A phase II trial evaluating the efficacy and safety of repeated high dose medroxyprogesterone acetate (MPA) therapy for patients with recurrent early-stage endometrial cancer or atypical endometrial hyperplasia: Japanese Gynecologic Oncology Group study (JGOG2051/KGOG2031, REMPA trial).

The number of patients with endometrial cancer (EC) has been steadily increasing throughout Japan. Additionally, the number of adolescence and young adults with EC who desire fertility-sparing treatment has also increased [ 1 ]. Hormonal therapy involving progesterone has been considered effective for patients with stage IA non-myoinvasive endometrioid carcinoma grade 1 or atypical endometrial hyperplasia (AEH) who desire fertility preservation [ 2 3 4 ]. Progestin-based therapies include medroxyprogesterone acetate (MPA) and megestrol acetate as oral medications and a levonorgestrel-releasing intrauterine system as an intrauterine treatment option [ 2 ]. However, MPA is the only medicine for hormone therapy that is covered by health insurance in Japan, with common doses being 400–600 mg/day. A previous meta-analysis showed that although the initial complete response rates to MPA therapy for EC and AEH were 76% and 86%, respectively, recurrence rates were 41% and 26%, respectively [ 3 ]. Moreover, a Korean retrospective study (Korean Gynecologic Oncology Group [KGOG] 2002) on 148 patients showed a complete response rate, recurrence rate, and 5-year recurrence-free survival rate of 77.7%, 30.4% (median observation period; 66 months), and 68%, respectively [ 4 ]. As such, high recurrence rates have remained one of the biggest problems with MPA therapy. However, the National Comprehensive Cancer Network guidelines recommended total hysterectomy in case of recurrence [ 5 ]. And the Japanese EC guidelines also recommended total hysterectomy in case of recurrence given the lack of high-quality evidence [ 6 ]. Our previous report on the efficacy of repeated MPA therapy for 82 cases showed a complete response rate of 97% and recurrence rate of 76% [ 7 ]. Another retrospective study in Korea that evaluated 33 recurrent patients found a complete response rate of 85% [ 8 ]. These findings suggest that complete response rates have been relatively high only in single-center retrospective studies. There is a lack of evidence to support repeated MPA therapy because these studies were done at single centers only. However, such retrospective studies may be accompanied by selection and publication biases, indicating the need for multicenter prospective studies. Based on these backgrounds, the Japanese Gynecologic Oncology Group (JGOG) initiated this study to verify the efficacy and feasibility of repeated MPA therapy.

This is the first prospective study to evaluate the efficacy and safety of repeated MPA therapy. This phase II trial was designed to determine the impact of repeated MPA therapy. If repeated MPA therapy provides equivalent outcomes to initial MPA therapy, repeated MPA therapy can be recommended with evidence. Our prospective trial requires a large sample size and collaboration with multiple institutions. This JGOG2051/KGOG2031 REMPA trial has registered in the Japan Registry of Clinical Trials (jRCTs031200256). Up to October 16th, 2023, 72 patients have been enrolled. To enroll more patients promptly, JGOG has prepared to collaborate with KGOG, and international trials (JGOG2051/KGOG2031) with KGOG are expected to start in Spring 2024. The results of this study will contribute toward the establishment of a new standard approach for fertility preservation not only in Japan but also globally.

This prospective, single-arm, a multicenter phase II trial on repeated MPA therapy for intrauterine recurrence following fertility-preserving therapy for AEH or EC had been planned by the JGOG ( Fig. 1 ). The study concept was agreed on by the JGOG and KGOG (trial number JGOG2051/KGOG2031). CR, complete response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; MPA, medroxyprogesterone acetate; OS, overall survival; PD, progressive disease; RFS, recurrence-free survival. Pre-operative mandatory work-up included pelvic magnetic resonance imaging (MRI), abdominal and pelvic computed tomography (CT), and dilation and curettage (D&C) before enrollment. All patients will be treated with oral MPA (500–600 mg/day). Monthly interviews, transvaginal examination and ultrasound, and tumor marker CA125 (only in endometrioid carcinoma grade 1 cases) will be required. Pathological assessments through D&C were conducted every 2 months until complete response. Complete response is defined as the pathological disappearance of the endometrial hyperplasia on D&C. If pathological complete response is diagnosed at 2 months, at least total of 4 months of oral administration will be required ( Fig. 2 ). If pathological complete response is not achieved by oral medication and D&C, CT and MRI should be performed every 4 months to confirm the absence of progressive disease. Moreover, when the treatment duration exceeds 10 months or if the patient is diagnosed with progressive disease, the patient has to withdraw from the trial and a hysterectomy will be recommended. CR, complete response; D&C, dilation and curettage; PD, progressive disease; SD, stable disease. All adverse events will be assessed via a monthly check-up using the Common Terminology Criteria for Adverse Events; version 5.0; National Institutes of Health, Bethesda, MA, USA. The occurrence of adverse effects (nonhematological toxicity ≥ grade 3) will require MPA dose reduction according to Table 1 regardless of the causal relationship with MPA therapy. Once the dose is reduced, treatment will be continued at that dose without increasing the dose. However, despite dose reduction to level −1, if a patient develops an adverse event requiring further dose reduction as per the criteria (level −2), MPA therapy will be discontinued in this patient. Because of the variation in dosage forms between Japan and Korea, 2 patterns of dose reduction are defined. NA, not available. After the end of MPA therapy, patients will undergo interviews, vaginal examination, endometrial biopsy (EMB), and transvaginal ultrasonography every 12 weeks for 2 years. For patients who are pregnant or possibly pregnant, EMB will not be performed, and only interviews are mandatory, whereas vaginal examination and transvaginal ultrasonography will be optional. Follow-up will be resumed 12 weeks after pregnancy completion (delivery or abortion). Endometrial cytology, imaging tests (MRI and CT), hysteroscopy, and tumor marker tests will be performed on an as-needed basis. If any abnormality is detected on these tests, D&C must be performed. Patients will be considered to have a recurrence if the pathological findings from EMB or D&C indicate AEH or cancer (endometrioid carcinoma or non-endometrioid carcinoma). AEH and cancer are treated similarly as recurrences. The following information will be collected during follow-up: survival status, presence/absence of recurrence, whether patients received post-treatment (hormone therapy, total hysterectomy, etc.) and infertility treatment (if they received, type of infertility treatment), and whether patients became pregnant (if they are/were pregnant, how the pregnancy was established, pregnancy course, gestational week at delivery, and the type of delivery). In the event of recurrence, subsequent interviews and examinations are optional, but survival confirmation and interviews for 2 years after MPA treatment, which corresponds to the final follow-up survey, will be performed. This study protocol does not specify matters related to infertility treatment after complete remission or maintenance therapies, such as low-dose progestins, in patients who do not wish to be pregnant immediately. The use of ovulation-inducing drugs and estrogens will be allowed. All pathological specimens before and at the end of the treatment require a central pathology review to monitor the quality of this trial. Estrogen receptor, progesterone receptor, and p53 status will be reviewed by immunohistochemistry in all patients via central pathology review. Patients with recurrent stage IA (FIGO 2008) non-myoinvasive endometrioid carcinoma grade 1 or AEH who desire fertility preservation following fertility-preserving MPA therapy are eligible for this study. The major inclusion criteria are 1) intrauterine recurrence of AEH or stage IA (FIGO 2008) endometrioid carcinoma grade 1 without myometrial invasion or extrauterine spread confirmed by imaging tests after complete remission with the previous fertility-sparing MPA therapy, 2) The number of recurrences should be up to twice, 3) histologically diagnosed as AEH or endometrioid carcinoma grade 1, 4) myometrial invasion ruled out via MRI, 5) extrauterine lesions ruled out via CT, 6) 20–42 years of age, and 7) strong desire and consent for fertility-sparing treatment ( Table 2 ). ALT, alanine transaminase; AST, aspartate aminotransferase; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase. The major exclusion criteria are 1) incidences of recurrence ≥3, 2) patients who have not been confirmed of pathological disappearance of the lesion observed by D&C after the previous treatment (pathological disappearance is defined as disappearance of endometrial hyperplasia), 3) body mass index ≥45 kg/m 2 , 4) previous medical history of thrombosis, 5) with multiple cancers with a disease-free interval <5 years, and 6) with severe hepatic dysfunction ( Table 3 ). If complete response rate of 2 times recurrent patients is clearly poor, the registration of 2 times recurrent patients will not be discontinued. BMI, body mass index; MRI, magnetic resonance imaging. The primary endpoint is a 2-year recurrence-free survival rate during the follow-up period of 2 years. The secondary endpoints are overall survival, recurrence-free survival, complete response rate, pregnancy rate, adverse events, number of D&C, hysterectomy rate, infertility treatment rate and procedure, perinatal and pregnancy prognosis, a family history of cancer, etc. This study started in December 2020 in Japan and required 115 cases to be recruited within 4 years, and the patients will be followed up with during a period of 2 years. The sample size was calculated based on the expected 4-year recurrence-free rates of 53% [ 9 ]. The estimated 2-year recurrence-free rate of the initial MPA therapy was calculated as 73% from this multiple-center prospective study [ 9 ]. Assuming a 2-year recurrence-free survival rate of 58% and 73% for the null and alternative hypotheses, a minimum of 99 patients were required to achieve a 5% 2-sided type I error and 90% power based on the Brookmeyer-Crowley type test. A target sample size of 115 was set to account for an expected patient dropout of 15%. Statistical analyses and reporting will be conducted in accordance with the Consolidated Standards of Reporting Trials guidelines, with the primary analyses being based on the intent-to-treat principle without imputing any missing observations. All efficacy analyses will be based primarily on the full analysis set, and safety analysis will be conducted using data from the safety analysis population. For baseline variables, summary statistics will be performed using frequencies and proportions for categorical data and means and standard deviations for continuous variables. In the primary analysis, recurrence-free survival will be calculated using the Kaplan–Meier method, whereas its 95% confidence interval (CI) was estimated using Greenwood’s formula. If the lower bound of the 95% CI exceeds 58%, the efficacy of the repeated MPA therapy will be confirmed. Regarding secondary endpoint analyses, the complete response rate, pregnancy, hysterectomy, infertility treatment, and number of D&C will be calculated using the Clopper–Pearson method to construct a 2-sided 95% CI. This study has been performing in accordance with the guidelines of the Declaration of Helsinki. The protocol and amendments were approved by the Central Institutional Review Board of Keio University School of Medicine (N20194001). The trial was registered at the Japan Registry of Clinical Trials (jRCTs031200256; https://jrct.niph.go.jp/ ).