Role of nutritional status in predicting quality of life outcomes in cancer – a systematic review of the epidemiological literature

Malnutrition is a significant factor in predicting cancer patients’ quality of life (QoL). We systematically reviewed the literature on the role of nutritional status in predicting QoL in cancer. We searched MEDLINE database using the terms “nutritional status” in combination with “quality of life” together with “cancer”. Human studies published in English, having nutritional status as one of the predictor variables, and QoL as one of the outcome measures were included. Of the 26 included studies, 6 investigated head and neck cancer, 8 gastrointestinal, 1 lung, 1 gynecologic and 10 heterogeneous cancers. 24 studies concluded that better nutritional status was associated with better QoL, 1 study showed that better nutritional status was associated with better QoL only in high-risk patients, while 1 study concluded that there was no association between nutritional status and QoL. Nutritional status is a strong predictor of QoL in cancer patients. We recommend that more providers implement the American Society of Parenteral and Enteral Nutrition (ASPEN) guidelines for oncology patients, which includes nutritional screening, nutritional assessment and intervention as appropriate. Correcting malnutrition may improve QoL in cancer patients, an important outcome of interest to cancer patients, their caregivers, and families.


Introduction
Disease-related malnutrition occurs frequently in patients with cancer and is a major cause of morbidity and mortality. [1] The incidence of malnutrition in cancer patients ranges between 40 and 80% [2] while the prevalence ranges from 50% to 80% [3] depending on tumor type, tumor location, stage of disease, treatment received and the type of nutritional assessment method used. [4] Decreased dietary intake, cancer cachexia (characterized mainly by weight loss and muscle wasting), and nutrition impact symptoms may all contribute to cancer-related malnutrition. [3] Additionally, the treatment modalities involving combinations of chemotherapeutic, radiotherapeutic and surgical regimens are known to produce various acute and chronic symptoms that limit eating and, thereby, exert a profound impact on nutritional status. [1,5] As a result, it is important to assess every cancer patient's nutritional status using one or more methodologies that are developed for this purpose. Anthropometric measurements [such as weight change, arm muscle circumference (AMC), triceps skin-fold thickness (TSF)] and biochemical parameters (such as serum albumin) [6] are often used. Other instruments, such as Subjective Global Assessment (SGA) [7] and Patient-Generated Subjective Global Assessment (PG-SGA), which has been adapted from the SGA and designed specifically for patients with cancer [3,8] are also used. Still other tools have been recommended by the European Society for Clinical Nutrition and Metabolism, including Nutritional Risk Screening (NRS-2002), which has demonstrated high sensitivity and specificity at hospital admission; the Malnutrition Universal Screening Tool (MUST), which was devised for people who live in a community setting and relates their nutrition to their functions; and the Mini Nutritional Assessment (MNA), which was designed specifically for elderly people. [9] Tools such as phase angle determined by Bioelectric Impedance Analysis (BIA) and hand grip strength measured by dynamometry are also used as markers of nutritional status. [10] The utility of these nutritional screening tools has been evaluated by their ability to predict relevant clinical outcomes such as complications, treatment response, survival and quality of life (QoL).
Quality of life for cancer patients is a subjective multidimensional construct that represents the patient's functional status, psychosocial well-being, health perceptions and disease/treatment-related symptoms. [7] In all, QoL reflects health status in cancer patients, which, in turn, is largely influenced by nutritional factors. [9] Cancer and treatment-induced changes in metabolism can lead to alterations in physiological and psychological functions, which, in turn, can reduce a patient's QoL by negatively influencing nutritional status. [11] Measuring a patient's QoL is contingent upon clinical goals and may require a variety of different instruments. Among them are the European Organization for Research and Treatment of Cancer quality-of-life core questionnaires (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy-General (FACT-G), Functional Living Index cancer questionnaire (FLIC), Spitzer Quality of Life Index (QLI), Rotterdam Symptom Check List (RSCL), the Medical Outcome Study 36-item short form (MOS SF-36), EuroQol (EQ-5D) [9], the Cancer Rehabilitation Evaluation System (CARES) [12] and the Symptom Distress Scale. [13] Researchers have studied the correlation between nutritional status and QoL for some time and there are a number of articles in the literature that provide data on this association in cancer patients. Because these studies differ from each other with respect to patient population, study design, sample size and type of nutritional and QoL assessment used, it can be difficult to interpret and synthesize common findings. Our goal was to systematically review the available literature, summarize the vast amount of information on the topic of nutrition and QoL in cancer patients, and provide direction for future research.

Data sources
We attempted to plan, conduct, and report this metaanalysis in accordance with the PRISMA statement. [14,15] MEDLINE database was used to identify all articles investigating the relationship between nutritional status and QoL in cancer published between January 01, 1990 and June 30, 2011. We also searched the bibliographies of selected papers to identify relevant articles we might have missed during the primary MEDLINE search.

Study eligibility criteria
To be included in this review, an article must have: been published in English, reported on data collected in humans with cancer, had malnutrition/nutritional status/ assessment/screening as one of the predictor variables, had QoL as one of the outcome measures (primary or secondary), and had any of the following study designs (case-control, cohort, cross-sectional, prospective, retrospective, case series, longitudinal, clinical trial, meta-analysis). There were no restrictions based on age, ethnicity, type or stage of cancer.

Search
We searched the MEDLINE database using the terms "nutritional status" or "nutritional assessment" or "nutritional screening" or "malnutrition" in combination with the following terms: "quality of life", and "health-related quality of life" together with "cancer" or "oncology".

Study selection
Study selection was based on an initial screen of identified abstracts or titles and a second screen of full-text articles. Articles to be included in this review were screened for eligibility by two reviewers working independently. Disagreements between reviewers were resolved by consensus.

Data collection process
One review author extracted the required data elements from included articles and the second author verified the extracted data. Disagreements were resolved by discussion between the two review authors. Tables 1, 2, 3, 4, 5 reflect the template for data collection.

Data items
Instead of providing aggregate quality scores, we assessed the quality of individual studies by reporting the key components of study designs. The following information was extracted for each article: first author, year of publication, study place, data collection period, study design, sample size, nutritional assessment method, QoL assessment method, nutritional groups being compared, key results and conclusions.

Synthesis of results
The authors summarized all studies reviewed in this paper in separate tables based on the cancer type. Within each table, studies are arranged chronologically by the year of publication, beginning with the most recently published study.

Study selection
The MEDLINE search identified a total of 676 articles based on different combinations of search terms described above. The authors reviewed the titles and abstracts of these 676 articles to identify the relevant    Patients with a BMI decrease of at least 20 per cent experienced more appetite loss (mean score difference 26; P = 0Á002), eating difficulties (mean score difference 18; P < 0Á002) and odynophagia (mean score difference 12; P = 0Á044) than patients without postoperative weight loss, whereas scores for dysphagia and gastro-oesophageal reflux were similar between these groups.
Malnutrition is a considerable problem after oesophagectomy, and is linked to appetite loss, eating difficulties and odynophagia. Gupta    Weight loss** defined as loss of more than 5% pre-illness weight in the previous 6 months
Of the 676 original articles, the authors excluded 641 from this review because it was clear from the abstracts that these papers did not meet the selection criteria. The authors then obtained the full texts of the remaining 35 articles for review. Thirteen of the 35 articles failed to meet the selection criteria and were excluded. The authors then identified 4 additional articles from the bibliographies of the selected 35 articles. Twenty-six articles were then included in the final review for this manuscript. Figure 1 is a flow chart that describes this process and its results.

Characteristics of included studies
All 26 articles included in this review were published in English. The authors extracted the following data from each included study: first author, year of publication, study place, data collection period, study design, sample size, nutritional assessment method, QoL assessment method, nutritional groups being compared, key results and conclusions.

Synthesis of results
Nutritional status and QoL in head and neck cancer Table 1 describes studies exploring the relationship between nutritional status and QoL in patients with head and neck cancer. Of the six studies, one was a retrospective consecutive case series [17], one was cross-sectional [16] and four were prospective. [8,12,18,19] The sample size in these studies ranged from 36 [17] to a maximum of 115 [16] patients. The study populations included locally advanced head and neck cancers, cancers of the oropharynx, oral cavity/nasopharynx, larynx, maxillary sinuses/submandibular glands/pharyngeal and hyopharyngeal regions. Weight loss was the most commonly used nutritional assessment method, which was measured exclusively [18,19] or in combination with PG-SGA [8] or together with anthropometric measurements [AMC and TSF], weight index (WI), body mass index (BMI) and serum albumin (S-alb) level. [12] One of the studies assessed nutritional status in terms of the drop in BMI over a period of 12 months. [17] The studies also employed various tools for assessment of QoL, which included the EORTC-QLQ-C30, either singly [8] or together with a head and neck specific module EORTC-QLQ-H&N35either alone [18] or in combination with Hospital Anxiety and Depression Scale (HADS). [19] One of the studies used the EORTC-QLQ-C30 together with a head and neck module developed in Norway [12] while another used the University of Washington Head and Neck Disease-Specific Measure (UW-QOL). [17] Weight loss was the principal criterion used to categorize the study population into comparison groups. Two studies categorized the patients based on their weight loss percentage (≥ 10% and < 10%) [18,19] while another study categorized its sample population based on unintentional weight loss of < 5% (non-malnourished) and ≥ 5% (malnourished) respectively. [8] Still another study used the change in BMI as a continuous variable [17], and another grouped its study population based on malnourished vs. normal nutrition, weight loss vs. no weight loss and negative vs. positive energy balance. [12] All six studies concluded that better nutritional status was positively associated with better QoL in the study patients. Interestingly, 3 studies [12,17,18] found an association between weight loss & swallowing function. Swallowing difficulty can cause weight loss, and as people lose weight, swallowing function can be further compromised due to muscle function loss and contribute to decline in QoL.        cross-sectional [20,21] and three were prospective [22,23,27]. The sample size ranged from 48 [22] to 1,555 [26] patients. The population under study had been diagnosed with cancer of the gastric/gastrointestinal region, esophagus or cardia, colorectal region or pancreas. The most commonly used nutritional assessment methods were the percentage of weight loss, either alone [26,27,34] or in combination with PG-SGA, phase angle measured in terms of BIA or Fat Free Mass Index (FFMI) and hand-grip dynamometry. [22] One study assessed nutritional status in terms of postoperative weight loss measured by the difference in BMI. [23] Another study used several different assessment measures including serum albumin, prealbumin, serum transferrin, phase angle by BIA and SGA. [24] The studies also employed various tools to assess the patients' QoL. The most commonly used was the EORTC-QLQ-C30, either exclusively [22,24,26,34] or together with other tools like EuroQol EQ-5D [27] or together with an esophageal cancer specific module EORTC OES-18. [23] Weight loss was the primary criterion for segregation of the study population into groups for comparison. The studies used a variety of criteria to divide the patients into groups, including wellnourished vs. malnourished individuals [24], weight-stable vs. weight-losing patients [27], and patients with and without weight loss. [26] One study compared patient groups based on a BMI decline of ≥ 20% and < 20%. [23] Another study segregated its population based on several parameters that included > 10% weight loss in the previous six months or > 5% weight loss in the last month and < 10% weight loss in the previous six months or < 5% weight loss in the last month, or as well-nourished, moderately malnourished and severely malnourished (in terms of PG-SGA scores), or grip strength below 85% & above 85% (based on gand-grip dynamometry). [22] All 8 studies concluded that better nutritional status was positively associated with better QoL in the study patients. Table 3 describes the lone prospective study that assessed the association between nutritional status and QoL in 106 stage III and IV patients who had been diagnosed with inoperable non-small cell lung cancer (NSCLC). The patients' nutritional status was assessed in terms of weight loss while QoL was assessed using EORTC-QLQ-C30. The sample population was subdivided into two groups: weight-stable and weight-losing based on whether they had lost < 5% or > 5% weight. The weight-stable patients reported better global QoL and less fatigue and pain than the weight-losing group. [28] Nutritional status and QoL in gynecological cancer Table 4 describes the lone prospective study that assessed the association between nutritional status and QoL in 157 gynecological cancer patients who required surgery for a pelvic mass or who had a positive endometrial biopsy. Nutritional status was assessed in terms of BMI (used as a continuous variable) while QoL was assessed using the SF-36 and FACT-G questionnaires. More than 70% of the patients were either overweight or obese. The study showed that higher BMI was negatively correlated with QoL upon both univariate and multivariate analyses. [29] Nutritional status and QoL in heterogeneous cancer patient populations Table 5 describes the relationship between nutritional status and QoL in heterogeneous cancer patient populations. Of a total of 10 studies listed in this table, one was a transverse observational longitudinal study [31], three were prospective longitudinal [2,3,7], one was descriptive cross-sectional [6] and two were prospective cross-sectional. [30,32] The remaining three studies were prospective. [5,10,33] The sample size ranged from 50 [6] to 883 patients. [31] The population studied included patients with solid or hematologic tumor disease; evolving cancer at different management stages; non-terminal cancer patients; ambulatory patients with head and neck, esophageal, stomach and colorectal cancer; ambulatory patients who were receiving radiation therapy to the head, neck, rectal or abdominal area; patients with tumors of the head and neck, gastrointestinal tract (high-risk: HR), prostate, breast, lung, brain, gallbladder or uterus (low-risk: LR); or biopsy-proven breast, ovarian, or small cell lung cancer. The patients' nutritional status was most commonly assessed with the SGA, either singly [7] or in combination with phase angle determined by BIA [10] or in the form of PG-SGA scores. [2,3,5] Three studies used weight loss as the nutritional assessment tool [31][32][33] while another study assessed nutritional status using multiple parameters, including BMI, percentage of usual weight, ideal weight percentage of ideal weight, percentage of weight loss, triceps skinfold thickness, mid-upper arm circumference, serum albumin, prealbumin, total proteins and total cholesterol. [6] The principal tool used for the measurement of QoL was EORTC-QLQ-C30, either alone [2,5,6,31,32] or in combination with EuroQoL. [7] The remaining three studies used different QoL tools, including the Life Satisfaction Scale [3], Hospice Quality of Life Index (HQLI) [5], and the General Health Questionnaire (GHQ) together with the Quality of Life Index (QL). [33] Two studies classified their sample population into three distinct categories: well nourished, moderately malnourished and severely malnourished on the basis of SGA/PG-SGA scores. [5,7] One study used PG-SGA scores as a continuous variable [3] while another study treated PG-SGA scores as a continuous variable despite having categorized its patients as being well nourished and malnourished. [2] Three studies divided their sample into two categories each based on percentage of weight loss using the cut-off criteria of 10% (i.e. < 10% & > 10% weight loss) [10,32] and 5% [i.e. ≥ 5% (weight-losing or -weight loss) and < 5% (weightstable or + weight loss)] [33] respectively. Another study grouped its sample population based on the quantity of protein intake (< 0.9 g/kg/d & ≥ 0.9 g/kg/d). [6] One study used two criteria to categorize its sample population: SGA levels and BIA. The three groups included well nourished, moderately malnourished and severely malnourished based on SGA. Patients were also categorized in two groups: below and above the fifth percentile of the phase angle as measured by BIA. [10] Of the 10 studies, one showed that nutritional status was significantly associated with QoL only for high-risk patients. This was true when both EuroQoL and EORTC-QLQ-C30 were used as tools for measurement of QoL. [7] Another study concluded that nutritional status was not significantly associated with QoL. [6] The remaining 8 studies showed a positive correlation between nutritional status and QoL [2,3,5,10,[31][32][33][34].

Conclusion
Patient QoL is an extremely important outcome measure for cancer patients. How patients feel, physically and emotionally, while they are fighting cancer can have an enormous effect on their ability to carry out normal daily functions as well as on their interpersonal relationships and their ability to work. Cancer and its treatment affects the nutritional status of patients by altering their metabolic function and reducing their food intake. [5,6] Research has proven that malnutrition is a predictor of morbidity in advanced cancer; therefore, malnutrition is also likely to assume a significant role in patients' QoL. [24] The present study aimed to systematically review the relationship between nutritional status and QoL in cancer patients. A total of 26 original studies were included in this review. Of the 26 studies, 6 investigated the correlation in head and neck cancer patients, 8 in gastrointestinal cancer patients, 1 in lung cancer patients, 1 in gynecologic cancer patients and 10 in heterogeneous cancer populations.
Better nutritional status was associated with better QoL in all 6 studies of head and neck cancer patients with each study identifying different reasons for the correlation. One study reported that weight loss in some patients was related to loss of speech and swallowing capabilities, which may have affected patients' ability to take food by mouth. [17] Another study concluded that weight loss of more than 10% had significant impact on QoL scores at time of diagnosis and that it seemed to significantly worsen global QoL, fatigue and pain. The same study advised that patient weight loss should be limited as much as possible starting at diagnosis and continuing until six months after treatment. [18] Another study showed that patients in the ≥10% weight-loss group reported extreme problems (>80 points) with dry mouth and sticky saliva at 3 months, 1 year and 3 years after diagnosis. This effect was attributed, on the basis of previous studies, to the fact that this patient population was comprised of more people who lived alone, more smokers/ex-smokers, a higher percentage of patients with stage III to IV disease (95% vs 50%), a higher percentage of patients with pharyngeal cancer, and more patients who received chemotherapy. [19] In summary, these 8 studies indicate that poor nutritional status, measured primarily using weight loss, was a strong predictor of patient QoL, measured primarily through EORTC QLQ-C30, in head and neck cancer patients.
All 8 studies that explored the association between nutritional status and QoL in gastrointestinal cancer patients concluded that better nutritional status was associated with better QoL. One study theorized that an inflammatory response may contribute to weight loss in advanced gastrointestinal cancer patients by increasing energy expenditure and the turnover of specific amino acids, which reprioritizes the body's protein metabolism away from peripheral tissues and toward the liver. This process appears to contribute to the preferential loss of protein (in particular, skeletal muscle) in such patients. This in turn may be a cause of appetite loss and lowered QoL in gastrointestinal cancer patients. [27] The lone study that reported a significant relationship between nutritional status and QoL in lung cancer patients speculated that the relationship between pain and more than 5% prior weight loss may simply be a result of more advanced disease, as there were a greater number of weight loss patients in this group who had been diagnosed with stage IV disease. [28] The lone study that explored the association between nutritional status and QoL in gynecological cancer patients indicated that nutritional status (in terms of BMI) was significantly associated with QoL. [29] More than 70% of the patients were either overweight or obese suggesting that obesity is another form of malnutrition that is often overlooked in clinical settings, and can have a negative impact on patient QoL.
Of the 10 studies that investigated the relationship between nutritional status and QoL in a heterogeneous cancer population, eight concluded that nutritional status was significantly associated with QoL, one found nutritional status to be significantly associated with QoL only for high-risk patients [7], and one found no association between the two. [6] Of the eight studies reporting significant association, one reported that although an association between malnutrition and impaired QoL was observed in all sub-groups of patients, it was not possible to identify which was the cause and which was the consequence: weight loss or QoL. The authors attributed this issue to the study design (transversal study). [31] Another study also inferred that it was not possible to conclude which came firstinsufficient food intake, decreased QoL or weight lossalthough the authors did establish that the three variables were interdependent. [33].
Overall, among the 26 studies reviewed in this article, 24 concluded that better nutritional status was associated with better QoL, one study showed that better nutritional status was associated with better QoL only in high-risk patients, and one concluded that there was no association between nutritional status and QoL.
The majority of the studies reviewed in this article used weight loss (expressed as weight loss or unintentional weight loss or percentage of weight loss) as the tool for assessment of nutritional status, either exclusively [18,19,[26][27][28][31][32][33] or in combination with other methods. [8,12,22] The results described by these papers suggest that weight loss is a good prognosticator of QoL irrespective of the type of cancer for a number of reasons. One, weight loss is a common feature of advanced cancer due to patient distress and loss of independence. [27] Weight loss is a known cause of morbidity and mortality in cancer patients that also decreases patient tolerance to both radiotherapy and chemotherapy. [19] Weight loss as low as 5% can alter important, measurable physiological parameters such as immune response, lung and cardiac function tests and autonomic autoregulation. [26] More than 10% weight loss at diagnosis has a great impact on QoL scores. [18] A total weight loss of ≥ 20% significantly correlates with treatment interruption, infections, early mortality, hospital re-admission rate after treatment completion as well as survival. [8] Recent work suggests that an inflammatory response might contribute to the weight loss in advanced gastrointestinal cancer patients by increasing energy expenditure and the turnover of specific amino acids, which reprioritizes the body's protein metabolism away from peripheral tissues and toward the liver. This process apparently contributes to the preferential loss of protein (in particular, skeletal muscle) in such patients. The reprioritization of metabolism may also impact patient appetite and, along with it, the QoL of gastrointestinal cancer patients. [27] There is evidence in the literature reviewed that the use of "percentage weight loss since the start of the illness" is a relatively objective measure, although the patient's usual or "normal" weight is often only approximately known. On the other hand, percentage weight loss does not appear to account for the kinetics of weight loss, presence of edemas, water retention and clinical-biological effects. [31] On the contrary, SGA is the only malnutrition screening tool recommended by the ASPEN board of directors. [35] SGA is a simple, easy-to-apply and cost-effective method that has been validated for diverse groups of patients. SGA is one of the better available assessment methods, not only because it is patient centred and incorporates clinical history and physical examination, but also does not require laboratory testing or medical imaging exams. [36,37] Reliable SGA grading, however, depends on collection of correct history and physical observation and requires a skilled dietician to carry out the assessment. Nutrition assessment tools such as the scored PG-SGA enable nutritional status to be assessed quickly, nutrition impact symptoms identified and appropriate nutrition support implemented. An advantage of the PG-SGA as a nutrition assessment tool is that the score can be used as an outcome measure in nutrition intervention studies as it may be more sensitive to changes in nutritional status than the global SGA rating. [38] Also, by performing serial measurements, the change in the PG-SGA score may be used to demonstrate subtle changes in nutritional status.
The majority of the studies reviewed here used EORTC-QLQ-C30 to assess patient QoL, either exclusively [2,8,10,22,24,26,28,31,32] or in combination with other QoL tools. [7,12,18,19,23,27] The EORTC QLQ-C30 questionnaire is a validated instrument for assessing QoL in patients with cancer. [31] It is usually completed by self-assessment [12,27] and covers more items and scales, identifies more domains and specific complaints, and assesses cancer and radiotherapy specific symptoms, and is, therefore, a more comprehensive and sensible measure than some others.
Collectively, the studies reviewed in this article suffered from certain limitations. Three studies involved small sample sizes, which made comparisons and statistical analyses difficult. [5,17,24] Non-responders contributed toward bias in one study [17], while another made no assessment of inter-rater reliability of the users of SGA and BIA. These studies minimized this bias by using only BIA-trained dieticians. [24] Two studies reported exclusion of patients with physical, cognitive, language or emotional problems that prevented them from completing the respective QoL questionnaires. [2,5] Another study was a secondary analysis and was not designed as a nutrition trial. As a result, some of the nutritional parameters included in the survey were limited. Also, there was significant attrition between T2 and T3 and, apparently, more stage IV patients were lost to attrition. Thus, the prevalence of nutrition impact symptoms in these patients may have been underreported. [3] One study reported that its outcome data may have been misclassified, but then ruled out the probability of error on the grounds that 1) the analysis of self-reported preoperative body weight compared with body weight measured by surgical staff before operation showed good validity and 2) that the questionnaires covering nutritional issues had been previously validated. [23] Like most other systematic reviews of the literature, this review suffers from potential publication bias. In general, this bias exists because studies that report positive associations are more likely to be published. Therefore, it is possible that studies containing valuable data may not have been published and have gone undetected. Since we restricted this systematic review to studies published in English, it is possible that language bias may have affected our conclusions. Finally, our review simply focused on the relationship between nutritional status and QoL in cancer, which does not by any means imply causation. As a result, a logical next step would be to systematically review the available literature, if any, to investigate whether nutritional intervention can have a favorable impact on QoL outcomes in cancer patients. Despite these limitations, our review and analysis of the extensive available literature demonstrates a strong association between nutritional status and QoL in cancer.
Also as a result of our review, we have identified new avenues for further research in this area. One is to identify the best management practices for timing of nutritional assessment and intervention in cancer patients as, currently, there is no consensus on how to manage patients based on any of the nutritional metrics reviewed here. Nonetheless, this review of the literature provides a strong rationale for devising such standards of practice and testing their value in controlled clinical studies. All clinical manifestations of malnutrition should be included, as well as specific situations where a causative relationship with QoL is apparent.
Our review of the current literature supports the hypothesis that nutritional status is a strong predictor of QoL in cancer patients. It also supports an approach to cancer treatment that takes all aspects of the patient's life into account. Further, the current literature supports the implementation of the ASPEN guidelines for oncology patients, which include nutritional screening, assessment, and intervention as appropriate. Correcting malnutrition in cancer patients can have a significant positive impact on their QoL.