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Understanding cachexia in the context of metastatic progression. Biswas Anup K,Acharyya Swarnali Nature reviews. Cancer Tumours reprogram host physiology, metabolism and immune responses during cancer progression. The release of soluble factors, exosomes and metabolites from tumours leads to systemic changes in distant organs, where cancer cells metastasize and grow. These tumour-derived circulating factors also profoundly impact tissues that are rarely inhabited by metastatic cancer cells such as skeletal muscle and adipose tissue. In fact, the majority of patients with metastatic cancer develop a debilitating muscle-wasting syndrome, known as cachexia, that is associated with decreased tolerance to antineoplastic therapy, poor prognosis and accelerated death, with no approved treatments. In this Perspective, we discuss the development of cachexia in the context of metastatic progression. We briefly discuss how circulating factors either directly or indirectly promote cachexia development and examine how signals from the metastatic process can trigger and amplify this process. Finally, we highlight promising therapeutic opportunities for targeting cachexia in the context of metastatic cancers. 10.1038/s41568-020-0251-4
DHA effect on chemotherapy-induced body weight loss: an exploratory study in a rodent model of mammary tumors. Hajjaji Nawale,Couet Charles,Besson Pierre,Bougnoux Philippe Nutrition and cancer Body weight loss during the course of cancer disease has been associated with poor prognosis. Beside cancer-associated cachexia, weight loss can also result from chemotherapy. This work explored whether a model of mammary tumors in female Sprague Dawley rats could be appropriate to study the effect of doxorubicin on body weight, described weight change in this model, and assessed the effect of DHA on weight during chemotherapy. After tumor induction, rats were randomly assigned to a control or a DHA-enriched diet, and treated with doxorubicin or placebo twice a week for 2.5 wk (n = 6 in each group). Body weight, food intake, and tumor growth were monitored. Neither the induction of tumors nor their initial development impaired body weight gain. No reduction in food intake was observed. Tumor growth was similar between groups from day 1 to day 11. Although doxorubicin induced body weight loss from day 4 compared to placebo (P< 0.01) in rats fed the control diet, it did not induce body weight loss in rats fed the DHA-enriched diet (P = 0.02), indicating that DHA had a protective effect. These results indicate that doxorubicin can induce body weight loss in this model and that a DHA-enriched diet can prevent this effect. 10.1080/01635581.2012.714832
A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice. Plas Rogier L C,Poland Mieke,Faber Joyce,Argilès Josep,van Dijk Miriam,Laviano Alessandro,Meijerink Jocelijn,Witkamp Renger F,van Helvoort Ardy,van Norren Klaske International journal of molecular sciences BACKGROUND:Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). METHODS:CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. RESULTS:The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. CONCLUSION:Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour. 10.3390/ijms20204978
α-Linolenic Fatty Acid Supplementation Decreases Tumor Growth and Cachexia Parameters in Walker 256 Tumor-Bearing Rats. Schiessel Dalton Luiz,Yamazaki Ricardo K,Kryczyk Marcelo,Coelho Isabela,Yamaguchi Adriana A,Pequito Daniele C T,Brito Gleisson A P,Borghetti Gina,Fernandes Luiz C Nutrition and cancer Fish oil (FO) has been shown to affect cancer cachexia, tumor mass, and immunity cell. n-3 PUFA, specifically α-linolenic fatty acid (ALA), has controversial effects. We investigated this in nontumor-bearing Wistar rats fed regular chow (C), fed regular chow and supplemented with FO or Oro Inca oil (OI), and Walker 256 tumor-bearing rats fed regular chow (W), fed regular chow and supplemented with FO (WFO) or OI (WOI). Rats were supplemented (1g/kg body weight/day) during 4 wk and then the groups tumor-bearing were inoculated with Walker 256 tumor cells suspension and 14 days later the animals were killed. WFO increased EPA fivefold and DHA 1.5-fold in the tumor tissue compared to W (P < 0.05). OI supplementation increased of threefold of ALA when compared to W (P < 0.05). Tumor mass in WFO and OI was of 2.3-fold lower, as well as tumor cell proliferation of 3.0-fold tumor tissue lipoperoxidation increased of 76.6% and cox-2 expression was 20% lower. Cachexia parameters were attenuate, blood glucose (25% higher), Triacylglycerolemia (50% lower), and plasma TNF-α (65% lower; P < 0.05) and IL-6 (62.5% lower). OI, rich in ALA, caused the same effect on cancer as those seen in FO. 10.1080/01635581.2015.1043021
CONJUGATED LINOLEIC ACIDS (CLA) DECREASE THE BREAST CANCER RISK IN DMBA-TREATED RATS. Białek Agnieszka,Tokarz Andrzej,Zagrodzki Paweł Acta poloniae pharmaceutica The aim of this study was to investigate how supplementation of diet of female Sprague-Dawley rats with different doses of conjugated linoleic acids and for a varied period of time influences breast cancer risk, fatty acids profile and lipids peroxidation in chemically induced mammary tumors. Animals were divided into nine groups with different modifications of diet (vegetable oil, 1.0 or 2.0% of CLA) and period of supplementation, which lasted after (A), before (B) and before and after (BA) carcinogenic agent--7,12-dimethylbenz[a]anthracene administration at 50th day of life. Mammary adenocarcinomas occurred in all groups, but CLA supplementation decreased the cancer morbidity. Two percent CLA seems to be excessive because of the coexisting cachexia. Two CLA isomers (9-cis, 11-trans and 10-trans, 12-cis) were detected in tumors but content of rumenic acid was higher. Dietary supplementation significantly influenced some unsaturated fatty acids content (C18:2 n-6 trans, C20:1, C20:5 n-3, C22:2), but the anti- or prooxidant properties of CLA were not confirmed. CLA can inhibit chemically induced mammary tumors development in female rats, but their cytotoxic action seems not to be connected with lipids peroxidation. CLA isomers differ with their incorporation into cancerous tissues and they influence the content of some other fatty acids.
Liver lipid metabolism disruption in cancer cachexia is aggravated by cla supplementation -induced inflammation. Gonçalves Daniela Caetano,Lira Fábio Santos,Yamashita Alex Shimura,Carnevali Junior Luiz Carlos,Eder Robson,Laviano Alessandro,Seelaender Marília Cerqueira Leite Clinical nutrition (Edinburgh, Scotland) BACKGROUND & AIMS:The liver is the main organ regulating metabolism. In spite of that, few studies examine liver metabolism in cachexia, a wasting syndrome associated with increased morbidity and mortality in cancer. Cachexia induces major metabolic disruption, inflammation and fat and lean mass loss. We have previously shown impairment of hepatic lipid metabolism in cancer cachexia that contributes to the aggravation of the symptoms. The present study addresses the effects of Conjugated Linoleic Acid supplementation upon liver lipid metabolism in cachectic rats. METHODS:Male Wistar rats were randomly assigned to control groups (C) receiving 0.9 NaCl (Placebo CP); or to groups supplemented with sunflower oil (CSF), supplemented with CLA (CCLA), or still, to tumour bearing animals (T) receiving NaCl (TP), sunflower oil (TSF), or CLA (TCLA). Supplementation (0.5 ml) by gavage was carried out for 14 days. Body weight, dietary intake, glucose, cholesterol and triacylglycerol plasma content, liver glycogen and triacylglycerol content and mRNA expression of liver carnitine palmitoyltransferase I and II (CPT I and II), as well as microsomal triglyceride transfer protein (MTP), liver fatty acid-binding protein (L-FABP), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and apolipoprotein B (apoB), were assessed. RESULTS:Liver CPT II activity was reduced in all groups, when compared with CP. Hepatic mRNA expression of MTP, apoB and FABP was reduced in TCLA, when compared with all groups. TCLA also presented increased hepatic and plasma triacylglycerol content, when compared with all T groups. Adipose tissue-derived inflammatory factors were assessed. No differences among the groups were observed in regard to Retro Peritoneal Adipose Tissue cytokine (IL-1β, IL-6, and TNF-α) protein content and expression, with the exception of IL-10 in tumour-bearing animals. In the Epididymal Adipose Tissue, the inflammatory cytokines were augmented in TCLA, compared with all other groups. CONCLUSION:CLA supplementation fails to promote the re-establishment of hepatic lipid metabolism in tumour-bearing animals, and therefore is not recommended in cancer-related cachexia. 10.1016/j.clnu.2018.09.023
c9t11-Conjugated linoleic acid-rich oil fails to attenuate wasting in colon-26 tumor-induced late-stage cancer cachexia in male CD2F1 mice. Tian Min,Kliewer Kara L,Asp Michelle L,Stout Michael B,Belury Martha A Molecular nutrition & food research SCOPE:Cancer cachexia is characterized by muscle and adipose tissue wasting caused partly by chronic, systemic inflammation. Conjugated linoleic acids (CLAs) are a group of fatty acids with various properties including anti-inflammatory cis9, trans11 (c9t11)-CLA and lipid-mobilizing trans10, cis12 (t10c12)-CLA. The purpose of this study was to test whether dietary supplementation of a c9t11-CLA-rich oil (6:1 c9t11:t10c12) could attenuate wasting of muscle and adipose tissue in colon-26 adenocarcinoma-induced cachexia in mice. METHODS AND RESULTS:Loss of body weight, muscle and adipose tissue mass caused by tumors were not rescued by supplementation with the c9t11-CLA-rich oil. In quadriceps muscle, c9t11-CLA-rich oil exacerbated tumor-induced gene expression of inflammatory markers tumor necrosis factor-α, IL-6 receptor and the E3 ligase MuRF-1 involved in muscle proteolysis. In epididymal adipose tissue, tumor-driven delipidation and atrophy was aggravated by the c9,t11-CLA-rich oil, demonstrated by further reduced adipocyte size and lower adiponectin expression. However, expression of inflammatory cytokines and macrophage markers were not altered by tumors, or CLA supplementation. CONCLUSION:These data suggest that addition of c9t11-CLA-rich oil (0.6% c9t11, 0.1% t10c12) in diet did not ameliorate wasting in mice with cancer cachexia. Instead, it increased expression of inflammatory markers in the muscle and increased adipose delipidation. 10.1002/mnfr.201000176
A systematic review on the role of fish oil for the treatment of cachexia in advanced cancer: an EPCRC cachexia guidelines project. Ries Anke,Trottenberg Peter,Elsner Frank,Stiel Stephanie,Haugen Dagny,Kaasa Stein,Radbruch Lukas Palliative medicine BACKGROUND:The European Palliative Care Research Collaboration is developing clinical guidelines on cachexia in patients with advanced cancer. A systematic review on the use of fish oil/omega-3-fatty acids (n-3-FA)/eicosapentaenoic acids (EPA) in advanced cancer patients suffering from cancer cachexia was performed as part of the guideline development. METHODS:The systematic literature search in Medline on the use of fish oil/n-3-FA/EPA identified 244 papers, with 38 publications included in the final evaluation. Some smaller trials, often unrandomized and without a control group, reported a good effect of n-3-FA in patients with advanced cancer and cachexia. However, the results of the larger randomized controlled trials could not support the positive results, as they mostly did not find a significant effect. RESULTS:Adverse effects such as abdominal discomfort, fish belching, fish aftertaste, nausea and diarrhoea were reported with a low incidence. No serious adverse effects were documented, but adverse effects often had an impact on quality of life. This often limited dose escalations or even led to discontinuation of n-3-FA. CONCLUSION:There is not enough evidence to support a net benefit of n-3-FA in cachexia in advanced cancer. On the other hand, adverse effects were infrequent, with no severe adverse effects. The results from the review led to a weak negative GRADE recommendation. 10.1177/0269216311418709
Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia. Shirai Yumiko,Okugawa Yoshinaga,Hishida Asahi,Ogawa Aki,Okamoto Kyoko,Shintani Miki,Morimoto Yuki,Nishikawa Ryutaro,Yokoe Takeshi,Tanaka Koji,Urata Hisashi,Toiyama Yuji,Inoue Yasuhiro,Tanaka Motoyoshi,Mohri Yasuhiko,Goel Ajay,Kusunoki Masato,McMillan Donald C,Miki Chikao Scientific reports Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2). 10.1038/s41598-017-05278-0
New insights on the regulation of cancer cachexia by N-3 polyunsaturated fatty acids. Gorjao Renata,Dos Santos Cesar Miguel Momesso,Serdan Tamires Duarte Afonso,Diniz Vinicius Leonardo Sousa,Alba-Loureiro Tatiana Carolina,Cury-Boaventura Maria Fernanda,Hatanaka Elaine,Levada-Pires Adriana Cristina,Sato Fábio Takeo,Pithon-Curi Tania Cristina,Fernandes Luiz Claudio,Curi Rui,Hirabara Sandro Massao Pharmacology & therapeutics Cancer cachexia is a multifactorial syndrome that develops during malignant tumor growth. Changes in plasma levels of several hormones and inflammatory factors result in an intense catabolic state, decreased activity of anabolic pathways, anorexia, and marked weight loss, leading to cachexia development and/or accentuation. Inflammatory mediators appear to be related to the control of a highly regulated process of muscle protein degradation that accelerates the process of cachexia. Several mediators have been postulated to participate in this process, including TNF-α, myostatin, and activated protein degradation pathways. Some interventional therapies have been proposed, including nutritional (dietary, omega-3 fatty acid supplementation), hormonal (insulin), pharmacological (clenbuterol), and nonpharmacological (physical exercise) therapies. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid, are recognized for their anti-inflammatory properties and have been used in therapeutic approaches to treat or attenuate cancer cachexia. In this review, we discuss recent findings on cellular and molecular mechanisms involved in inflammation in the cancer cachexia syndrome and the effectiveness of n-3 PUFAs to attenuate or prevent cancer cachexia. 10.1016/j.pharmthera.2018.12.001
Should omega-3 fatty acids be used for adjuvant treatment of cancer cachexia? Lavriv Daryna Sergiyivna,Neves Pedro Miguel,Ravasco Paula Clinical nutrition ESPEN OBJECTIVES:Cancer cachexia is characterised by a progressive loss of muscle, resulting in functional impairment and shorter survival. Therefore, omega-3 has been studied for its role as an anti-cachectic therapy. This systematic review identified studies published on use of omega-3 in cancer cachexia in order to examine the potential benefit. METHODS:A systematic review of the literature using PubMed and B-on databases was conducted to identify clinical trials published between 2000 and 2015, to evaluate the effect of n-3 PUFAs on nutritional features and Quality of Life in cancer cachexia. Of 140 publications, 7 were selected on the basis of their methodological quality, according to the Delphi List. The collected data was summarized and written in text format and in tables. RESULTS:Only one study, made in pre-cachectic population, show statistically and clinically positive intervention. No benefits were observed with the 4 g EPA/day, but a potentially clinically relevant treatment effect with 2 g EPA/day. Lung tumours showed the highest CRP levels and while the weight of patients with gastrointestinal cancer increased significantly, patients with lung cancer showed no significant response. CONCLUSIONS:Future cachexia trials would likely benefit from studying a single tumour type with earlier stage disease, with probably different dosage depending on the cancer type and its inflammatory profile. 10.1016/j.clnesp.2018.02.006
Anorexia-cachexia syndrome: a systematic review of the role of dietary polyunsaturated Fatty acids in the management of symptoms, survival, and quality of life. Mazzotta Paolo,Jeney Christa M Journal of pain and symptom management To provide a systematic review on the clinical utility of anti-inflammatory polyunsaturated fatty acids (PUFAs) in cancer-associated anorexia-cachexia syndrome (ACS), clinical trials involving eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for the management of ACS were identified in the medical literature using MEDLINE (1966 to October 2006) and EMBASE (1980 to October 2006). Review Manager 4.1 was used to compare trials based on outcome measures of interest, including weight change, lean muscle mass change, survival, and quality of life (QoL). Seven randomized controlled trials (RCTs) were identified. Various outcome measures were used in each study. Variability in study populations, dose of EPA and DHA, and standardized scales did not allow for analysis using Review Manager 4.1. Therefore, trials were summarized based on their individual outcomes. Except for one trial showing a positive effect on weight, none of the trials found a clinically or statistically significant difference in outcome measures reviewed. EPA and DHA alone have not shown significant clinical effect in altering weight, lean muscle mass, survival, or QoL in patients with ACS associated with cancer. 10.1016/j.jpainsymman.2008.06.005
Cancer cachexia and tumor growth reduction in Walker 256 tumor-bearing rats supplemented with N-3 polyunsaturated fatty acids for one generation. Togni Valéria,Ota Claudia C C,Folador Alessandra,Júnior O Tchaikovski,Aikawa Júlia,Yamazaki Ricardo K,Freitas Fábio A,Longo Rita,Martins Edgair F,Calder Philip C,Curi Rui,Fernandes Luiz C Nutrition and cancer In this study we investigated the effect of lifelong supplementation of the diet with coconut oil (CO, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids, PUFAs) on tumor growth, animal survival, and metabolic indicators of cachexia in adult rats. Female Wistar rats were supplemented with CO or FO prior to mating and then throughout pregnancy and gestation, and then the male offspring were supplemented from weaning until 90 days of age. Then they were inoculated subcutaneously with Walker 256 tumor cells. Tumor weight at 14 days in control rats (those fed standard chow) was approximately 20 g. These animals displayed cancer cachexia, which was characterized by loss of weight, hypoglycemia, hyperlacticidemia, hypertriacylglycerolemia, and depletion of glycogen stores. Supplementation of the diet with CO did not change these parameters, except that there was a smaller decrease in serum triacylglycerol concentration. Supplementation of the diet with FO significantly decreased tumor growth (by approximately 60%), increased survival (50% at 30 days postinoculation vs. 30% in the controls and 13.5% in the CO group), and prevented the fall in body weight. Furthermore, FO supplementation partly abolished the fall in serum glucose, totally prevented the elevation in serum lactate concentrations, partly prevented the hypertriacylgylcerolemia, and preserved tissue glycogen stores. Lifelong consumption of FO, rich in n-3 PUFAs, protects against tumor growth and cancer cachexia and improves survival. 10.1207/S15327914NC4601_07
Dietary supplementation with n-3-fatty acids in patients with pancreatic cancer and cachexia: marine phospholipids versus fish oil - a randomized controlled double-blind trial. Werner Kristin,Küllenberg de Gaudry Daniela,Taylor Lenka A,Keck Tobias,Unger Clemens,Hopt Ulrich T,Massing Ulrich Lipids in health and disease BACKGROUND:Like many other cancer patients, most pancreatic carcinoma patients suffer from severe weight loss. As shown in numerous studies with fish oil (FO) supplementation, a minimum daily intake of 1.5 g n-3-fatty acids (n-3-FA) contributes to weight stabilization and improvement of quality of life (QoL) of cancer patients. Given n-3-FA not as triglycerides (FO), but mainly bound to marine phospholipids (MPL), weight stabilization and improvement of QoL has already been seen at much lower doses of n-3-FA (0,3 g), and MPL were much better tolerated. The objective of this double-blind randomized controlled trial was to compare low dose MPL and FO formulations, which had the same n-3-FA amount and composition, on weight and appetite stabilization, global health enhancement (QoL), and plasma FA-profiles in patients suffering from pancreatic cancer. METHODS:Sixty pancreatic cancer patients were included into the study and randomized to take either FO- or MPL supplementation. Patients were treated with 0.3 g of n-3-fatty acids per day over six weeks. Since the n-3-FA content of FO is usually higher than that of MPL, FO was diluted with 40% of medium chain triglycerides (MCT) to achieve the same capsule size in both intervention groups and therefore assure blinding. Routine blood parameters, lipid profiles, body weight, and appetite were measured before and after intervention. Patient compliance was assessed through a patient diary. Quality of life and nutritional habits were assessed with validated questionnaires (EORTC-QLQ-C30, PAN26). Thirty one patients finalized the study protocol and were analyzed (per-protocol-analysis). RESULTS:Intervention with low dose n-3-FAs, either as FO or MPL supplementation, resulted in similar and promising weight and appetite stabilization in pancreatic cancer patients. MPL capsules were slightly better tolerated and showed fewer side effects, when compared to FO supplementation. CONCLUSION:The similar effects between both interventions were unexpected but reliable, since the MPL and FO formulations caused identical increases of n-3-FAs in plasma lipids of included patients after supplementation. The effects of FO with very low n-3-FA content might be explained by the addition of MCT. The results of this study suggest the need for further investigations of marine phospholipids for the improvement of QoL of cancer patients, optionally in combination with MCT. 10.1186/s12944-017-0495-5
Polyunsaturated fatty acids, polyphenols, amino acids, prebiotics: can they help to tackle cancer cachexia and related inflammation? Pötgens Sarah A,Sboarina Martina,Bindels Laure B Current opinion in clinical nutrition and metabolic care PURPOSE OF REVIEW:Recent studies have highlighted the importance of developing a multimodal therapeutic strategy for cancer cachectic patients. Considering the central role of metabolism and anorexia in this disease, optimized nutritional advice should be an integral part of this strategy. Current recommendations mainly focus on meeting caloric requirements. However, a few studies suggest the great potential of foods naturally enriched in nutrients presenting interesting physiological properties and the interest of using them in the management of cachectic patients. Among them, prebiotics show the capacity to control inflammation in several debilitating diseases. In this context, this review aims to summarize the most recent findings related to functional foods and nutrients and cancer cachexia, and to discuss the potential use of prebiotics in this context. RECENT FINDINGS:Even though there is a clear need for more research in the field, data from both humans and animal models support the promising benefits of functional foods and nutrients in cancer cachexia. SUMMARY:Altogether, these studies offer new insights into the potential contribution of nutrition to cancer patient management. Functional foods, by downregulating inflammatory pathways, could decrease cachexia severity and contribute to the improvement of cancer patients' quality of life. 10.1097/MCO.0000000000000505