Introduction

Recently, the incidence of endometrial carcinomas has been increasing [1]. The standard primary treatment for operable patients with endometrial carcinoma is surgery followed by pelvic irradiation or chemotherapy, according to classification of postoperative recurrence risk [2]. In Japan, chemotherapy as adjuvant treatment has gained popularity, based on the results of the Japanese Gynecologic Oncology Group (JGOG) 2033 [3] and the Gynecologic Oncology Group (GOG) 122 [4] studies.

The concept of platinum-free interval exists as a maker for the selection of second-line chemotherapy for ovarian carcinoma [5]. However, a similar interval to define chemo-sensitive or chemo-resistant tumor in prediction of response to second-line chemotherapy does not exist for endometrial carcinoma [6]. Recently, several drugs have been developed for recurrent endometrial carcinoma; however, the response rate (RR) ranges from 4 to 27% for cytotoxic drugs [7,8,9,10,11,12,13,14,15,16,17] and from 0 to 18% for targeted molecular therapeutic agents [18,19,20,21,22,23,24,25,26,27,28]. So far, a biomarker to aid in the choice of drugs, and an effective second-line chemotherapy regimen for recurrent endometrial carcinoma, has not been established.

An active metabolite of irinotecan hydrochloride (CPT), SN-38, was effective as an anti-proliferative agent in four of five human endometrial cancer cell lines (Ishikawa, HEC-1A, HEC-50B, HEC-59, and HEC-108), and had synergic effects with cisplatin in vitro [29]. A tetrazolium dye (MTT) assay showed that CPT had anti-tumor efficacy in about 40% of endometrial carcinomas [30]. In addition, more cases with UDP-glucuronosyltransferase 1A1 (UGT1A1) *6, *28, and *28*6 polymorphisms develop grade 3/4 toxicities than those with wild-type UGT1A1 [31]. The efficacy of combination therapy with CPT and nedaplatin (N) has not been examined yet.

The aim of the present study was to evaluate effects and toxicities of CPT-N in recurrent and refractory endometrial carcinoma as second- or third-line chemotherapy and the correlation between UGT1A1 genotype and adverse effects, retrospectively.

Materials and methods

Among patients treated with endometrial carcinoma at our hospital between 2009 and 2017, 21 patients with recurrent and refractory endometrial carcinoma who received CPT-N as second- or third-line chemotherapy were identified. The CPT-N regimen consisted of 40–70 mg/m2 of CPT on days 1, 8, and 15, and 50 mg/m2 of nedaplatin on day 1, q4 weeks. The criteria for therapy administration were: granulocyte count greater than 1500/μL, platelet count greater than 100,000/μL, hemoglobin levels greater than 7 g/dL, and less than the grade 1 non-hematologic toxicity. If these criteria were not met on days 7 and 14, the drug administrations on days 8 and 15 were skipped. If these criteria were not met on day 1 at the next cycle, the administration on day 1 was delayed for 1 week. Patients who did not receive CPT-N according to these administration criteria were excluded.

Performance status was evaluated by the World Health Organization (WHO) performance status. Surgical stage was evaluated according to the International Federation of Gynecology and Obstetrics 2014 staging system. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) [32]. Response rate (RR) was defined as the ratio of complete remission (CR) to partial remission (PR). Clinical benefit rate (CBR) was defined as the combined percentages of CR, PR, and stable disease (SD). Serum levels of tumor markers including cancer antigen 125 (CA-125) were not used for evaluating progression in this study. Assessment of toxicities was carried out and graded according to the National Cancer Institute Common Toxicity Criteria Version 4.0 (CTCAE v3.0).

Polymorphisms of UGT1A1 were analyzed using the Invader UGT1A1 Molecular Assay (BML, Kawagoe, Japan). The UGT1A1*6 and *28 polymorphisms were defined as non-wild type.

The Stat View software ver. 5.0 (SAS Institution Inc., NC, USA) was used for statistical analysis. Progression-free survival (PFS) was calculated from the date of administration of CPT-N to recurrence or cancer-specific death. Overall survival (OS) was calculated from the date of the administration of CPT-N to cancer-specific death. Survival curves of PFS and OS were generated by Kaplan–Meier analysis. The Fisher exact test was used to evaluate differences in the correlations between UGT1A1 polymorphisms, treatment efficacy, and toxicities. Statistical significance was defined as a p < 0.05.

Results

The patient characteristics are summarized in Table 1. The median age of patients was 63 years (range: 41–77). Seventeen patients out of 21 (81%) had a performance status of 0 or 1. Four patients had stage Ib, 1 had stage IIIa, 2 had stage IIIc1, 1 had stage IIIc2, and 14 had stage IVb disease. All patients had received at least 1 course of platinum-based chemotherapy as prior chemotherapy. Two (9.5%) patients had a history of prior radiation therapy.

Table 1 Patient characteristics
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The details of drug cycles and response to chemotherapy are listed in Table 2. The median number of cycles was 3 (range 1–6). Three patients had CR, 6 patients had SD, and 12 patients had progressive disease (PD). The RR and CBR were 14 and 43%, respectively. The hematologic and non-hematologic adverse effects observed in patients are shown in Table 3. Four (19%) patients experienced grade 3 neutropenia. Among them, 3 (14%) patients developed grade 3 febrile neutropenia, but recovered with antibiotic therapy. Three (14%) patients developed grade 3 diarrhea which resolved naturally within 1 day. No treatment-related deaths were reported. The PFS and OS are presented in Fig. 1.

Table 2 Response and number of cycles of combination chemotherapy with irinotecan hydrochloride and nedaplatin
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Table 3 Adverse effects in patients treated with a combination chemotherapy of irinotecan hydrochloride and nedaplatin (CTCAE v4.0)
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Fig. 1
figure 1

Kaplan–Meier analyses of progression-free and overall survival of patients treated with an irinotecan hydrochloride and nedaplatin combination therapy

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The UGT1A1 genotyping results revealed a wild-type status in ten patients, UGT1A1*6 polymorphism in eight patients, UGT1A1*28 polymorphism in 2 patients, and UGT1A1*6*28 polymorphism in one patient. Compared with patients presenting with non-wild-type status, more patients with a wild-type status received a higher dose of CPT (p = 0.048). There were no statistical differences in RR and CBR between wild-type and non-wild-type patients (p = 0.59 and p = 0.67, respectively). Furthermore, there were no statistical significant differences in frequencies of hematological and non-hematological toxicities, regardless of UGT1A1 status (Table 4).

Table 4 Dose distributions of irinotecan hydrochloride and adverse effects according UDP-glucuronosyltransferase 1A1 (UGT1A1) genotype
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Discussion

Tables 5 and 6 list several cytotoxic drugs and targeted molecular therapeutic agents that have been evaluated as second-line chemotherapy for recurrent endometrial carcinoma in the GOG phase II study. The RR of cytotoxic agents described in the literature ranges from 4 to 27% [7,8,9,10,11,12,13,14,15,16,17], and drugs with high efficacies have not been developed yet. Due to the anti-tumor effects displayed in recurrent ovarian cancer, bevacizumab, an anti-angiogenic agent, [33, 34] along with other anti-angiogenic agents including thalidomide, bevacizumab, aflibercept, sorafenib, sunitinib, brivanib, nintedanib, and trebananib, were expected to also show anti-tumor efficacy. However, none among these drugs has proved to be significantly effective. On the other hand, mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and evelorimus has shown significant efficacy in endometrial carcinoma, which may be due to the dysregulation of phosphatase and tensin homolog (PTEN) expression and activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/ mTOR pathway in such carcinomas [21, 22]. However, all targeted molecular therapeutic agents displayed a lower RR, ranging from 0 to 14%. Although RR may not be the only relevant metric for drug selection, it is clear that there are no definitive single agent therapies for recurrent and refractory endometrial carcinomas.

Table 5 Literature-reported response rate and adverse effects of cytotoxic agents for recurrent endometrial carcinomas
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Table 6 Literature-reported response rate and adverse effects of targeted molecular therapeutic agents for recurrent and refractory endometrial carcinomas
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Although literature evidence suggests that CPT displays antitumor effects in endometrial cancer cells [29], the clinical benefit of a CPT regimen has not been examined previously. The results of our study demonstrated that CPT-N conferred a RR comparable to other agents without side effects (an important factor to consider in the case of recurrent or refractory endometrial carcinomas). As the view point, there was the biomarker to predict the developing side effects using CPT. The active metabolite of CPT, SN-38, is glucuronidated by UGT1A1 and inactivated. The toxicities of CPT were associated with UGT1A1 polymorphisms [35, 36]. Particularly, patients with a UGT1A1*6 genotype developed more severe toxicities compared to those with a wild-type genotype [31]. In this study, CPT dose modification according to UGT1A1 status ensured that a lower dose of CPT was administered to patients with a non-wild-type genotype. Interestingly, even with a lower dose of CPT, such patients showed RRs and toxicities comparable to those with a wild-type genotype. Thus, CPT dose modification based on UGT1A1 polymorphism status could decrease adverse effects and preserve RR in endometrial carcinoma patients.

Literature evidence shows that in colon cancer, a CPT-containing regimen, conferred a significant clinical benefit, and loss of tumor microsatellite instability (MSI) may serve as an effective biomarker to predict improved outcome in patients [37]. MSI was discovered in 40% of endometrioid carcinomas [38], and since CPT is efficacious against endometrioid carcinoma, further studies examining the association between MSI and response to CPT regimen in endometrial carcinoma patients would be useful.

This limitation of our study was that it was a single-institutional and retrospective study with a small sample size. In addition, CPT-N did not confer a higher RR than other popular regimens, although the side effects profile was relatively better.

In conclusion, this study showed that the CPT-N regimen tested here had a satisfactory RR with tolerable adverse effects. Furthermore, utilizing UGT1A1 polymorphism status to aid in dose determination might lower the incidence of side effects while preserving anti-tumor effects. The CPT-N regimen needs to be further explored as a candidate second-line chemotherapy option for endometrial carcinomas.