Skip to content
2000
Volume 11, Issue 1
  • ISSN: 2212-697X
  • E-ISSN: 2212-6988

Abstract

Cancer cachexia is a complex, multifactorial syndrome commonly seen in patients with advanced cancer. Characterized by progressive weight loss, muscle and fat wasting, systemic inflammation, and impaired immune responses, cachexia involves a dysregulated host-tumor interaction that alters metabolism and disrupts immune homeostasis. Unlike malnutrition, cancer cachexia significantly affects the quality of life (QoL), treatment response, and overall survival. Despite its clinical relevance, particularly in cancers such as pancreatic, lung, liver, and gastrointestinal malignancies, there is a lack of standardized, effective treatments, and the immunological mechanisms underlying cachexia are not yet fully understood. Therefore, a better understanding of not just the pathways but also the underlying factors that influence the occurrence of cancer cachexia is vital to develop targeted therapeutic strategies. This review aims to explore the pathophysiology of cancer cachexia and also highlight a few key factors influencing cachexia occurrence, such as age, gender, comorbidities, cancer type, and stage. It also evaluates current and emerging therapeutic approaches, potential immunomodulatory strategies, and identifies the gaps in research and proposes future directions for the personalized management of cancer cachexia. Therapeutic strategies such as exercise, nutritional support, ghrelin agonists, myostatin inhibitors, and anti-inflammatory agents offer partial benefits. Promising immunomodulatory approaches, including agents like R-ketorolac and gut microbiota-targeted therapies, demonstrate potential in some clinical studies. However, cancer cachexia necessitates a multimodal treatment framework incorporating immunological insights and integrating physical activity and nutritional support along with pharmacological intervention, personalized as per the patients’ needs.

Loading

Article metrics loading...

/content/journals/ccand/10.2174/012212697X400236250630115449
2025-07-14
2025-12-07
Loading full text...

Full text loading...

References

  1. ArendsJ. StrasserF. GonellaS. Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines.ESMO Open20216310009210.1016/j.esmoop.2021.100092 34144781
    [Google Scholar]
  2. PandeyS. BradleyL. Del FabbroE. Updates in cancer cachexia: Clinical management and pharmacologic interventions.Cancers2024169169610.3390/cancers16091696 38730648
    [Google Scholar]
  3. ZhangL. BonomiP.D. Immune system disorder and cancer-associated cachexia.Cancers2024169170910.3390/cancers16091709 38730660
    [Google Scholar]
  4. GaaferO.U. ZimmersT.A. Nutrition challenges of cancer cachexia.JPEN J. Parenter. Enteral Nutr.202145S2162510.1002/jpen.2287 34897740
    [Google Scholar]
  5. VagnildhaugO.M. BalstadT.R. AlmbergS.S. A cross-sectional study examining the prevalence of cachexia and areas of unmet need in patients with cancer.Support. Care Cancer20182661871188010.1007/s00520‑017‑4022‑z 29274028
    [Google Scholar]
  6. RyanA.M. PowerD.G. DalyL. CushenS.J. Ní BhuachallaĒ. PradoC.M. Cancer-associated malnutrition, cachexia and sarcopenia: The skeleton in the hospital closet 40 years later.Proc. Nutr. Soc.201675219921110.1017/S002966511500419X 26786393
    [Google Scholar]
  7. KimuraM. NaitoT. KenmotsuH. Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer.Support. Care Cancer20152361699170810.1007/s00520‑014‑2534‑3 25430482
    [Google Scholar]
  8. BiswasA.K. AcharyyaS. The etiology and impact of muscle wasting in metastatic cancer.Cold Spring Harb. Perspect. Med.20201010a03741610.1101/cshperspect.a037416 31615873
    [Google Scholar]
  9. FuruseJ. OsugiF. MachiiK. NiibeK. EndoT. Effect of cancer cachexia on first-line chemotherapy in patients with advanced pancreatic cancer: A claims database study in Japan.Int. J. Clin. Oncol.202429445646310.1007/s10147‑024‑02467‑6 38353906
    [Google Scholar]
  10. EzeokeC.C. MorleyJ.E. Pathophysiology of anorexia in the cancer cachexia syndrome.J. Cachexia Sarcopenia Muscle20156428730210.1002/jcsm.12059 26675762
    [Google Scholar]
  11. SiddiquiJ.A. PothurajuR. JainM. BatraS.K. NasserM.W. Advances in cancer cachexia: Intersection between affected organs, mediators, and pharmacological interventions.Biochim. Biophys. Acta Rev. Cancer20201873218835910.1016/j.bbcan.2020.188359 32222610
    [Google Scholar]
  12. WatanabeH. OshimaT. The latest treatments for cancer cachexia: An overview.Anticancer Res.202343251152110.21873/anticanres.16188 36697073
    [Google Scholar]
  13. BrownJ. Protein imbalance in the development of skeletal muscle wasting in tumour-bearing mice.J. Cachexia Sarcopenia Muscle2019103712210.1002/jcsm.12354 31246374
    [Google Scholar]
  14. AlvesM.J. FiguerêdoR.G. AzevedoF.F. Adipose tissue fibrosis in human cancer cachexia: The role of TGFβ pathway.BMC Cancer201717119010.1186/s12885‑017‑3178‑8 28288584
    [Google Scholar]
  15. SetiawanT. SariI.N. WijayaY.T. Cancer cachexia: Molecular mechanisms and treatment strategies.J. Hematol. Oncol.20231615410.1186/s13045‑023‑01454‑0 37217930
    [Google Scholar]
  16. MolfinoA. CarlettiR. ImbimboG. Histomorphological and inflammatory changes of white adipose tissue in gastrointestinal cancer patients with and without cachexia.J. Cachexia Sarcopenia Muscle202213133334210.1002/jcsm.12893 34939367
    [Google Scholar]
  17. LuanY. ZhangY. YuS.Y. Development of ovarian tumour causes significant loss of muscle and adipose tissue: A novel mouse model for cancer cachexia study.J. Cachexia Sarcopenia Muscle20221321289130110.1002/jcsm.12864 35044098
    [Google Scholar]
  18. MachadoS.A. Pasquarelli-do-NascimentoG. da SilvaD.S. Browning of the white adipose tissue regulation: New insights into nutritional and metabolic relevance in health and diseases.Nutr. Metab.20221916110.1186/s12986‑022‑00694‑0 36068578
    [Google Scholar]
  19. RuanG.T. GeY.Z. XieH.L. Association between systemic inflammation and malnutrition with survival in patients with cancer sarcopenia—a prospective multicenter study.Front. Nutr.2022881128810.3389/fnut.2021.811288 35198586
    [Google Scholar]
  20. MarieanC.R. TiucăO.M. MarieanA. CotoiO.S. Cancer cachexia: New insights and future directions.Cancers20231523559010.3390/cancers15235590 38067294
    [Google Scholar]
  21. BaracosV.E. MartinL. KorcM. GuttridgeD.C. FearonK.C.H. Cancer-associated cachexia.Nat. Rev. Dis. Primers2018411710510.1038/nrdp.2017.105 29345251
    [Google Scholar]
  22. TakayoshiK. UchinoK. NakanoM. IkejiriK. BabaE. Weight loss during initial chemotherapy predicts survival in patients with advanced gastric cancer.Nutr. Cancer201769340841510.1080/01635581.2017.1267774 28102709
    [Google Scholar]
  23. NiJ. ZhangL. Cancer cachexia: Definition, staging, and emerging treatments.Cancer Manag. Res.2020125597560510.2147/CMAR.S261585 32753972
    [Google Scholar]
  24. PennaF. RubiniG. CostelliP. Immunomodulation: A new approach to cancer cachexia, potentially suitable for aging.Mol. Aspects Med.202410010131810.1016/j.mam.2024.101318 39260232
    [Google Scholar]
  25. ArgilésJ.M. BetancourtA. Guàrdia-OlmosJ. Validation of the CAchexia SCOre (CASCO). Staging cancer patients: The use of miniCASCO as a simplified tool.Front. Physiol.201789210.3389/fphys.2017.00092 28261113
    [Google Scholar]
  26. LawM.L. Cancer cachexia: Pathophysiology and association with cancer-related pain.Front. Pain Res.2022397129510.3389/fpain.2022.971295 36072367
    [Google Scholar]
  27. NishieK. YamamotoS. NagataC. KoizumiT. HanaokaM. Anamorelin for advanced non-small-cell lung cancer with cachexia: Systematic review and meta-analysis.Lung Cancer2017112253410.1016/j.lungcan.2017.07.023 29191597
    [Google Scholar]
  28. NishieK. NishieT. SatoS. HanaokaM. Update on the treatment of cancer cachexia.Drug Discov. Today202328910368910.1016/j.drudis.2023.103689 37385369
    [Google Scholar]
  29. BianchiniC. BonomoP. BossiP. CaccialanzaR. FabiA. Bridging gaps in cancer cachexia Care: Current insights and future perspectives.Cancer Treat. Rev.202412510271710.1016/j.ctrv.2024.102717 38518714
    [Google Scholar]
  30. FerraraM. SamadenM. RuggieriE. VénéreauE. Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene.Front. Cell Dev. Biol.20221096034110.3389/fcell.2022.960341 36158184
    [Google Scholar]
  31. MarcecaG.P. LondheP. CaloreF. Management of cancer cachexia: Attempting to develop new pharmacological agents for new effective therapeutic options.Front. Oncol.20201029810.3389/fonc.2020.00298 32195193
    [Google Scholar]
  32. ZhangL. A new study uncovering the cause of health deterioration and mortality in late-stage cancer patients.J. Cancer Immunol.20246311912410.33696/cancerimmunol.6.092
    [Google Scholar]
  33. YuY. YanL. HuangT. WuZ. LiuJ. Cancer cachexia reduces the efficacy of immune checkpoint inhibitors in cancer patients.Aging20241665354536910.18632/aging.205652 38466657
    [Google Scholar]
  34. BaazimH. Antonio-HerreraL. BergthalerA. The interplay of immunology and cachexia in infection and cancer.Nat. Rev. Immunol.202222530932110.1038/s41577‑021‑00624‑w 34608281
    [Google Scholar]
  35. McGovernJ. DolanR.D. SkipworthR.J. LairdB.J. McMillanD.C. Cancer cachexia: A nutritional or a systemic inflammatory syndrome?Br. J. Cancer2022127337938210.1038/s41416‑022‑01826‑2 35523879
    [Google Scholar]
  36. ShuklaS.K. MarkovS.D. AttriK.S. Macrophages potentiate STAT3 signaling in skeletal muscles and regulate pancreatic cancer cachexia.Cancer Lett.2020484293910.1016/j.canlet.2020.04.017 32344015
    [Google Scholar]
  37. OlguínJ.E. FernándezJ. SalinasN. Adoptive transfer of CD4+Foxp3+ regulatory T cells to C57BL/6J mice during acute infection with Toxoplasma gondii down modulates the exacerbated Th1 immune response.Microbes Infect.201517858659510.1016/j.micinf.2015.04.002 25899946
    [Google Scholar]
  38. VanhoutteG. van de WielM. WoutersK. Cachexia in cancer: What is in the definition?BMJ Open Gastroenterol.20163100009710.1136/bmjgast‑2016‑000097 27843571
    [Google Scholar]
  39. SayersJ. SkipworthR.J.E. LairdB.J.A. Cancer cachexia – Adopting a systems wide approach.Curr. Opin. Clin. Nutr. Metab. Care202326439339810.1097/MCO.0000000000000951 37265093
    [Google Scholar]
  40. YuY. ZengD. OuQ. Association of survival and immune-related biomarkers with immunotherapy in patients with non–small cell lung cancer: A meta-analysis and individual patient–level analysis.JAMA Netw. Open201927e196879e910.1001/jamanetworkopen.2019.6879 31290993
    [Google Scholar]
  41. MiyawakiT. NaitoT. KodamaA. Desensitizing effect of cancer cachexia on immune checkpoint inhibitors in patients with advanced NSCLC.JTO Clin. Res. Rep.20201210002010.1016/j.jtocrr.2020.100020 34589927
    [Google Scholar]
  42. BossiP. DelrioP. MascheroniA. ZanettiM. The spectrum of malnutrition/cachexia/sarcopenia in oncology according to different cancer types and settings: A narrative review.Nutrients2021136198010.3390/nu13061980 34207529
    [Google Scholar]
  43. FerrerM. AnthonyT.G. AyresJ.S. Cachexia: A systemic consequence of progressive, unresolved disease.Cell202318691824184510.1016/j.cell.2023.03.028 37116469
    [Google Scholar]
  44. DunneR.F. LohK.P. WilliamsG.R. JatoiA. MustianK.M. MohileS.G. Cachexia and sarcopenia in older adults with cancer: A comprehensive review.Cancers20191112186110.3390/cancers11121861 31769421
    [Google Scholar]
  45. DupontJ. Revised sarcopenia consensus: Are we missing the preclinical stage? Online comment on.Age Ageing201848111
    [Google Scholar]
  46. FerrucciL. FabbriE. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty.Nat. Rev. Cardiol.201815950552210.1038/s41569‑018‑0064‑2 30065258
    [Google Scholar]
  47. NelkeC. DziewasR. MinnerupJ. MeuthS.G. RuckT. Skeletal muscle as potential central link between sarcopenia and immune senescence.EBioMedicine20194938138810.1016/j.ebiom.2019.10.034 31662290
    [Google Scholar]
  48. GeppertJ. WalthA. Terrón ExpósitoR. Aging aggravates cachexia in tumor-bearing mice.Cancers20211419010.3390/cancers14010090 35008253
    [Google Scholar]
  49. ZhongX. ZimmersT.A. Sex differences in cancer cachexia.Curr. Osteoporos. Rep.202018664665410.1007/s11914‑020‑00628‑w 33044689
    [Google Scholar]
  50. PryceB.R. WangD.J. ZimmersT.A. OstrowskiM.C. GuttridgeD.C. Cancer cachexia: Involvement of an expanding macroenvironment.Cancer Cell202341358158410.1016/j.ccell.2023.02.007 36868225
    [Google Scholar]
  51. HetzlerK.L. HardeeJ.P. PuppaM.J. Sex differences in the relationship of IL-6 signaling to cancer cachexia progression.Biochim. Biophys. Acta Mol. Basis Dis.20151852581682510.1016/j.bbadis.2014.12.015 25555992
    [Google Scholar]
  52. BryantJ. YiP. MillerL. PeekK. LeeD. Potential sex bias exists in orthopaedic basic science and translational research.J. Bone Joint Surg. Am.2018100212413010.2106/JBJS.17.00458 29342062
    [Google Scholar]
  53. HaizlipK.M. HarrisonB.C. LeinwandL.A. Sex-based differences in skeletal muscle kinetics and fiber-type composition.Physiology2015301303910.1152/physiol.00024.2014 25559153
    [Google Scholar]
  54. BrownL.R. LairdB.J.A. WigmoreS.J. SkipworthR.J.E. Understanding cancer cachexia and its implications in upper gastrointestinal cancers.Curr. Treat. Options Oncol.202223121732174710.1007/s11864‑022‑01028‑1 36269458
    [Google Scholar]
  55. LiaoW.C. ChenP.R. HuangC.C. Relationship between pancreatic cancer‐associated diabetes and cachexia.J. Cachexia Sarcopenia Muscle202011489990810.1002/jcsm.12553 32100478
    [Google Scholar]
  56. HoltedahlK. Challenges in early diagnosis of cancer: the fast track.20202512
    [Google Scholar]
  57. KaruppannanM. MuthannaF.M.S. Mohd FauziF. Breaking down Cachexia: A narrative review on the prevalence of Cachexia in Cancer patients and its Associated Risk factors.Nutr. Cancer202476540441810.1080/01635581.2024.2321654 38546174
    [Google Scholar]
  58. LoyalaJ.V. DownB. WongE. TanB. Treatment of cachexia in gastric cancer: Exploring the use of anti-inflammatory natural products and their derivatives.Nutrients2024168124610.3390/nu16081246 38674936
    [Google Scholar]
  59. BruggemanA.R. KamalA.H. LeBlancT.W. MaJ.D. BaracosV.E. RoelandE.J. Cancer cachexia: Beyond weight loss.J. Oncol. Pract.201612111163117110.1200/JOP.2016.016832 27858548
    [Google Scholar]
  60. Garcia-CastilloL. RubiniG. CostelliP. Pharmacotherapeutic options for cancer cachexia: Emerging drugs and recent approvals.Expert Opin. Pharmacother.20232491053106510.1080/14656566.2023.2209316 37132359
    [Google Scholar]
  61. BowersM. PetrassoC. McLuskieA. Multicomponent interventions for adults with cancer cachexia: A systematic review.J. Cachexia Sarcopenia Muscle20251621371610.1002/jcsm.13716 40012451
    [Google Scholar]
  62. DevR. Del FabbroE. DalalS. Endocrinopathies and cancer cachexia.Curr. Opin. Support. Palliat. Care201913428629110.1097/SPC.0000000000000464 31567482
    [Google Scholar]
  63. ArendsJ. BaracosV. BertzH. ESPEN expert group recommendations for action against cancer-related malnutrition.Clin. Nutr.20173651187119610.1016/j.clnu.2017.06.017 28689670
    [Google Scholar]
  64. BrahaA. AlbaiA. TimarB. Nutritional interventions to improve cachexia outcomes in cancer—A systematic review.Medicina202258796610.3390/medicina58070966 35888685
    [Google Scholar]
  65. MadedduC. MantovaniG. GramignanoG. MacciòA. Advances in pharmacologic strategies for cancer cachexia.Expert Opin. Pharmacother.201516142163217710.1517/14656566.2015.1079621 26330024
    [Google Scholar]
  66. MolfinoA. AmabileM.I. GiorgiA. MontiM. D’AndreaV. MuscaritoliM. Investigational drugs for the treatment of cancer cachexia: A focus on phase I and phase II clinical trials.Expert Opin. Investig. Drugs201928873374010.1080/13543784.2019.1646727 31347405
    [Google Scholar]
  67. KadakiaK.C. Hamilton-ReevesJ.M. BaracosV.E. Current therapeutic targets in cancer cachexia: A pathophysiologic approach.Am. Soc. Clin. Oncol. Educ. Book2023434338994210.1200/EDBK_389942 37290034
    [Google Scholar]
  68. CrawfordJ. CalleR.A. CollinsS.M. A phase Ib first-in-patient study assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponsegromab in participants with cancer and cachexia.Clin. Cancer Res.202430348949710.1158/1078‑0432.CCR‑23‑1631 37982848
    [Google Scholar]
  69. da FonsecaG.W.P. SatoR. de Nazaré Nunes AlvesM.J. von HaehlingS. Current advancements in pharmacotherapy for cancer cachexia.Expert Opin. Pharmacother.202324562963910.1080/14656566.2023.2194489 36995115
    [Google Scholar]
  70. ChenH. IshiharaM. KazahariH. Efficacy and safety of pharmacotherapy for cancer cachexia: A systematic review and network meta‐analysis.Cancer Med.202413177016610.1002/cam4.70166 39225556
    [Google Scholar]
  71. SandhyaL. Devi SreenivasanN. GoenkaL. Randomized double-blind placebo-controlled study of olanzapine for chemotherapy-related anorexia in patients with locally advanced or metastatic gastric, hepatopancreaticobiliary, and lung cancer.J. Clin. Oncol.202341142617262710.1200/JCO.22.01997 36977285
    [Google Scholar]
  72. Stewart CoatsA.J. HoG.F. PrabhashK. Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non‐small cell lung cancer or colorectal cancer: A randomized, double‐blind, placebo‐controlled, international multicentre phase II study (the ACT‐ONE trial).J. Cachexia Sarcopenia Muscle20167335536510.1002/jcsm.12126 27386169
    [Google Scholar]
  73. PanebiancoC. VillaniA. PotenzaA. Targeting gut microbiota in cancer cachexia: Towards new treatment options.Int. J. Mol. Sci.2023243184910.3390/ijms24031849 36768173
    [Google Scholar]
  74. LeviA. Effect of ketorolac on serum GDF-15 and IL-8 in patients with pancreatic cancer with cachexia.American Society of Clinical Oncology202510.1200/JCO.2025.43.4_suppl.713
    [Google Scholar]
  75. BowersM. CucchiaroB. ReidJ. SleeA. Non‐steroidal anti‐inflammatory drugs for treatment of cancer cachexia: A systematic review.J. Cachexia Sarcopenia Muscle20231462473249710.1002/jcsm.13327 37750475
    [Google Scholar]
/content/journals/ccand/10.2174/012212697X400236250630115449
Loading
/content/journals/ccand/10.2174/012212697X400236250630115449
Loading

Data & Media loading...


  • Article Type:
    Review Article
Keyword(s): anorexia; Cachexia; cancer; homeostasis; immunomodulation; metabolism
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test