Clinical implication of megestrol acetate in advanced cancer: A big data analysis from Health Insurance Review and Assessment (HIRA) database

Abstract

Purpose Megestrol acetate (MA) is used to manage anorexia and cachexia in patients with advanced cancer. This study investigated prescription patterns and impact on the survival and the venous thromboembolism (VTE) of MA in patients with advanced cancer.

Methods In this study, a Health Insurance Review and Assessment (HIRA) service database was used to investigate differences in baseline characteristics, survival, and the incidence of VTE according to MA prescription patterns (i.e., prescription vs. no prescription) in patients diagnosed with metastatic gastric, colorectal, and pancreatobiliary cancers from July 2014 to December 2015.

Results A total of 5,920 patients were included in this study. In total, 66.9% of the patients were prescribed MA. Pancreatobiliary cancer, older age, treatment in tertiary hospitals, and palliative chemotherapy were statistically significant predictive factors for MA prescription. Continuous prescription of MA was observed in 42.2% of patients. There was no statistically significant difference in survival between the MA and non-MA prescription groups. Among the 4,081 patients included in the analysis for VTE incidence, 5.4% and 2.9% were diagnosed with VTE during the follow-up period in the MA and non-MA prescription groups, respectively. However, there was no statistically significant difference in VTE diagnosis between the groups on multivariate analysis.

Conclusions This study demonstrated that most patients with advanced gastrointestinal and pancreatobiliary cancer required MA prescription. The difference in the incidence of VTE was modest between the MA and non-MA prescription groups (not at the level of statistical significance on multivariate analyses).

Introduction

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support [1]. Cancer cachexia is associated with a decline in performance status, increased treatment-associated toxicity, and reduced survival [2–4]. Nevertheless, it is not routinely assessed and is underdiagnosed and inappropriately managed in many cases [5, 6].

Megestrol acetate (MA), a synthetic oral derivative of progesterone, has been used to manage anorexia and cachexia in patients with acquired immune deficiency syndrome (AIDS) and cancer [7]. Preclinical studies have suggested that MA promotes appetite by increasing the synthesis and secretion of neuropeptide Y and by decreasing the synthesis of serotonin and cytokines [8–10]. Prior clinical studies found that MA promotes appetite, increases body weight, and improves nutritional status and quality of life in patients with advanced cancer [11–15]. Moreover, a recent phase 3 trial reported that the use of MA results in improved performance status and muscular strength in patients with gastrointestinal cancer [16].

The recommended dose of MA is 400–800 mg/day [7, 17], and previous studies have assessed an MA prescription period of 2–3 months [18]. Common adverse effects of MA include adrenal insufficiency, edema, cutaneous alterations, gastrointestinal dysfunction, impotence, insomnia, hyperglycemia, and thromboembolism [19]. Among these, thromboembolism is an especially serious adverse event that may offset the benefits of MA [20]. Previous meta-analyses have reported that MA increases the risk of thromboembolism by 84% and does not affect survival (though these findings were based on a very low quality of evidence) [18, 21].

There is little data available on prescription patterns and adverse effects for MA in real world settings. Hence, this study aimed to investigate the characteristics of patients who were prescribed MA, MA prescription patterns, and MA-associated adverse events (e.g., venous thromboembolism [VTE] and death) through an evaluation conducted in a Health Insurance Review and Assessment (HIRA) service database.

Methods

Data source

The HIRA database examined herein includes information on healthcare services for approximately 50 million people (i.e., more than 98% of the Korean population). This database is the primary data source through which healthcare insurance costs are claimed and reimbursed and includes detailed information regarding patients demographics, the treating medical institutions, disease codes, treatment history, and prescription drugs. To protect personal privacy, all data are encrypted and only variables approved by the HIRA are granted limited distribution to registered investigators either at the designated analysis center or via prespecified static Internet Protocol addresses.

Study design and population

This retrospective study assessed prescription patterns as well as safety and efficacy of MA prescribed to patients with metastatic cancer registered in the HIRA database. Patients newly diagnosed with gastric, colorectal, and pancreatobiliary cancer between July 1, 2014, and December 31, 2015 (i.e., the index period) were followed for up to 36 months (i.e., the follow-up period) after their date of diagnosis (i.e., the index date) (Online Resource 1). The following inclusion and exclusion criteria were applied to select patients with metastatic cancer: 1) patients with diagnostic codes for gastric (C16), colorectal (C18, C19, C20), biliary (C23 and C24), and pancreatic (C25) cancer, classified according to the International Classification of Diseases (tenth revision; ICD-10), as well as the supplementary code of the copayment decreasing policy (V193), which records data on nearly all cancer patients in Korea; 2) no prior diagnostic code of cancer during the last 12 months prior to the index date (i.e., the baseline period) to reduce the risk of misclassifying secondary metastatic tumors are primary cancers and to exclude complicated presentations and comorbidities; and 3) patients with a diagnostic code of metastatic cancer (C76-C79.9) received within 90 days after the index date. Patients for whom MA was prescribed during the baseline period, those with another diagnostic code of cancer recorded during the follow-up period, and those aged less than 18 years were excluded from this study. Additional exclusion criteria were used to identify patients with metastatic cancer more accurately, as follows: 1) patients treated with curative surgery within 180 days after the index date (Online Resource 2), as well as patients receiving concurrent chemoradiotherapy (CCRT; operationally defined as more than 10 fractions of radiotherapy concurrently administered during one or more days of chemotherapy within 35 days following the first date of radiotherapy); 2) patients who survived for more than two years after the index date who did not receive any active anticancer therapies, including surgery, radiotherapy, and chemotherapy (these cases might be misclassified in the database because it is rare that patients with metastatic cancer survive long-term without active anticancer therapy). This study was approved by the Institutional Review Board of Gyeongsang National University Changwon Hospital (GNUCH 2019-11-027) and was conducted in accordance with the principles of the Declaration of Helsinki and its later amendments. Informed consent was waived due to the retrospective nature of the study.

Definitions and assessments

The prescription patterns for MA evaluated herein included the presence of MA prescriptions (any vs. none), the time from the index date to the first prescription, the total days of the prescriptions and the average daily dose, and prescription continuity. Patients who were prescribed MA at least once and those who were never prescribed MA during the follow-up period were grouped into MA prescription and non-MA prescription groups, respectively. The average daily dose of MA was calculated as the total number of prescriptions divided by total days of prescription. The continuity of prescription was assessed using the medication possession ratio (MPR), which was calculated as the total number of days of prescription divided by the days elapsing between the first and last prescription date. MPR values ≥0.8 and <0.8 were defined as continuous and intermittent prescriptions, respectively. Patient characteristics including demographic information, insurance and hospital type, modified Charlson Comorbidity Index (mCCI) values, and treatment status were abstracted and compared according to MA prescription pattern status.

VTE was defined as a case diagnosed with deep vein thrombosis (DVT, ICD-10 code I80 and related codes) or pulmonary thromboembolism (PTE, I26 and related codes). If the patient was diagnosed with VTE, treated with VTE-associated procedures, and/or received anticoagulation during the baseline period, this case was excluded from the VTE assessment. The incidence of VTE was compared based on the prescription patterns for MA, with adjustment for covariates. Death was indicated if there was an insurance claim in which a death-related code was recorded during the follow-up period, and the death date was determined as the expiration date within the national health insurance system. In this study, we evaluated the impact of MA prescription patterns on survival.

Statistical analysis

Categorical and continuous variables were compared using chi-square and Fisher’s exact tests and independent t-test or Wilcoxon rank-sum tests as appropriate (i.e., according to the distribution of the data). Logistic regression was performed with adjustment for baseline characteristics to elucidate the factors affecting MA prescriptions and VTE occurrence. Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. Time-dependent Cox regression was performed to assess hazard ratios (HR) and associated 95% confidence intervals (CI) for death-associated covariates. Missing data were excluded from this analysis. A two-sided p-value of less than .01 was considered statistically significant given the large sample size. All statistical analyses were performed using SAS statistical software (version 9.4; SAS Institute, Cary, NC, USA).

Results

Patient characteristics according to MA prescription status

We screened 13,358 adult patients with newly diagnosed metastatic gastric, colorectal, and pancreatobiliary cancers presenting during the index period. Among these patients, we excluded 72 patients with a history of MA prescription at baseline, 6,038 patients who were treated with curative surgery and CCRT, 933 patients who survived for more than two years following the index date without any active anticancer therapy, and 395 patients with double primary cancer that occurred during the follow-up period. Finally, a total of 5,920 patients (1,938 with gastric cancer, 1,612 with colorectal cancer, and 2,370 with pancreatobiliary cancer) were included in the current analysis (Fig. 1).

Baseline characteristics according to MA prescription patterns are listed in Table 1. There were 3,959 patients in the MA prescription group (out of a total of 5,920; 66.9%), 1,726 of whom had in pancreatobiliary cancer (1,726/2,370; 72.8%), 1,260 of whom had gastric cancer (1,260/1,938; 65.0%), and 973 of whom had colorectal cancer (973/1,612; 60.4%). We found that younger patients with a lower mCCI as well as those treated in a tertiary hospital were more likely to be prescribed MA. Among patients treated or not treated with palliative chemotherapy, MA was prescribed in 2,624/3,292 (79.7%) and 1,335/2,628 (50.8%) patients, respectively. On multivariate analysis, we found that elderly patients were more frequently prescribed MA than younger patients (OR for a 10-year increase, 1.165, 95% CI 1.106-1.226, p<.001; Online Resource 3). Palliative chemotherapy was the most important factor predicting MA prescription (OR 4.176, 95% CI 3.641-4.789, p<.001). The proportion of patients treated with palliative chemotherapy decreased with increasing age (from 91.8% in patients aged <40 years to 15.9% in those aged ≥80 years). This indicates that a higher rate of MA prescription in younger patients on univariate analysis was resulted from a higher proportion of receiving palliative chemotherapy in those patients. Similar trends were observed for each cancer type.

Prescription patterns for MA

The continuity of MA prescription was assessed in 2,921 patients who were prescribed MA at least twice (Online Resource 4). Continuous and intermittent prescription was performed in 1,232 (42.2%) and 1,689 (57.8%) patients in total, in 648 (50.9%) and 625 (49.1%) patients with pancreatobiliary cancer, in 343 (37.0%) and 583 (63.0%) with gastric cancer, and in 241 (33.4%) and 481 (66.6%) patients with colorectal cancer, respectively. Elderly patients, those with higher mCCI values, and patients not treated with palliative chemotherapy were more commonly found in the continuous prescription group (vs. the intermittent prescription group). Similar findings were observed in the analyses for each cancer type, with the exclusion of the mCCI.

The median time from the index date to the first MA prescription was 24 days (IQR [interquartile range], 2-73 days). The median time was shortest in pancreatobiliary cancer (16 days, IQR 1-46), followed by gastric cancer (31 days, IQR 8-91.5) and colorectal cancer (36 days, IQR 8-139). The median time became shorter with increasing age (53 days in those aged <40 years, 41 days in those aged 40-49 years, 37 days in those aged 50-59 years, 29 days in those aged 60-69 years, 18 days in those aged 70-79 years, and eight days in those aged ≥80 years). The median total number of MA prescription days was 40 days (IQR 16-84). The most frequent range for the average daily MA dose was 600-<800 mg/day (in 42.4% of evaluated patients), followed by 800-<1,000 mg/day (28.6%) and 400-600 mg/day (19.5%). Average daily MA doses of <400 mg/day and ≥1,000 mg/day were observed in 3.2% and 6.2% of the evaluated patients, respectively.

Survival

Differences in survival according to the MA prescription patterns were assessed by cancer type and as well as according to whether palliative chemotherapy was administered (Fig. 2). In patients treated with palliative chemotherapy, MA prescription did not affect survival in gastric and pancreatobiliary cancers (Fig. 2A and 2C), while a shorter survival time was observed in patients who were prescribed MA for colorectal cancer (Fig. 2B). In patients not treated with palliative chemotherapy, we found a longer survival time in the MA prescription group than in the non-MA prescription group, irrespective of cancer type (Fig. 2D-F).

However, in multivariate analyses, we found that MA prescription had little impact on survival. Although there was a statistically significant difference in survival, the HR for MA prescription was only 1.001 in patients treated with palliative chemotherapy, irrespective of cancer type. There was no statistically significant difference in survival between the MA and non-MA prescription groups in patients not treated with palliative chemotherapy (Online Resource 5).

Venous thromboembolism

VTE was newly diagnosed in 188 of 4,081 (4.6%) patients in total, in 55/1,427 (3.9%) gastric cancer patients, 56/1,137 (4.9%) colorectal cancer patients, and 77/1,517 (5.1%) patients with pancreatobiliary cancer during the follow-up period (Table 2). The incidence of VTE was higher in the MA prescription group than in the non-prescription group (5.4% vs. 2.9% in total, 4.3% vs. 2.9% in gastric cancer, 6.3% vs. 2.7% in colorectal cancer, and 5.8% vs. 3.1% in pancreatobiliary cancer).

On multivariate analysis (Table 3), palliative chemotherapy was the most powerful predictive factor for VTE occurrence (HR 2.119, 95% CI 1.427-3.148, p<.001). MA prescription was not a predictive factor for VTE occurrence, achieving borderline significance (HR 1.499, 95% CI 1.033-2.175, p=0.03). When the analysis was stratified by cancer type and palliative chemotherapy, we found that there were no statistically significant differences in VTE occurrence between MA prescription and non-prescription groups (Online Resource 6). When considering prescription patterns for MA (Online Resource 7), we found that continuous prescription did not affect VTE occurrence (HR 1.538, 95% CI 1.053-2.246, p=.03). An average daily dose of <650 mg/day (HR 1.778, 95% CI 1.186-2.667, p=.005), but not a higher dose (≥650 mg/day), was associated with VTE occurrence. In subgroup analyses according to cancer type, prescription patterns for MA were not associated with VTE occurrence (Table 3).

Discussion

This study evaluated MA prescription patterns as well as the impact of MA on survival and VTE occurrence in nearly 6,000 patients with metastatic gastrointestinal and pancreatobiliary cancer. Two-thirds of the evaluated patients were prescribed MA in the following order of frequency: pancreatobiliary, gastric, and colorectal cancer. This order was maintained with respect to early and continuous MA prescriptions. Palliative chemotherapy was the strongest predictor of the need for MA prescription. Patients treated with palliative chemotherapy were prescribed MA at a rate that was as much as four times higher than those not treated with palliative chemotherapy. However, we found that the proportion of continuous MA prescriptions was higher in patients not treated with palliative chemotherapy. This may mean that palliative chemotherapy is the primary factor inducing anorexia. Moreover, some patients who respond to palliative chemotherapy have their appetite restored and thus no longer require continuous MA prescription. We note that aging is also an important determinant of MA prescription patterns. Compared with younger patients, elderly patients were prescribed MA earlier and more frequently and were also more likely to be prescribed MA continuously. These findings indicate that early and continuous nutritional support as well as effective chemotherapy are needed to alleviate anorexia in elderly cancer patients.

Among patients not treated with palliative chemotherapy, we note the longer survival time observed in the MA prescription group on univariate analysis. The impact of MA on survival has been debated in previous studies [18, 21, 22]. In the current study, we found that MA prescription patterns did not affect survival when adjusting for age, sex, type of hospital, and type of cancer on multivariate analysis; these factors are known to be the main determinants of survival. Of note, MA is prescribed in patients with malnutrition and poor appetite, although these clinical aspects and potential predictive and prognostic factors could not be reviewed in this cohort. Additional clinical studies are needed to confirm whether MA overcomes these worse clinical characteristics and positively affects survival in cachectic patients with cancer.

As previously reported, the incidence of VTE was higher in the MA prescription group than in the non-prescription group (5.4% vs. 2.9%). This finding was consistent with the reported subgroup analyses conducted according to cancer type. However, on multivariate analysis, we found no statistically significant associations for the difference in VTE occurrence between the MA prescription and non-prescription groups based on a pre-specified significance level of p < 0.01. Moreover, when the analysis was stratified by treatment status (i.e., the strongest predictive factor for VTE occurrence in this study), we found that MA prescriptions did not affect VTE occurrence. Although continuous MA prescription seemed to be a risk factor for VTE occurrence as compared with non-MA prescription as well as intermittent MA prescription, results based on stratification according to cancer type as well as treatment status were inconsistent. A higher average daily dose of MA was not a risk factor for VTE occurrence. Moreover, the incidence of VTE is known to be lower in Asian populations as compared to Western populations [23]. Given the heterogeneity of thrombosis risk according to ethnicity and the inconsistent results (with borderline significance) within the multivariate analyses conducted in this study, we conclude that all Asian cancer patients should not be discouraged from MA prescription based solely on concerns about VTE occurrence. Instead, we suggest caution and periodic follow-up for VTE occurrence in patients at high risk of VTE who were prescribed MA continuously, regardless of their average daily dose of MA.

The main limitation of this study is that unclaimed data (including medical records and laboratory, radiologic, and histologic findings) were not available in the HIRA database. Because of this, treatment efficacy and complications (other than VTE) arising from MA prescription, as well as many clinical factors associated with survival, could not be evaluated herein. Another drawback of this study is its retrospective design, which inevitably causes selection bias and inconsistency in baseline characteristics between groups. However, these limitations were overcome to some extent by the enrolled sample size and comprehensive investigation methodology implemented during the pre-specified period. Our results need to be validated in other clinical studies.

In conclusion, MA is widely prescribed in metastatic cancer patients, especially in elderly patients, those with pancreatobiliary cancer, and those treated with palliative chemotherapy. We found that MA did not adversely affect survival regardless of cancer type and treatment status, though it slightly elevated the risk for VTE. Therefore, active nutritional support, including MA prescription, should be encouraged in this population, though with careful consideration of patients at high risk for VTE. Our findings inform future research directions and, if confirmed, will directly inform medical guidelines.

Declarations

Acknowledgements

The authors would like to thank Jin-Seul Kwak, Jung-Ae Kim, Stella Jung-Hyun Kim, and Hee-Jin Kang of the IQVIA Korea for their help to data collection and analysis, Hye-Jung Park, the health information manager of the Gyeongsang National University Hospital for her help to data curation, and the Health Insurance Review and Assessment (HIRA) Services for their cooperation.

Author contribution

Chang Min Lee was responsible for the formal analysis, investigation, writing-original draft, and writing-review and editing. Jung Hun Kang was responsible for the conceptualization, data curation, investigation, methodology, supervision, writing-original draft, and writing-review and editing. Se-Il Go was responsible for the data curation, formal analysis, investigation, methodology, supervision, validation, writing-original draft, and writing-review and editing.

Funding

This work was supported by a grant from Boryung Pharmaceutical Ltd. Seoul, the Republic of Korea.

Data availability

The data are not publicly available due to institutional (HIRA) policy.

Code availability

Not available.

Ethics approval

This study was approved by the Institutional Review Board of Gyeongsang National University Changwon Hospital (GNUCH 2019-11-027) and was conducted in accordance with the principles of the Declaration of Helsinki and its later amendments.

Consent to participate

Informed consent was waived due to the retrospective nature of the study.

Consent to publication

Not available.

Competing interests

The authors declared no potential conflicts of interests.

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Tables

Table 1 Baseline characteristics by prescription of megestrol acetate

MA, megestrol acetate; mCCI, modified Charlson Comorbidity Index; BSC, best supportive care

Table 2 Incidence of venous thromboembolism

MA, megestrol acetate; VTE, venous thromboembolism

Table 3 Multivariate logistic regression for occurrence of venous thromboembolism

OR, odds ratio; CI, confidence interval; mCCI, modified Charlson Comorbidity Index; MA, megestrol acetate; BSC, best supportive care