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. 2021 May;9(10):914. doi: 10.21037/atm-20-4969

Matched pair analysis to evaluate weight loss during radiation therapy for head and neck cancer as a prognostic factor for survival

Hye Ri Han 1,^, Gregory M Hermann 2,^, Sung Jun Ma 2,^, Austin J Iovoli 2,^, Kimberly E Wooten 3, Hassan Arshad 3, Vishal Gupta 3, Ryan P McSpadden 3,^, Moni A Kuriakose 3, Michael R Markiewicz 3,4,5, Jon M Chan 3, Mary E Platek 2,6,7, Andrew D Ray 6, Fangyi Gu 6,^, Wesley L Hicks Jr 3, Anurag K Singh 2,^,✉
PMCID: PMC8184423  PMID: 34164548

Abstract

Background

One frequent consequence of radiation therapy (RT) for head and neck cancer (HNC) is weight loss (WL). HNC patients reportedly lose about 9% of their weight during treatment, regardless of pre-treatment WL and nutritional support. We investigated whether high WL during RT has an association with overall (OS) and cancer-specific survival (CSS).

Methods

We retrospectively reviewed weight during RT in HNC patients treated at Roswell Park Comprehensive Cancer Center between 2003 and 2017. High WL was defined as greater than or equal to the median WL. Logistic regression analysis was performed to identify predictors for WL during RT. Multivariate Cox regression and Kaplan-Meier analyses were used to estimate survival outcomes. Propensity score matching was performed to obtain balanced matched-pairs and compare survival outcomes.

Results

A total of 843 patients received either definitive (71%) or post-operative (29%) RT. Median follow-up was 53.6 months [interquartile range (IQR) 35.7–88.9]. Median WL was 5.8% (IQR 0.24–10.6) from baseline weight. Patients with high WL had better OS [hazard ratio (HR) 0.75, 95% confidence interval (CI), 0.61–0.93, P=0.01] and CSS (HR 0.71, 95% CI, 0.55–0.93, P=0.01). 258 matched-pairs were analyzed. Median follow-up was 54.8 months (IQR 35.8–90.4). Median OS was 39.2 months (IQR 21.4–75.7) for high WL versus 36.7 months (IQR 14.6–61.7) for low WL cohorts (P=0.047).

Conclusions

Different from previous reports, this study shows that patients with less WL have worse OS. WL during RT may not be a reliable marker for worse prognosis. A better way to evaluate malnutrition in patients undergoing RT is warranted.

Keywords: Head and neck cancer (HNC), weight loss (WL), radiotherapy, overall survival (OS), cancer specific survival

Introduction

Among various cancer types, head and neck cancer (HNC) reports the second highest prevalence of malnutrition, which frequently presents as weight loss (WL) that is exacerbated by progression of disease and consequences of treatment including radiotherapy (RT) (1). HNC is also one of the most adversely affected cancers by cachexia, a paraneoplastic syndrome characterized by anorexia, sarcopenia, and systemic inflammation (1,2). Malnutrition and cachexia are associated with decreased quality of life and increased risk of morbidity and mortality (3,4). Pretreatment WL has also been shown to increase the risk of RT-induced toxicities, treatment interruptions, and mortality (5-8). Many efforts have thus been made to prevent WL during RT via diet modification and artificial support of nutrition.

Conversely, many studies have investigated the potential of calorie restriction to counter cancer growth and potentiate response to RT (9-12). Calorie restriction without causing malnutrition has shown to provide protective and therapeutic effects against cancer and other metabolic diseases by reducing adiposity and expression of pro-inflammatory and pro-angiogenic factors (13,14). HNC patients reportedly lose about 9% of their body weight during treatment, regardless of pretreatment WL and nutritional support (15). The purpose of this retrospective study was to identify factors that are associated with WL during RT and investigate the impact of WL during RT on overall survival (OS) or cancer-specific survival (CSS) of a large group of HNC patients treated at our institution. We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4969).

Methods

Patient population

A retrospective single-institution database of HNC patients treated with definitive or post-operative RT between 2003 and 2017 at Roswell Park Comprehensive Cancer Center was used. Patients who received RT with non-curative intent were excluded. Pre-RT and post-RT weight records were retrospectively reviewed to assess the level of WL in patients from start to end of RT. Median percentage of WL was identified and patients were classified into one of two groups: low WL (if change in weight is less than the median WL) or high WL (if change in weight is greater than or equal to the median WL). Length of follow-up, for those still alive, was defined as time between date of diagnosis to last date of follow-up visit.

Statistical analysis

Univariate (UVA) logistic regression and multivariate (MVA) logistic regression analyses were performed using backward selection of potential confounders to identify patient and treatment factors associated with high WL during RT. All P values were two-sided and factors with P values ≤0.05 were considered statistically significant. MVA Cox regression analysis was performed to analyze factors that are associated with survival outcomes and Kaplan-Meier analysis was used to estimate OS and CSS of unmatched and matched cohorts.

Propensity score matching in patients with low and high WL was performed and survival outcomes were compared. Baseline characteristics, including age, gender, pre-RT weight, smoking status, p16 status, tumor staging, primary tumor site, and treatments received were matched to create well-balanced matched-pairs. Matching was based on nearest neighbor matching without replacement (NNWOR) method for 1:1 ratio using a caliper width of 0.1 of the standard deviation of the logit of the propensity score (16). SAS (SAS Institute, Cary, NC) and R (version 3.6.1, R Project for Statistical Computing, Vienna, Austria) software were used for statistical analysis.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of Roswell Park Comprehensive Cancer Center (EDR-103707) and individual consent for this retrospective analysis was waived.

Results

Baseline characteristics

A total of 843 patients in the database were identified. They were 649 males (77%) and 194 females (23%) with a median age at time of diagnosis of 61 years [interquartile range (IQR) 54–69]. The baseline characteristics of these unmatched patients are summarized in Table 1. Median follow-up was 53.6 months (IQR 35.7–88.9). All patients received either definitive (71%) or post-operative (29%) RT, with RT start date ranging from May 2003 to August 2017. Median RT dose was 67.5 Gy (IQR 65–70) for patients with low WL and 70 Gy (IQR 70–70) for patients with high WL.

Table 1. Baseline characteristics of patients before matching.

Characteristics Low weight loss High weight loss P
N % N %
Gender 0.54
   Male 320 76 329 78
   Female 101 24 93 22
   Total 421 100 422 100
Age (years) 0.02
   <61 190 45 225 53
   ≥61 231 55 197 47
   Total 421 100 422 100
Pre-RT weight (kg) <0.001
   Median 75.7 83.5
   IQR 62.3–87.2 70.7–97.7
Smoker 0.93
   Never 97 23 102 24
   Former 216 51 213 50
   Current 108 26 107 25
   Total 421 100 422 100
HPV <0.001
   Negative 91 22 82 19
   Positive 77 18 161 38
   NA 253 60 179 42
   Total 421 100 422 100
Comorbidity (No.) 0.15
   0 68 16 83 20
   1 110 26 127 30
   2 124 29 101 24
   3 119 28 111 26
   Total 421 100 422 100
T stage <0.001
   X 2 0 3 1
   0–2 196 47 217 51
   3–4 189 45 194 46
   NA 34 8 8 2
   Total 421 100 422 100
N stage <0.001
   0–1 211 50 146 35
   2–3 175 42 267 63
   NA 35 8 9 2
   Total 421 100 422 100
M stage <0.001
   0 368 87 405 96
   1 13 3 7 2
   NA 40 10 10 2
   Total 421 100 422 100
Primary site <0.001
   NA 87 21 50 12
   Oral cavity 84 20 34 8
   Nasopharynx 11 3 9 2
   Oropharynx 88 21 189 45
   Hypopharynx 21 5 25 6
   Glottis 62 15 47 11
   Salivary 24 6 8 2
   Other 11 3 4 1
   Unknown 16 4 34 8
   Multiple 17 4 22 5
   Total 421 100 422 100
Histology <0.001
   Squamous 355 84 400 95
   Others 66 16 22 5
   Total 421 100 422 100
Laterality <0.001
   Unilateral 69 16 69 16
   Bilateral 88 21 167 40
   NA 264 63 186 44
   Total 421 100 422 100
RT type <0.001
   Definitive 253 60 345 82
   Post-operative 168 40 77 18
   Total 421 100 422 100
RT total dose (Gy) <0.001
   Median 67.5 70
   IQR 65.3–70.0 70.0–70.0
RT duration (days) <0.001
   <46 215 51 131 31
   ≥46 205 49 291 69
   NA 1 0 0 0
   Total 421 100 422 100
RT start year 0.55
   <2011 138 33 130 31
   ≥2011 283 67 292 69
   Total 421 100 422 100
RT complete <0.001
   No 29 7 10 2
   Yes 353 84 398 94
   NA 39 9 14 3
   Total 421 100 422 100
Treatment response 0.003
   None 27 6 17 4
   Partial 285 68 333 79
   Complete 61 14 44 10
   NA 48 11 28 7
   Total 421 100 422 100
Surgery <0.001
   No 253 60 342 81
   Yes 168 40 80 19
   Total 421 100 422 100
Chemo <0.001
   No 159 38 37 9
   Yes 262 62 385 91
   Total 421 100 422 100
Chemo type <0.001
   None 175 42 45 11
   Cis q21d 101 24 182 43
   Cis wkly 76 18 113 27
   Cetux wkly 23 5 14 3
   NA 5 1 3 1
   Carbo wkly 23 5 26 6
   Pt regimen NOS 10 2 17 4
   Crossover to cetux 7 2 13 3
   Crossover to carbo 1 0 9 2
   Total 421 100 422 100
Chemo frequency <0.001
   Weekly 135 32 170 40
   Q21d 104 25 196 46
   NA 182 43 56 13
   Total 421 100 422 100
Nutrition support <0.001
   No 221 52 167 40
   Yes 199 47 254 60
   NA 1 0 1 0
   Total 421 100 422 100
Hospitalized 0.006
   No 351 83 317 75
   Yes 68 16 103 24
   NA 2 0 2 0
   Total 421 100 422 100
Hemoglobin (g/dL) <0.001
   <12 161 38 301 71
   ≥12 85 20 78 18
   NA 175 42 43 10
   Total 421 100 422 100
WBC count <0.001
   Normal 208 49 337 80
   Low 7 2 8 2
   High 31 7 34 8
   NA 175 42 43 10
   Total 421 100 422 100
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RT, radiotherapy; IQR, interquartile range; HPV, human papilloma virus; NA, not available; Chemo, chemotherapy; Cis, cisplatin; Q21d, every 21 days; wkly, weekly; cetux, cetuximab; Carbo, carboplatin; Pt, platinum; NOS, not otherwise specified; WBC, white blood cell.

Median percentage of WL was 5.8% (IQR 0.24–10.6). There were 421 patients who had low (<5.8%) WL and 422 patients who had high (≥5.8%) WL. Patients of each gender were evenly divided between the two categories of WL (Table 1). Median pre-RT weight was 75.7 kg (IQR 62.3–87.2) in low WL and 83.5 kg (IQR 70.7–97.7) in high WL cohorts (Table 1, P<0.001).

Factors associated with WL

Patients with no treatment response [odds ratio (OR) 0.18; 95% confidence interval (CI), 0.05–0.67; P=0.03] were less likely to have high (≥5.8%) WL and patients with higher hemoglobin [OR 1.81; 95% CI, 1.33–2.47; P<0.001] were more likely to have high WL.

Survival outcome

Multivariate analysis showed that high WL predicted better OS [hazard ratio (HR) 0.75, 95% CI, 0.61–0.93, P=0.01] and better CSS (HR 0.71, 95% CI, 0.55–0.93, P=0.01). The associative factors for better and worse survival outcome are summarized in Table 2.

Table 2. UVA-MVA Cox regression analysis of survival outcome.

Variables OS CSS
UVA MVA UVA MVA
HR 95% CI P HR 95% CI P HR 95% CI P HR 95% CI P
Weight loss
   Low 1 Ref 1 Ref 1 Ref 1 Ref
   High 0.67 0.55–0.81 <0.001 0.75 0.61–0.93 0.01 0.62 0.49–0.78 <0.001 0.71 0.55–0.93 0.01
Pre-RT weight (kg)
   <80 1 Ref 1 Ref 1 Ref 1 Ref
   ≥80 0.6 0.49–0.74 <0.001 0.88 0.70–1.11 0.27 0.58 0.45–0.75 <0.001 1.01 0.75–1.34 0.97
Gender
   Male 1 Ref 1 Ref
   Female 1.07 0.86–1.35 0.53 1.09 0.83–1.43 0.52
Age
   <61 1 Ref 1 Ref 1 Ref 1 Ref
   ≥61 1.52 1.25–1.84 <0.001 1.45 1.17–1.80 <0.001 1.47 1.16–1.86 0.001 1.41 1.09–1.84 0.009
Smoker
   Never 1 Ref 1 Ref 1 Ref 1 Ref
   Former 1.49 1.14–1.95 0.004 1.16 0.88–1.54 0.30 1.45 1.05–2.00 0.02 1.07 0.76–1.50 0.70
   Current 2.12 1.59–2.83 <0.001 1.84 1.36–2.49 <0.001 2.07 1.47–2.92 <0.001 1.66 1.16–2.39 0.006
HPV
   Negative 1 Ref 1 Ref 1 Ref 1 Ref
   Positive 0.5 0.37–0.67 <0.001 0.85 0.62–1.17 0.32 0.52 0.37–0.74 <0.001 1.02 0.66–1.56 0.94
Comorb (No.)
   0 1 Ref 1 Ref
   1 0.84 0.62–1.14 0.25 0.84 0.59–1.19 0.33
   2 1.13 0.84–1.52 0.41 0.96 0.68–1.36 0.81
   3 1.31 0.98–1.75 0.07 1.03 0.73–1.46 0.85
T stage
   0–2 1 Ref 1 Ref 1 Ref 1 Ref
   3–4 2.1 1.71–2.58 <0.001 1.9 1.52–2.36 <0.001 2.52 1.96–3.26 <0.001 2.19 1.67–2.88 <0.001
   X 1.6 0.40–6.46 0.51 1.22 0.17–8.78 0.84
N stage
   0–1 1 Ref 1 Ref
   2–3 1 0.82–1.22 0.97 1.18 0.92–1.50 0.20
M stage
   0 1 Ref 1 Ref 1 Ref 1 Ref
   1 3.78 2.35–6.08 <0.001 1.7 0.99–2.91 0.052 3.94 2.29–6.76 <0.001 1.51 0.81–2.82 0.2
Primary site
   NA 1 Ref 1 Ref 1 Ref 1 Ref
   OC 0.97 0.71–1.33 0.86 1.05 0.73–1.51 0.8
   NP 0.85 0.44–1.64 0.63 1.05 0.52–2.11 0.9
   OP 0.45 0.34–0.60 <0.001 0.97 0.68–1.38 0.86 0.42 0.30–0.60 <0.001 1.03 0.67–1.59 0.88
   HP 1.09 0.72–1.65 0.68 1.05 0.64–1.74 0.83
   Glottis 0.69 0.49–0.98 0.04 0.83 0.57–1.21 0.33 0.63 0.41–0.97 0.04 0.86 0.54–1.38 0.53
   Salivary 0.61 0.36–1.03 0.07 0.81 0.46–1.44 0.48
   Other 0.48 0.20–1.19 0.11 0.56 0.20–1.53 0.26
   Unk 0.4 0.24–0.69 <0.001 0.93 0.51–1.69 0.81 0.33 0.16–0.66 0.002 0.95 0.43–2.08 0.89
   Mult 1.19 0.77–1.83 0.43 1.08 0.64–1.83 0.77
Histo
   SCC 1 Ref 1 Ref 1 Ref 1 Ref
   Others 1.4 1.05–1.86 0.02 0.73 0.49–1.10 0.14 1.53 1.10–2.13 0.01 0.74 0.45–1.21 0.23
RT total dose (Gy)
   <70 1 Ref 1 Ref 1 Ref 1 Ref
   ≥70 0.81 0.66–0.99 0.04 1 0.75–1.34 0.99 0.75 0.58–0.95 0.02 0.83 0.61–1.13 0.23
RT start year
   <2011 1 Ref 1 Ref
   ≥2011 0.82 0.67–1.01 0.06 0.86 0.68–1.09 0.22
RT compl
   No 1 Ref 1 Ref 1 Ref 1 Ref
   Yes 0.23 0.16–0.33 <0.001 0.59 0.39–0.89 0.01 0.2 0.13–0.30 <0.001 0.57 0.36–0.89 0.01
Resp
   None 1 Ref 1 Ref 1 Ref 1 Ref
   Partial 0.14 0.10–0.19 <0.001 0.12 0.08–0.18 <0.001 0.08 0.06–012 <0.001 0.07 0.05–0.11 <0.001
   Compl 0.67 0.46–0.98 0.04 0.59 0.40–0.88 0.01 0.58 0.39–0.86 0.006 0.5 0.33–0.77 0.001
Surgery
   No 1 Ref 1 Ref
   Yes 0.96 0.77–1.18 0.68 0.99 0.77–1.27 0.93
Chemo type
   None 1 Ref 1 Ref 1 Ref 1 Ref
   Cis q21d 0.6 0.46–0.78 <0.001 0.5 0.34–0.74 <0.001 0.52 0.38–0.72 <0.001 0.49 0.30–0.80 0.004
   Cis wkly 0.8 0.61–1.05 0.11 0.87 0.64–1.19 0.38
   Cetux wkly 1.78 1.17–2.73 0.007 0.85 0.51–1.39 0.51 1.66 1.00–2.77 0.05 0.82 0.45–1.48 0.51
   NA 2.52 1.17–5.40 0.02 0.74 0.32–1.72 0.49 2.77 1.21–6.36 0.02 0.75 0.30–1.89 0.54
   Carbo wkly 0.87 0.58–1.31 0.51 0.83 0.50–1.36 0.45
   Pt reg NOS 1.04 0.61–1.77 0.9 1.18 0.65–2.16 0.59
   CO to cetux 0.77 0.43–1.37 0.37 0.69 0.32–1.50 0.35
   CO to carbo 0.6 0.22–1.63 0.32 0.44 0.11–1.80 0.25
Nut support
   No 1 Ref 1 Ref 1 Ref 1 Ref
   Yes 1.3 1.06–1.58 0.01 1.34 1.06–1.70 0.02 1.33 1.05–1.69 0.02 1.39 1.04–1.85 0.03
Hosp
   No 1 Ref 1 Ref 1 Ref 1 Ref
   Yes 1.58 1.26–1.98 <0.001 1.61 1.26–2.06 <0.001 1.49 1.13–1.96 0.004 1.45 1.07–1.95 0.02
Hgb (g/dL)
   ≥12 1 Ref 1 Ref 1 Ref 1 Ref
   <12 2.4 1.90–3.03 <0.001 1.27 0.98–1.65 0.07 2.57 1.95–3.40 <0.001 1.2 0.87–1.65 0.27
WBC count
   Normal 1 Ref 1 Ref 1 Ref 1 Ref
   Low 2.4 1.31–4.39 0.005 2.03 1.09–3.78 0.02 2.77 1.42–5.43 0.003 2.34 1.17–4.67 0.02
   High 1.96 1.43–2.68 <0.001 1.19 0.85–1.68 0.31 2.28 1.59–3.27 <0.001 1.28 0.86–1.90 0.23
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UVA, univariate analysis; MVA, multivariate analysis; OS, overall survival; CSS, cancer-specific survival; HR, hazard ratio; CI, confidence interval; Ref, reference; RT, radiotherapy; HPV, human papilloma virus; Comorb, comorbidity; NA, not available; OC, oral cavity; NP, nasopharynx; OP, oropharynx; HP, hypopharynx; Unk, unknown; Mult, multiple; Histo, histology; SCC, squamous cell carcinoma; Compl, complete; Resp, response; Chemo, chemotherapy; Cis, cisplatin; Q21d, every 21 days; Wkly, weekly; cetux, cetuximab; Carbo, carboplatin; Pt, platinum; Reg, regimen; NOS, not otherwise specified; CO, crossover; Nut, nutrition; Hosp, hospitalized; Hgb, hemoglobin; WBC, white blood cell.

Prior to matching, median OS was 35.2 months (IQR 14.4–61.1) for patients with low WL and 40.6 months (IQR 23.8–76.5) for patients with high WL (P<0.001). OS at 5 years was 48.5% (95% CI, 43.5–54.0) and 60.6% (95% CI, 55.8–65.9) for patients with low and high WL, respectively (P<0.001). CSS at 5 years was 57.2% (95% CI, 52.0–62.9) and 70.2% (95% CI, 65.5–75.2) for patients with low and high WL, respectively (P<0.001).

A total of 258 pairs were matched, with all variables well-balanced (Table 3). After matching, median pre-RT weight was 76.8 kg (IQR 66.7–91.2) in patients with low WL and 82.8 kg (IQR 68.5–96.8) in patients with high WL (Table 3, P=0.054). Median overall follow-up was 54.8 months (IQR 35.8–90.4). Median OS was 36.7 months (IQR 14.6–61.7) and 39.2 months (IQR 21.4–75.7) for low WL and high WL cohorts, respectively (P=0.047). OS at 5 years was 48.8% (95% CI, 42.6–55.9) for patients with low WL and 54.9% (95% CI, 48.7–61.9) for patients with high WL (P=0.047, Figure 1). CSS at 5 years was 58.2% (95% CI, 51.8–65.4) for patients with low WL and 64.0% (95% CI, 57.8–71.0) for patients with high WL (P=0.036, Figure 2).

Table 3. Baseline characteristics of matched pairs.

Variables Low weight loss High weight loss P
N % N %
Gender 0.29
   Male 206 80 195 76
   Female 52 20 63 24
   Total 258 100 258 100
Age (years) 0.38
   <61 124 48 135 52
   ≥61 134 52 123 48
   Total 258 100 258 100
Pre-RT weight (kg) 0.05
   Median 76.8 82.8
   IQR 66.7–91.2 68.5–96.8
Smoker 0.29
   Never 50 19 65 25
   Former 139 54 129 50
   Current 69 27 64 25
   Total 258 100 258 100
HPV 0.70
   Negative 61 24 56 22
   Positive 69 27 77 30
   NA 128 50 125 48
   Total 258 100 258 100
Comorbidity (No.) 0.72
   0 45 17 40 16
   1 73 28 83 32
   2 67 26 60 23
   3 73 28 75 29
   Total 258 100 258 100
T stage 0.73
   X 1 0 3 1
   0–2 113 44 118 46
   3–4 134 52 129 50
   NA 10 4 8 3
   Total 258 100 258 100
N stage 0.78
   0–1 106 41 101 39
   2–3 142 55 149 58
   NA 10 4 8 3
   Total 258 100 258 100
M stage 0.47
   0 238 92 243 94
   1 10 4 5 2
   NA 10 4 10 4
   Total 258 100 258 100
Primary site 0.48
   NA 36 14 44 17
   Oral cavity 33 13 29 11
   Nasopharynx 10 4 6 2
   Oropharynx 75 29 95 37
   Hypopharynx 19 7 17 7
   Glottis 44 17 28 11
   Salivary 8 3 8 3
   Other 5 2 3 1
   Unknown 15 6 16 6
   Multiple 13 5 12 5
   Total 258 100 258 100
Histology 1
   Squamous 241 93 240 93
   Other 17 7 18 7
   Total 258 100 258 100
RT complete 0.23
   No 15 6 7 3
   Yes 233 90 239 93
   NA 10 4 12 5
   Total 258 100 258 100
Treatment response 0.13
   None 20 8 13 5
   Partial 175 68 198 77
   Complete 36 14 24 9
   NA 27 10 23 9
   Total 258 100 258 100
Surgery 0.76
   No 190 74 194 75
   Yes 68 26 64 25
   Total 258 100 258 100
Chemotherapy type 0.28
   None 51 20 40 16
   Cis q21d 86 33 101 39
   Cis wkly 62 24 64 25
   Cetux wkly 20 8 11 4
   NA 4 2 2 1
   Carbo wkly 20 8 15 6
   Pt regimen NOS 7 3 12 5
   Crossover to cetux 7 3 9 3
   Crossover to carbo 1 0 4 2
   Total 258 100 258 100
Nutrition support 0.59
   No 107 41 100 39
   Yes 151 59 158 61
   Total 258 100 258 100
Hospitalized 0.39
   No 208 81 199 77
   Yes 50 19 58 22
   NA 0 0 1 0
   Total 258 100 258 100
Hemoglobin (g/dL) 0.52
   <12 150 58 158 61
   ≥12 69 27 58 22
   NA 39 15 42 16
   Total 258 100 258 100
WBC count 0.81
   Normal 188 73 191 74
   Low 7 3 7 3
   High 24 9 18 7
   NA 39 15 42 16
   Total 258 100 258 100
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RT, radiotherapy; IQR, interquartile range; HPV, human papilloma virus; NA, not available; Cis, cisplatin; Q21d, every 21 days; Wkly, weekly; Cetux, cetuximab; Carbo, carboplatin; Pt, platinum; NOS, not otherwise specified; WBC, white blood cell.

Figure 1.

Figure 1

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Overall survival for patients with high or low weight loss (WL) after matching.

Figure 2.

Figure 2

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Cancer-specific survival for patients with high or low weight loss (WL) after matching.

Discussion

WL greater than 5–10% in HNC patients is considered one of the significant parameters of malnutrition, which impedes treatment tolerance, response, and completion and thereby compromises survival (5-7). This study is the first to report that high WL (≥5.8% of pre-treatment body weight) in HNC patients receiving RT with curative intent portends better OS and CSS. As previously reported, in our expanded cohort, unexpected hospitalization, nutrition support, older age, advanced tumor stage, and current smoking status continued to be associated with worse OS and CSS (17). We controlled for these and other variables (HPV status, comorbidities, treatments received, etc.) by performing propensity score matching in patients with low and high WL and created well-balanced matched-pairs (Table 3). Analysis of these matched pairs (Figures 1 and 2) showed better 5-year OS [54.9% vs. 48.8%, P=0.047] and CSS (64.0% vs. 58.2%, P=0.036) in the high WL cohort. Median OS was increased to 39.2 months for patients with high WL compared to 36.7 months for patients with low WL (P=0.047).

These findings of improved survival with high WL contrast with several existing reports in the literature. Cho et al. reported, among 226 oral squamous cell cancer patients treated with RT, high WL (>10%) had lower disease-free survival (52.5% vs. 77.1%, P<0.01) (18). Langius et al., in a cohort of 1,340 HNC patients adjusted for potential confounding variables (age, gender, primary tumor site, TNM stage, treatment modality, etc.), found 57% incidence of high WL (defined as >5% WL from start of RT until week 8 or >7.5% WL until week 12) which was significantly associated with worse disease-specific survival (HR 1.7; 95% CI, 1.2–2.4; P=0.004) (19).

Other studies have reported no association between WL during RT and survival. Ghadjar et al. prospectively randomized 224 HNC patients to either RT alone or concurrent chemoradiotherapy (CCRT) and compared patient weights 6 months before RT, at start of RT, and at end of RT (20). After close to 10 years of median follow-up, WL before RT was found to be associated with worse CSS and OS, but WL during RT did not show to influence survival outcomes (20). Pai et al. also reported lack of association between WL during RT and survival outcomes in 1,562 HNC patients; however, lower pre-RT body mass index (BMI) was associated with poorer CSS and OS (21).

Despite such varied findings, to identify patients for assessment of malnutrition, studies continue to investigate predictors of WL during RT (22-25). Zhao et al. performed a systematic review of 22 observational studies including 6,159 HNC patients undergoing RT and found advanced tumor stage, higher pre-RT BMI, and use of CCRT to be independent risk factors for WL (22). Lønbro et al. also found advanced tumor stage (III–IV, P=0.03) and higher pre-RT BMI (>25, P<0.001), as well as primary tumor site (pharyngeal, oral cavity, supraglottic tumors; P<0.001) to be predictors of WL (>5%) during RT (23). Mallick et al. retrospectively analyzed 103 HNC patients treated with RT and identified total planning target volume (PTV) >615 cc, prescription dose PTV >235 cc, and CCRT vs. RT alone as predictors of WL (>5%) during RT (24). Langius et al. more recently investigated a cohort of 910 HNC patients, about half of whom experienced WL (>5%), and identified RT on neck lymph nodes (P<0.001), higher RT dose (>65 Gy, P<0.001) on primary tumor, use of three-dimensional conformal RT vs. intensity-modulated RT (P=0.001), and younger age (per 10 years, P=0.01) to be predictors of WL (>5%) (25).

In our study, all patients were treated with intensity-modulated RT to the lymph nodes and had dose of >65 Gy to the primary; age was controlled by matching. We found that patients with higher baseline hemoglobin levels were more likely to experience high WL (OR 1.81; 95% CI, 1.33–2.47; P<0.001) while patients with no treatment response were less likely to have high WL (OR 0.18; 95% CI, 0.05–0.67; P=0.03).

Caveats

Although WL has shown to be more prevalent and significant during RT than before treatment (19,20), our study did not investigate pre-RT WL or pre-RT BMI, both of which have shown to be poor prognostic markers (5-8,19-21). Patients who had WL before RT may have lost comparatively less weight during RT; these patients may have contributed to the poorer prognosis of patients with low WL (<5.8%) based on significant pre-RT WL. In fact, patients with low WL had significantly lower pre-RT weight (75.7 kg, IQR 62.3–87.2) than patients with high WL (83.5, IQR 70.7–97.7) prior to matching (Table 1, P<0.001), raising the possibility that our low WL cohort might have had pre-RT WL that contributed to worse outcome. Although our matched pairs were well-balanced, the median pre-RT weight between the two WL cohorts showed a non-significant difference of 6 kg (Table 3, P=0.054). Nevertheless, pre-RT weight showed no association with OS (P=0.11) or CSS (P=0.51). On the other hand, patients with greater pre-RT BMI may have benefited from WL during RT due to reduced adiposity and inflammatory markers that aided treatment response and disease course (9,12,14); these patients may have contributed to the better prognosis of patients with high WL (≥5.8%).

Future directions

Preclinical studies show promising effects of calorie restriction in not only stunting the growth of tumors but also potentiating response of cancer cells to treatment including RT (9-14). The results of our study suggest that WL may not be directly proportional to the level of malnutrition; WL without causing malnutrition may produce some of the beneficial effects of calorie restriction. Thus, WL during RT may not be a reliable prognostic marker in HNC patients.

WL alone may not fully capture dynamic changes in the nutritional status of cancer patients, potentially resulting in heterogeneous findings of its association with survival outcomes in current literature. WL also may need to be interpreted individually in the context of one’s clinical and nutritional status.

A comprehensive, multidisciplinary method to evaluate malnutrition in HNC patients undergoing RT is needed. Though the efficacy of nutrition support in improving outcomes remains controversial (26-28), we fully support evaluation of all head and neck patients by a registered dietician (RD). Unfortunately, there are far too few RDs in the country to meet the need (29). Moreover, we do not endorse calorie restriction or any other intentional or otherwise sanctioned WL during RT except on clinical trial.

Conclusions

This study mitigates the concern for poor prognosis in HNC patients experiencing WL during RT. On matched-pair analysis, greater than or equal to the median WL (≥5.8%) predicted better 5-year OS and CSS. Further research on specifics of patient nutritional status and effects on survival is warranted.

Supplementary

The article’s supplementary files as

atm-09-10-914-rc.pdf (62.9KB, pdf)
DOI: 10.21037/atm-20-4969
atm-09-10-914-dss.pdf (51KB, pdf)
DOI: 10.21037/atm-20-4969
atm-09-10-914-coif.pdf (249.2KB, pdf)
DOI: 10.21037/atm-20-4969

Acknowledgments

We are grateful for the preclinical work of Elizabeth A. Repasky on the effect of physiologic stress on outcomes following radiation which inspired this analysis. The authors thank Adam Oberkircher PA and Kelsey Smith PA for their tireless efforts to provide excellent care of these patients.

Funding: This work was supported by the National Cancer Institute Cancer Center Support Grant (P30CA016056). Funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review board of Roswell Park Comprehensive Cancer Center (EDR-103707) and individual consent for this retrospective analysis was waived.

Footnotes

Provenance and Peer Review: This article was commissioned by the Guest Editor (Dr. Mukund Seshadri) for the series “Head and Neck Cancers – Disease Biology, Diagnostics, Prevention and Management” published in Annals of Translational Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4969

Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4969

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4969). The series “Head and Neck Cancers – Disease Biology, Diagnostics, Prevention and Management” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

The article’s supplementary files as

atm-09-10-914-rc.pdf (62.9KB, pdf)
DOI: 10.21037/atm-20-4969
atm-09-10-914-dss.pdf (51KB, pdf)
DOI: 10.21037/atm-20-4969
atm-09-10-914-coif.pdf (249.2KB, pdf)
DOI: 10.21037/atm-20-4969

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