Pharmacological Treatments for Cancer-Related Anorexia-Cachexia Syndrome: An Umbrella Review of Systematic Reviews and Meta-Analyses

Cancer-related anorexia-cachexia syndrome (CACS) is a debilitating condition afflicting up to 80% of advanced-stage cancer patients. Characterized by progressive weight loss, muscle wasting, and metabolic abnormalities, CACS significantly compromises patients’ quality of life and treatment outcomes. This comprehensive review navigates through its intricate physiopathology, elucidating its stages and diagnostic methodologies. CACS manifests in three distinct stages: pre-cachexia, established cachexia, and refractory cachexia. Early detection is pivotal for effective intervention and is facilitated by screening tools, complemented by nutritional assessments and professional evaluations. The diagnostic process unravels the complex interplay of metabolic dysregulation and tumor-induced factors contributing to CACS. Management strategies, tailored to individual patient profiles, encompass a spectrum of nutritional interventions. These include dietary counseling, oral nutritional supplements, and, when necessary, enteral nutrition and a judicious use of parenteral nutrition. Specific recommendations for caloric intake, protein requirements, and essential nutrients address the unique challenges posed by CACS. While pharmacological agents like megestrol acetate may be considered, their use requires careful evaluation of potential risks. At its core, this review underscores the imperative for a holistic and personalized approach to managing CACS, integrating nutritional interventions and pharmacological strategies based on a nuanced understanding of patient’s condition.

Cancer-related anorexia/cachexia syndrome (CACS) is characterized by anorexia and loss of body weight. Evidence is insufficient to strongly endorse any pharmacologic agent for the treatment of CACS. In this systematic review, we assessed the efficacy of oral anamorelin treatment for patients with CACS. On July 6, 2022, we systematically searched the following databases for randomized controlled trials (RCTs) of adults with CACS comparing oral anamorelin versus placebo: CENTRAL, PubMed, EMBASE, and ICHUSHI. The primary outcomes were total body weight (TBW), patient-reported quality of life (QOL), and adverse events (AEs). Secondary outcomes included lean body mass (LBM), overall survival (OS), non-dominant hand grip strength (HGS), and appetite. We included seven RCTs with a total of 1944 CACS patients. Anamorelin significantly increased TBW (mean difference (MD) 1.73, 95% confidence interval (CI) 1.34–2.13, p < 0.00001), LBM (MD 1.06, 95% CI 0.30–1.81, p = 0.006), and QOL (standardized mean difference (SMD) 0.16, 95% CI 0.04–0.27, p = 0.006) compared with placebo without a significant difference in all AEs, severe AEs, OS, HGS or appetite. Anamorelin may be an effective treatment for CACS patients; however, further studies are needed to confirm the efficacy and safety of this drug.

e20556 Background: To test the safety and efficacy of a combination treatment (including nutraceuticals, i.e. quercetin, alpha lipoic acid and curcumin) with carnitine + celecoxib for the treatment of cancer-related anorexia/cachexia syndrome (CACS) in the clinical practice. Primary endpoints: safety, increase of lean body mass (LBM) and improvement of quality of life. Secondary endpoints: increase of physical performance (tested by grip strength and 6-min walk test, 6MWT) and decrease of inflammation (assessed by serum levels of IL-6 and Glasgow prognostic score, GPS). Methods: Outpatients with advanced cancer at different sites with CACS (i.e. loss of body weight &gt;5% of the pre-illness or ideal weight in the previous 3 months) were eligible to receive: L-carnitine 4 g/day + Celecoxib 300 mg/day. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C, all orally. Treatment duration was 4 months. Results: From June 2011 to April 2012, 75 patients with advanced cancer (all stage IV) at different sites were enrolled: 40 completed the treatment and were evaluable (mean age 65 ± 9.6, range 32-82 years). Results showed a significant increase of LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) from baseline as well as physical performance assessed by 6MWT. Quality of life (assessed by EORTC-QLQ-C30) as well as fatigue (assessed by MFSI-SF) also improved significantly. ECOG PS and GPS decreased significantly. The treatment was safe, no grade 3–4 toxicities occurred and no patient had to discontinue the treatment due to severe adverse events. Conclusions: The results of the present study confirm the efficacy and safety of the two-drug combination regimen previously shown in a randomized clinical trial (Madeddu et al, Clinical Nutrition 31:176-182,2012). Therefore, this simple, feasible, effective, safe, with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice as a treatment for CACS.

e19733 Background: Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterized by loss of lean body mass (LBM), metabolic alterations, chronic inflammation and fatigue. Methods: In October 2009 we started a phase III randomised study to establish which was the most effective and safest treatment to improve the “key” variables of CACS: increase of LBM, decrease of resting energy expenditure (REE), improvement of fatigue (MFSI-SF) and physical activity (ArmBand). As secondary endpoints we evaluated: grip strength, six minute walk test (6MW), appetite, serum levels of IL-6 and TNF-a, EORTC-QLQ-C30, Glasgow Prognostic Score (GPS), ECOG PS. All patients received as basic oral treatment poliphenols + alpha lipoic acid + carbocysteine + Vitamins A,C,E and were then randomly assigned to: L-carnitine 4 g/d + Celecoxib 300 mg/d (Arm 1) or the same treatment + megestrol acetate (MA) 320 mg/d (Arm 2). Treatment duration: 4 months. The planned sample size was 70 patients for each arm. An interim analysis (intent-to treat) was planned. Results: Sixty cachectic patients (mean age 65.2 ± 8.7 years) with tumors at different sites were enrolled and 57 were evaluable (3 died early due to disease progression). Analysis of changes from baseline showed that LBM assessed by DEXA as well as by L3-CT improved in both arms. Fatigue improved significantly in both arms. REE and physical activity did not show significant changes. As for secondary endpoints, the 6MW test, appetite, GPS and ECOG PS improved significantly. The comparison between the 2 arms by ANOVA test did not show a significant difference. Toxicity was substantially negligible and comparable between arms (1 grade 3 diarrhea in arm 1 and 2, which led to the withdrawal of carnitine for 2 weeks). Conclusions: Both arms showed to be effective as for primary efficacy endpoints (improvement of LBM and fatigue) and some important secondary endpoints. The results of the present trial confirm the efficacy of a combined approach for the treatment of CACS: arm 1, without MA, could be the treatment of choice as it was effective and easier to administer. The trial is ongoing.

1422O - Efficacy and Safety of a Two Drug-Combination Regimen for Cancer-Related Cachexia in the Clinical Practice

Cancer cachexia is a multifactorial syndrome marked by progressive weight loss, muscle wasting, and systemic inflammation, commonly associated with advanced cancer. Its management poses a significant challenge due to the complex interplay of metabolic alterations, reduced appetite, and inflammation. Addressing the nutritional needs of patients with cachexia is a cornerstone of care, aiming to mitigate weight loss, preserve lean body mass, and enhance quality of life (QOL). Effective nutritional strategies include individualized meal plans enriched with energy-dense and protein-rich foods, alongside the use of specialized nutritional supplements. Pharmacotherapy, such as appetite stimulants, anabolic agents, and anti-inflammatory drugs, plays a crucial role in modulating metabolic dysfunction and supporting nutritional goals. Additionally, physical activity tailored to the patient's abilities has been shown to complement nutritional and pharmacological interventions by promoting muscle retention and functional independence. A multidisciplinary approach that integrates dietary support, pharmacotherapy, and exercise is essential for optimizing outcomes in cancer cachexia management and improving patient well-being. Keywords: Cancer cachexia, Nutritional management in cancer, Malnutrition in cancer

Aims: A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib +/− megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and six minute walk test. Methods: Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. Results: The results did not show a significant difference between treatment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. Conclusions: The results of the present study showed a non-inferiority of arm 1 (two drug-combination) vs arm 2 (two drug-combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favourable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2652. doi:1538-7445.AM2012-2652

Background: The management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge in clinical practice. To date, practice guidelines for the prevention and treatment of CACS are lacking. The authors conducted a randomized study to confirm the effectiveness and safety of treatment of CACS utilizing megestrol acetate (MA) plus thalidomide. Methods: One hundred and two candidates with CACS were randomly assigned to two treatment groups (trial group and control group): the trial group received MA (160 mg po, bid) plus thalidomide (50 mg po, bid), while the control group received MA (160 mg po, bid) alone. Treatment duration was 8 weeks. Results: Analysis of the trial group demonstrated a significant increase from baseline in body weight (<0.01), quality of life (p = 0.02), appetite (p = 0.01), and grip strength (p = 0.01), and a significant decrease in fatigue, Glasgow Prognostic Score (p = 0.05), Eastern Cooperative Oncology Group performance status (p = 0.03), IL-6 (p < 0.01), and tumor necrosis factor-α (p = 0.02). In contrast, in the control group, endpoints with a significant improvement from baseline included body weight (p < 0.02) and appetite (p = 0.02). The mean changes in the endpoints from baseline in the trial group were significantly greater compared with the control group: in the primary endpoints, body weight (p = 0.05), fatigue (p < 0.01) and quality of life (p = 0.01), and in the secondary endpoints, grip strength (p = 0.05), Glasgow Prognostic Score (p = 0.02), Eastern Cooperative Oncology Group performance status (p = 0.02), IL-6 (p < 0.01) and tumor necrosis factor-α (p = 0.01). Toxicity was found to be relatively negligible in both groups. Conclusion: A combination regimen of MA and thalidomide is more effective than MA alone in the treatment of CACS.

Skeletal Muscle Weakness: A Novel Treatable Trait in Asthma?

Pharmacological interventions for pruritus in adult palliative care patients.

Nearly 80% of patients with pancreatic ductal adenocarcinoma (PDAC) develop cachexia along their disease course. Cachexia is characterized by progressive weight loss, muscle wasting, and systemic inflammation and has been linked to poorer outcomes and impairments in quality of life. Management of PDAC cachexia has historically involved a multidisciplinary effort comprised of nutritional support, pancreatic enzyme replacement therapy, and/or pharmacologic interventions. Despite current interventions to mitigate PDAC cachexia, a significant proportion of patients continue to die from complications associated with cachexia underscoring the need for novel insights and treatments for this syndrome. We highlight the feasibility and effectiveness of a recent enteral feeding prospective trial at our institution to improve cachexia outcomes in patients with advanced PDAC. Additionally, we were among the first to characterize the stool microbiome composition in patients with advanced PDAC receiving enteral feeding for the treatment of cachexia. Novel insights into the relationship between enteral nutritional support, cachexia, and the gut microbiome are presented. These promising results are discussed in the context of a potential ability to modulate the stool microbiome as a new interventional strategy to mitigate PDAC cachexia.

Background/Objectives: Irritable bowel syndrome (IBS) is a common and heterogeneous gastrointestinal disorder. Although numerous systematic reviews (SRs) have evaluated the effects of probiotics in IBS, uncertainty persists regarding their clinical effectiveness, methodological quality, and certainty of evidence. This umbrella review aimed to critically appraise SRs on probiotics in IBS, quantify overlap among reviews, and assess the certainty of evidence using the GRADE approach. Methods: We conducted an umbrella review of SRs of randomized controlled trials evaluating probiotics in adults with IBS. Searches were performed in MEDLINE/PubMed, Embase, the Cochrane Database of Systematic Reviews, Scopus, and Web of Science from inception to September 2025. Overlap between reviews was assessed using the corrected covered area (CCA). Methodological quality was evaluated with AMSTAR-2, risk of bias with ROBIS, and certainty of evidence with GRADE. Results: Twenty-seven SRs published between 2009 and 2025 were included, encompassing 5-82 randomized trials and 243-10,332 participants per review. Methodological quality was low or critically low across all SRs, with 66.7% rated as critically low by AMSTAR-2 and 85.2% judged at high risk of bias by ROBIS. A high degree of overlap was observed between reviews (CCA: 12%). Probiotics were associated with modest improvements in symptom persistence (risk ratio ≈ 0.78-0.79; number needed to treat 4-7), small-to-moderate effects on abdominal pain (standardized mean difference -0.31 to -0.94) with substantial heterogeneity, and small or inconsistent effects on bloating and quality of life. Adverse events were comparable to placebo. Overall, certainty of evidence was predominantly low or very low, with only 1% of outcomes rated as high certainty. Conclusions: Although probiotics demonstrate statistically significant benefits for some IBS outcomes, the certainty of evidence remains predominantly low or very low due to methodological limitations, inconsistency, imprecision, and substantial overlap between reviews. The accumulation of redundant SRs has not increased confidence in effect estimates. Future efforts should prioritize well-designed, standardized primary trials rather than additional systematic reviews.

To compare the effects of cannabis extract (CE), delta-9-tetrahydrocannabinol (THC), and placebo (PL) on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS). Adult patients with advanced cancer, CACS, weight loss (> or = 5% over 6 months), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 were randomly assigned (2:2:1) to receive CE (standardized for 2.5 mg THC and 1 mg cannabidiol) or THC (2.5 mg) or PL orally, twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily with a visual analog scale (VAS); QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (composite score: questions 29 and 30). Cannabinoid-related toxicity was assessed every 2 weeks. Of 289 patients screened, 243 were randomly assigned and 164 (CE, 66 of 95 patients; THC, 65 of 100 patients; and PL, 33 of 48 patients) completed treatment. At baseline, groups were comparable for age (mean, 61 years), sex (54% men), weight loss (32% > or = 10%), PS (13% ECOG = 2), antineoplastic treatment (50%), appetite (mean VAS score, 31/100 mm), and QOL (mean score, 30/100). Intent-to-treat analysis showed no significant differences between the three arms for appetite, QOL, or cannabinoid-related toxicity. Increased appetite was reported by 73%, 58%, and 69% of patients receiving CE, THC, or PL, respectively. An independent data review board recommended termination of recruitment because of insufficient differences between study arms. CE at the oral dose administered was well tolerated by these patients with CACS. No differences in patients' appetite or QOL were found either between CE, THC, and PL or between CE and THC at the dosages investigated.

“Comparison of Orally Administered Cannabis Extract and Delta-9-Tetrahydrocannabinol in Treating Patients With Cancer-Related Anorexia-Cachexia Syndrome: A Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial From the Cannabis-In-Cachexia-Study-Group,” is a randomized controlled trial which studied 243 patients with cancer-related anorexia-cachexia syndrome (CACS) over a 6 week period. This trial investigated the effects of cannabis extract (CE), THC (delta-9-tetrahydrocannabinol), and placebo on appetite and quality of life (QOL). Results revealed no significant differences between the CE, THC, and placebo arms in QOL, appetite, nausea, mood, and cannabinoid-related toxicity. There was early closure of the trial due to insufficient differences between study arms. Increase in appetite was noted in other studies3, however THC dosing was variable. No strong recommendation of cannabinoids for palliation of appetite and QOL can be made on the basis of this study. Further studies on larger sample sizes are needed to characterize the palliative and adverse effects of cannabinoids.

Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterised by tissue wasting, particularly lean body mass (LBM), metabolic alterations, fatigue, anorexia and reduced food intake. In April 2005 we started a phase III randomised study to establish the most effective and safest treatment for CACS addressing as primary endpoints: LBM, resting energy expenditure (REE), total daily physical activity, interleukin (IL)-6 and tumour necrosis factor (TNF)-α levels, and fatigue. According to the statistical design the sample size was 475 patients (95 per arm). Eligibility criteria: histologically confirmed tumours of any site; weight loss −5% in the last 3 months and/or abnormal laboratory values; life expectancy >4 months. Patients were treated with either antineoplastic therapy or supportive care. All patients received as basic oral treatment polyphenols plus alpha lipoic acid plus carbocysteine plus vitamins A, C and E. Patients were then randomised to one of the following 5 arms: (1) medroxyprogesterone acetate (MPA)/megestrol acetate (MA); (2) pharmaconutritional support containing eicosapentaenoic acid (EPA); (3) l-carnitine; (4) thalidomide; and (5) a combination of all the above agents. Treatment duration was 4 months. Interim analyses were planned after every 100 randomised patients. In September 2008, 280 patients were randomised and 240 were evaluable: M/F 167/113, mean age 62 years (range 30-84), 96% stage IV. A first interim analysis on 125 patients showed a worsening of LBM, REE and fatigue in arm 2 in comparison to the others and therefore it was withdrawn from the study. A second interim analysis after the enrolment of 204 patients showed that arm 1 was clearly significantly less effective than the others for primary efficacy endpoints, therefore it was withdrawn from the study. Statistical analysis in September 2008 showed a significant improvement of LBM (by dual X-ray energy absorptiometry), REE and fatigue in arm 5, a decrease of IL-6 in arms 3 and 5, and a decrease of TNF-α in arms 3 and 4. As for toxicity, 1 patient discontinued MPA because of deep vein thrombosis and 1 patient discontinued L-carnitine because of severe diarrhoea. In conclusion, the interim results seem to suggest that the most effective treatment for cancer patients with CACS/oxidative stress (OS) should be the combination regimen. The study is in progress.