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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 4  |  Page : 168-171

Megestrol acetate in cancer cachexia and anorexia: Tertiary care experience


Department of Radiation Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India

Date of Submission08-Sep-2021
Date of Decision14-Sep-2021
Date of Acceptance25-Sep-2021
Date of Web Publication09-Dec-2021

Correspondence Address:
Dr. Kaneez Fatima
Department of Radiation Oncology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_33_21

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  Abstract 


Background: In clinical practice, the management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge. We conducted an observational study to find the effectiveness and safety of megestrol acetate (MA) for the treatment of CACS. Patients and Methods: One hundred patients of advanced cancer were randomly assigned in the study. Patients received MA 160 mg/oral twice daily. The duration of treatment was 8 weeks. Results: The analysis of the study group demonstrated a statistically significant increase from baseline in body weight (P ≤ 0.01), quality of life (P = 0.02), appetite (P = 0.01), and the Eastern Cooperative Oncology Group performance status (P = 0.03). Conclusion: We concluded that MA is effective and safe in the treatment of CACS.

Keywords: Anorexia, cancer cachexia, megestrol acetate, quality of life, weight loss


How to cite this article:
Fatima K, Andleeb A, Hussain I, Sofi MA, Fir A, Qadri SK. Megestrol acetate in cancer cachexia and anorexia: Tertiary care experience. J Radiat Cancer Res 2021;12:168-71

How to cite this URL:
Fatima K, Andleeb A, Hussain I, Sofi MA, Fir A, Qadri SK. Megestrol acetate in cancer cachexia and anorexia: Tertiary care experience. J Radiat Cancer Res [serial online] 2021 [cited 2022 Jun 26];12:168-71. Available from: https://www.journalrcr.org/text.asp?2021/12/4/168/332110




  Introduction Top


As per the American Society of Clinical Oncology guidelines (2015): cancer cachexia is defined through a consensus definition of weight loss of >5% of body weight in the past 6 months or >2%–5% loss of body weight in patients with body mass index of <20 kg/m2 or loss of skeletal muscle mass.[1]

Cancer-related anorexia/cachexia syndrome (CACS) is a multisystem syndrome, characterized by anorexia, weight loss, loss of skeletal muscle and body fats, systemic inflammation, and functional decline of cancer patients.[2],[3],[4] Cancer cachexia affects 50%–80% patients in the advanced stage and is responsible for 20% of cancer-related deaths.[5]

The etiology of cancer cachexia remains unknown. The certain types of cancers such as lung, esophagus, pancreases, and head-and-neck cancers are at a higher risk to experience cancer cachexia than patients with breast cancers and sarcomas.[6]

The cancer cachexia management is challenging because of multiple reasons such as differences in predisposition of cancer types, underlying multiple pathophysiological processes, and concomitant disease process among cancer patients. A number of randomized clinical trials involving variety of agents have been done, but no single gold standard or Food and Drug Administration approved agent exists for cachexia management. In 2005, a systematic review was published, which proves strong evidence in favor of progestins such as megestrol acetate (MA) and short course of corticosteroids as appetite stimulant in cancer patients.[7]

MA is primarily used as an appetite stimulant in a number of conditions and also used as an antineoplastic agent in the treatment of endometrial, breast, and prostate cancers.[8] It can substantially increase appetite in most individuals when given in relatively high doses, even in patients with advanced stages of cancer, hence is often used to boost appetite and induce weight gain in patients with cancer-associated cachexia.[9]


  Patients and Methods Top


Study design

A total of 110 patients were enrolled in the study by the department of radiation oncology between January 2019 and March 2021. Ten patients were excluded from the study because of the following reasons: (1) one patient died; (2) two patients defaulted; (3) five patients developed thromboembolism; and (4) Two patients had edema. Informed consent had been obtained from all patients. The protocol was approved by the Institutional Ethics Committee. Eligible patients received MA 160 mg per oral twice daily for 8 weeks.

Eligibility criteria

Inclusion criteria

The inclusion criteria were as follows: (1) Aged >18 years with histologically confirmed advanced cancer at any site; (2) loss of >5% preillness body weight in the previous 3 months; (3) patients receiving concomitant chemotherapy, radiotherapy, and/or palliative supportive care; (4) life expectancy ≥4 months; and (5) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of II, III, and IV.

Exclusion criteria

The exclusion criteria were as follows: (1) history of hypertension and diabetes mellitus; (2) mechanical obstruction to feeding; (3) history of thromboembolism and edema; and (4) patients on medication that significantly changes patients body metabolism or body weight.

Efficacy endpoints

The efficacy endpoints were evaluated before the start of treatment and then at 8 weeks after the completion of treatment.

Primary endpoints

Body weight was measured with the digital weighing machine available. The body weight scale was used according to the directions provided by the manufacturer. Body weight was measured three times a day before meals. The average of three body weight measurements was adopted.

Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30 V 3.0),[10] which includes five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, nausea and vomiting, and pain), and six single items (dyspnea, insomnia, anorexia, constipation, diarrhea, and financial impact and 1 global QOL scale. It employs a 1-week time frame with a 4-point Likert scale type responses (ranging from not at all to very much) and 7-point response scales (numbered Visual Analog Scales). The scores of the QLQ-C30 (V 3.0) were linearly transformed to a 0–100 numerical scale.

Secondary endpoints

We evaluated appetite with 10-point response scales (numbered Visual Analog Scales).

PS was used according to the ECOG performance score.

Safety endpoints

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V 5.0) was used to classify the adverse events.

Statistical analysis

All statistical analyses were performed using the SPSS software version 26 (IBM SPSS, Chicago, USA). All categorical variables are shown in the form of frequency and percentage. Furthermore, student t-test and Chi-square test were used for significance. All values discussed at 5% level of significance (P < 0.05).

Sample size calculation

The sample size was determined by having Type I error of 0.05 and estimation proportion was 0.11 and estimation of error (d) was 0.06 and our sample size was 100.


  Results Top


A total of 110 patients were enrolled in the study by the department of radiation oncology, between March 2019 and January 2021. Ten patients were dropped from the study. A total of 100 patients were enrolled in the study.

We included patients of Stage III and Stage IV of sites lung, stomach, esophagus, breast, and head-and-neck cancers with the ECOG PS of II and III [Table 1].
Table 1: Clinical characteristics

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Efficacy endpoints

Patients were compared before and after treatment. The comparisons are as follows [Table 2] and [Table 3].
Table 2: Endpoints before and after treatment

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Table 3: Mean changes±standard deviations of the endpoints before and after treatment

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Body weight was significantly improved (P ≤ 0.01) and a significant improvement in the QOL (P = 0.02). The ECOG PS decreased significantly (P = 0.03) and appetite improved significantly (P = 0.01).

Toxicity

The most common toxicities associated were thromboembolism, somnolence, edema, and constipation. The patients who developed thromboembolism were withdrawn from the study. Overall, compliance of the patient was good [Table 4].
Table 4: Toxicities assessed

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  Discussion Top


The management of CACS remains unsatisfied in the field of oncology. The management of cachexia poses significant challenge due to underlying multisystem pathways that play a role in inducing cachexia. In addition, differences in outcomes based on the stage and type of the disease possess extra challenge.

The aim of our study was to find out the possible effective treatment for CACS. As far as the present study is concerned, MA is the most effective treatment for the primary efficacy endpoints (body weight and QOL) and for the secondary endpoints (appetite and ECOG PS).

Weight loss, fatigue, anorexia, and poor QOL are the main symptoms of CACS, which were customarily selected as the efficacy endpoints of CACS.[11],[12]

The mechanism behind CACS is a multisystem inflammatory response. Cytokines IL-6 and tumor necrosis factor-alpha play a vital role in the pathophysiology of CACS.[13],[14]

To treat CACS, a variety of single intervention have had limited success to date. Currently, synthetic progestogen medroxyprogesterone or MA are the only approved drugs for CACS.

The two main mechanisms in cancer cachexia syndrome are a reduced food intake and abnormal host metabolism resulting from the factors produced by the cancer or by the host in response to the cancer such as cytokines.[15] To manage CACS, we need to address both these main mechanisms and this explains why only increasing nutritional intake alone is generally ineffective.[16],[17],[18] The mechanism of synthetic progestogen to treat CACS is related partly to the glucocorticoid activity and the ability to down regulate the proinflammatory cytokines and the release of neuropeptide Y to increase the food intake.[19],[20]

Randomized trials have shown that MA significantly improves appetite resulting in increased food intake, and increased body weight, whereas some trials show no definite improvement in QOL.[21],[22],[23] Another Cochrane database systematic review shows that in cancer patients MA improves the appetite and decreases weight loss, but no overall conclusion about QOL could be drawn.[24]

MA is known to stimulate appetite and weight gain in patients with cancer. Systematic review of 30 trials (30) involving more than four thousand (>4000) patients concluded that appetite and weight was improved in patients with cancer. There was no difference between a low (<800 mg) and a high (>800 mg) daily dose.[25],[26] In our study, we have also used low daily dose of MA 320 mg to treat CACS, and our results are comparable to other trials. We have also observed a significant improvement in the QOL.

The most serious side effects in our study were thromboembolism which required discontinuation of the drug. Edema could result in an unwanted gain in body weight. Therefore, patients suffering from thromboembolism or edema were not included in the study. Overall, the patient compliance was very good.

The only limitation of our study was that lean body mass data were not included as an endpoint. Lean body mass is been used in the evaluation of CACS in recent years.[27] However, in CACS keeping fat mass within optimum levels is still the aim of intervention which can have a positive impact on QOL, treatment response, and prognosis. Therefore, improvement in body weight and QOL could be utilized as the primary endpoint of the CACS study.


  Conclusion Top


We concluded that MA is a safe and effective treatment for CACS.

Financial support and sponsorship

Radiation oncology.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: An international consensus. Lancet Oncol 2011;12:489-95.  Back to cited text no. 1
    
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Zilbermint MF, Dobs AS. Non steroidal selective androgen receptor modulator ostarine in cancer cachexia. Future Oncol 2009;5:1211-20.  Back to cited text no. 2
    
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Madeddu C, Mantovani G. An update on promising agents for the treatment of cancer cachexia. Curr Opin Support Palliat Care 2009;3:258-62.  Back to cited text no. 3
    
4.
Madeddu C, Macciò A, Panzone F, Tanca FM, Mantovani G. Medroxyprogesterone acetate in the management of cancer cachexia. Expert Opin Pharmacother 2009;10:1359-66.  Back to cited text no. 4
    
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Mantovani G. Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer cachexia. Eur Rev Med Pharmacol Sci 2010;14:292-301.  Back to cited text no. 5
    
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Laviano A, Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Therapy inside: Cancer anorexia-cachexia syndrome – When all you can eat is yourself. Nat Rev Clin Oncol 2005;2:158.  Back to cited text no. 6
    
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Yavuzsen T, Davis MP, Walsh D, LeGrand S, Lagman R. Systematic review of the treatment of cancer-associated anorexia and weight loss. J Clin Oncol 2005;23:8500-11.  Back to cited text no. 7
    
8.
Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens – A short review. Postgrad Med J 1978;54 Suppl 2:11-24.  Back to cited text no. 8
    
9.
Becker KL. Principles and Practice of Endocrinology and Metabolism. New York: Lip-pincott, Williams and Wilkins; 2001.  Back to cited text no. 9
    
10.
Masika GM, Wettergren L, Kohi TW, von Essen L. Health-related quality of life and needs of care and support of adult Tanzanians with cancer: A mixed-methods study. Health Qual Life Outcomes 2012;10:133.  Back to cited text no. 10
    
11.
Mantovani G, Macciò A, Lai P, Massa E, Ghiani M, Santona MC. Cytokine involvement in cancer anorexia/cachexia: Role of megestrol acetate and medroxyprogesterone acetate on cytokine downregulation and improvement of clinical symptoms. Crit Rev Oncog 1998;9:99-106.  Back to cited text no. 11
    
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Argiles JM, Lopez-Soriano FJ, Busquets S. Counteracting inflammation: A promissing therapy in cachexia. Crit Rev Oncog 2012;17:253-62.  Back to cited text no. 12
    
13.
Kim HJ, Kim HJ, Yun J, Kim KH, Kim SH, Lee SC, et al. Pathophysiological role of hormones and cytokines in cancer cachexia. J Korean Med Sci 2012;27:128-34.  Back to cited text no. 13
    
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Gordon JN, Green SR, Goggin PM. Cancer cachexia. QJM. 2005;98:779-88. doi:10.1093/qjmed/hci127. Epub 2005 Oct 7. PMID:16214835.  Back to cited text no. 14
    
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Davis MP, Dreicer R, Walsh D, Lagman R, LeGrand SB. Appetite and cancer- associated anorexia: A review. J Clin Oncol 2004;22:1510-7.  Back to cited text no. 15
    
16.
Ramos EJ, Suzuki S, Marks D, Inui A, Asakawa A, Meguid MM. Cancer anorexia-cachexia syndrome: Cytokines and neuropeptides. Curr Opin Clin Nutr Metab Care 2004;7:427-34.  Back to cited text no. 16
    
17.
Laviano A, Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Therapy insight – When all you can eat is yourself. Nat Clin Pract Oncol 2005;2:158-65.  Back to cited text no. 17
    
18.
Mantovani G, Maccio A, Esu S, Lai P, Santona MC, Massa E, et al. Medroxyprogesterone acetate reduces the production of cytokines and serotonin involved in annorexia/cachexia and emesis by peripheral blood mononuclear cells of cancer patients. Biochem Soc Trans 1997;25:296.  Back to cited text no. 18
    
19.
Yeh SS, Schuster MW. Megestrol acetate in cachexia and anorexia. Int J Nanomedicine 2006;1:411-6.  Back to cited text no. 19
    
20.
Tomíska M, Tomisková M, Salajka F, Adam Z, Vorlícek J. Palliative treatment of cancer anorexia with oral suspension of megestrol acetate. Neoplasma 2003;50:227-33.  Back to cited text no. 20
    
21.
De Conno F, Martini C, Zecca F, Balzarini A, Venturino P, Groff L, et al. Megestrol acetate for anorexia in patients with far advanced cancer: A double-blind clinical trial. Eur J Cancer 1998;34:1705-9.  Back to cited text no. 21
    
22.
Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Sanna E, et al. A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: Evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecol Oncol 2012;124:417-25.  Back to cited text no. 22
    
23.
EG, Ortiz Z. Megestrol acetate for the treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev 2005:CD004310.  Back to cited text no. 23
    
24.
Pascual Lopez A, Roqué i Figuls M, Urrútia Cuchi G, Berenstein EG, Almenar Pasies B, Balcells Alegre M, et al. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom Manage 2004;27:360-9.  Back to cited text no. 24
    
25.
Madeddu C, Dessì M, Panzone F, Serpe R, Antoni G, Cau MC, et al. Randomized phase III clinical trial of a combined treatment with carnitine+celecoxib±megestrol acetate for patients with cancer-related anorexia/cachexia syndrome. Clin Nutr 2012;31:176-82.  Back to cited text no. 25
    
26.
Van der Meij BS, Schoonbeek CP, Smit EF, Muscaritoli M, van Leeuwen PA, Langius JA. Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: An exploratory study comparing two consensus-based frameworks. Br J Nutr 2012;16:1-9.  Back to cited text no. 26
    
27.
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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