CANCER CACHEXIA, AN UNMET CLINICAL NEED

Cancer-associated cachexia is an underestimated consequence of many cancers. Up to 80% of cancer patients with advanced cancer develop cachexia with a subsequent 1-year mortality rate that can reach 20%–60%1. According to the current consensus definition, “cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment”.2 Skeletal muscle wasting, low skeletal muscle mass (often termed “sarcopenia”3), and weight loss are independent prognostic factors for overall survival of cancer patients.4, 5 Cancer patients with weight loss experience more-frequent and more-severe chemotherapy-associated toxicities compared with patients with stable weight. Consequently, they ultimately receive less chemotherapy and demonstrate lower survival rates.5 Cachexia also associates with poorer outcomes from surgery, radiotherapy, and immunotherapy and increased cost of care.6 Across cancer types and interventions, cachexia decreases patients’ quality of life (QOL), as reflected by increased fatigue and decreased physical and social functioning.7 Currently, there is no effective, approved therapy for cancer cachexia in most of the world, underscoring both the need and the opportunity for further research and development in this condition.

CHALLENGES FOR INTERVENTION IN CANCER CACHEXIA

There are no targeted therapies or standardized supportive care regimens for cancer cachexia, despite its outsized impact on patient QOL and length of life. The disappointing state of the field can be attributed to a lack of clarity on clinical definitions; lack of high-quality data for nutrition or other supportive care interventions, thereby hampering treatment consensus and reimbursements; and lack of clinical data supporting novel pharmaceutical interventions. Furthermore, the preclinical data defining key mechanisms and targetable pathways are generally small and not rigorously tested in gold-standard models of site-specific cancer and anticancer therapy. We consider these challenges in turn here.

DIAGNOSTIC CRITERIA OF CANCER CACHEXIA

According to the framework developed by Fearon et al,2 cachexia syndrome includes three stages of severity—precachexia, cachexia, and refractory cachexia. At the precachectic stage, the patient exhibits simple weight loss (<5%) accompanied by clinical and metabolic symptoms such as anorexia and glucose intolerance. The patient is considered cachectic given the presence of one or more of these symptoms: (1) weight loss >5% over past 6 months, (2) weight loss >2% and body mass index (BMI) <20, or (3) weight loss >2% and sarcopenia as detected by mid-upper arm muscle area (MUMA) (men, <32 cm2; women, <18 cm2), appendicular skeletal muscle index by dual-energy x-ray absorptiometry (DXA) (men, <7.26 kg/m2; women, <5.45 kg/m2), lumbar skeletal muscle index by computed tomography (CT) (men, <55 cm2/m2; women, <39 cm2/m2), or fat-free mass index without bone by bioelectrical impedance (BIA) (men, <14.6 kg/m2; women, <11.4 kg/m2). Refractory cachexia represents the terminal stage corresponding to limited self-care or complete disability on World Health Organization (WHO) performance status and life expectancy <3 months. At this point, patients are not expected to benefit from any weight management therapy, and therapeutic intervention is limited to alleviating cachexia-associated complications,2 thus highlighting the importance of early detection.

Although the consensus definition associates cachexia with mortality8 and has propelled substantial research in the field, garnering nearly 1200 citations to date, the current criteria are insufficient to make a distinction between no-cachexia and precachexia8 and are often difficult to implement in clinical practice. In this definition, cutoffs for weight loss and muscle mass lacked rigorous evidence to be predictive of clinical outcomes. In addition, weight loss can be masked by fluid retention and ascites or overlooked owing to measurement error or patients’ inaccurate recall. Measurement of muscle mass is also challenging in the clinic. MUMA measurement is accessible but requires special training to ensure measurement consistency and minimize interpersonnel error. DXA and BIA are not readily available at cancer centers or typically ordered or reimbursed for cancer patients. Muscle mass can be determined from diagnostic CT scans, often readily available in oncology practice. However, CT measurements of muscle require both specialized software and training.9 Another complicating factor is the large discrepancy among different measurement methods in detecting low muscle mass. Blauwhoff-Buskermolen et al (2017) reported that prevalence of cachexia in the same group of cancer patients varied from 37% with MUMA as a measurement method to 48% with BIA.10 This underscores the need for revisitin

g current cutoffs for each method. Finally, the suitability of these cutoffs for different ethnicities and races requires further investigation.11 Functional assessments might ultimately complement or supersede body composition measurements. Grip strength has been shown to correlate with sarcopenia, inflammation, and survival,12 for example, and stair climb power and upper body strength associate to cachexia.13 However, robust data to support specific functional assessments in diagnosis, staging, or monitoring of cachexia are currently lacking.14

More-recent efforts to define and classify cachexia include a grading system incorporating both BMI and history of weight loss15; criterion values for food intake impairment and the inflammatory biomarker C-reactive protein (CRP)16; the combination of weight loss, BMI, and MUMA17; a combination of routine biochemistry with food intake, weight loss, and performance status, among others18; or even the abridged Patient-Generated Subjective Global Assessment.19 Against this backdrop of new studies, an expert panel is currently engaged in review of these and other grading systems to develop a new consensus framework for the diagnosis and staging of cancer cachexia.

MANIFESTATIONS AND MECHANISMS OF CANCER CACHEXIA

Anker et al estimated that 527,100 US patients in 2014 and 800,300 European Union patients in 2013 suffered from any kind of cancer cachexia.20 Findings differ, but generally, cachexia is most prevalent and severe in cancers of the upper gastrointestinal tract, with incidence of cachexia in pancreatic and liver cancers reaching 70%–85%.21, 22 Over half of patients with gastroesophageal and head and neck cancers will suffer cachexia, along with 50% of patients with non–small cell lung cancer. Cachexia is significant in patients with breast (25%) and prostate (15%) cancer also. It is believed that weight loss severity increases with disease progression, such that most patients with metastatic disease develop cachexia.23 Magnitude of weight loss generally follows prevalence among disease conditions, with the greatest average weight loss in gastrointestinal cancers and least in breast and prostate cancers.

Importantly, although patients with severe cachexia become emaciated, cachexia is distinct from starvation. Anorexia is a major though not a solo player in cachexia. Large numbers of patents with advanced cancer report loss of appetite, early satiety, or both leading to weight loss and malnutrition.24, 25 Multiple factors contribute to cancer-associated appetite changes—notably, depression and anxiety due to diagnosis and/or therapy. Nausea and vomiting are common side effects of chemotherapy, and both radio and chemotherapy can cause stomatitis and esophagitis as side effects, leading to a further decrease in food intake.25 Factors produced by tumors, such as lactic acid, or caused by host-tumor interaction, such as inflammatory cytokines, also cause appetite suppression through direct action on the hypothalamus.26 However, the limited effectiveness of nutrition support and dietary counseling in improving cancer cachexia27, 28 highlights the role of metabolic dysregulation in weight loss in cachexia.

Despite the shared outcome of weight loss with starvation and protein malnutrition, cancer cachexia manifests unique metabolic reprogramming and behavior, as reviewed by Olson and colleagues.29 Under starvation, resting metabolic rate decreases to minimize energy expenditure, with a preferential utilization of fat stores over lean mass to meet energy demands. However, patients with cachexia show an increase in resting metabolic rate compared with patients with precachexia, followed by a decrease during late stages of cachexia that is probably due to the depletion of energy stores. Behaviorally, starved subjects exhibit increased appetite and foraging activity searching for a food source. Patients with cancer cachexia, however, display decreased appetite and feeding disinterest. Even though there is an increase in catabolism of muscles in protein malnutrition, possibly to compensate for lacking amino acid(s), it is much milder than what happens in cachexia. Like individuals experiencing starvation, protein-malnourished individuals exhibit an increase in foraging activity and appetite—however, in this case, to protein-rich food.29

Muscle and fat wasting are prominent hallmarks of cancer cachexia. In cachexia, muscle and lipid catabolism are estimated to rise by 40%–60% and 30%–80%, respectively. Muscle wasting is mediated by an increase in protein-degradation rate and suppression of protein synthesis.30, 31 Both the ubiquitin-proteasome system and autophagy play a role in protein degradation.32-34 The decrease in protein synthesis can, at least partially, be attributed to suppression of the mammalian target of rapamycin complex 1 (mTORC1) signaling that induces protein synthesis.35 In addition, a recent study has pointed out a possible role for decreased ribosomal capacity in the downregulation of muscle protein synthesis through downregulation of ribosomal DNA.36 Cardiac atrophy in patients with advanced cancer, involving a reduction in both the size and number of cardiac muscle fibers, has been documented for many years,37 and heart failure due to cardiac muscle wasting is hypothesized to play a role in high mortality among patients with cachexia.38 White adipose tissue (WAT) wasting is an early step in cancer cachexia. The importance of adipose tissue wasting is indicated by a study showing that Adipose triglyceride lipase (ATGL) lipase knockout mice were not only protected from WAT loss but also had attenuated muscle loss.39 In addition to lipolysis, at least in rodents, WAT undergoes a process called browning that is characterized by shifting from energy-storing phenotype (white) to energy-spending phenotype (brown) through upregulation of Uncoupling Protein 1 (UCP1) protein that uncouples the electron transport chain from adenosine triphosphate (ATP) synthesis. This, in turn, contributes to an increase in energy expenditure seen in cachectic animals.40 Recent evidence indicates that inflammation-induced lipolysis from adipose tissue in cancer cachexia contributes to myofiber atrophy and is additive to inflammation-induced protein catabolism in muscle, suggesting that adipose loss can drive muscle loss in cancer.41

CIRCULATING MEDIATORS OF CACHEXIA

Cachexia results from the host response to the tumor. As such, inflammatory cytokines produced at the tumor-host interface are major mediators of cancer cachexia.42 Major players in this interaction include the cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). IL-6 is overexpressed in patients with cancer cachexia compared with patients with cancer but not cachexia.43, 44 IL-6 promotes lipolysis and browning of WAT.45 Treatment of myotubes with IL-6 induces autophagy46 and inhibits protein synthesis through suppression of the mTORC1 pathway.35 In models of cancer cachexia, inhibition of IL-6 and downstream Stat3 signaling alleviates weight loss and muscle wasting.33, 47, 48 Some studies have even reported favorable response to anti—IL-6 antibody therapy in patients with cancer cachexia, making it a promising drug target.49, 50 TNF-α inhibits expression of Glucose transporter type 4 (GLUT-4), thus inhibiting glucose uptake in adipose and promoting lipolysis. TNF and other inflammatory cytokines can also activate Nuclear factor kappa B (NF-KB) signaling in muscles, which in turns inhibits myogenic differentiation and upregulates expression of genes involved in the ubiquitin-proteasome system.42

The transforming growth factor-β (TGF-β) family members activin, myostatin, and growth/differentiation factor 15 (GDF-15) have been interrogated in cancer cachexia to the point of clinical trials. Exogenous administration of each of these induces cachexia.51, 52 Activin is produced by the tumor and/or host in experimental systems of pancreatic, ovarian, colon, and other cancer cachexia, and its inhibition with neutralizing antibodies or a soluble receptor trap mitigates wasting in the absence or presence of antitumor therapy.53-57 Unfortunately, a phase 2 trial of an anti-activin antibody, bimagrumab, failed to show promise in patients with cancer cachexia due to lung or pancreatic cancer (ClinicalTrials.gov NCT01433263); bimagrumab is now under investigation to promote fat loss in diabesity.58 Targeting of the related factor, myostatin, which plays an essential role in limiting muscle mass and binds the same receptors as activin, also failed to confer clinical benefit in a phase 2 trial of patients with pancreatic cancer.59 GDF-15 is overexpressed in most inflammatory disease conditions and has been shown to promote anorexia through nausea and emesis.60, 61 GDF-15 is increased in human and experimental cancer cachexia.62 Neutralization of GDF-15 signaling through GDNF Family Receptor Alpha Like (GFRAL)63 reduces nausea and vomiting, improves food intake, and restores body weight in rodent models of cancer cachexia and cancer therapy.64 Clinical studies are underway to determine the efficacy of GDF-15/GFRAL neutralization in patients with cancer cachexia.

Along with these well-described molecular targets, preclinical studies have led to a considerable expansion of causal mediators of cancer cachexia of late. Rodent studies have implicated tumor-derived Fibroblast growth factor-inducible 14 (Fn14),65 extracellular Heat shock protein (HSP70) and HSP90,66 and leukemia inhibitory factor,67 along with host-derived Ataxin-10,68 Vascular endothelial growth factor A (VEGF-A),69 lipocalin 2,70 and tumor/host IL-8,71 among others.

MANAGEMENT OF CANCER CACHEXIA

Multiple recent consensus guidelines for the management of cancer cachexia highlight the struggle to find effective therapies for cancer cachexia. In 2017, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommended (1) screening for nutrition risk regardless of BMI or history of weight loss; (2) assessment of food intake, body composition, inflammation, energy expenditure, and physical function; and (3) treatment with individualized multimodal therapy to improve nutrition intake, lessen inflammation and metabolic stress, and increase physical activity.72 By contrast, the American Society of Clinical Oncology (ASCO) in 2020 recommended only dietary counseling and appropriate use of corticosteroids and progesterone analogues.73 Both ESPEN and ASCO stressed that artificial feeding (enteral and parenteral) should only be applied for patients with impaired oral intake or intestinal dysfunction. They advise against nonconditional tube feeding, given no proven benefit, and to avoid unnecessary complications such as diarrhea, infection, refeeding syndrome, etc.72 In 2021, the European Society of Medical Oncology (ESMO) confirmed the need for (1) nutrition screening and (2) comprehensive assessments of the patient's clinical, psychological, and social condition, along with medications and tumor status, to (3) arrive at a tailored intervention addressing nutrition, social support, and exercise; recommending corticosteroids, olanzapine, and progestins to improve appetite; and cautioning the risk of serious side effects, including thromboembolism in the case of progestins.74

Malnutrition is prevalent among patients with cancer owing to disease- and/or therapy-associated gastrointestinal dysfunction or anorexia.75 Malnutrition decreases QOL and increases infection risk, treatment toxicity, and mortality.76, 77 Countering malnutrition in cancer patients requires early and continuous nutrition screening, regardless of patient weight/BMI,78 to identify patients at risk of malnutrition and to ensure early intervention. At diagnosis, all cancer patients should receive nutrition counseling to educate them about their energy, protein, and micronutrient needs and practices to maintain lean mass. Screening tools should check for signs of anorexia and changes in appetite and physical function in addition to symptoms that may affect food intake, such as constipation and nausea.72, 79 When possible, using a body composition analysis technique can facilitate early detection of sarcopenia and cachexia, which may be masked in obese patients.78 Measures of systemic inflammation level, such as Glasgow Prognostic Score,80 which depends on serum levels of CRP and albumin, can help to predict which patients are at risk of malnutrition and cachexia.81 Calorimetry measures can enhance accurate estimation of energy and protein needs79—notably, that resting energy expenditure is enhanced in some patients with cachexia.28 When needed, a personalized nutrition management plan should be developed, and suitable nutrition supplements can be provided.72, 79

Progesterone analogues are synthetic versions of female hormone progesterone that were shown to improve appetite through unknown mechanism(s). Megestrol acetate (MA), a widely investigated analogue, was approved by the US Food and Drug Administration (FDA) in 1993 as a therapy for anorexia, cachexia, and unexplained weight loss in AIDS patients.82 Clinical trials have shown a positive effect of MA on patients with cancer cachexia in terms of their appetite and non-fluid weight gain.83, 84 However, reported effects of MA treatment on QOL were inconsistent, probably because of variation in the tools used to assess QOL, patients’ inclusion and exclusion criteria, and/or used dosage. Major side effects include edema, impotence in male patients, and, to a lesser extent, thrombosis.82, 85

Corticosteroids are synthetic analogues of steroid hormones—more precisely, glucocorticoids. Like glucocorticoids, corticosteroids have an anti-inflammatory effect.86 They are frequently used in palliative care to improve anorexia, fatigue, pain, and QOL.87, 88 They are also an established treatment for chemotherapy-associated nausea and vomiting.89 Clinical trials showed that corticosteroids improve anorexia and fatigue in cancer patients.90, 91 Many mechanisms may mediate steroids’ positive effects: maintenance of physiological levels of glucocorticoids that are necessary for general well-being, anti-inflammatory effect, and inhibition of prostaglandins and substance P production (both of which are implicated in vomiting response92). Treatment usually lasts 7–14 days, likely to avoid the notorious side effects of steroids. Major side effects include hyperglycemia, immune suppression, and adrenal suppression.93 However, adverse effects are usually observed with higher doses and/or long-term treatment.

PRECLINICAL MODELING OF CANCER CACHEXIA

Challenges to defining appropriate nutrition or other targeted interventions for cancer cachexia include low strength of evidence from clinical trials, as reflected in the consensus guidelines, but also a scarcity of robust, rigorous, and reproduced studies in preclinical models. Although much of what we know about cancer cachexia has been learned through rodent models, most mechanisms have been inferred from a small number of models with rather low fidelity to human tumor biology. Such mechanisms are generally extrapolated to diverse cancer types and treatment contexts without robust direct experimental testing. Although such studies have pointed to important biological underpinnings and revealed potential targets, almost no studies of interventions for cancer cachexia have been tested in the context of both a tumor and a clinical therapy. Thus, the current state of cancer cachexia research is akin to the early days of cancer research, in which tumors, mechanisms, and treatments were conflated. Hence, there is an opportunity to improve the preclinical modeling of this condition. With the intent of spurring additional research in mechanisms of cancer cachexia, particularly among nutrition experts, we review here the more historical models as well as newer models as the field grows in sophistication.

Lewis lung carcinoma

Lewis lung carcinoma (LLC) cells were isolated from spontaneous carcinoma in the lung of a C57BL mouse. In 1992, Ohira et al reported that implantation of LLC cells transfected with IL-6 complementary DNA in C57BL/6 mice induces a cachexia-like phenotype.94 The model improved over time, and wild-type LLC cells are now implanted intramuscularly to induce cachexia. After 2–3 weeks of implantation, this model exhibits a decline in physical activity, increased systemic lipid oxidation, and subsequent fat and muscle wasting without appreciable reduction in energy intake compared with that of normal controls.95 Muscle loss correlates to tumor burden and is due to an increase in protein-degradation rate, mainly through ATP-dependent proteolysis,34, 96 without change in protein synthesis rate. This leads to a decline in muscle and about 5% loss in bone density,34 as well as cardiac atrophy.97 Recent studies have revealed alterations of diaphragm function, hepatic metabolism, and the gut microbiome in LLC cachexia. This model has revealed important roles for host-derived initiators of cachexia as well as potential therapeutics, in part because of its compatibility with C57BL/6 strains of genetically modified mice. However, limitations include the ectopic tumor location, low tumor resemblance to human lung carcinomas with little complexity in the microenvironment, high heterogeneity in tumor size, and short time course.

C26 colon carcinoma

The C26 colon cancer model, heavily used in cancer cachexia, was originally developed by Tanaka et al98 and later was molecularly, cellularly, and physiologically characterized.99 This model is generated by subcutaneous or intramuscular injection of C26 murine colon cancer cells into CD2F1 or BALB/c mice. The mice usually show weight loss with fat and muscle wasting within 15 days of implantation without significant reduction in food intake. This is accompanied by hyperglycemia, an acute phase response, and an increase in serum levels of inflammatory cytokines,98 notably IL-6,47, 100 which was shown to be downstream of the related cytokine, leukemia inhibitor factor. The mice also exhibit a decrease in muscle strength and increase in fatigability.99 By the time of euthanasia, weight loss reaches up to 40% in carcass weight compared with that of controls.98 Investigators have used intrasplenic injection of C26 cells to produce liver metastases to model metastatic colorectal cancer, resulting in greater cachexia severity than that of the original model.

Genetic model of intestinal cancer

Apcmin mice are heterogenous for a truncating mutation in adenomatous polyposis coli (APC) gene.101 This gene encodes a tumor suppressor protein that regulates Wnt signaling pathway,102 and it is frequently mutated in both hereditary and sporadic colorectal adenomas and carcinomas.103, 104 This model develops spontaneous intestinal adenomas and tumors detectable at 4 weeks of age.105 Early cachexia is observed around 16 weeks of age.33 The mice exhibit both fat and muscle loss without change in food intake compared with wild-type controls. They show an increase in the rate of muscle protein degradation initially through ATP-dependent ubiquitination system and then by ATP-independent autophagy as well at more-advanced stages.33 Also, the plasma IL-6 level is elevated in this model and has been shown to mediate muscle wasting in this model.33 These mice develop cardiac atrophy106; however, cardiac muscle loss appears to be mediated by autophagy and not the ubiquitin-proteasome system as in skeletal muscle. Both skeletal and cardiac muscle wasting is accompanied by a decrease in activation of mTOR signaling pathway that activates protein synthesis.33, 106 As in humans, polyp burden in Apcmin is influenced by diet107 and genetic factors. Thus, traditionally, they are kept at C57BL/6J background. Although much has been learned about the mechanisms of cancer cachexia in this model, including sex specificity of cachexia mechanisms and phenotypes108, 109 and bone loss110, the prevalence of intestinal polyps over colon tumors limits the utility of this mouse for modeling colorectal cancer cachexia.

Genetically engineered models of pancreatic cancer

Tumor suppressor Trp53 and proto-oncogene Kras are mutated in >50% and 80%, respectively, of pancreatic ductal adenocarcinoma (PDAC) patients. Using this knowledge, Hingorani et al employed the Cre-Lox system to target a Kras activating mutation and Trp53 dominant negative mutation into mouse pancreatic cells, generating the first genetically engineered KPC PDAC mouse model.111 Disease burden reaches significance levels in these mice as early as 10 weeks of age. These tumors are highly metastatic, with a preference of liver and lungs. Most of the animals develop cachexia and achieve 100% mortality by 12 months. These and related strains also show both muscle and WAT wasting.112, 113 The spontaneous occurrence of tumors in this model and the relatively long survival of tumor-bearing mice allow the study of cachexia throughout different progression stages.

Orthotopic pancreatic tumor models

Several groups have isolated cell lines from PDAC lesions of KPC mice and implant them into the pancreases of recipient mice as syngeneic allograft giving rise to KPC orthotopic model.41, 114, 115 Such models exhibit anorexia, reflected by decreased food intake around 8 days after implantation. They also show loss of both lean mass and fat and decreased locomotor activity. IL-6 and IL-6 trans-signaling via soluble IL-6 receptor seem to play a significant role in this model of cachexia.41 Usually, mortality is reached 14–21 days after implantation.114 A clear limitation of this model is that the observed phenotypes depend largely on the cell line used, which varies among different laboratories. Use of highly characterized lines—specifically, multiple isolates of the several defined molecular phenotypes in PDAC—across laboratories would enable replication and improve the rigor and reproducibility of results.

Other cancer types and metastatic disease

In addition to those above, novel models used in pivotal mechanistic studies have included cell implantation of variant isolates of lung adenocarcinoma,116 renal cell carcinoma,117 ovarian cancer,118 and other primary tumors (reviewed in Tomasin et al119), as well as genetic models of lung cancer120, 121 and others, but there exist only a handful of studies for each to date. Given the prevalence of cachexia in patients with metastatic disease, investigators have also sought to model cachexia in mice with induced metastasis. This has included the MMTV-PyMT transgenic model of metastatic mammary cancer122 as well as intratibial123 and intracardiac injection124 to induce osteolytic breast tumors, along with the previously mentioned intrasplenic injection of colon cancer to induce seeding of tumors in the liver.125 Implantation of tumor cells followed by resection and relapse led to the development of multiple metastatic cancer cachexia models by Wang et al.126 However, overall use of metastatic models for cachexia research has been limited to a handful of laboratories.119

In general, cancer cachexia models that use cell lines to induce cancer share common disadvantages. For example, tumors in these models can reach up to 10% of body weight,99 which typically does not happen in patients with cachexia-associated tumors. The location of implanted cancer cells (ectopic vs orthotopic) is also likely to affect tumor microenvironment and hence cancer cell behavior. Orthotopic vs ectopic implantation of PDAC cells has been shown to produce different cachexia phenotypes.114 A study has shown that difference in cells’ storage condition affects plasma IL-6 levels and degree of decline in voluntary wheel-running activity as a measure of fatigue in the C26 model.127 Thus, possible effects of passage number, number of implanted cells, and suspension buffer (Matrigel, phosphate-buffered saline, media) on observed phenotype need further investigation. Furthermore, fast disease progression does not allow the study of early stages of cachexia. Finally, it is not known if cachexia in different patients, disease contexts, or therapies is driven by different mechanisms. Increasing the sophistication of models should begin to address these limitations and opportunities for discovery.

CONCLUSIONS

Despite considerable effort by a rather small number of dedicated researchers around the globe, cancer cachexia remains a major unmet medical need. This is to be expected, however, given the relatively low research volume in cancer cachexia to date. As of August 2021, the 4433 primary publications on “cancer cachexia” in PubMed constituted only 0.12% of all 3,718,027 papers on “cancer.” The 192 interventional clinical trials in cancer cachexia registered on ClinicalTrials.gov were only 0.28% of the 68,551 interventional trials for cancer. This contrasts with the 7040 interventional trials for lung cancer, a disease in which substantial progress has been made in the past few years. Importantly, such statistics hide the current state of exponential growth in research and trials in cancer cachexia (Figure 1), in addition to the growth in investment from funding agencies and pharmaceutical companies and considerable activity in looking for pathways to regulatory approvals.20 It is expected that continued growth, investment, and coordination of research in this topic will ultimately yield robust biomarkers, widely accepted classification and staging algorithms, targetable pathways, pivotal clinical trials, and ultimately, cures.

Growth in cancer cachexia research. Primary publications by year returned when searching for “cancer” (left axis, blue) vs “cancer cachexia” (right axis, pink) in PubMed, accessed August 2021

ACKNOWLEDGMENTS

Teresa A. Zimmers is supported in part by grants from the US National Cancer Institute (P01CA236778 and P30CA082709), National Institute of General Medical Sciences (R01GM137656), National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR072581), and the US Department of Veterans Affairs (I01CX002046 and I01BX004177).

FINANCIAL DISCLOSURES

The content of this article was presented during the virtual course Comprehensive Nutritional Therapy: Tactical Approaches in 2021 (Part 1, March 19, 2021; Part 2, March 20, 2021), which was organized by the ASPEN Physician Engagement Committee and preceded the ASPEN 2021 Nutrition Science & Practice Conference. The author(s) received a modest monetary honorarium. The conference recordings were posted to the ASPEN eLearning Center https://aspen.digitellinc.com/aspen/store/6/index/6.