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

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. 2021 Annals of Translational Medicine. All rights reserved.

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 . 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

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 (). 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 (, 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

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

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 (). 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 (, 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, ). 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, ).

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

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

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

Figure 2

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 (). Analysis of these matched pairs () 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 (, 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 (, 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.

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