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

Objective Megestrol acetate (MA) is used to manage anorexia and cachexia in patients with advanced cancer. This study investigated the prescription patterns of MA in patients with metastatic gastric cancer, as well as evaluated its impact on survival outcomes and the incidence of venous thromboembolism (VTE). Methods 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 cancer from July 2014 to December 2015. Results A total of 1,938 patients were included in this study. In total, 65% of the patients were prescribed MA. Older age, treatment in tertiary hospitals, and palliative chemotherapy were statistically signi�cant predictive factors for MA prescription. Continuous prescription of MA was observed in 37% of patients. There was no statistically signi�cant difference in survival between the MA and non-MA prescription groups on multivariate analysis. Among the 1,427 patients included in the analysis for VTE incidence, 4.3% 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 signi�cant difference in VTE diagnosis between the groups on multivariate analysis.


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][3][4].Among patients with gastric cancer, cachexia is highly prevalent, with estimates exceeding 70% [5,6].
Signi cantly, decreased e cacy of immune checkpoint inhibitors and poorer survival rates have been reported in cachexic patients with advanced gastric cancer [7,8].Nevertheless, it is not routinely assessed and is underdiagnosed and inappropriately managed in many cases [9,10].
Megestrol acetate (MA), a synthetic oral derivative of progesterone, has been used to manage anorexia and cachexia in patients with acquired immune de ciency syndrome (AIDS) and cancer [11].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 [12][13][14].Prior clinical studies found that MA promotes appetite, increases body weight, and improves nutritional status and quality of life in patients with advanced cancer [15][16][17][18][19].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 [20].
The recommended dose of MA is 400-800 mg/day [11,21], and previous studies have assessed an MA prescription period of 2-3 months [22].Common adverse effects of MA include adrenal insu ciency, edema, cutaneous alterations, gastrointestinal dysfunction, impotence, insomnia, hyperglycemia, and thromboembolism [23].Among these, thromboembolism is an especially serious adverse event that may offset the bene ts of MA [24].Previous meta-analyses have reported that MA increases the risk of thromboembolism by 84% and does not affect survival (though these ndings were based on a very low quality of evidence) [22,25].
There is little data available on prescription patterns, adverse effects, and survival for MA in patients with advanced gastric cancer in real world settings.Hence, this study aimed to investigate the characteristics of patients with metastatic gastric cancer who were prescribed MA, MA prescription patterns, and MAassociated adverse events (e.g., venous thromboembolism [VTE] and death) through an evaluation conducted in a Health Insurance Review and Assessment (HIRA) service database.

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 prespeci ed static Internet Protocol addresses.

Study design and population
This retrospective study assessed prescription patterns, safety, and survival outcomes associated with MA prescription in patients with metastatic gastric cancer registered in the HIRA database.Patients newly diagnosed with digestive malignancies 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 gastric cancer: 1) patients with diagnostic codes for digestive malignancies (C16, C18-C20, C23-C25), classi ed according to the International Classi cation 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 gastric 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 de ned as more than 10 fractions of radiotherapy concurrently administered during one or more days of chemotherapy within 35 days following the rst 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 misclassi ed in the database because it is rare that patients with metastatic cancer survive long-term without active anticancer therapy).Lastly, patients with non-gastric cancer such as colorectal and pancreatobiliary cancers were excluded.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.

De nitions 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 rst 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 rst and last prescription date.MPR values ≥0.8 and <0.8 were de ned as continuous and intermittent prescriptions, respectively.Patient characteristics including demographic information, insurance and hospital type, modi ed Charlson Comorbidity Index (mCCI) values, and treatment status were abstracted and compared according to MA prescription pattern status.VTE was de ned 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.

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% con dence 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 signi cant given the large sample size.All statistical analyses were performed using SAS statistical software (version 9.4; SAS Institute, Cary, NC, USA).

Patient characteristics according to MA prescription status
We screened 13,358 adult patients with newly diagnosed metastatic digestive malignancies 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.Then, 3,982 patients with nongastric cancer were excluded.Finally, a total of 1,938 patients with metastatic gastric cancer were included in the current analysis (Fig. 1).
Baseline characteristics according to MA prescription patterns are listed in Table 1.There were 1,260 patients in the MA prescription group (out of a total of 1,938; 65.0%).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 974/1,251 (77.9%) and 286/687 (41.6%) patients, respectively.On multivariate analysis, we found that elderly patients were more frequently prescribed MA than younger patients (OR [odds ratio] for a 10-year increase, 1.138, 95% CI 1.049-1.234,p=.002; Online Resource 3).Palliative chemotherapy was the most important factor predicting MA prescription (OR 5.612, 95% CI 4.413-7.137,p<.001).The proportion of patients treated with palliative chemotherapy decreased with increasing age (from 94.2% in patients aged <40 years to 23.3% 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.

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 343 (37.0%) and 583 (63.0%) patients, respectively.Elderly patients and patients not treated with palliative chemotherapy were more commonly found in the continuous prescription group (vs. the intermittent prescription group).
The median time from the index date to the rst MA prescription was 31 days (IQR [interquartile range], 8-92 days).The median time became shorter with increasing age (59 days in those aged <40 years, 40 days in those aged 40-49 years, 37 days in those aged 50-59 years, 36 days in those aged 60-69 years, 28 days in those aged 70-79 years, and 10 days in those aged ≥80 years).The median total number of MA prescription days was 39 days (IQR 16-83).The most frequent range for the average daily MA dose was 600-<800 mg/day (in 43.0% of evaluated patients), followed by 800-<1,000 mg/day (28.4%) and 400-600 mg/day (20.2%).Average daily MA doses of <400 mg/day and ≥1,000 mg/day were observed in 2.4% and 6.0% of the evaluated patients, respectively.

Survival
Differences in survival according to the MA prescription patterns were assessed according to whether palliative chemotherapy was administered.In patients treated with palliative chemotherapy, the prescription of MA did not in uence survival outcome (Fig. 2A).However, in those who did not receive palliative chemotherapy, the group prescribed MA exhibited a longer survival time compared to the group that was not prescribed MA (Fig. 2B).
However, in multivariate analyses, we found that MA prescription had little impact on survival.Although there was a statistically signi cant difference in survival, the HR for MA prescription was only 1.001 in patients treated with palliative chemotherapy.There was no statistically signi cant 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 55/1,427 (3.9%) patients with metastatic gastric cancer during the follow-up period (Table 2).The incidence of VTE was higher in the MA prescription group than in the nonprescription group (4.3% vs. 2.9%).
However, on multivariate analysis (Table 3), MA prescription was not a predictive factor for VTE occurrence (OR 1.310, 95% CI 0.692-2.480,p=0.41).When the analysis was strati ed by treatment status, we found that there were no statistically signi cant 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 neither continuous prescription nor the average daily dose of MA had any impact on the incidence of VTE.

Discussion
This study evaluated MA prescription patterns as well as the impact of MA on survival and VTE occurrence in nearly 2,000 patients with metastatic gastric cancer.Two-thirds of the evaluated patients were prescribed MA.Palliative chemotherapy was the strongest predictor of the need for MA prescription.However, we found that the proportion of continuous MA prescriptions was higher in patients not treated with palliative chemotherapy.This may mean that while palliative chemotherapy is the primary factor inducing anorexia, 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 ndings indicate that early and continuous nutritional support as well as effective chemotherapy are needed to alleviate anorexia in elderly patients with metastatic gastric cancer.
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 [22,25,26].In the current study, we found that MA prescription patterns did not affect survival when adjusting for age, sex, and type of hospital 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 con rm 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 nonprescription group.However, on multivariate analysis, we found no statistically signi cant associations for the difference in VTE occurrence between the MA prescription and non-prescription groups.Additionally, when strati ed by treatment status, we found that MA prescriptions had no in uence on VTE incidence.While continuous MA prescription seemed to be a potential risk factor for VTE, as compared to both non-MA and intermittent MA prescriptions, the ndings were not consistent.A higher average daily dose of MA did not present as a risk factor for VTE occurrence.It is recognized that VTE incidence tends to be lower in Asian populations as compared to Western ones [27].Given the heterogeneity of thrombosis risk according to ethnicity and the inconsistent ndings in this study's multivariate analyses, we conclude that it is inappropriate to universally discourage Asian cancer patients from MA prescriptions based solely on potential VTE concerns.Instead, we recommend careful monitoring and regular follow-up for VTE occurrence in high-risk patients who have been prescribed MA on a continuous basis, irrespective of their average daily dosage of MA.
The main limitation of this study is that unclaimed data (including medical records and laboratory, radiologic, and histologic ndings) were not available in the HIRA database.Because of this, treatment e cacy 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-speci ed period.Our results need to be validated in other clinical studies.
In conclusion, MA is widely prescribed in metastatic gastric cancer patients, especially in elderly patients and those treated with palliative chemotherapy.We found that MA did not adversely affect survival regardless of 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.

Figures Figure 1 Flow
Figures

Table 1
Baseline characteristics by prescription of megestrol acetate MA, megestrol acetate; mCCI, modi ed Charlson Comorbidity Index; BSC, best supportive care

Table 3
Multivariate logistic regression for occurrence of venous thromboembolism mCCI, modi ed Charlson Comorbidity Index; MA, megestrol acetate; BSC, best supportive care