etoposide, methotrexate, and actinomycin D (EP-EMA) regimen

International Journal of Gynecology and Obstetrics (2007) 98, 44–47

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / i j g o

CLINICAL ARTICLE

Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/ etoposide, methotrexate, and actinomycin D (EP-EMA) regimen Yuyan Mao, Xiaoyun Wan ⁎, Weiguo Lv, Xing Xie Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China Received 30 November 2006; received in revised form 8 March 2007; accepted 8 March 2007

KEYWORDS Gestational trophoblastic neoplasia; Drug resistance; Etoposide and cisplatin/etoposide; Methotrexate; Actinomycin D regimen; Recurrence

Abstract Objective: To evaluate the effectiveness of the etoposide and cisplatin/etoposide, methotrexate and actinomycin D (EP-EMA) regimen in patients with gestational trophoblastic neoplasia who had been successfully treated with the etoposide, methotrexate, and actinomycin D/cyclophosphamide and vincristine (EMA-CO) regimen but experienced a relapse, or who became refractory to EMA−CO treatment. Methods: From January 1999 to December 2005, 18 patients with gestational trophoblastic neoplasia who had been successfully treated with the EMA-CO regimen but sustained a relapse (n = 7) or who became refractory to it (n = 11) were treated with the EP-EMA regimen. The effectiveness, adverse effects, and tolerated dose intensity of the EP-EMA regimen were retrospectively analyzed. Results: The 18 patients received a total of 74 cycles of the EPEMA regimen and 12 (66.7%) achieved complete remission. Nine of the 11 patients (81.8%) apparently resistant to the EMA-CO regimen achieved complete remission. However, only 3 of the 7 patients (42.9%) who experienced a relapse after treatment with the EMA-CO regimen achieved complete remission. The main adverse effects of the EP-EMA regimen were myelosuppression and gastrointestinal problems. Because of myelosuppression and hepatotoxicity, only 56.8% of the patients could be treated with the planned dose intensity. Conclusion: EP-EMA may be an effective option for the treatment of gestational trophoblastic neoplasia in patients resistant to treatment with the EMA-CO regimen. However, it does not seem to benefit all the patients who experienced a relapse after treatment with the EMA-CO regimen. © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

⁎ Corresponding author. Women's Hospital, School of Medicine, Zhejiang University, Xueshi Road #2, Hangzhou 310006, China. Tel.: +86 571 87061501; fax: +86 571 87061878. E-mail address: [email protected] (X. Wan). 0020-7292/$ - see front matter © 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2007.03.037

Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide

1. Introduction

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Table 2 Factors affecting outcome in 18 patients treated with the EP-EMA regimen

In the late 1950s, Hertz and colleague from the US National Cancer Institute were the first to introduce a pharmacotherapy for the treatment of gestational trophoblastic neoplasia (GTN). Since the early 1960s, the cure rate for GTN has steadily increased. Despite the success of chemotherapy in inducing complete clinical responses in most patients, approximately 5% of patients with low-risk GTN and 25% with high-risk GTN have an incomplete response to first-line sequential single-agent or multi-agent chemotherapy, or have a relapse from remission [1,2]. The aim of this retrospective study was to evaluate the effectiveness of chemotherapy with etoposide and cisplatin/ etoposide, methotrexate and actinomycin D (EP-EMA) in patients with GTN who are resistant to or have had a relapse following treatment with EMA-CO.

2. Materials and methods 2.1. Patient characteristics From January 1999 to December 2005, 18 patients with GTN were treated with the EP-EMA regimen at Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Of these patients 11 were resistant to EMA-CO chemotherapy, and the disease relapsed in the remaining 7 who were in remission. For the latter, the interval of recurrence was 6 to 35 months after cessation of EMA-CO chemotherapy. The patients' age ranged from 25 to 58 years (median, 30 years). Serum β-subunit human chorionic gonadotropin (β-hCG) levels at the time of salvage therapy ranged from 17.3 to 155,379.0 IU/L (median, 585.0 IU/L). Six patients had International Federation of Gynecology and Obstetrics (FIGO) stage I disease, 2 had stage II, 8 had stage III, and 2 had stage IV. The FIGO prognostic scores ranged from 5 to 20 (median, 12). The patients' pregnancy histories included 13 complete moles, 3 term deliveries, and 2 abortions.

2.2. Estimation of the curative effect and toxicity criteria of the EP-EMA regimen The EP-EMA regimen (Table 1) was repeated every 2 weeks. The used drugs included actinomycin D (Act-D), methotrexate

Table 1 EP-EMA treatment schedule of intravenous administration Regimen

Time

Drug

Dose

EP

Day 1

EMA

Day 8

DDP VP-16 VP-16 Act-D MTX( a) MTX

80 mg/m2 100 mg/m2 100 mg/m2 500 μg/d 100 mg/m2 200 mg/m2( b)

Abbreviations: Act-D, actinomycin D; DDP, cisplatin; EMA, etoposide and cisplatin/etoposide, methotrexate, and actinomycin D; EP, etoposide and cisplatin; MTX, methotrexate; VP, eptoside; IV, intravenous. a Folinic acid, 15 mg intramuscularly, is administrated twice daily for a total 4 doses 24 h after starting of MTX treatment; moreover, urine hydration during Day 1 through Day 3 and urine alkalization when using MTX are necessary. b This dose is administered over 12 h.

Factor Age, y b 40 ≥ 40 Interval since previous pregnancy, y b2 ≥2 Previous pregnancy Molar Non-molar hCG levels, IU/L b 585 ≥ 585 Original no. of metastatic sites 1 ≥2 Original FIGO stage I II–III IV Original FIGO prognostic score b 12 ≥ 12 Surgery Yes No

Complete remission, no. (%) 8/12 (75.0) 4/6 (66.7) 9/13 (69.2) 3/5 (60.0) 9/13 (69.2) 3/5 (60.0) 5/8 (62.5) 7/10 (70.0) 3/4 (75.0) 5/8 (62.5) 4/6 (66.7) 7/10 (70.0) 1/2 (50.0) 6/7 (85.7) 6/11(54.5) 7/8 (87.5) 5/10 (50.0)

Abbreviations: EP, etoposide, cisplatin; EMA, Etoposide and Cisplatin/Etoposide, Methotrexate, and Actinomycin D.

(MTX) (Zhejiang Hisun Pharmaceutical Co., Ltd., China), cisplatin (DDP, Hansenpharm Co, Ltd, China), and etoposide (Vp16-213, Jiangsu Hengrui Medicine Co, Ltd, China). Response to chemotherapy was assessed weekly by measuring serum hCG levels, and monthly by a physical examination including a pelvic examination and a chest radiograph or a computed tomographic scan. Chemotherapy was continued for at least 3 cycles after serum hCG levels were less than 10 IU/ L for the purpose of eradicating all tumor cells. Complete remission was defined as serum hCG levels remaining below the detectable level, with no evidence of lesions in the uterus or at the metastatic sites. Drug resistance was defined as a logarithm decrease less than 1 in serum hCG levels, or a plateau, or an increase in serum hCG levels after 2 cycles of chemotherapy. Relapse was defined as serum hCG levels increased again 3 months after chemotherapy cessation. Complete blood count as well as liver and renal function tests were regularly performed. Toxicity was evaluated for every cycle using the National Cancer Institute common toxicity criteria [3].

2.3. Adjuvant surgery Adjuvant surgery was performed in 8 patients during the period of salvage chemotherapy. There were 5 hysterectomies, 2 wedge resections of choriocarcinoma from the uterus, and 1 pulmonary resection. No patient incurred surgery complications.

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Y. Mao et al.

3. Results

3.3. Follow-up and pregnancy outcome

3.1. Remission rates

Twelve patients who achieved complete remission were followed up for a period of 4.0 years (range, 0.5–6.0 years). Unfortunately, disease recurred 6 months later in 1 patient, but salvage therapy with 4 courses of treatment with paclitaxel was successfully, and she has remained in remission for more than 2 years. The remaining 11 patients have not presented any evidence of recurrence. Of the 6 patients who desired to carry a pregnancy and retained a normal menstrual cycle after treatment, 3 had successful pregnancies followed by 3 live births.

Eighteen patients with GTN received a total of 74 cycles of EP-EMA chemotherapy. The median number of cycles for each patient was 4.0 (range, 2–6). Of the 18 patients, 12 (66.7%) achieved complete remission. A median number of 2.0 cycles (range, 1–3) was required for a return to normal hCG levels. Of the 11 patients who had shown resistance to the EMA-CO regimen, 9 (81.8%) achieved complete remission; and of the 7 patients who experienced a relapse after treatment with the EMA-CO regimen, 3 (42.9%) achieved complete remission. Of the 8 patients who underwent adjuvant surgical procedures (6 who were resistant to treatment with the EMA-CO regimen and 2 who had a relapse following this treatment), 7 (87.5%) achieved complete remission. The factors affecting outcome in patients treated with the EP-EMA regimen for relapsed or refractory GTN are listed in Table 2.

3.2. Toxicity The forms of toxicity associated with the EP-EMA regimen are shown in Table 3. Granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Crawley, UK) was administered daily in the course of chemotherapy to prevent nausea and vomiting. No grade 4 gastrointestinal symptoms occurred. When total white blood cell count fell below 3500 × 109/L, recombinant human granulocyte colony-stimulating factor (G-CSF) (rhG-CSF; Qilinkunpeng Pharmaceutical Co, LTD, China) was administered subcutaneously. If platelet count fell below b70,000 × 109/L, recombinant human Iinterleukin 11 (Ju Heli; Qilu Pharmaceutical Co., LTD, China) was administered subcutaneously. Three patients received a blood transfusion because of anemia or thrombocytopenia but chemotherapy was not delayed. No obvious renal toxicity occurred during EP-EMA chemotherapy. Marrow suppression was the most common adverse effect. A total of 42 cycles (56.8%) were carried out with the planned dose intensity and the other 32 cycles were delayed, 28 (37.8%) because of neutropenia, 2 (2.7%) because of hepatotoxicity, and 2 (2.7%) because of other factors. The main factors that prevented the planned dose intensity to be given on schedule were neutropenia and hepatotoxicity.

Table 3

It has been demonstrated that single-agent chemotherapy using methotrexate or dactinomycin is superior to other protocols for non-metastatic GTN and low-risk GTN, with a cure rate that exceeds 95%. However, approximately 5% of patients with low-risk and 25% with high-risk GTN have an incomplete response to first-line single-agent or to multiagent chemotherapy, or they have a relapse after remission. Treating these patients with EMA-CO is effective and well tolerated. In a 1997 study, Bower and colleagues [4] reported 78% of patients to be in complete remission following this regimen, with a cumulative 5-year survival rate of 86.2%. Since the late 1980s, EMA-CO treatment has been used at Zhejiang University's Women's Hospital in patients with highrisk GTN and in those who were initially resistant to singleagent treatment (with methotrexate or dactinomycin) or to the methotrexate, dactinomycin, and cyclophosphamide (MAC) regimen [5]. Adjuvant surgical interventions, such as hysterectomy, wedge resection of GTN lesions in the uterus, and pulmonary resection, were performed in some patients. The overall rate of response to EMA-CO treatment was greater than 85%. The main adverse effects were myelosuppression and gastrointestinal symptoms. The EMA-CO regimen is effective, and its toxicity is well tolerated. However, it is difficult to achieve satisfactory response rates if patients do not respond to primary treatment with EMA-CO or if the disease relapses after remission. An unusual feature of GTN is that salvation therapy can be successful after primary therapy has failed. In 2003, Escobar and colleagues [6] reported a 92% survival rate using a cisplatin-based regimen as salvage therapy, along with surgical intervention when indicated. Reports on salvage chemotherapy with a cisplatin-based regimen have shown a

Toxicity observed with the EP-EMA (cycles)

Adverse effect

Neutropenia Anemia Thrombocytopenia Nausea, vomiting Hepatotoxicity a

4. Discussion

Total no. of cycles( a)

66 24 22 63 17

(89.2) (32.4) (30.0) (85.1) (23.0)

Toxicity Grade I

Grade II

Grade III

Grade IV

26 15 14 27 12

19 6 6 25 3

16 3 2 11 2

5 0 0 0 0

The values are given as number of cycles (percentage) at which the toxicity occurred.

Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide response rate ranging from 63% to 81% [4,7,8]. Bower and colleagues [4] also reported on their experience of the EP-EMA regimen, which has been increasingly used in many centers treating GTN. Because cisplatin is the main active agent in EP, but is not included in the composition of EMA-CO [9], it is rational to include cisplatin in a salvage therapy for patients with GTN who are resistant to EMA-CO. Separating nephrotoxic cisplatin from the renally excreted methotrexate reduces the problems involved in combining these agents in the same schedule. Newlands and coworkers [10] reported that 30 (88%) of 34 patients with GTN refractory to EMA-CO were cured by treatment with EP-EMA, and all 3 patients in whom the disease relapsed after EMA-CO treatment were in remission. In the present study conducted with 18 patients who received a total of 74 cycles of chemotherapy, along with surgical interventions when appropriate, 12 (66.7%) achieved complete remission, which is similar to results in other series. Nine of 11 patients with an apparent drug resistance to the EMA-CO regimen achieved complete remission, but only 3 of 7 in whom GTN had relapsed after they achieved complete remission with that regimen. Complete remission may be affected by factors such as age, hCG levels, type of previous pregnancy, interval since the previous pregnancy, number of metastatic sites, surgical intervention, and FIGO stage and scores. However, the FIGO score was the most important factor affecting complete remission. The rate of complete remission was higher in patients with scores less than 12 than in those with scores of 12 or higher. Therefore, a novel alternative chemotherapy regimen was needed for these patients with GTN. From the limited available data, it may be deduced that EP-EMA is the treatment choice for patients whose disease is resistant to the EMA-CO regimen, but that it seems to benefit only a limited number of patients whose disease has relapsed after treatment with EMA-CO. Many more patients are needed, unfortunately, to confirm this observation. Adjuvant surgical procedures, especially hysterectomy and thoracotomy, allow the removal of known foci of chemotherapy-resistant disease in selected patients with persistent or recurrent GTN [11,12]. If drug-resistant foci are confined to the uterus, hysterectomy or wedge resection may be considered, in accordance with the patient's desire to preserve her reproductive function. Resecting pulmonary nodules is also feasible in highly selected patients with solitary, drug-resistant pulmonary nodules and no evidence of lesions in the uterus or at other metastatic sites. In this study, surgical procedures were performed in 8 patients, of whom 7 were cured and 3 carried a pregnancy to term. The rate of complete remissions was found to be higher among patients who underwent surgery. This is in agreement with the findings of other authors, who report that surgery can reduce the residual drug-resistant malignant cells, thereby reducing number of courses of chemotherapy as well. Chemotherapy combined with salvage surgery must be recommended for these patients. Newlands [10] reported on 42 patients who received salvage therapy with EP-EMA, but that the toxicity of this schedule was significant, as 68% of the patients had grade 3/4 leukocytopenia and 40% had thrombocytopenia. In this 74-cycle study, toxicity chiefly resulted in myelosuppression and gastrointestinal symptoms (nausea and vomiting).

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The myelosuppression was cumulative in some patients. Thrombocytopenia was common but did not warrant treatment interruption. Only a few of patients needed a blood transfusion because of anemia and thrombocytopenia. Although G-CSF was used as soon as possible in patients with neutropenia, only 56.8% of the patients were treated with the planned dose intensity because they had neutropenia. The importance of monitoring and treating the myelosuppression in time must be stressed; and if G-CSF were prophylactically administered to patients who had neutropenia in previous cycles, it is likely that fewer of them would have to be treated with a reduced dose intensity. The second common adverse reaction caused by the EP-EMA regimen in this study was nausea and vomiting. Fortunately, grade 4 gastrointestinal symptoms were not observed because antiemetic drugs were used routinely throughout the treatment period. Although both cisplatin and methotrexate are nephrotoxic reagents, renal toxicity can be avoided by routinely using hydration and urine alkalization, as was done in this study. Therefore, treatment for toxicity should be individualized according to the patient's condition and the center's experience.

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