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Oral etoposide monotherapy is effective for metastatic breast cancer with heavy prior therapy Authors: Peng YUAN, Binghe XU, Jiayu WANG, Fei MA, Ying FAN, Qing LI and Pin ZHANG Affiliations: Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100021, 1 China Requests for reprints Dr. Binghe Xu, Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100021, China; TEL: 8610-8778-8826 FAX: 8610-8771-5711 2 E-mail: [email protected] Key words: etoposide; oral;metastatic breast cancer ; chemotherapy PS: The abstract of this paper was presented as a poster at the 2011 ASCO (American Society of Clinical Oncology) Meeting (Abstract ID: 1107). 3 Abstract Purpose Treatment option for metastatic breast cancer (MBC) patients pretreated with chemotherapy is limited. Oral etopside has shown some promises in these patients. However, patients who received heavy prior 4 chemotherapy may have poor tolerance to prolonged oral etoposide exposure. This study is a single-arm clinical trial that evaluates the efficacy and safety of short-term oral etoposide in Chinese patients with MBC who had received heavy prior therapy. Methods MBC patients receiving at least 2 chemotherapy regimens prior to the enrollment were treated with repeated cycles of oral etoposide (60 mg/m 2/d on days 1-10, followed by 11-day of rest). The primary end point was the progression free survival (PFS). The secondary end points were objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and 5 toxicity profiles. Results Thirty-two patients received 230 cycles with a median of 6 cycles (range: 2 to 20 cycles) per patient. Eight patients (25%) had partial response (PR), 14 patients achieved stable disease (SD). The ORR was 25%. Nine patients achieved SD for more than 24 weeks and CBR was 53%. The median PFS and OS were 5 (range: 1.5-17.0 months) and 16 months (range: 3.0-51.0 months), respectively. The patients who achieved clinical benefit had longer survival time than those who did not (25.0 verses 11.0 months, P<.01). Among the 16 patients who received more than 4 regimens prior to this study, 4 6 patients achieved PR, and 4 achieved SD for more than 24 weeks, with a CBR of 50%. The most common hematologic adverse events were anemia (43.8%) and neutropenia (38.5%). Nausea/vomiting (75.0%) and alopecia (62.5%) were the most frequent non-hematologic toxicity. Conclusions Oral etoposide is effective and well tolerated in Chinese women with heavily pretreated MBC. INTRODUCTION 7 Progresses in early detection and comprehensive treatment in recent years have improved the survival of breast cancer patients worldwide. Hormone treatment plays important roles in the treatment of breast cancer. For metastatic breast cancer (MBS) not sensitive to hormone therapy, novel agents that target specific tumor signaling pathways are important breakthroughs. However, at least 30% of patients initially diagnosed with early stage breast cancer will eventually develop MBC. Anthracycline, taxane and trastuzumab are preferred drugs for MBC. Other 8 drugs, e.g., capecitabine[1], vinorelbine[2-4], gemcitabine[5-7] and platinum-based antineoplastics[8-10] also demonstrated some efficacy, and can be used in cases that are resistant to anthracycline and taxanes. For patients treated previously with three or more chemotherapy regimens, there are no standard therapeutic schedules. Most guidelines suggest best supportive therapy or participating in clinical trials[11,12]. Etoposide is a semi-synthetic derivatives of podophyllotoxin, and arrest cell cycle at the late S phase and early G2 phase[13]. Etoposide injection has weak efficacy on MBC[14]. However, a phase I clinical trial indicated that a 9 variety of solid tumors respond to prolonged exposure to etoposide[15]. Sensitivity to oral etoposide has been demonstrated n small cell lung cancer, non-small-cell lung cancer and non-Hodgkin lymphoma[16]. The maximum-tolerated dosage upon oral administration (each cycle consisted of 21 consecutive days of treatment followed by 7-day “drug holiday”) was 50 mg/m2/day[17]. In a phase II clinical trial for recurrent breast carcinoma, however, poor tolerance at this dosage was noticed[18]. In summary, optimal dosage and duration of the treatment remain unknown. Also, there is lack of data for oral etoposide in Chinese patients with MBC. 10 In the current study, we investigated the efficacy and safety of short-term oral etoposide in a group of Chinese patients with MBC whose disease progressed despite extensive prior chemotherapy. METHODS Patients Written informed consent was obtained from all participants. The inclusion 11 criteria were: (1) histologically confirmed MBC; (2) aged between 18 and 80 years; (3) At least two previous chemotherapeutic regimens for MBC; (4) ECOG performance status (PS) score ≤2; (5) adequate bone marrow reserve (hemoglobin≥10.0g/dl, neutrophils≥1.5×109 /L, platelet≥100×109 /L; (6) relatively normal liver (serum bilirubin 1.5×upper limits of normal [ULN], AKP, AST and ALT 2.5×ULN or 5.0 ULN if liver metastasis was present) and renal function (serum creatinine <1.5 times the upper limit of normal [ULN] or a creatinine clearance of ≥60 ml/minute); (7) normal cardiac function (assessed by electrocardiogram or thoracic radiography). 12 The exclusion criteria included: previous chemotherapy or radiotherapy not completed at least 4 weeks prior to the enrollment; patients not recovered from the toxic effects of previous chemotherapy or radiotherapy (except alopecia); previous radiation therapy targeted more than 25% of whole body bone; known or suspected brain metastasis or second primary malignancy (except basal cell carcinoma and in situ cervical carcinoma). Treatment Plan 13 In this single site, one arm clinical trial, patients received oral etoposide (60 mg/m2/d, given in single dose) on days 1-10 at home. Treatment cycle was repeated every 3 weeks until confirmed disease progression, or intolerable toxicity. Dose modification was pre-planned as following: reduction to 75% after the first episode of grade 3 hematologic toxicity and/or grade 2 non-hematologic toxicity; reduction to 50% after the second episode of grade 3 hematological toxicity and/or grade 2 non-hematological toxicity; discontinuation upon the third episode of grade 3 hematologic toxicity and/or grade 2 non-hematologic toxicity, or a second episode of grade 4 toxicity. 14 Efficacy and Safety Assessment Prior to the enrollment, all the patients received baseline assessment that included medical history, somatoscopy, chest X-ray or CT, complete blood count, and full clinical chemistry workups. Whole blood cell counts and full clinical chemistry workups were carried out during each cycle. CT scanning (with magnetic resonance imaging [MRI] as indicated) was performed every 2 cycles. 15 The primary end point was progression free survival (PFS). The secondary end points included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and toxicity profiles. Tumor evaluation was performed every two cycles according to the RECIST criteria (version 1.0). PFS was defined as the period from the start of the treatment until disease progression. OS was calculated from the start of the treatment to death by any cause or to the last date the patient was known to be alive. Objective response was defined as complete response (CR) plus partial response (PR). Objective responses, stable disease (SD), and disease progression (PD) were evaluated 16 in accordance with RECIST criteria. Clinical benefit rate (CBR) was defined as CR+PR+SD≥24 weeks. Safety was assessed on the basis of reported adverse events and laboratory abnormalities. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0). Statistics Intention-to-treat(ITT)analyses were carried out for both efficacy and safety 17 measures. Descriptive statistics were used to summarize safety and laboratory observations. Median PFS and OS, with 95% confidence interval (CI), were estimated by Kaplan-Meier method. Response rate in subgroups was analyzed by cross-tabulation and Chi-squared testing. RESULTS Patient population 18 Thirty two patients were enrolled between May 2005 and May 2008. Patient demographics at baseline are summarized in Table 1. Median follow-up was 17.2 months with a range from 3.2 to 51.2 months. Majority of the patients (75.0%) had visceral disease involving the lung and/or liver. The cancer had metastasized to at least two distant sites in 78.0% of the patients. Half of the patients had received four chemotherapeutic regimens for MBC. Most of the patients (31/32) received anthracycline and/or taxane-containing regimen as adjuvant or metastatic therapy. 84% of the patients received capecitabine, two third of the patients received venorelbine and platinum-containing regimen, 19 and a quarter of the patients received gemcitabine as metastatic therapy. Treatment Compliance A total of 230 treatment cycles were given, with a median of 6 cycles (range 2 -20 cycles). A total of 3 treatment cycles were delayed for 3 to 10 days (median, 7 days), as a result of grade 2 leukopenia or neutropenia (2 patients) and liver dysfunction (1 patient). The median time of the delay was 5 days with a range from 2 to 10 days. Etoposide dosage was reduced in one patient. 97% of 20 patients received full dosage. Response and survival Of the 32 patients, 8 (25%) patients achieved PR, 14 patients (44%) achieved SD, 9 patients (28%) had SD for more than 24 weeks (long SD); and 10 patients (31%) experienced PD during treatment. The median PFS was 5.0 months with a range from 1.5 to 17 months. The median OS was 16.0 months (range: 3-51 months) (Table 2). The CBR was 53% (17/32). Eight patients are 21 still alive at the latest follow-up. Of the 16 patients who received ≥4 regimens prior to this study, 4 patients had PR, 6 patients had SD, and 4 patients had long SD, with a CBR of 50%. The median OS was 25.0 months (range: 16.9-33.0 months) in patients who had clinical benefit versus 11.0 months (range: 9.1-12.9 months) in patients without ( P=.000) (Figure 1). Safety Hematological and non-hematological toxicities are summarized in Table 3. 22 There were no treatment-related deaths. The most common hematologic adverse events were leucopenia (31%), neutropenia (38%) and anemia (42%). Treatment-related hematologic adverse events were grade1/2 and reversible. No grade 3 or grade 4 hematological adverse events were observed. Nausea/vomiting were the most frequent non-hematologic adverse events, with an incidence of 75%. Grade 3 nausea/vomiting occurred in one patient. No grade 4 non-hematologic adverse events were observed. Peripheral neuropathy was observed in 34% (11/32) of the patients (grade Ⅰ, 8 patients; grade Ⅱ, 3 patients). Other treatment-related non-hematologic adverse events 23 are summarized in Table 3. DISCUSSION In the first reported phase I clinical trial of oral etoposide, Hainsworth et al. [17] demonstrated that etoposide could be tolerated at up to 50 mg/m 2/d upon 21 consecutive days of treatment followed by 7-day break. Such a regiment has since then been adopted for patients with MBC by many investigators [19-23]. Martin et al. [23] and Palombo et al [24] reported an objective response rate of 24 30% and 22% in patients who had received one prior chemotherapy regimen, respectively. Neskovic-Konstantinovic et al. [19] observed a response rate of 33% in previously untreated MBC patients. Atienza et al. [22] reported 19% objective response rate; approximately 25% of their patients were chemotherapy naive, and fewer than 10% had failed two previous chemotherapy regimens. In contrast, Bontenbal et al. [20] observed a response rate of only 10% in patients who had failed one previous chemotherapy regimen. Pusztai et al. [21] reported only one partial response in 24 patients when oral etoposide was given as third- or fourth-line therapy in 25 heavily pretreated patients and a 25% dose reduction was required in four patients because of hematologic toxicity. The most common non-hematologic toxicities included alopecia, nausea, and mucositis. Grade 2 or greater alopecia, nausea, and mucositis affected 80%, 53%, and 40% of patients, respectively. Pusztai et al. concluded oral etoposide has limited activity and may cause severe toxicity as a third- or fourth-line therapy in heavily pretreated MBC patients. In another phase II trial, Saphner et al. [18] observed higher response rate in patients who never received chemotherapy vs. those who had received prior chemotherapy (57% vs. 6%, P = 0.004). There were 26 two treatment-related deaths, both owing to myelosuppression and infection. In our study, oral etoposide was given for 10 consecutive days in a 21-day cycle. Most patients received prior treatments with anthracycline and taxane-containing regimens. Half of the patients received four regimens after establishing a diagnosis of MBC, and a quarter of the patients received more than 5 regimens. The current study achieved a partial response rate of 25%, CBR of 53%, median PFS of 5.0 months and OS of 16.0 months. These outcomes are compare to that of capecitabine monotherapy in MBC as third line treatment and indicate relatively higher control rate and longer tumor 27 control time of oral etopside than that of capecitabine monotherapy[22,25-27]. Leukopenia, neutropenia and anemia were the most common hematologic toxicities in our study, with 31%, 38% and 42% patients developing grade I/II toxicities, respectively. No grade 3 or grade 4 hematological adverse events was observed. Nausea/vomiting was the most frequent non-hematologic toxicity, with an incidence of 75%, but grade 3 nausea/vomiting occurred in only one patient only, and no grade 4 non-hematologic toxicities were observed. Peripheral neuropathy was observed in 34% (11/32) of the patients (grade Ⅰ, 8 patients; grade Ⅱ, 3 patients). The safety profile of the etoposide 28 regimen used in this study seems to be better than that with 21 days of treatment in 28-day cycle. An obvious explanation for this finding is shorter exposure time. 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