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Journal of Clinical Oncology, Vol 24, No 34 (December 1), 2006: pp. 5403-5407 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8065 Phase II Study of Cisplatin Plus Epirubicin Salvage Chemotherapy in Refractory Germ Cell Tumors
From the Division of Hematology-Oncology and Biostatistics, Indiana University Medical Center and Walther Cancer Institute, Indianapolis, IN Address reprint requests to Pablo M. Bedano, Indiana University School of Medicine, Indiana Cancer Pavilion, 535 Barnhill Dr, Rm 473, Indianapolis, IN 46202; e-mail: pabedano{at}iupui.edu
PURPOSE: Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer. This phase II clinical trial evaluated the combination of CIS plus epirubicin (CIS-EPI) in patients with metastatic germ cell tumors (GCT) not amenable to cure with standard salvage therapy. PATIENTS AND METHODS: Between March 2001 and August 2005, 30 patients with GCT, who had received at least one previous CIS-based regimen, were enrolled. All patients were males, with median age 36 (range, 24 to 45 years). Twenty-one patients (70%) had experienced late relapses (> 2 years). Patients received EPI 90 mg/m2 on day 1 and CIS 20 mg/m2 on days 1 to 5 every 3 weeks for maximum of four cycles. RESULTS: Nineteen (63%) of 30 patients received all four cycles. Toxicity was primarily hematologic: grade 3/4 neutropenia, four patients (one neutropenic fever); two patients had grade 3 thrombocytopenia, and five patients had grade 3/4 anemia. Nonhematologic toxicity was grade 3 acute renal failure in two patients; grade 3 electrolyte wasting in two patients; grade 3 nausea/vomiting in eight patients; grade 3 elevation of aminotransferases in one patient; and grade 3 diarrhea in one patient. There were no occurrences of severe mucositis, cardiotoxicity, or treatment-related deaths. Nine patients achieved a complete remission; seven of these patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. One patient remains alive with stable pulmonary nodules at 28+ months. CONCLUSION: CIS-EPI is an active regimen in metastatic GCT, with an acceptable toxicity profile. This regimen offers potential for long-term disease-free survival in this population.
Germ cell tumors (GCTs) are the most common solid tumors in men between the ages of 15 and 35 years, with an estimated 8,250 new cases expected in the United States in 2006.1 Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer, making it one of the most chemotherapy-sensitive solid tumors, and a model for a curable neoplasm.2 Of the patients not cured with first-line therapy, approximately one third will be cured with subsequent salvage therapy.3-8 Several regimens have shown activity in the salvage setting. Loehrer et al4,5 demonstrated that ifosfamide combination chemotherapy as third-line or greater therapy could produce durable complete remissions (CRs) in approximately 25% of patients. The combination of paclitaxel, ifosfamide, and CIS has shown a CR rate of 70%, with a 2-year progression-free survival rate of 65% in patients with favorable prognostic features.6 Two cycles of high-dose chemotherapy (HDCT) followed by stem-cell transplantation resulted in an overall disease-free survival of 60%, and a continuous disease-free survival rate of 53% in a study published by Bhatia et al.7 Because of the significant long-term survival achieved with HDCT, this has become the standard approach at our institution for the treatment of patients in first relapse who do not have primary mediastinal nonseminomatous GCT or late relapse (> 2 years after prior chemotherapy). A challenging group of patients are those who have relapsed primary mediastinal nonseminomatous GCT, in whom standard salvage therapies have limited activity.9,10 Patients with late relapse GCTs as a group do not respond well to salvage chemotherapy, and long-term survivors tend to be those with local recurrences who can undergo surgical resection.11-13 In addition, those patients who experience relapse after salvage HDCT have little chance of durable remission with additional chemotherapy.14 Some responses may be obtained with daily oral etoposide, although long-term survival is rare, and often depends on surgical resection of residual disease.15 For patients with poor prognosis for response to salvage chemotherapy, new strategies are needed. Multiple trials have evaluated the role of anthracyclines in testicular cancer, with varied results.16-25 A prospective trial in which a group of 171 previously untreated patients were randomly assigned to treatment consisting of CIS, vinblastine, and bleomycin, or these drugs plus doxorubicin, failed to show any difference between these two induction regimens.20 Other groups have used anthracycline-containing regimens in the first-line setting with good results, although these have not been compared directly with standard first-line regimens in prospective randomized trials.26 Single-agent epirubicin (EPI) has shown activity in patients with relapsed germ cell tumors in a phase II trial previously conducted at our institution.23 This article reports the results of using the combination of CIS and EPI (CIS-EPI) in the treatment of patients with GCT not amenable to cure with surgery or standard platinum salvage chemotherapy.
Eligibility requirements included histologic or serologic proof of progressive metastatic germ cell neoplasm (gonadal or extragonadal primary) with disease not amenable to cure with either surgery or chemotherapy. Patients were required to have histologic proof of recurrence or the presence of an increasing serum beta human chorionic gonadotrophin (hCG) or alpha fetoprotein (AFP; if an increasing marker was the only evidence of progressive disease, at least two consecutive determinations had to be performed that exhibited serologic progression). Patients whose only measurable evidence of progressive disease was an increasing serum concentration of hCG or AFP were eligible provided alternative causes for increased serum levels of these substances were excluded (including cross reaction with luteinizing hormone [tested if necessary by testosterone suppression of luteinizing hormone], ingestion of marijuana, or hepatitis).
Patients must have experienced treatment failure after initial CIS combination therapy administered with curative intent. Patients who were absolutely refractory to CIS (progression within 4 weeks of last course of CIS combination chemotherapy) were ineligible. In addition, patients should have experienced treatment failure and demonstrated progressive disease after the administration of at least one salvage regimen, with the exception of primary mediastinal nonseminomatous GCTs or late-relapse GCTs. Treatment failure after prior regimens was defined as a
Patients were also required to be
The treatment regimen consisted of EPI 90 mg/m2 intravenously during 15 to 30 minutes on day 1, and CIS 20 mg/m2 intravenously days 1 through 5, repeated every 21 days for a maximum of four cycles. Day 1 of a new cycle began only when the absolute neutrophil count was
Any patient who experienced a granulocytopenic fever, thrombocytopenic bleeding, or platelets less than 50,000/µL had 25% reduction in EPI and therapy was delayed until recovery to grade Patients were assessed with respect to response every cycle for disease measurable by physical examination, standard radiographs, or serum tumor markers. CR was defined as disappearance of all clinically detectable malignant disease (including normalization of elevated hCG and AFP concentrations) and return of abnormal test results to normal levels for at least 4 weeks. For patients whose only measurable disease was an increase in hCG or AFP, the values had to decrease below the upper limit of normal for the assay used and remain at that level for 4 weeks. Partial remission (PR) was defined as a decrease by at least 50% of the sum of the cross-sectional areas of all measured lesions in the absence of progression of any lesion or the appearance of any new lesion present on at least two measurements 1 month apart. Duration of CR and PR was measured from the date remission was achieved to the termination of remission. A two-stage design was used whereby 17 eligible patients were to be enrolled at the first stage. The study was designed to distinguish between true response rates (RR) of 20% v 40%, with an RR 20% or less considered as a negative study and an RR of 40% or higher worthy of additional accrual. The original study had an 85% power to detect a response rate of at least 40%, while maintaining an overall type I error of less than 5%.
Between March 2001 and August 2005, 30 patients with relapsed GCT were enrolled. The required three responses were seen among the first 17 eligible patients, and enrollment continued. All patients were males, with median age 36 years (range, 24 to 45 years). Other patient characteristics are listed in Table 1. Five of the patients had extragonadal nonseminomatous germ cell tumor. Twenty-four patients had elevated AFP (median, 2,335 ng/mL; range, 27.6 to 517,022 ng/mL), six patients had elevated hCG (median, 334 mU/mL; range, 2.88 to 38,372 mU/mL). Twenty-one patients (70%) experienced late relapses (> 2 years) and AFP was elevated in 19 (95%) of them.
The median number of cycles administered was four (range, one to six); 21 of 30 patients (70%) received all four cycles, and nine patients (30%) did not complete all four cycles (eight of them because of progressive disease and one because of toxicity). One patient received a total of six cycles after institutional review board approval because of a delayed decrease in markers. Table 2 lists the grade 3 and 4 toxicities. Toxicity was primarily hematologic: grade 3/4 neutropenia in four patients (one neutropenic fever); two patients had grade 3 thrombocytopenia, and five patients had grade 3/4 anemia. Nonhematologic toxicity was grade 3 acute renal failure in two patients; grade 3 electrolyte wasting in two patients; grade 3 nausea/vomiting in eight patients; grade 3 elevation of aminotransferases in one patient; and grade 3 diarrhea in one patient. There were no occurrences of severe mucositis or cardiotoxicity, and no treatment-related deaths.
Seventeen (57%) of 30 patients responded. The median survival was 14.5 months (95% CI, 10.0 to 25.0 months; Fig 1). Seven (23%) of the 30 patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. Table 3 summarizes the characteristics of these patients, all of whom were believed to be incurable with surgery alone at the time of relapse. Two patients were rendered disease free with chemotherapy alone. One of these patients had experienced progression after HDCT, and the other patient experienced a late relapse. Both of these patients continue without evidence of disease at 45+ and 46+ months. Four patients achieved a continuous CR with CIS-EPI followed by surgical resection of GCT (two patients) or teratoma (two patients). Patient 7 received radiotherapy to a residual mediastinal mass of unknown pathology after CIS-EPI. One additional patient with late-relapse GCT remains alive with stable pulmonary nodules at 28+ months. There were 20 patients entered onto this trial who experienced late relapse; six (30%) of these 20 remain without evidence of disease at 25 to 48 months from initiation of CIS-EPI. In contrast, only one of the 10 patients without late relapse remains disease free (patient 2; Table 3).
There is no established treatment for patients who have experienced relapse after CIS-based combination chemotherapy and carboplatin-based HDCT used as salvage therapy. In a series published by Porcu et al,14 47 patients received additional chemotherapy after HDCT, with a response rate of 18%. Of the 15 who received a platinum based-regimen, only one obtained an objective response. Oral etoposide has demonstrated activity in patients with refractory GCT; three of 21 patients experienced PRs (14%), and three other patients had a more than 90% decrease in serologic disease, but stable radiographic disease.15 No long-term survival was achieved, and oral etoposide remains primarily a palliative option for these patients. Paclitaxel and gemcitabine have shown single-agent activity in this population, with a response rate of 11% to 26% for paclitaxel, and 15% to 19% for gemcitabine.8,27-30 Combination chemotherapy with paclitaxel and gemcitabine was shown to be effective in the treatment of refractory GCT in a phase II trial conducted by Eastern Cooperative Oncology Group.8 In this study, 28 patients with refractory GCT, including 10 patients who were overtly platinum refractory, received paclitaxel 110 mg/m2 followed by gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 4-week cycle for a maximum of six cycles. Six (21.4%) of 28 patients were coded as responders, including three CRs. Two patients remained in CR at 15+ and 25+ months at the time of study publication, including one patient who was absolutely CIS refractory. Single-agent oxaliplatin has also shown activity in patients with relapsed or CIS-refractory germ cell cancer.31 Kollmannsberger et al32 reported an RR of 46% for the combination of gemcitabine and oxaliplatin in 35 patients who experienced relapse after CIS-based regimens. Three patients achieved CR, and were alive at 16+, 12+, and 4+ months, respectively. Twenty-one (70%) of the 30 patients in our study experienced relapse more than 2 years after the initial treatment of GCT. From previously published series, late-relapsing tumors seem to be slow growing, and typically are not cured by chemotherapy.11-13 These tumors tend to respond initially to chemotherapy, but relapse soon afterward, and the long-term survivors are usually those who have localized recurrences in which surgery is part of the therapy. Ronnen et al13 published a retrospective analysis of outcomes to salvage therapy of late-relapse GCT at the Memorial Sloan-Kettering Cancer Center. In this study, 29 patients were identified as having late relapses from nine different clinical trials of salvage therapy at Memorial Sloan-Kettering Cancer Center. Seven of these patients were identified as long-term survivors; six of these seven patients had CR after resection of persistent abnormalities, and one attained CR after chemotherapy alone. All of the long-term survivors had been treated with combination chemotherapy, including paclitaxel, ifosfamide, and CIS. Of the seven patients with late relapse treated with HDCT, none had a CR, but one patient who received sequential paclitaxel plus ifosfamide followed by HDCT had a PR, and was marker negative with persistent radiographic abnormalities. This has led the authors to conclude that the inclusion of paclitaxel into combination chemotherapy is important in overcoming resistance in late-relapse GCT. Our series confirms the activity of EPI in refractory GCT, and shows that combination CIS-EPI offers the possibility of long-term survival in this group of high-risk patients, with acceptable toxicity. In the case of late-relapse GCT, our series adds to the growing body of knowledge regarding these tumors. It seems from our results that CIS-EPI, followed by resection of persistent abnormalities, offers the possibility to render disease free patients who were not surgical candidates at relapse. In at least one patient with late relapse, we also observed long-term survival after chemotherapy alone.
The authors indicated no potential conflicts of interest.
Supported in part by Pharmacia. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13:1170-1176, 1995[Abstract] 13. Ronnen EA, Kondagunta GV, Bacik J, et al: Incidence of late-relapse germ cell tumor and outcome to salvage therapy. J Clin Oncol 23:6999-7004, 2005 14. Porcu P, Bahtia S, Sharma M, et al: Results of treatment after relapse from high-dose chemotherapy in germ cell tumors. J Clin Oncol 18:1181-1186, 2000 15. Miller JC, Einhorn LH: A phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17:36-39, 1990[Medline] 16. Monfardini S, Bajetta E, Musumeci R, et al: Clinical use of adriamycin in advanced testicular cancer. J Urol 108:293-296, 1972[Medline] 17. Einhorn LH, Donohue JP: Improved chemotherapy in disseminated testicular cancer. J Urol 117:65-69, 1977[Medline] 18. Higby DJ, Wallace HJ, Henderson ES, et al: Adriamycin-cyclophosphamide and adriamycin-cis-dichloro-diammineplatinum(II) combination chemotherapy in patients with advanced cancer. 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Lecesne A, Droz JP, Azab M, et al: Phase II trial with single agent epirubicin (EPI) as salvage chemotherapy (CT) in refractory germ cell tumours (RGCT). Proc Am Soc Clin Oncol 9:145, 1990 (abstr 563) 25. Harstrick A, Schmoll HJ, Wilke H, et al: High dose epirubicin in refractory or relapsed non-seminomatous testicular cancer: A phase II study. Ann Oncol 1:375-376, 1990 26. Fizazi K, Do KA, Wang X, el al: A 20% dose reduction of the original CISCA/VB regimen allows better tolerance and similar survival rate in disseminated testicular non-seminomatous germ-cell tumors: Final results of a phase III randomized trial. Ann Oncol 113:125-134, 2002 27. Bokemeyer C, Beyer J, Metzner B, et al: Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer. Ann Oncol 7:31-34, 1996 28. Sandler AB, Cristou A, Fox S, et al: A phase II trial of paclitaxel in refractory germ cell tumors. Cancer 82:1381-1386, 1998[CrossRef][Medline] 29. Einhorn LH, Stender MJ, Williams SD, et al: Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 17:509-511, 1999 30. Bokemeyer C, Gerl A, Schoffski P, et al: Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. J Clin Oncol 17:512-516, 1999 31. Kollmannsberger C, Rick O, Derigs HG, et al: Activity of oxaliplatin in patients with relapsed or cisplatin-refractory germ cell cancer: A study of the German Testicular Cancer Study Group. J Clin Oncol 20:2031-2037, 2002 32. Kollmannsberger C, Beyer J, Liersch R, et al: Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: A study of the German Testicular Cancer Study Group. J Clin Oncol 22:108-114, 2004 Submitted February 7, 2006; accepted September 20, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25% increase in the product of perpendicular diameters of measurable tumor masses during prior therapy, new lesions, or an increasing AFP or hCG. Patients with the clinical situation of a growing teratoma (normal or declining markers and radiographic evidence of progression, or clinical progression) were considered for surgery and were not eligible for this trial. 
4x normal and bilirubin 
