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Jin-Zhi Zhao, MD Hong Zheng, MD Li-Ya Li, MD Li-Yuan Zhang, MD Yue Zhao, PhD Nan Jiang, MD
Predictors for Weight Loss in Head and Neck Cancer Patients Undergoing Radiotherapy A Systematic Review
K E Y
W O R D S
Background: Head and neck cancer patients are at high risk of weight loss
Head and neck cancer
because of their disease process and the treatment of their disease. Recognition of
Predictor
predictors for weight loss may be able to give proactive or reactive nutritional
Radiotherapy
treatment to patients at risk. Objective: The aim of this study is to identify the
Systematic review
independent risk factors for head and neck cancer patients developing weight loss
Weight loss
undergoing radiotherapy. Methods: A comprehensive literature search was performed on January 2014. Articles reporting studies of the predictors for weight loss in head and neck cancer patients undergoing radiotherapy were included. These studies were published between 1982 and 2014. Study quality was assessed using a modified quality assessment tool that was designed previously for an observational study. The effects of studies were combined with the study quality score using a best-evidence synthesis model. Results: Twenty-two observational studies involving 6159 patients were included. There was strong evidence for 3 predictors, including advanced tumor stage, a higher body mass index before treatment, and the use of concurrent chemoradiotherapy. We also identified 8 moderate evidence predictors and 30 limited evidence predictors. Conclusion: The scientific literature to date indicates that patients with advanced tumor stage, or a higher body mass index before treatment, or the use of concurrent chemotherapy are at high risk to have weight loss during radiotherapy. Implications for Practice: These data provide evidence to guide healthcare professionals in admitting patients who will have weight loss and choosing an optimal prophylactic strategy.
Author Affiliation: School of Nursing, Tianjin Medical University, China. The authors have no funding or conflicts of interest to disclose.
Predictors for Weight Loss
Correspondence: Nan Jiang, MD, School of Nursing, Tianjin Medical University, Heping District 22, Tianjin 300070, China ([email protected]). Accepted for publication December 5, 2014. DOI: 10.1097/NCC.0000000000000231
Cancer NursingTM, Vol. 38, No. 6, 2015
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ach year, there are approximately 560 000 new cases of head and neck cancer (HNC) in the world, making it the sixth most frequent cancer worldwide.1 Patients with HNC are at high risk of weight loss owing to their disease process and the treatment of their disease.2,3 Specifically, radiotherapy (RT) delivered to the head and neck region confers a predictable morbidity on the patient in terms of severe weight loss during treatment.4,5 Substantial weight loss could alter the anatomical contour of the neck and lead to dosimetric changes in the volumes treated with RT.6 Severe weight loss has been implicated as a cause of lower quality-of-life (QoL) scores, poorer treatment tolerance, delayed recovery, prolonged hospital stay, and unfavorable prognosis.2,7Y10 Recognition of predictors for weight loss may trigger giving proactively or reactively nutritional treatment to patients at risk. Therefore, it is important to identify the risk factors related to weight loss in HNC patients undergoing RT. Recently, an increasing number of studies have been conducted to identify the risk factors of weight loss in patients with HNC undergoing RT.2,7,11,12 However, the study results are often inconclusive or contradictory. A variety of risk factors for weight loss in HNC patients undergoing RT identified to date include tumor stage, body mass index (BMI), RT dose, dysphagia, fatigue, and anorexia.6,12Y14 However, the importance of these predictors is not completely clear, and it is likely that the strongest predictors for weight loss have not yet been identified. To the best of our knowledge, there has been no systematic evaluation of the risk factors used to predict weight loss. We performed this systematic review of the literature to identify the risk factors for weight loss in HNC patients undergoing RT and to grade the evidence according to the quality of the reviewed studies. This synthesis will provide an evidence base from which clinicians can assess the probability of weight loss for each HNC patient.
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and case-series studies were eligible for inclusion, and the predictors could be identified by multivariate analysis, univariate analysis, or discussion without statistical analysis. However, articles published in languages other than English were excluded. Other excluding criteria included editorials, reviews, and animal studies.
Study Selection Two reviewers independently analyzed each of the titles and abstracts based on the eligibility criteria. Articles that could not be excluded from our study based on the title and abstract were retrieved for independent full-text review by the same 2 reviewers. Any disagreements were resolved by consensus. In the case of discrepancies, the third reviewer was involved.
Data Abstraction The 2 independent reviewers extracted the data from the qualifying articles. A form for extracting data, which had been previously piloted, was used to record information about population, study design, sample size, study duration, follow-up period, and independent risk factors for weight loss. The corresponding author of each study was contacted to obtain any missing information that was required.
Quality Assessment The quality of the included studies was independently assessed by 2 authors. The methodological quality of studies was evaluated using a previously designed criteria list (Table 1), which was adapted from the Duckitt and Harrington review.17 These systems were designed for the methodological quality assessment of observational studies and have been used in previous observational systematic review articles.18Y20 Based on our criteria, studies could receive up to 9 assessment points. The score for
Table 1 & Criteria for Assessment of the
Materials and Methods
Search Strategy and Eligibility Criteria All methods used in this review followed the Center for Reviews and Dissemination, Preferred Reporting Items for Systematic Reviews and Meta-analyses,15 and Meta-analysis of Observational Studies in Epidemiology16 guidelines. The primary sources of the reviewed studies were PubMed, EMBASE, and the Cochrane Library. The search included literature published exclusively in English from 1982 and up to and including January 2014. Searches included the terms weight loss, head and neck cancer, radiotherapy, malnutrition, radiation, predict, factor, and determinants. The electronic search was reinforced with manual searches for reference lists of all retrieved articles. In addition, all relevant conference databases that provided grey literature were also searched. We included studies that (1) were observational in design, (2) consisted of a clearly defined group of patients with HNC who (3) underwent RT, and (4) reported data on the independent risk factors for weight loss. Cohorts, cross-sectional, case-control,
Methodological Quality of Observational Studies
Item
Criterion
Score
Study population Sample size Q50 and participation rate Q80% Patient selection For cohort studies: cases and controls draw from the same population; for case control studies: selected group was representative of the HNC population Study design Cohort design Retrospective case control design Reported the duration of follow-up Study withdrawal rate e20% Analysis and data Appropriate analysis techniques presentation were used Multivariate analysis performed Frequencies of most important outcomes were given
1 1
2 1 1 1 1 1 1
Abbreviation: HNC, head and neck cancer.
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Zhao et al
study design was 4 (eg, retrospective case control design) or 5 (eg, cohort design) and analysis and data presentation was 3 (Table 1). Studies were classified according to quality level on the basis of their methodological quality score (Table 2).
for analysis.2,4,6,11Y14,23Y37 The Figure shows a depiction of the review process.
Evidence Synthesis
Characteristics of the selected studies are presented in Table 3. The 22 studies included involved 6159 patients. The mean/ median age ranged from 46 to 66 years. Each study evaluated predictors for weight loss in patients with HNC undergoing RT and was published between 1982 and January 2014. Of the studies, 12 (54.5%) were cohort studies (2201 patients) and 10 (45.5%) were case-control studies (3958 patients). The sample size ranged from 31 patients25 to 2433 patients.32 There were 5 studies undertaken in Sweden, 4 in China, 3 each in Canada and the Netherlands, 2 each in the United States and India, and 1 each in Turkey, Korea, and the United Kingdom. Although 2 studies did not provide data on the sex of the patients, most of the reported patients were men. The percentage of men ranged from 53.4% to 90.2%. Eighteen studies provided data on the mean/median age of patients. Most studies did not differentiate sites of HNC,2,6,11Y14,23Y25,28,29,33,35Y37 whereas 3 studies reported risk factors for weight loss in nasopharyngeal cancer,30Y32 2 studies in oral or oropharyngeal cancer,26,34 and 2 studies in laryngeal cancer.4,27 The mean duration of follow-up ranged from 1 month6 to 85 months.32 Although 3 studies did not report mean weight loss, the average ranged from 1% to 11.7%.
Given the heterogeneity of the included studies and independent risk factors, we were unable to perform a meta-analysis directly. In addition to assessing the quality of the studies, we graded the body of evidence. Therefore, we summarized the results using the model of ‘‘best-evidence synthesis’’ (Table 2) by which the potential risk factors were classified. The risk factors of the reviewed studies with different methodological qualities were summarized according to the quantity and quality of relevant studies. This is a less common approach but is increasingly recognized as pertinent because it provides a conclusion that incorporates both the quality of studies and their outcomes.18Y21 Using the key elements for grading systems suggested by the US Agency for Healthcare Research and Quality,22 we rated the evidence by synthesis according to 5 levels: no, conflicting, limited, moderate, or strong evidence. ‘‘Strong evidence’’ means that further study is very unlikely to change our confidence in the estimate of effect. ‘‘Moderate evidence’’ means that further research is likely to have an impact on our confidence in the estimate of the effect and may change the results. ‘‘Low evidence’’ means that further research is very likely to change the results. ‘‘Conflicting evidence’’ means that any estimate of effect is very uncertain. ‘‘No evidence’’ means that no statistically analyzed or discussed factors are presented.
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Result
Identification of Relevant Studies From our research, we identified 390 potential citations after duplications were excluded. After screening their titles and abstracts, 90 publications were selected for further screening. After reading the full text of each publication, articles were excluded because of failure to meet inclusion (n = 55), not in English (n = 2), risk factors not related to weight loss (n = 5), not all participants had HNC (n = 4), did not report the relationship between energy intake and weight loss during treatment (n = 1), and sample size fewer than 10 (n = 1). Finally, we selected 22 studies
Study Characteristics
Quality of Included Studies According to the methodological quality criteria, 1 study (4.5%) scored 9 points, 10 studies (45.5%) scored 8 points, 7 studies (31.8%) scored 6 points, 2 studies (9.1%) scored 5 points, and 2 studies (9.1%) scored 4 points. According to the quality assessment criteria, 11 studies were classified as high quality (2912 patients), 7 as moderate quality (3070 patients), and 4 as low quality (227 patients) (Table 4).
Evidence Level for the Identified Predictors There were 41 potential risk factors identified by more than 1 of the studies that were included in the final evaluation. The predictors evaluated in the original studies included advanced tumor stage, a higher BMI before treatment, the use of concurrent chemoradiotherapy (CRT), a lower Karnofsky performance status
Table 2 & Criteria for Assessment of the Quality of the Included Studies and Best-Evidence Synthesis Item Level of studies
Level of evidence
Level
Criteria for Inclusion
High-quality studies Moderate-quality studies Low-quality studies Strong Moderate Limited Conflicting None
Multivariate analysis performed and had a quality score Q8 Multivariate analysis performed but had a quality score G8 No multivariate analysis performed and had a quality score Q6 No multivariate analysis performed and a quality score G6 Minimum of 3 high-quality studies with generally consistent findings Minimum of 2 moderate-quality studies with generally consistent findings Minimum of 1 low-quality study with generally consistent findings Converse findings in 925% of the studies No studies could be found
Predictors for Weight Loss
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Figure n Flow diagram of the selection process for relevant studies.
(KPS) baseline score, oropharyngeal tumor site, the presence of xerostomia, a higher European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) fatigue baseline level, the presence of dysphagia at baseline, oral cavity tumor site, severe oral mucositis, higher RT dose, the presence of posttreatment recurrence, a higher pain level, a lower score of global QoL, a higher score of insomnia, the presence of RT on the neck nodes, nonglottic tumor sites, hypopharynx tumor site, supraglottic laryngeal cancer tumor site, prescription large planning target volume greater than 235 cm3, total planning target volume greater than 615 cm3, conventional RT, a higher pre-RT body weight, the absence of tube feeding at the start of RT, accelerated RT, negative energy balance at end-RT, the rise of percentage creatine, rise in blood urea nitrogen value, a higher +-glutamyl transpeptidase level at beginning of RT, and being female. As presented in Table 5, 3 factors were identified as strongevidence risk factors. The identification of advanced tumor stage as a strong-evidence factor was supported by 5 high-quality studies and 1 moderate-quality study. The identification of a higher BMI before treatment as a strong risk factor was supported by 4 high-quality studies, 1 moderate-quality study, and 1 low-quality study. The identification of the use of CRT as a strong risk factor was supported by 3 high-quality studies and 4 moderate-quality studies. Eight moderate-evidence risk factors were identified, including a lower KPS baseline score, oropharyngeal tumor site, the presence of xerostomia, a higher EORTC QLQ-C30 fatigue baseline level, the presence of dysphagia at baseline, oral cavity
tumor site, severe oral mucositis, and higher RT dose. Thirty limited-evidence predictors were also identified (Table 6).
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Discussion
Weight loss is common among HNC patients before, during, and after cancer treatment. In a systematic review, weight loss was reported to range from 6% to 12% of body weight in HNC.38 Radiotherapy is an effective modality in the treatment of head and neck malignancies. However, involuntary weight loss commonly occurs in patients undergoing RT. Several studies have shown that weight loss is an important prognostic factor in the management of advanced HNC.39,40 Although a variety of studies have investigated the risk factors of weight loss in patients with HNC, findings related to risk factors are controversial. Therefore, it is important to identify the variables that increase the risk of weight loss so that strategies can be developed to minimize patient risk. Because of study heterogeneity, it was impossible to pool data between studies and conduct a meta-analysis to determine the estimates of the effects of each risk factor. However, the evidence synthesis method is also a useful method for arriving at clinical recommendations. In the present systematic review, we included only observational studies, which might result in an incomplete detection of a higher bias of risk. In addition, heterogeneity of the included studies was induced, to a certain degree, by study population, RT technique, nutritional supplementation, and follow-up
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Predictors for Weight Loss
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2014 2013
2013 2013 2013 2013 2013
2013 2012 2011
2011 2011
2010 2010 2005 2005 2005 2004
2003 2001 1999 1982
van den Berg et al36 Cho et al34
Kubrak et al11 Mallick et al6 Ottosson et al23 Unal et al13 Shen et al32
Silander et al37 Ehrsson et al24 Jager-Wittenaar et al26
Petersen et al33 Qiu et al31
Langius et al27 Nourissat et al12 Larsson et al35 Lin et al29 Petruson et al14 Ng et al30
Munshi et al2 Beaver et al28 Collins et al4 Johnston et al25
India United States United Kingdom Canada
the Netherlands Canada Sweden United States Sweden China
China China
Sweden Sweden the Netherlands
Canada India Sweden Turkey China
the Netherlands Korea
Country
Abbreviations: HNC, head and neck cancer; NR, not reported.
Year
Study
2002 1985Y1996 1993Y1995 NR
1997Y2007 1994Y2000 NR 1995Y2001 1996Y1997 1999Y2000
NR 2007Y2010
NR 2000Y2004 2004Y2006
2007Y2008 2011Y2012 1998Y2006 NR 2000Y2004
2003Y2007 2005Y2010
Study Duration
Table 3 & Characteristics of the Selected Studies
Prospective Retrospective Prospective Prospective Retrospective
Case-control Case-control Case-control Cohort
Case-control Cohort Cohort Case-control Cohort Cohort Retrospective Retrospective Retrospective Prospective
Retrospective Prospective Prospective Retrospective Prospective Prospective
Case-control Retrospective Cohort Prospective
Cohort Prospective Cohort Prospective Case-control Retrospective
Cohort Case-control Cohort Cohort Case-control
Case-control Retrospective Cohort Prospective
Design
Date Collection
140 249 61 31
238 535 50 96 49 38
490 159
134 178 116
38 103 712 51 2433
32 226
NR 57.6 NR 58
66 62.4 64.7 NR 60 46
NR 54
61 60.4 59.7
54.0 53.3 62.0 57.6 46
58 57
Sample Age, Mean/ Size Median, y
116/24 186/63 51/10 NR
207/31 422/113 34/16 75/21 39/10 30/8
NR 116/43
81/38 125/53 62/38
31/7 84/19 530/182 46/5 1851/582
23/9 165/61
M/F
HNC Oral or oropharyngeal cancer HNC HNC HNC HNC Nasopharyngeal cancer HNC HNC Oral or oropharyngeal cancer HNC Nasopharyngeal cancer Laryngeal cancer HNC HNC HNC HNC Nasopharyngeal cancer HNC HNC Laryngeal cancer HNC
Site of Cancer
1 NR 24 1
2 1.5 12 1.5 36 6
2 3
6 24 4
2.5 1 5 1.5 85
44 30
NR NR 6.4% 10%
5.0% 3.0% 10.1% 8.5% 2.7% 10.8%
7.3% 11.7%
2.9% 7.5% 3.4%
5.7% 3.8% 11.3% NR 5%
1% 9.4%
Mean Follow-up, Mean mo Weight Loss
Table 4 & Quality Assessment of the Selected Studies Study 36
van den Berg et al Cho et al34 Kubrak et al11 Mallick et al6 Ottosson et al23 Unal et al13 Shen et al32 Silander et al37 Ehrsson et al24 Jager-Wittenaar et al26 Petersen et al33 Qiu et al31 Langius et al27 Nourissat et al12 Larsson et al35 Lin et al29 Petruson et al14 Ng et al30 Munshi et al2 Beaver et al28 Collins et al4 Johnston et al25
Study Population
Patient Selection
Study Design
Analysis and Data Presentation
Total Score
Level of Studies
0 1 0 1 1 1 1 1 0 0 1 1 1 1 1 1 0 0 1 1 1 0
0 0 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 1 1 0 1
2 4 4 3 4 3 3 4 4 3 3 4 4 3 3 2 4 4 2 2 3 4
2 3 3 3 3 1 2 3 3 3 3 3 3 3 1 1 3 1 2 2 1 1
4 8 8 8 9 6 6 8 8 6 8 8 8 8 6 5 8 5 6 6 4 6
Low High High High High Moderate Moderate High High Moderate High High High High Moderate Low High Low Moderate Moderate Low Moderate
periods. Accordingly, although the results of this systematic review should be considered valid, these methodological quality considerations should be taken into account when interpreting the findings. By conducting this systematic review of the current evidence base of 22 reviewed studies, we have identified 3 strong-evidence independent risk factors, including advanced tumor stage, a higher BMI before treatment, and the use of CRT. Advanced tumor stage was found to be an independent risk factor for weight loss. The patients who had advanced stage cancer often undergo trimodality therapyVsurgery, radiation, and chemotherapyVconsequently
enhancing the incidence of toxicity effects such as mucositis, xerostomia, and dysphagia, which then, in turn, cause severe weight loss.31,32 Combined modality treatments and more treatment toxicities may be the main reasons for a higher weight loss in patients with higher stage disease. In this systematic review, the use of CRT was another important strong risk factor for weight loss.6,31,37 An argument has been made by Garden and colleagues that CRT is not the treatment of choice for all patients with stage III or IV HNC.41 Thus, the current recommendations for advanced stage patients are focused on selecting appropriate treatment modalities and the use of supportive and palliative
Table 5 & Strong and Moderate Evidence Risk Factor of Weight Loss
Category
Level of Evidence
Disease status
Strong evidence Moderate evidence
Metabolic indictors Strong evidence Treatment Strong evidence Moderate evidence QoL issues Moderate evidence Others
Moderate evidence
Predictors for Weight Loss
Patient Number in High-Quality Study
Advanced tumor stage 158812,24,31,33,34 Oropharyngeal tumor site 124712,23 Oral cavity tumor site 53512 Severe oral mucositis 3811 Presence of xerostomia 27611,27 Presence of dysphagia at baseline 53512 Higher BMI before treatment 149523,31,33.37 Use of CRT 3966,31,37 Higher RT dose 1912,13 Higher EORTC QLQ-C30 20814,31 fatigue baseline level Lower KPS baseline score 69412,31
Patient Number in Patient Number Moderate-Quality in Low-Quality Study Study 243332 3125 28025,28 5113 3125 24813,25,26,35 243332 28732,13,28,32
3236
1402
Abbreviations: BMI, body mass index; CRT, concurrent chemoradiotherapy; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire; KPS, Karnofsky performance status; RT, radiotherapy; QoL, quality of life.
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Table 6 & Limited Evidence Risk Factor of Weight Loss
Category
Patient Number in High-Quality Study
Predictors for Weight Loss
Disease status
Presence of posttreatment recurrence Presence of RT on the neck nodes Nonglottic tumor sites Hypopharynx tumor site Supraglottic laryngeal tumor site Nasopharynx tumor site Base of tongue tumor site Dysguesia Presence of mouth pain A higher pain level A higher ECOG score after RT Metabolic indictors Absence of tube feeding at the start of RT Absence of tube feeding before the onset of RT Severe pretreatment weight loss Insufficient protein intake of the last week before RT Lower prealbumin level before the beginning of RT Higher SGA score after RT Negative energy balance at end-RT Rise in percentage creatine Rise in blood urea nitrogen value Higher +-glutamyl transpeptidase level at beginning of RT Treatment Prescription PTV 9235 cm3 Total PTV 9615 cm3 Conventional RT Field size Q8 8 cm Accelerated RT QoL issues Lower score of global QoL Higher score of insomnia Others Women
Patient Number in Moderate-Quality Study
Patient Number in Low-Quality Study
22634 23827 49033 53512 53512 24928 24928 3125 3125 3811 5113 23
712
24928 24928 11626 5113 5113 3830 9629 9629 614 1036 1036 15931 3125 49033 15931 15931 3236
Abbreviations: ECOG, Eastern Cooperative Oncology Group; QoL, quality of life; PTV, large planning target volume; RT, radiotherapy; SGA, subjective global assessment.
care, including limiting the incidence and severity of toxicity effects, nutritional surveillance, and the use of feeding tubes. This study also showed that a higher BMI before treatment was a strong risk factor for weight loss in HNC patients undergoing RT. Patients with overweight or obesity according to the BMI classification demonstrated significantly greater weight loss than did patients with normal weight.23,31,33,37 One previous study had conflicting results when considering pretreatment BMI as a predictor for weight loss and use of nutritional support during RT.42 Tube feeding is often initiated for patients with a low BMI before treatment. The reason patients with a low BMI experienced less weight loss may be that these patients were more likely to receive tube feeding.23 Both healthcare professionals and patients need to reconsider their belief that patients with a higher BMI might be in better nutritional balance than patients with a lower BMI. We suggest that using nutritional supplementation for higher BMI patients undergoing RT is equally important to using it with lower BMI patients. We also identified 8 moderate-evidence predictors and 30 limited-evidence predictors. Although some of these potential risk factors (eg, multimodal therapy, QoL issues, and metabolic indictors) are not strong evidence factors, a better understanding
Predictors for Weight Loss
of these risk factors still contributes to identify patients at different degrees of risk for weight loss and helps to develop preventative measures. There are several limitations of this systematic review. Systematic reviews of observational studies are controversial in research.43Y45 Although the criteria of methodological quality assessment and evidence synthesis have been used in several systematic reviews recently, 43Y45 the choice of this method is still under dispute. Observational studies are sensitive to selection, detection, confounders, performance bias, and publication bias. Publication bias occurs when significant conclusions are published in the literature at a disproportionately high rate compared with insignificant findings. Moreover, most authors preferred significant results obtained by multivariate analysis. In addition, there can be potential bias resulting from patient selection, especially in the case of the 1-center studies. There was heterogeneity among the selected studies regarding site of the HNC, RT technique, nutritional supplementation, and follow-up periods. Different lengths for follow-up may result in inconsistencies in terms of the reported incidence of weight loss. Because a finite number of studies were included and several studies either did not differentiate between short- and long-term follow-up or Cancer NursingTM, Vol. 38, No. 6, 2015
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did not report the mean duration of follow-up, subgroup analysis could not be performed with regard to the follow-up periods. As the location of HNC was not differentiated in the analysis of the individual studies, stratification could not be performed in this study. The classification of the evidence was weakened by heterogeneity and the varying methodological quality of the included studies. Evidence synthesis might overestimate the predicted effects and should be interpreted in the context of the limitations described earlier. Although all of the results of this systematic review should be interpreted with the above limitations, the results may disclose a trend.
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Conclusion
This systematic review provided an overview of the current knowledge concerning the independent predictors of weight loss in patients with HNC undergoing RT. It included 22 studies involving 6159 patients. We have identified 3 strong-evidence predictors: advanced tumor stage, a higher BMI before treatment, and the use of CRT. We also identified 8 moderate-evidence predictors (including a lower KPS baseline score, oropharyngeal tumor site, the presence of xerostomia, a higher EORTC QLQC30 fatigue baseline level, the presence of dysphagia at baseline, oral cavity tumor site, severe oral mucositis, and higher RT dose) and 30 limited-evidence predictors. We believe the analysis of these data will provide evidence to guide healthcare professionals who treat weight loss in HNC patients undergoing RT. However, high-quality prospective studies are still required to clarify and evaluate the strength of these predictors. In addition, the effect of weight loss might be due to a complex interaction of multiple factors, so future studies should be performed to present whether multiple factors compounded the effect of weight loss.
References 1. International Agency for Research on Cancer. World Cancer Report 2008. Lyon, France: IARC; 2008. 2. Munshi A, Pandey MB, Durga T, et al. Weight loss during radiotherapy for head and neck malignancies: what factors impact it? Nutr Cancer. 2003; 47(2):136Y140. 3. Pressoir M, Desne´ S, Berchery D, et al. Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres. Br J Cancer. 2010;102(6):966Y971. 4. Collins MM, Wight RG, Partridge G. Nutritional consequences of radiotherapy in early laryngeal carcinoma. Ann R Coll Surg Engl. 1999;81(6): 376Y381. 5. Nayel H, el-Ghoreimy E, el-Haddad S. Impact of nutritional supplementation on treatment delay and morbidity in patients with head and neck tumors treated with irradiation. Nutrition. 1992;8(1):13Y18. 6. Mallick I, Gupta SK, Ray R, et al. Predictors of weight loss during conformal radiotherapy for head and neck cancersVhow important are planning target volumes? Clin Oncol (R Coll Radiol). 2013;25(9):557Y563. 7. Nourissat A, Vasson MP, Merrouche Y, et al. Relationship between nutritional status and quality of life in patients with cancer. Eur J Cancer. 2008;44(9):1238Y1242. 8. Caro MMM, Laviano A, Pichard C. Nutritional intervention and quality of life in adult oncology patients. Clin Nutr. 2007;26(3):289Y301. 9. van der Schueren M, van Leeuwen PAM, Kuik DJ, et al. The impact of nutritional status on the prognoses of patients with advanced head and neck cancer. Cancer. 1999;86(3):519Y527.
10. Ravasco P, Monteiro-Grillo I, Marques Vidal P, Camilo ME. Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy. Head Neck. 2005; 27(8):659Y668. 11. Kubrak C, Olson K, Jha N, et al. Clinical determinants of weight loss in patients receiving radiation and chemoirradiation for head and neck cancer: a prospective longitudinal view. Head Neck. 2013;35(5):695Y703. 12. Nourissat A, Bairati I, Samson E, et al. Predictors of weight loss during radiotherapy in patients with stage I or II head and neck cancer. Cancer. 2010;116(9):2275Y2283. 13. Unal D, Orhan O, Eroglu C, Kaplan B. Prealbumin is a more sensitive marker than albumin to assess the nutritional status in patients undergoing radiotherapy for head and neck cancer. Wspolczesna Onkol. 2013;17(3): 276Y280. 14. Petruson KM, Silander EM, Hammerlid EB. Quality of life as predictor of weight loss in patients with head and neck cancer. Head Neck. 2005; 27(4):302Y310. 15. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336Y341. 16. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of Observational Studies in Epidemiology: a proposal for reporting: Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15): 2008Y2012. 17. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005;330(7491):565. 18. Gomes B, Higginson IJ. Factors influencing death at home in terminally ill patients with cancer: systematic review. BMJ. 2006;332(7540):515Y521. 19. Zhou X, Xie H, Xie L, Li J, Fu W. Factors associated with lymph node metastasis in radically resected rectal carcinoids: a systematic review and meta analysis. J Gastrointest Surg. 2013;17(9):1689Y1697. 20. Xing D, Ma JX, Ma XL, et al. A methodological, systematic review of evidence-based independent risk factors for surgical site infections after spinal surgery. Eur Spine J. 2013;22(3):605Y615. 21. Lievense AM, Bierma-Zeinstra SM, Verhagen AP, et al. Influence of obesity on the development of osteoarthritis of the hip: a systematic review. Rheumatology (Oxford). 2002;41(10):1155Y1162. 22. West S, King V, Carey TS, et al. Systems to rate the strength of scientific evidence. Evid Rep Technol Assess (Summ). 2002;3(47):1Y11. 23. Ottosson S, Zackrisson B, Kjelle´n E, Nilsson P, Laurell G. Weight loss in patients with head and neck cancer during and after conventional and accelerated radiotherapy. Acta Oncol. 2013;52(4):711Y718. 24. Ehrsson YT, Langius-Eklo¨f A, Laurell G. Nutritional surveillance and weight loss in head and neck cancer patients. Support Care Cancer. 2012;20(4): 757Y765. 25. Johnston CA, Keane TJ, Prudo SM. Weight loss in patients receiving radical radiation therapy for head and neck cancer: a prospective study. JPEN J Parenter Enteral Nutr. 1982;6(5):399Y402. 26. Jager-Wittenaar H, Dijkstra PU, Vissink A, et al. Malnutrition in patients treated for oral or oropharyngeal cancerVprevalence and relationship with oral symptoms: an explorative study. Support Care Cancer. 2011;19(10): 1675Y1683. 27. Langius JA, Doornaert P, Spreeuwenberg MD, et al. Radiotherapy on the neck nodes predicts severe weight loss in patients with early stage laryngeal cancer. Radiother Oncol. 2010;97(1):80Y85. 28. Beaver ME, Matheny KE, Roberts DB, Myers JN. Predictors of weight loss during radiation therapy. Otolaryngol Head Neck Surg. 2001;125(6): 645Y648. 29. Lin A, Jabbari S, Worden FP, et al. Metabolic abnormalities associated with weight loss during chemoirradiation of head and neck cancer. Int J Radiat Oncol Biol Phys. 2005;63(5):1413Y1418. 30. Ng K, Leung SF, Johnson PJ, Woo J. Nutritional consequences of radiotherapy in nasopharynx cancer patients. Nutr Cancer. 2004;49(2):156Y161. 31. Qiu C, Yang N, Tian G, Liu H. Weight loss during radiotherapy for nasopharyngeal carcinoma: a prospective study from northern China. Nutr Cancer. 2011;63(6):873Y879. 32. Shen LJ, Chen C, Li BF, Gao J, Xia YF. High weight loss during radiation treatment changes the prognosis in under-/normal weight nasopharyngeal
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carcinoma patients for the worse: a retrospective analysis of 2433 cases. PloS One. 2013;8(7):e68660. Petersen GB, Andersen JR, Johansen J. Predictive factors of critical weight loss during radiotherapy of head and neck cancer. Eur J Cancer. 2011;S1: 548Y549. Cho YW, Roh JL, Jung JH, et al. Prediction of posttreatment significant body weight loss and its correlation with disease-free survival in patients with oral squamous cell carcinomas. Nutr Cancer. 2013;65(3):417Y423. Larsson M, Hedelin B, Johansson I, Athlin E. Eating problems and weight loss for patients with head and neck cancer: a chart review from diagnosis until one year after treatment. Cancer Nurs. 2005;28(6):425Y435. van den Berg MG, R[tten H, Rasmussen-Conrad EL, et al. Nutritional status, food intake, and dysphagia in long-term survivors with head and neck cancer treated with chemoradiotherapy: a cross-sectional study. Head Neck. 2014;36(1):60Y65. Silander E, Nyman J, Hammerlid E. An exploration of factors predicting malnutrition in patients with advanced head and neck cancer. Laryngoscope. 2013;123(10):2428Y2434. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol. 2003;66(3):253Y262. Pedruzzi PA, Kowalski LP, Nishimoto IN, Oliveira BV, Tironi F, Ramos GH.
Predictors for Weight Loss
40.
41.
42.
43.
44.
45.
Analysis of prognostic factors in patients with oropharyngeal squamous cell carcinoma treated with radiotherapy alone or in combination with systemic chemotherapy. Arch Otolaryngol Head Neck Surg. 2008;134(11):1196Y1204. Platek ME, Myrick E, McCloskey SA, et al. Pretreatment weight status and weight loss among head and neck cancer patients receiving definitive concurrent chemoradiation therapy: implications for nutrition integrated treatment pathways. Support Care Cancer. 2013;21(10):2825Y2833. Garden AS, Asper JA, Morrison WH, et al. Is concurrent chemoradiation the treatment of choice for all patients with stage III or IV head and neck carcinoma? Cancer. 2004;100(6):1171Y1178. Mangar S, Slevin N, Mais K, Sykes A. Evaluating predictive factors for determining enteral nutrition in patients receiving radical radiotherapy for head and neck cancer: a retrospective review. Radiother Oncol. 2006;78(2): 152Y158. Battle CE, Hutchings H, Evans PA. Risk factors that predict mortality in patients with blunt chest wall trauma: a systematic review and meta-analysis. Injury. 2012;43(1):8Y17. Urquhart DM, Hanna FS, Brennan SL, et al. Incidence and risk factors for deep surgical site infection after primary total hip arthroplasty: a systematic review. J Arthroplasty. 2010;25(8):1216Y1222. Ma X, Xing D, Ma J, et al. Risk factors for new vertebral compression fractures after percutaneous vertebroplasty: qualitative evidence synthesized from a systematic review. Spine. 2013;38(12):713Y722.
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Jin-Zhi Zhao, MD Hong Zheng, MD Li-Ya Li, MD Li-Yuan Zhang, MD Yue Zhao, PhD Nan Jiang, MD
Predictors for Weight Loss in Head and Neck Cancer Patients Undergoing Radiotherapy A Systematic Review
K E Y
W O R D S
Background: Head and neck cancer patients are at high risk of weight loss
Head and neck cancer
because of their disease process and the treatment of their disease. Recognition of
Predictor
predictors for weight loss may be able to give proactive or reactive nutritional
Radiotherapy
treatment to patients at risk. Objective: The aim of this study is to identify the
Systematic review
independent risk factors for head and neck cancer patients developing weight loss
Weight loss
undergoing radiotherapy. Methods: A comprehensive literature search was performed on January 2014. Articles reporting studies of the predictors for weight loss in head and neck cancer patients undergoing radiotherapy were included. These studies were published between 1982 and 2014. Study quality was assessed using a modified quality assessment tool that was designed previously for an observational study. The effects of studies were combined with the study quality score using a best-evidence synthesis model. Results: Twenty-two observational studies involving 6159 patients were included. There was strong evidence for 3 predictors, including advanced tumor stage, a higher body mass index before treatment, and the use of concurrent chemoradiotherapy. We also identified 8 moderate evidence predictors and 30 limited evidence predictors. Conclusion: The scientific literature to date indicates that patients with advanced tumor stage, or a higher body mass index before treatment, or the use of concurrent chemotherapy are at high risk to have weight loss during radiotherapy. Implications for Practice: These data provide evidence to guide healthcare professionals in admitting patients who will have weight loss and choosing an optimal prophylactic strategy.
Author Affiliation: School of Nursing, Tianjin Medical University, China. The authors have no funding or conflicts of interest to disclose.
Predictors for Weight Loss
Correspondence: Nan Jiang, MD, School of Nursing, Tianjin Medical University, Heping District 22, Tianjin 300070, China ([email protected]). Accepted for publication December 5, 2014. DOI: 10.1097/NCC.0000000000000231
Cancer NursingTM, Vol. 38, No. 6, 2015
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E
ach year, there are approximately 560 000 new cases of head and neck cancer (HNC) in the world, making it the sixth most frequent cancer worldwide.1 Patients with HNC are at high risk of weight loss owing to their disease process and the treatment of their disease.2,3 Specifically, radiotherapy (RT) delivered to the head and neck region confers a predictable morbidity on the patient in terms of severe weight loss during treatment.4,5 Substantial weight loss could alter the anatomical contour of the neck and lead to dosimetric changes in the volumes treated with RT.6 Severe weight loss has been implicated as a cause of lower quality-of-life (QoL) scores, poorer treatment tolerance, delayed recovery, prolonged hospital stay, and unfavorable prognosis.2,7Y10 Recognition of predictors for weight loss may trigger giving proactively or reactively nutritional treatment to patients at risk. Therefore, it is important to identify the risk factors related to weight loss in HNC patients undergoing RT. Recently, an increasing number of studies have been conducted to identify the risk factors of weight loss in patients with HNC undergoing RT.2,7,11,12 However, the study results are often inconclusive or contradictory. A variety of risk factors for weight loss in HNC patients undergoing RT identified to date include tumor stage, body mass index (BMI), RT dose, dysphagia, fatigue, and anorexia.6,12Y14 However, the importance of these predictors is not completely clear, and it is likely that the strongest predictors for weight loss have not yet been identified. To the best of our knowledge, there has been no systematic evaluation of the risk factors used to predict weight loss. We performed this systematic review of the literature to identify the risk factors for weight loss in HNC patients undergoing RT and to grade the evidence according to the quality of the reviewed studies. This synthesis will provide an evidence base from which clinicians can assess the probability of weight loss for each HNC patient.
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and case-series studies were eligible for inclusion, and the predictors could be identified by multivariate analysis, univariate analysis, or discussion without statistical analysis. However, articles published in languages other than English were excluded. Other excluding criteria included editorials, reviews, and animal studies.
Study Selection Two reviewers independently analyzed each of the titles and abstracts based on the eligibility criteria. Articles that could not be excluded from our study based on the title and abstract were retrieved for independent full-text review by the same 2 reviewers. Any disagreements were resolved by consensus. In the case of discrepancies, the third reviewer was involved.
Data Abstraction The 2 independent reviewers extracted the data from the qualifying articles. A form for extracting data, which had been previously piloted, was used to record information about population, study design, sample size, study duration, follow-up period, and independent risk factors for weight loss. The corresponding author of each study was contacted to obtain any missing information that was required.
Quality Assessment The quality of the included studies was independently assessed by 2 authors. The methodological quality of studies was evaluated using a previously designed criteria list (Table 1), which was adapted from the Duckitt and Harrington review.17 These systems were designed for the methodological quality assessment of observational studies and have been used in previous observational systematic review articles.18Y20 Based on our criteria, studies could receive up to 9 assessment points. The score for
Table 1 & Criteria for Assessment of the
Materials and Methods
Search Strategy and Eligibility Criteria All methods used in this review followed the Center for Reviews and Dissemination, Preferred Reporting Items for Systematic Reviews and Meta-analyses,15 and Meta-analysis of Observational Studies in Epidemiology16 guidelines. The primary sources of the reviewed studies were PubMed, EMBASE, and the Cochrane Library. The search included literature published exclusively in English from 1982 and up to and including January 2014. Searches included the terms weight loss, head and neck cancer, radiotherapy, malnutrition, radiation, predict, factor, and determinants. The electronic search was reinforced with manual searches for reference lists of all retrieved articles. In addition, all relevant conference databases that provided grey literature were also searched. We included studies that (1) were observational in design, (2) consisted of a clearly defined group of patients with HNC who (3) underwent RT, and (4) reported data on the independent risk factors for weight loss. Cohorts, cross-sectional, case-control,
Methodological Quality of Observational Studies
Item
Criterion
Score
Study population Sample size Q50 and participation rate Q80% Patient selection For cohort studies: cases and controls draw from the same population; for case control studies: selected group was representative of the HNC population Study design Cohort design Retrospective case control design Reported the duration of follow-up Study withdrawal rate e20% Analysis and data Appropriate analysis techniques presentation were used Multivariate analysis performed Frequencies of most important outcomes were given
1 1
2 1 1 1 1 1 1
Abbreviation: HNC, head and neck cancer.
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study design was 4 (eg, retrospective case control design) or 5 (eg, cohort design) and analysis and data presentation was 3 (Table 1). Studies were classified according to quality level on the basis of their methodological quality score (Table 2).
for analysis.2,4,6,11Y14,23Y37 The Figure shows a depiction of the review process.
Evidence Synthesis
Characteristics of the selected studies are presented in Table 3. The 22 studies included involved 6159 patients. The mean/ median age ranged from 46 to 66 years. Each study evaluated predictors for weight loss in patients with HNC undergoing RT and was published between 1982 and January 2014. Of the studies, 12 (54.5%) were cohort studies (2201 patients) and 10 (45.5%) were case-control studies (3958 patients). The sample size ranged from 31 patients25 to 2433 patients.32 There were 5 studies undertaken in Sweden, 4 in China, 3 each in Canada and the Netherlands, 2 each in the United States and India, and 1 each in Turkey, Korea, and the United Kingdom. Although 2 studies did not provide data on the sex of the patients, most of the reported patients were men. The percentage of men ranged from 53.4% to 90.2%. Eighteen studies provided data on the mean/median age of patients. Most studies did not differentiate sites of HNC,2,6,11Y14,23Y25,28,29,33,35Y37 whereas 3 studies reported risk factors for weight loss in nasopharyngeal cancer,30Y32 2 studies in oral or oropharyngeal cancer,26,34 and 2 studies in laryngeal cancer.4,27 The mean duration of follow-up ranged from 1 month6 to 85 months.32 Although 3 studies did not report mean weight loss, the average ranged from 1% to 11.7%.
Given the heterogeneity of the included studies and independent risk factors, we were unable to perform a meta-analysis directly. In addition to assessing the quality of the studies, we graded the body of evidence. Therefore, we summarized the results using the model of ‘‘best-evidence synthesis’’ (Table 2) by which the potential risk factors were classified. The risk factors of the reviewed studies with different methodological qualities were summarized according to the quantity and quality of relevant studies. This is a less common approach but is increasingly recognized as pertinent because it provides a conclusion that incorporates both the quality of studies and their outcomes.18Y21 Using the key elements for grading systems suggested by the US Agency for Healthcare Research and Quality,22 we rated the evidence by synthesis according to 5 levels: no, conflicting, limited, moderate, or strong evidence. ‘‘Strong evidence’’ means that further study is very unlikely to change our confidence in the estimate of effect. ‘‘Moderate evidence’’ means that further research is likely to have an impact on our confidence in the estimate of the effect and may change the results. ‘‘Low evidence’’ means that further research is very likely to change the results. ‘‘Conflicting evidence’’ means that any estimate of effect is very uncertain. ‘‘No evidence’’ means that no statistically analyzed or discussed factors are presented.
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Result
Identification of Relevant Studies From our research, we identified 390 potential citations after duplications were excluded. After screening their titles and abstracts, 90 publications were selected for further screening. After reading the full text of each publication, articles were excluded because of failure to meet inclusion (n = 55), not in English (n = 2), risk factors not related to weight loss (n = 5), not all participants had HNC (n = 4), did not report the relationship between energy intake and weight loss during treatment (n = 1), and sample size fewer than 10 (n = 1). Finally, we selected 22 studies
Study Characteristics
Quality of Included Studies According to the methodological quality criteria, 1 study (4.5%) scored 9 points, 10 studies (45.5%) scored 8 points, 7 studies (31.8%) scored 6 points, 2 studies (9.1%) scored 5 points, and 2 studies (9.1%) scored 4 points. According to the quality assessment criteria, 11 studies were classified as high quality (2912 patients), 7 as moderate quality (3070 patients), and 4 as low quality (227 patients) (Table 4).
Evidence Level for the Identified Predictors There were 41 potential risk factors identified by more than 1 of the studies that were included in the final evaluation. The predictors evaluated in the original studies included advanced tumor stage, a higher BMI before treatment, the use of concurrent chemoradiotherapy (CRT), a lower Karnofsky performance status
Table 2 & Criteria for Assessment of the Quality of the Included Studies and Best-Evidence Synthesis Item Level of studies
Level of evidence
Level
Criteria for Inclusion
High-quality studies Moderate-quality studies Low-quality studies Strong Moderate Limited Conflicting None
Multivariate analysis performed and had a quality score Q8 Multivariate analysis performed but had a quality score G8 No multivariate analysis performed and had a quality score Q6 No multivariate analysis performed and a quality score G6 Minimum of 3 high-quality studies with generally consistent findings Minimum of 2 moderate-quality studies with generally consistent findings Minimum of 1 low-quality study with generally consistent findings Converse findings in 925% of the studies No studies could be found
Predictors for Weight Loss
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Figure n Flow diagram of the selection process for relevant studies.
(KPS) baseline score, oropharyngeal tumor site, the presence of xerostomia, a higher European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) fatigue baseline level, the presence of dysphagia at baseline, oral cavity tumor site, severe oral mucositis, higher RT dose, the presence of posttreatment recurrence, a higher pain level, a lower score of global QoL, a higher score of insomnia, the presence of RT on the neck nodes, nonglottic tumor sites, hypopharynx tumor site, supraglottic laryngeal cancer tumor site, prescription large planning target volume greater than 235 cm3, total planning target volume greater than 615 cm3, conventional RT, a higher pre-RT body weight, the absence of tube feeding at the start of RT, accelerated RT, negative energy balance at end-RT, the rise of percentage creatine, rise in blood urea nitrogen value, a higher +-glutamyl transpeptidase level at beginning of RT, and being female. As presented in Table 5, 3 factors were identified as strongevidence risk factors. The identification of advanced tumor stage as a strong-evidence factor was supported by 5 high-quality studies and 1 moderate-quality study. The identification of a higher BMI before treatment as a strong risk factor was supported by 4 high-quality studies, 1 moderate-quality study, and 1 low-quality study. The identification of the use of CRT as a strong risk factor was supported by 3 high-quality studies and 4 moderate-quality studies. Eight moderate-evidence risk factors were identified, including a lower KPS baseline score, oropharyngeal tumor site, the presence of xerostomia, a higher EORTC QLQ-C30 fatigue baseline level, the presence of dysphagia at baseline, oral cavity
tumor site, severe oral mucositis, and higher RT dose. Thirty limited-evidence predictors were also identified (Table 6).
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Discussion
Weight loss is common among HNC patients before, during, and after cancer treatment. In a systematic review, weight loss was reported to range from 6% to 12% of body weight in HNC.38 Radiotherapy is an effective modality in the treatment of head and neck malignancies. However, involuntary weight loss commonly occurs in patients undergoing RT. Several studies have shown that weight loss is an important prognostic factor in the management of advanced HNC.39,40 Although a variety of studies have investigated the risk factors of weight loss in patients with HNC, findings related to risk factors are controversial. Therefore, it is important to identify the variables that increase the risk of weight loss so that strategies can be developed to minimize patient risk. Because of study heterogeneity, it was impossible to pool data between studies and conduct a meta-analysis to determine the estimates of the effects of each risk factor. However, the evidence synthesis method is also a useful method for arriving at clinical recommendations. In the present systematic review, we included only observational studies, which might result in an incomplete detection of a higher bias of risk. In addition, heterogeneity of the included studies was induced, to a certain degree, by study population, RT technique, nutritional supplementation, and follow-up
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Predictors for Weight Loss
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2014 2013
2013 2013 2013 2013 2013
2013 2012 2011
2011 2011
2010 2010 2005 2005 2005 2004
2003 2001 1999 1982
van den Berg et al36 Cho et al34
Kubrak et al11 Mallick et al6 Ottosson et al23 Unal et al13 Shen et al32
Silander et al37 Ehrsson et al24 Jager-Wittenaar et al26
Petersen et al33 Qiu et al31
Langius et al27 Nourissat et al12 Larsson et al35 Lin et al29 Petruson et al14 Ng et al30
Munshi et al2 Beaver et al28 Collins et al4 Johnston et al25
India United States United Kingdom Canada
the Netherlands Canada Sweden United States Sweden China
China China
Sweden Sweden the Netherlands
Canada India Sweden Turkey China
the Netherlands Korea
Country
Abbreviations: HNC, head and neck cancer; NR, not reported.
Year
Study
2002 1985Y1996 1993Y1995 NR
1997Y2007 1994Y2000 NR 1995Y2001 1996Y1997 1999Y2000
NR 2007Y2010
NR 2000Y2004 2004Y2006
2007Y2008 2011Y2012 1998Y2006 NR 2000Y2004
2003Y2007 2005Y2010
Study Duration
Table 3 & Characteristics of the Selected Studies
Prospective Retrospective Prospective Prospective Retrospective
Case-control Case-control Case-control Cohort
Case-control Cohort Cohort Case-control Cohort Cohort Retrospective Retrospective Retrospective Prospective
Retrospective Prospective Prospective Retrospective Prospective Prospective
Case-control Retrospective Cohort Prospective
Cohort Prospective Cohort Prospective Case-control Retrospective
Cohort Case-control Cohort Cohort Case-control
Case-control Retrospective Cohort Prospective
Design
Date Collection
140 249 61 31
238 535 50 96 49 38
490 159
134 178 116
38 103 712 51 2433
32 226
NR 57.6 NR 58
66 62.4 64.7 NR 60 46
NR 54
61 60.4 59.7
54.0 53.3 62.0 57.6 46
58 57
Sample Age, Mean/ Size Median, y
116/24 186/63 51/10 NR
207/31 422/113 34/16 75/21 39/10 30/8
NR 116/43
81/38 125/53 62/38
31/7 84/19 530/182 46/5 1851/582
23/9 165/61
M/F
HNC Oral or oropharyngeal cancer HNC HNC HNC HNC Nasopharyngeal cancer HNC HNC Oral or oropharyngeal cancer HNC Nasopharyngeal cancer Laryngeal cancer HNC HNC HNC HNC Nasopharyngeal cancer HNC HNC Laryngeal cancer HNC
Site of Cancer
1 NR 24 1
2 1.5 12 1.5 36 6
2 3
6 24 4
2.5 1 5 1.5 85
44 30
NR NR 6.4% 10%
5.0% 3.0% 10.1% 8.5% 2.7% 10.8%
7.3% 11.7%
2.9% 7.5% 3.4%
5.7% 3.8% 11.3% NR 5%
1% 9.4%
Mean Follow-up, Mean mo Weight Loss
Table 4 & Quality Assessment of the Selected Studies Study 36
van den Berg et al Cho et al34 Kubrak et al11 Mallick et al6 Ottosson et al23 Unal et al13 Shen et al32 Silander et al37 Ehrsson et al24 Jager-Wittenaar et al26 Petersen et al33 Qiu et al31 Langius et al27 Nourissat et al12 Larsson et al35 Lin et al29 Petruson et al14 Ng et al30 Munshi et al2 Beaver et al28 Collins et al4 Johnston et al25
Study Population
Patient Selection
Study Design
Analysis and Data Presentation
Total Score
Level of Studies
0 1 0 1 1 1 1 1 0 0 1 1 1 1 1 1 0 0 1 1 1 0
0 0 1 1 1 1 0 0 1 0 1 0 0 1 1 1 1 0 1 1 0 1
2 4 4 3 4 3 3 4 4 3 3 4 4 3 3 2 4 4 2 2 3 4
2 3 3 3 3 1 2 3 3 3 3 3 3 3 1 1 3 1 2 2 1 1
4 8 8 8 9 6 6 8 8 6 8 8 8 8 6 5 8 5 6 6 4 6
Low High High High High Moderate Moderate High High Moderate High High High High Moderate Low High Low Moderate Moderate Low Moderate
periods. Accordingly, although the results of this systematic review should be considered valid, these methodological quality considerations should be taken into account when interpreting the findings. By conducting this systematic review of the current evidence base of 22 reviewed studies, we have identified 3 strong-evidence independent risk factors, including advanced tumor stage, a higher BMI before treatment, and the use of CRT. Advanced tumor stage was found to be an independent risk factor for weight loss. The patients who had advanced stage cancer often undergo trimodality therapyVsurgery, radiation, and chemotherapyVconsequently
enhancing the incidence of toxicity effects such as mucositis, xerostomia, and dysphagia, which then, in turn, cause severe weight loss.31,32 Combined modality treatments and more treatment toxicities may be the main reasons for a higher weight loss in patients with higher stage disease. In this systematic review, the use of CRT was another important strong risk factor for weight loss.6,31,37 An argument has been made by Garden and colleagues that CRT is not the treatment of choice for all patients with stage III or IV HNC.41 Thus, the current recommendations for advanced stage patients are focused on selecting appropriate treatment modalities and the use of supportive and palliative
Table 5 & Strong and Moderate Evidence Risk Factor of Weight Loss
Category
Level of Evidence
Disease status
Strong evidence Moderate evidence
Metabolic indictors Strong evidence Treatment Strong evidence Moderate evidence QoL issues Moderate evidence Others
Moderate evidence
Predictors for Weight Loss
Patient Number in High-Quality Study
Advanced tumor stage 158812,24,31,33,34 Oropharyngeal tumor site 124712,23 Oral cavity tumor site 53512 Severe oral mucositis 3811 Presence of xerostomia 27611,27 Presence of dysphagia at baseline 53512 Higher BMI before treatment 149523,31,33.37 Use of CRT 3966,31,37 Higher RT dose 1912,13 Higher EORTC QLQ-C30 20814,31 fatigue baseline level Lower KPS baseline score 69412,31
Patient Number in Patient Number Moderate-Quality in Low-Quality Study Study 243332 3125 28025,28 5113 3125 24813,25,26,35 243332 28732,13,28,32
3236
1402
Abbreviations: BMI, body mass index; CRT, concurrent chemoradiotherapy; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire; KPS, Karnofsky performance status; RT, radiotherapy; QoL, quality of life.
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Table 6 & Limited Evidence Risk Factor of Weight Loss
Category
Patient Number in High-Quality Study
Predictors for Weight Loss
Disease status
Presence of posttreatment recurrence Presence of RT on the neck nodes Nonglottic tumor sites Hypopharynx tumor site Supraglottic laryngeal tumor site Nasopharynx tumor site Base of tongue tumor site Dysguesia Presence of mouth pain A higher pain level A higher ECOG score after RT Metabolic indictors Absence of tube feeding at the start of RT Absence of tube feeding before the onset of RT Severe pretreatment weight loss Insufficient protein intake of the last week before RT Lower prealbumin level before the beginning of RT Higher SGA score after RT Negative energy balance at end-RT Rise in percentage creatine Rise in blood urea nitrogen value Higher +-glutamyl transpeptidase level at beginning of RT Treatment Prescription PTV 9235 cm3 Total PTV 9615 cm3 Conventional RT Field size Q8 8 cm Accelerated RT QoL issues Lower score of global QoL Higher score of insomnia Others Women
Patient Number in Moderate-Quality Study
Patient Number in Low-Quality Study
22634 23827 49033 53512 53512 24928 24928 3125 3125 3811 5113 23
712
24928 24928 11626 5113 5113 3830 9629 9629 614 1036 1036 15931 3125 49033 15931 15931 3236
Abbreviations: ECOG, Eastern Cooperative Oncology Group; QoL, quality of life; PTV, large planning target volume; RT, radiotherapy; SGA, subjective global assessment.
care, including limiting the incidence and severity of toxicity effects, nutritional surveillance, and the use of feeding tubes. This study also showed that a higher BMI before treatment was a strong risk factor for weight loss in HNC patients undergoing RT. Patients with overweight or obesity according to the BMI classification demonstrated significantly greater weight loss than did patients with normal weight.23,31,33,37 One previous study had conflicting results when considering pretreatment BMI as a predictor for weight loss and use of nutritional support during RT.42 Tube feeding is often initiated for patients with a low BMI before treatment. The reason patients with a low BMI experienced less weight loss may be that these patients were more likely to receive tube feeding.23 Both healthcare professionals and patients need to reconsider their belief that patients with a higher BMI might be in better nutritional balance than patients with a lower BMI. We suggest that using nutritional supplementation for higher BMI patients undergoing RT is equally important to using it with lower BMI patients. We also identified 8 moderate-evidence predictors and 30 limited-evidence predictors. Although some of these potential risk factors (eg, multimodal therapy, QoL issues, and metabolic indictors) are not strong evidence factors, a better understanding
Predictors for Weight Loss
of these risk factors still contributes to identify patients at different degrees of risk for weight loss and helps to develop preventative measures. There are several limitations of this systematic review. Systematic reviews of observational studies are controversial in research.43Y45 Although the criteria of methodological quality assessment and evidence synthesis have been used in several systematic reviews recently, 43Y45 the choice of this method is still under dispute. Observational studies are sensitive to selection, detection, confounders, performance bias, and publication bias. Publication bias occurs when significant conclusions are published in the literature at a disproportionately high rate compared with insignificant findings. Moreover, most authors preferred significant results obtained by multivariate analysis. In addition, there can be potential bias resulting from patient selection, especially in the case of the 1-center studies. There was heterogeneity among the selected studies regarding site of the HNC, RT technique, nutritional supplementation, and follow-up periods. Different lengths for follow-up may result in inconsistencies in terms of the reported incidence of weight loss. Because a finite number of studies were included and several studies either did not differentiate between short- and long-term follow-up or Cancer NursingTM, Vol. 38, No. 6, 2015
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did not report the mean duration of follow-up, subgroup analysis could not be performed with regard to the follow-up periods. As the location of HNC was not differentiated in the analysis of the individual studies, stratification could not be performed in this study. The classification of the evidence was weakened by heterogeneity and the varying methodological quality of the included studies. Evidence synthesis might overestimate the predicted effects and should be interpreted in the context of the limitations described earlier. Although all of the results of this systematic review should be interpreted with the above limitations, the results may disclose a trend.
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Conclusion
This systematic review provided an overview of the current knowledge concerning the independent predictors of weight loss in patients with HNC undergoing RT. It included 22 studies involving 6159 patients. We have identified 3 strong-evidence predictors: advanced tumor stage, a higher BMI before treatment, and the use of CRT. We also identified 8 moderate-evidence predictors (including a lower KPS baseline score, oropharyngeal tumor site, the presence of xerostomia, a higher EORTC QLQC30 fatigue baseline level, the presence of dysphagia at baseline, oral cavity tumor site, severe oral mucositis, and higher RT dose) and 30 limited-evidence predictors. We believe the analysis of these data will provide evidence to guide healthcare professionals who treat weight loss in HNC patients undergoing RT. However, high-quality prospective studies are still required to clarify and evaluate the strength of these predictors. In addition, the effect of weight loss might be due to a complex interaction of multiple factors, so future studies should be performed to present whether multiple factors compounded the effect of weight loss.
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