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Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 513-516 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.7271 Phase II Study of Paclitaxel Plus Gemcitabine Salvage Chemotherapy for Germ Cell Tumors After Progression Following High-Dose Chemotherapy With Tandem Transplant
From the Divisions of Hematology-Oncology and Biostatistics, Indiana University School of Medicine, Walther Cancer Institute; and the Indiana University Cancer Center, Indianapolis, IN Address reprint requests to Lawrence H. Einhorn, MD, Indiana University Cancer Center, 535 Barnhill Dr Rm 473, Indianapolis, IN 46202; e-mail: leinhorn{at}iupui.edu
Purpose To determine long-term survival and potential cure with salvage chemotherapy with paclitaxel plus gemcitabine after progression after both cisplatin combination chemotherapy and subsequent high-dose chemotherapy with tandem transplantation. Patients and Methods One hundred eighty-four patients received salvage high-dose chemotherapy at Indiana University (Indianapolis, IN) from February 1996 to December 2004. After further evidence of progressive disease, 32 patients were subsequently treated with paclitaxel 100 mg/n2 over 1 hour plus gemcitabine 1,000 mg/m2 over 30 minutes, days 1, 8, and 15 every 4 weeks for a maximum of six courses. This is a retrospective review of this patient population. Patients were evaluated for response, duration of response, and survival. Patients were ineligible if they received prior paclitaxel or gemcitabine. Results Ten (31%) of 32 patients achieved objective response, including four partial remissions (2- to 6-month duration) and six complete responses (CRs). Four of these six CRs (12.5% of total patient population) are continuously disease free (NED) with paclitaxel plus gemcitabine alone (no postchemotherapy surgery) at more than 20, 40, 44, and 57 months from start of paclitaxel plus gemcitabine, respectively. One additional CR is currently NED more than 63 months after paclitaxel plus gemcitabine with two subsequent resections of carcinoma. Conclusion Long-term disease-free survival is possible with paclitaxel plus gemcitabine in this patient population that progressed after high-dose chemotherapy, and had not received prior paclitaxel or gemcitabine.
The introduction of cisplatin combination chemotherapy has transformed metastatic germ cell tumors from a dismal prognosis to a model for a curable neoplasm.1 Seventy percent of patients are cured with initial cisplatin induction therapy.2,3 Various strategies have been utilized as second-line therapy after failure to cure with initial cisplatin combination chemotherapy. This includes standard-dose regimens with cisplatin plus ifosfamide plus either vinblastine4 or paclitaxel5 or high-dose chemotherapy (HDCT) with marrow or peripheral-blood stem-cell transplantation.6 There are no randomized studies proving the superiority of one approach compared with another. However, for patients who are refractory to standard dose cisplatin (progression within 4 weeks of last course of chemotherapy), HDCT has been the most logical approach, with a distinct possibility for long-term survival and cure.7 Results of subsequent chemotherapy after relapse from HDCT have been disappointing. Porcu et al8 reported the Indiana University (Indianapolis, IN) experience. Forty-seven patients received further chemotherapy after HDCT. An additional seven patients underwent surgery alone. There were only three complete responses (CRs) and nine partial responses (PRs) for 66 chemotherapy regimens, for an overall response rate of 18.2% and a CR rate of 5%.8 Fifteen of these patients received platinum-based chemotherapy, usually combined with ifosfamide plus a third drug. There was only one PR, lasting 3 months, in these 15 patients. Overall, only five patients were continuously disease free (NED) after relapse from HDCT. Of these, three responded with a PR to daily oral etoposide9 with subsequent resection of germ cell cancer, one had salvage surgery,10 and the fifth patient had resection of germ cell cancer followed by daily oral etoposide. All five of these patients had surgical resection of germ cell cancer as part or all of their successful outcome. Paclitaxel and gemcitabine have been evaluated as single agents in germ cell tumor patients who experienced treatment failure with prior therapies. Responses with single-agent paclitaxel have ranged from 11% to 26%,11-14 presumably with higher responses in more favorable patient populations. Two studies of single-agent gemcitabine yielded similar 19% and 20% response rates.15-16 To the best of our knowledge, there was no long-term continuous disease-free survival in patients receiving single-agent paclitaxel or gemcitabine if they had previously been treated with HDCT. A phase I study combined these drugs, administered weekly for 3 consecutive weeks every 4 weeks in a variety of solid tumors.17 Responses were seen and the dose of 100 mg/m2 and 1,000 mg/m2 of paclitaxel and gemcitabine was chosen for a subsequent phase II Eastern Cooperative Oncology Group (ECOG) study in patients with pretreated germ cell tumors. Although only six responses (21.4%) in 28 patients were seen in this ECOG trial, there were three CRs, and two were durable.18 This study was conducted from January 1999 through December 2000. Approximately half of the patients on this ECOG trial were enrolled at Indiana University. Only 10 (36%) of the 28 patients were treated with prior HDCT. After completion of the ECOG trial, we continued to evaluate this two-drug combination in refractory germ cell tumor patients. This retrospective review details our experience at Indiana University with this regimen in patients who had experienced treatment failure with cisplatin combination chemotherapy, HDCT with or without other chemotherapy regimens. The primary objective was to define whether durable remission and potential cure was still possible in this heavily pretreated patient population.
One hundred eighty-four patients received HDCT at Indiana University as second-line or later therapy from February 1996 to December 2004. Sixty-five patients progressed after HDCT, utilizing tandem transplantation, with carboplatin 700 mg/m2 x 3 days plus etoposide 750 mg/m2 x 3 days.6 Thirty-two of these 65 patients subsequently started paclitaxel plus gemcitabine at Indiana University. The remainder were not eligible because they relapsed before the start of the ECOG phase II study or they had received paclitaxel or gemcitabine before HDCT. In addition, other patients relapsed outside of Indiana University and were treated (or not treated) with other regimens at the discretion of the local oncologist. There was one woman with ovarian germ cell tumor, and the remainder had testicular cancer. Paclitaxel was administered in a dosage of 100 mg/m2 intravenously (IV) over 1 hour followed by gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 4 weeks for a maximum of six cycles. Standard premedication with dexamethasone 20 mg (oral or IV), diphenhydramine 50 mg IV, and either cimetidine 300 mg IV or ranitidine 50 mg IV was administered 30 minutes before each dose. Generally speaking, day 1 of each new cycle began only when the absolute neutrophil count was at least 1,500/mm3 and platelets were at least 75,000/mm3. Likewise, dose reductions for days 8 and 15 were as previously published.18 However, this was not uniform because much of the subsequent paclitaxel/gemcitabine was administered by the local oncologist, and after completion of the ECOG phase II study in December 2000, there was no formal protocol. Hematopoietic growth factor with granulocyte colony-stimulating factor were usually used only for prolonged granulocytopenia. CR to chemotherapy alone was defined as disappearance of all clinical and radiologic evidence of disease, and normal serum human chorionic gonadotropin and alpha-fetoprotein for a minimum of 4 weeks. Overall survival was defined as time from initiation of paclitaxel plus gemcitabine to last follow-up or death. Survival times were estimated using the Kaplan-Meier method.19 All patients were treated with initial cisplatin plus etoposide (plus bleomycin in most patients) as well as HDCT. Patients were ineligible if they had received prior paclitaxel or gemcitabine. Patients received their initial paclitaxel plus gemcitabine at Indiana University. All patients who received a single dose of paclitaxel plus gemcitabine were eligible and assessable. Patients were entered from August 1999 through August 2005. This study was approved by the Indiana University human institutional review board.
Thirty-two patients were treated with paclitaxel plus gemcitabine. Twenty-five (78%) received this therapy as third-line chemotherapy, six patients (19%) as fourth-line, and one patient as fifth-line chemotherapy. All patients had progressed after HDCT. Most patients who achieved a CR to their HDCT also were treated with a subsequent 3 months of maintenance daily oral etoposide.20 Toxicity was as previously described.17,18 The main toxicities were myelosuppression and peripheral neuropathy. There was no treatment-related mortality, and no patient stopped therapy due to toxicity. Four patients (12.5%) achieved a PR; however, these were all of brief duration (2 to 6 months). Six patients (19%) achieved a CR, and four patients remain continuously NED for more than 20, 40, 44, and 57 months from the start of paclitaxel plus gemcitabine, respectively. None of these four patients had subsequent resection of teratoma or carcinoma. An additional CR patient is currently NED more than 63 months from start of paclitaxel plus gemcitabine, but he has had two subsequent resections of carcinoma (last surgery, March 2001). The clinical details for the six CR patients are depicted in Table 1. All six patients received prior bleomycin/etoposide/cisplatin (BEP) and HDCT. They also all received a single course of vinblastine/ifosfamide/cisplatin (VeIP) before HDCT, as previously described.6 One patient (Patient 3, Table 1) was treated as fifth-line therapy. Although he previously responded to all prior regimens, the prior remissions were all brief except for a 28-month CR with HDCT. He is now currently NED more than 44 months after initiation of paclitaxel plus gemcitabine. It is noteworthy that these six patients had relatively minimal tumor burden. Two patients, both of whom are NED, only had elevated markers with normal radiographic studies. Three other patients had elevated markers and progressive small-volume pulmonary metastases.
The median survival for the entire group of 32 patients was 8.0 months (95% CI, 5.0 to 12.0 months; range, 2 to > 63 months). Four patients are alive with disease at 7 to 12 months from initiation of paclitaxel plus gemcitabine. Overall survival curve is depicted in Figure 1. Analysis was performed using S-PLUS software (Insightful Corp, New York, NY). The purpose is to provide Kaplan-Meier median overall survival time with surviving patients as censored and 95% CI.
Germ cell tumors are remarkably chemosensitive and curable compared with other solid tumors. Furthermore, second-line therapy with cisplatin plus ifosfamide plus either vinblastine or paclitaxel has a higher cure rate than any other metastatic solid tumor enjoys as first-line chemotherapy.4,5 HDCT has been used in various testicular cancer centers around the world as second- or third- (or later) line chemotherapy.6,21,22 We first started using HDCT as third-line or later chemotherapy at Indiana University 20 years ago.23 We currently utilize peripheral blood rather than marrow stem-cell transplantation, and we usually use HDCT as initial salvage chemotherapy. However, even when HDCT is used as third-line chemotherapy (or later) there is still a potential for long-term survival and cure.23,24 Despite these successes, treatment options after relapse from HDCT have been largely palliative. Single-agent chemotherapy with daily oral etoposide,9 paclitaxel,11-14 gemcitabine,15,16 or oxaliplatin25 can produce 10% to 20% brief PRs with little or no chance for cure. Further cisplatin combination chemotherapy achieved only a single brief PR in 15 patients who relapsed after HDCT.8 Before the introduction of the two drug combination of paclitaxel plus gemcitabine, we had never accomplished a durable CR with any form of chemotherapy alone (without surgery) in this patient population. Furthermore, recent (2005) National Comprehensive Cancer Network (NCCN; www.nccn.org) guidelines for germ cell tumors state that "almost all who fail HDCT are incurable." The combination of gemcitabine plus oxaliplatin has been evaluated in heavily pretreated patients with germ cell tumors. Kollmannsberger et al26 utilized gemcitabine 1,000 mg/m2 days 1 and 8 plus oxaliplatin 130 mg/m2 every 3 weeks in 35 patients. Thirty-one of the 35 had prior HDCT. Nineteen of these 31 had tandem transplantation rather than a single course of HDCT. There were three CRs, and one patient achieved a marker-negative partial response. Two of these patients remain progression free after failure to cure with salvage HDCT, but with relatively brief follow-up of more than 4 and 16 months, respectively. Pectasides et al27 in Greece evaluated the same dose and schedule in 28 refractory patients. However, only four of these 28 patients had received prior HDCT. Four (14%) of 28 patients achieved CR, with three continuously disease free at more than 14, 19, and 28 months, respectively. It was not stated in the article whether any of these three patients had prior HDCT, nor whether post–gemcitabine-plus-oxaliplatin surgical resection of teratoma or cancer was performed. Thirty-two patients were treated at Indiana University with this weekly regimen of paclitaxel plus gemcitabine. This was a retrospective review, and patients were not offered this regimen if they had received prior paclitaxel or gemcitabine. Ten (31%) of 32 patients achieved an objective response. Four (12.5%) of 32 attained prolonged CRs with chemotherapy alone, including three patients who are continuously NED for more than 40 months. An additional patient is currently NED at more than 63 months, but with two separate postchemotherapy resections of cancer. Two additional points should be emphasized in this report. Paclitaxel/ifosfamide/cisplatin (TIP) has become a commonly utilized initial salvage chemotherapy regimen.5 In our opinion, paclitaxel/gemcitabine would not be expected to achieve long-term remission in patients with prior TIP or any other exposure to paclitaxel/gemcitabine. The four patients remaining NED had minimal tumor burden, with two of the four having only elevated markers. All four had achieved CR to their prior HDCT. The role of paclitaxel plus gemcitabine as components of first-line therapy for advanced disease or initial salvage therapy remains to be elucidated. During the last two decades, agents such as ifosfamide and paclitaxel that demonstrated modest single-agent activity subsequently became incorporated as components of curative cisplatin salvage chemotherapy regimens.4,5 The optimal dose and schedule of this two-drug regimen is unknown. However, as utilized in this study, we have achieved durable CRs in patients who relapsed after HDCT. However, this is not an easy regimen in heavily pretreated patients because of neurotoxicity and myelosuppression. As is true with salvage chemotherapy regimens in general, major benefit is seen only in patients who achieve a CR. Despite the limitations of a small sample size and data coming from a single institution, these data demonstrate that long-term disease-free survival and probable cure are possible in selected patients after progression after HDCT.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: Lawrence H. Einhorn, AMGEN, Glaxo, Biogenidec Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Manuscript writing: Lawrence H. Einhorn, Mary J. Brames, Beth Juliar, Stephen D. Williams
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Einhorn LH: Treatment of testicular cancer: A new and improved model. J Clin Oncol 8:1777-1781, 1990[Abstract] 2. Einhorn LH: Testicular Cancer. Proc Natl Acad Sci U S A 99:4592-4595, 2002 3. Bosl GJ, Motzer RJ: Testicular germ cell cancer. N Engl J Med 337:242-253, 1997 4. Loehrer P, Nichols C, Weathers T, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage chemotherapy in recurrent germ cell tumor. J Clin Oncol 16:2500-2504, 1998[Abstract] 5. Kondagunta GV, Bacik J, Donadio A, et al: Combination of paclitaxel, ifosfamide and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 23:6549-6555, 2005 6. Bhatia S, Abonour R, Porcu P, et al: High dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18:3346-3351, 2000 7. Vaena DA, Abonour R, Einhorn LH: Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables. J Clin Oncol 21:4100-4104, 2003 8. Porcu P, Bhatia 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 9. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17:36-39, 1990[Medline] 10. Murphy B, Breeden ES, Donohue JP, et al: Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 11:324-329, 1993 11. Motzer RJ, Bajorin DF, Schwartz LH, et al: Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors. J Clin Oncol 12:2277-2283, 1994 12. Nazario A, Amato R, Hutchinson L, et al: Paclitaxel in extensively pretreated nonseminomatous germ cell tumors. Urol Oncol 1:184-187, 1995[CrossRef] 13. 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 14. Sandler AB, Christous A, Fox S, et al: A phase II trial of paclitaxel in refractory germ cell tumors. Cancer 82:1381-1386, 1998[CrossRef][Medline] 15. Einhorn LH, Stender MJ, Williams SD: Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 17:509-511, 1999 16. 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 17. Einhorn L, Raghavan D, Kindler H, et al: A phase I trial of gemcitabine plus paclitaxel combination in patients with refractory solid tumors. Proc Am Soc Clin Oncol 17:207, 1998 (abstr 796) 18. Hinton S, Catalano P, Einhorn LH, et al: Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): A trial of the Eastern Co-operative Oncology Group. J Clin Oncol 20:1859-1863, 2002 19. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 20. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral VP-16 following salvage therapy in patients with germ cell tumors. J Clin Oncol 13:1167-1169, 1995[Abstract] 21. Motzer RJ, Mazumdar M, Bosl GJ, et al: High dose carboplatin, etoposide and cyclophosphamide for patients with refractory germ cell tumors: Treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14:1098-1105, 1996 22. Margolin K: High dose chemotherapy and stem cell support in the treatment of germ cell cancer. J Urol 169:1229-1233, 2003[CrossRef][Medline] 23. Broun ER, Nichols CR, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117:124-128, 1992 24. Einhorn LH, Williams S, Abonour R: Salvage chemotherapy with high dose carboplatin + etoposide and peripheral blood stem cell transplant in patients with germ cell tumors. J Clin Oncol 24:228, 2006 (suppl; abstr 4542) 25. 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 26. 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 27. Pectasides D, Pectasides M, Farmakis D, et al: Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: A phase II study. Ann Oncol 15:493-497, 2004 Submitted June 12, 2006; accepted November 16, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
