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Predictors for Weight Loss in Head and Neck Cancer Patients Undergoing Radiotherapy

A Systematic Review

Zhao, Jin-Zhi MD; Zheng, Hong MD; Li, Li-Ya MD; Zhang, Li-Yuan MD; Zhao, Yue PhD; Jiang, Nan MD

doi: 10.1097/NCC.0000000000000231
ARTICLES: ONLINE ONLY
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Background: Head and neck cancer patients are at high risk of weight loss because of their disease process and the treatment of their disease. Recognition of predictors for weight loss may be able to give proactive or reactive nutritional treatment to patients at risk.

Objective: The aim of this study is to identify the independent risk factors for head and neck cancer patients developing 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.

Correspondence: Nan Jiang, MD, School of Nursing, Tianjin Medical University, Heping District 22, Tianjin 300070, China (beifang24@126.com).

Accepted for publication December 5, 2014.

Each 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.2,7–10 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.6,12–14 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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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, 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.

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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.

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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.

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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.18–20 Based on our criteria, studies could receive up to 9 assessment points. The score for 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).

Table 1

Table 1

Table 2

Table 2

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Evidence Synthesis

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.18–21 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 for analysis.2,4,6,11–14,23–37 The Figure shows a depiction of the review process.

Figure. F

Figure. F

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Study Characteristics

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,2,6,11–14,23–25,28,29,33,35–37 whereas 3 studies reported risk factors for weight loss in nasopharyngeal cancer,30–32 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%.

Table 3

Table 3

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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).

Table 4

Table 4

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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 (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 γ-glutamyl transpeptidase level at beginning of RT, and being female.

As presented in Table 5, 3 factors were identified as strong-evidence 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).

Table 5

Table 5

Table 6

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 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 therapy—surgery, radiation, and chemotherapy—consequently 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 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 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.43–45 Although the criteria of methodological quality assessment and evidence synthesis have been used in several systematic reviews recently, 43–45 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 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 QLQ-C30 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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Keywords:

Head and neck cancer; Predictor; Radiotherapy; Systematic review; Weight loss

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