tumor variables as listed previously.
Propensity score matching was used to reduce selection bias.All baseline characteristics were considered for matching as deemed clinically pertinent.Matching was performed based on the nearest neighbor method in a 1:1 ratio with no replacements and a caliper distance of 0.2. 21Subgroup analyses were also performed to evaluate OS, PFS, LRF, and DF outcomes based on HPV status, which was assessed using p16 status among patients with oropharyngeal cancer.

Discussion
To our knowledge, this is the largest study involving patients in the US treated with chemoradiotherapy for head and neck cancer that evaluated the role of BMI as a factor associated with survival, treatment response, and tumor recurrence outcomes.Overweight BMI and obese BMI were associated with complete metabolic response on follow-up PET-CT; however, only overweight BMI was an independent factor favorably associated with improved OS and PFS and a reduction in LRF.No association for OS and BMI was observed among HPV-positive patients.
3][24][25][26][27][28][29] However, obese BMI was not associated with OS in our study.[25]28,29 Such discrepancies may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range. 33,34 our knowledge, this is the first report for head and neck cancer to show that overweight BMI and obese BMI are associated with complete metabolic response on follow-up PET-CT.[38][39] Reasons for this complex association may be multifactorial.Although obese BMI has been associated with worse postoperative complications, 31,40 chronic inflammation for tumor development, 41 and reduced antitumor immune response, 42 several studies have suggested that obese BMI is a nutrient reserve to overcome toxic effects from combined modality therapies, 33 which may be associated with improved LRF 24 and DF. 25,26Such a complex interplay may explain the conflicting association between treatment-associated weight loss and survival for patients with head and neck cancer. 15,27,43,44This interplay may also explain the variations seen in markers for systematic inflammation, 45 such as the neutrophil-lymphocyte ratio. 46Further complicating matters, studies have suggested that BMI alone may not be representative of one's body fat composition and cachexia. 47,48Another quantitative measure correlated with BMI is skeletal muscle depletion measured based on CT imaging, which has been shown to be associated with worse survival 24,49 and quality of life 50 among patients with head and neck cancer.
In our study, BMI was not associated with survival outcomes among HPV-positive patients, consistent with prior studies. 32,51Although a few other studies have suggested that a higher BMI is associated with improved survival, 41 they also included patients with an underweight BMI as a reference group, which was previously shown to be associated with worse survival outcomes. 33,34though a lack of association between BMI, HPV, and survival in our study may be due to smaller subgroup sample sizes, interaction among these variables warrants further investigation.For example, despite adipose tissue-promoting pathways, including PI3K-PTEN-Akt-mTOR and Ras-Raf-MAPK associated with HPV-associated head and neck cancers, 52 patients with a high BMI were more Obese BMI Obese BMI likely to have greater treatment-related weight loss 44,53 associated with changes in tumor microenvironment and inflammation that may potentiate treatments. 54

Limitations
Our retrospective study has inherent limitations.In our study, BMI was analyzed as a categorical variable with 3 different strata (normal, overweight, and obese) instead of as a continuous variable.
The association between BMI and survival outcomes has been previously shown to be complex and nonlinear, 33,34 and there may be more clinically pertinent, model-derived BMI cutoffs associated with clinical outcomes.Our BMI variable was also collected at a single time point, and our analysis did not include dynamic changes in BMI prior to the diagnosis of head and neck cancer, during chemoradiotherapy, or after the completion of all treatments.Such changes may be more clinically pertinent in prognosticating clinical outcomes than a single measure of BMI.In addition, only 40% to 45% of patients with overweight BMI and obese BMI were matched, suggesting that our matched cohort may not be representative of our overall cohort.However, our findings from the matched cohorts were consistent with those from the overall cohort.Other clinical outcomes, such as toxicity profiles, were unavailable for analysis.Furthermore, our findings may not be generalizable for other patient cohorts who underwent surgery, induction systemic therapy, or radiotherapy alone.

Conclusions
Our cohort study suggests that overweight BMI is an independent, favorable factor associated with complete response after treatments, OS, PFS, and LRF.Further investigations are warranted to improve our understanding on the role of BMI among patients with head and neck cancer.

Figure 1 .
Figure 1.Kaplan-Meier and Cumulative Incidence Curves for Overall Survival, Progression-Free Survival, Locoregional Failure, and Distant Failure for Overweight vs Normal Body Mass Index (BMI) After Propensity Score Matching
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HPV, human papillomavirus; KPS, Karnofsky performance status; NA, not available.a Among patients who self-reported other racial and ethnic backgrounds, they included African American, American Indian or Alaska Native, Asian, Hispanic, and those who were unknown or declined to answer.