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© 2002 American Society for Clinical Oncology Phase II Study of Paclitaxel Plus Gemcitabine in Refractory Germ Cell Tumors (E9897): A Trial of the Eastern Cooperative Oncology GroupByFrom the Indiana University Medical Center and Walther Cancer Institute, Indianapolis, IN; Dana-Farber Cancer Institute, Boston, MA; Northwestern University, Chicago, IL; University of Pennsylvania, Philadelphia, PA; and University of Wisconsin, Madison, WI. Address reprint requests to Lawrence Einhorn, MD, 535 Barnhill Dr, RT 473, Indianapolis, IN 46202.
PURPOSE: Despite great success in the treatment of disseminated germ cell tumors, 20% of patients are incurable and become candidates for investigational therapy. Paclitaxel and gemcitabine have shown activity as single agents in refractory germ cell tumors and can be combined with manageable toxicity. PATIENTS AND METHODS: Patients with germ cell tumors believed to be incurable with chemotherapy or surgery were treated with paclitaxel 110 mg/m2 and gemcitabine 1,000 mg/m2 intravenously on days 1, 8, and 15 of a 4-week cycle for a maximum of six cycles. Patients were evaluated for response and toxicity. RESULTS: Twenty-eight of 30 enrolled patients were assessable. Toxicity was primarily hematologic but was manageable with only a single case of neutropenic fever. Six (21.4%) of 28 patients responded, including three complete responses. Two of the complete responders were continuously disease-free at 15+ and 25+ months. CONCLUSION: Paclitaxel plus gemcitabine is an active regimen in refractory germ cell tumors, with an acceptable toxicity profile. This regimen has the possibility for long-term disease-free survival in this refractory patient population.
GERM CELL TUMORS are very chemosensitive tumors. Cisplatin-based combination chemotherapy, with appropriate surgical resection of residual disease if needed, will cure 70% to 80% of patients with disseminated disease.1,2 Salvage chemotherapy with standard doses of cisplatin and drugs not previously utilized (eg, ifosfamide and vinblastine) will cure 20% to 25% of relapsed patients.3 High-dose salvage chemotherapy with stem-cell rescue can cure some of those patients for whom second-line chemotherapy fails.4 Therefore, it has been studied as the initial salvage therapy, with a 60% overall disease-free survival rate. This now represents our standard salvage for relapsed germ cell tumor patients.5 Unfortunately, patients with relapsed primary mediastinal nonseminomatous germ cell tumors, those progressing during or within 4 weeks of initial cisplatin-based chemotherapy, or those relapsing 2 or more years after initial chemotherapy are much less likely to benefit from high-dose chemotherapy (HDCT) or any other standard-dose salvage chemotherapy.6 Patients who progress after salvage HDCT have low response rates to subsequent chemotherapy in general, and furthermore, only one of 15 patients treated at Indiana University with cisplatin-based chemotherapy given after unsuccessful HDCT achieved a partial response (PR).7 Some responses are noted with daily oral etoposide; however, long-term survival in this setting and those noted above is rare and generally depends on surgical resection of disease.8 Paclitaxel and gemcitabine are newer chemotherapeutic agents with differing mechanisms of action and activity in a wide range of malignancies. Both have been studied in refractory germ cell tumors. Several institutions have shown response rates of 11% to 26% for single-agent paclitaxel.9-12 Responses were seen in patients with poor prognostic features, such as primary mediastinal nonseminomatous tumors, HDCT failure, and cisplatin-refractory disease. Less data are available for single-agent gemcitabine, although a phase II study of 15 patients at Indiana University yielded three responses, including one complete response (CR) in a patient with extensive hepatic and retroperitoneal masses and a serum alpha-fetoprotein (AFP) level of 16,000 ng/mL.13 The German Testicular Cancer Study Group conducted a phase II study of gemcitabine in refractory germ cell tumor patients that demonstrated a response rate of 19%.14 A phase I trial conducted at Indiana University and Roswell Park achieved doses of paclitaxel 110 mg/m2 intravenously (IV) over 1 hour on days 1, 8, and 15 plus gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15 every 4 weeks with acceptable toxicity.15 The single-agent activity of each drug and the results of this phase I study are the basis for this phase II study testing the combination of paclitaxel and gemcitabine in refractory germ cell tumors.
Eligibility requirements included histologic or serologic proof of metastatic germ cell neoplasm (gonadal or extragonadal primary tumor) with disease not amenable to cure with either surgery or chemotherapy. Patients with seminoma and nonseminoma as well as women with ovarian germ cell tumors were eligible. For histologic proof of recurrent or metastatic carcinoma, patients had to have one or more of the following: the appearance of a metastatic lesion on chest x-ray or computed tomography scan and the presence of rising serum beta human chorionic gonadotropin (hCG) or AFP (if rising marker was the only evidence of progressive disease, at least two consecutive determinations must have been exhibited serologic progression). If the only evidence of progressive disease was rising serum concentration of hCG or AFP, patients were eligible provided alternative causes for increased serum levels of these substances were not present (cross-reaction with luteinizing hormone, tested if necessary by testosterone suppression of luteinizing hormone, ingestion of marijuana, or hepatitis).
Initial therapy with cisplatin combination therapy with curative intent (usually bleomycin, etoposide, and cisplatin [BEP]; etoposide and cisplatin; etoposide, ifosfamide, and cisplatin; or a similar regimen) must have failed, and one "salvage" regimen for advanced germ cell neoplasms must also have failed, unless the patient progressed during initial cisplatin chemotherapy. In addition, patients with primary mediastinal nonseminomatous germ cell tumors progressing after the initial regimen were eligible. Patients must not have had more than three prior regimens fail. Failure of prior regimens was defined as either
Patients were also required to be
The treatment regimen consisted of paclitaxel 110 mg/m2 IV over 1 hour followed by gemcitabine 1,000 mg/m2 IV over 30 minutes. Both drugs were given on days 1, 8, and 15 of a 4-week cycle for a maximum of six cycles. Paclitaxel premedication consisted of dexamethasone 20 mg (oral or IV), diphenhydramine 50 mg IV, and either cimetidine 300 mg IV or ranitidine 50 mg IV 30 to 60 minutes before each dose. Day 1 of a new cycle began only when the absolute neutrophil count was Doses for day 8 or day 15 were based on criteria listed in Tables 1 and 2. Doses of either drug omitted for toxicity or missed were not given at a later time. It the dose omitted was to be given on day 1, the next cycle was not considered to start until the drug was actually administered. If day 8 were omitted, the cycle would continue with one dose not given. If day 15 were omitted, this would be considered the week of rest and the following week a dose would be administered (if toxicity permitted) and considered the beginning (day 1) of a new 21-day cycle.
Granulocyte colony-stimulating factor was only used for patients who had an absolute neutrophil count less than 500/mm3 for more than 5 days, neutropenic fever, or documented infections while neutropenic. A patient who required a dose adjustment within a cycle for granulocytopenic fever or thrombocytopenia began the next cycle at a 25% dose reduction of each agent (reduction of starting dose from the previous cycle) once they recovered from toxicity. Patients were assessed for response at every cycle for disease measurable by physical examination, standard radiographs, or serum tumor markers. Patients who required more extensive diagnostic procedures for evaluation of measurable disease (ie, computed tomography scan) were assessed every other cycle. 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 increased hCG or AFP, the values had to fall below the upper limit of normal for the assay utilized and remain at that level for 4 weeks.
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. The hCG or AFP had to be stable or decreasing. If the hCG or the AFP was the only indicator of disease at baseline, one or both had to fall
Stable disease was defined as no appearance of new areas of malignant disease, decrease in malignant disease of less than 50% or increase in malignant disease of less than 25%, stable markers, or change that did not qualify for either CR, PR, or progression. Progressive disease was defined as development of new measurable or palpable areas of malignant disease, increase A two-stage design was used whereby 20 eligible patients were to be enrolled at the first stage.16 The study was designed to distinguish between true response rates of 20% versus 40%. If five or more responses were seen in the first 20 patients, and additional 20 eligible patients were to be accrued. The original design had at least 90% power to detect a true response rate of at least 40% while maintaining an overall type I error of less than 8%%. Survival curves were estimated by the method of Kaplan and Meier, and univariate time-to-event comparisons were performed using the log-rank test.
The study was activated on January 11, 1999. The required five responses were seen among the first 20 eligible cases, so the study continued enrollment. The study terminated on December 30, 2000, with 30 registrations. Indiana University was the leading accruer, with 16 (53.3%) of 30 patients. Of the 30 registered patients, two never started assigned therapy (one patient refused therapy and one patient did not receive a salvage regimen and did not progress during initial cisplatin therapy), resulting in 28 eligible patients. The median age of the patients was 32 years (range, 19 to 52 years). Other patient characteristics are listed in Table 3. Most patients had testicular primary tumors, and one patient had an ovarian germ cell tumor. Ten patients had elevations of serum AFP (range, 34.3 to 10,102 ng/mL). Nineteen patients had elevations of serum hCG (range, 79 to 14,490 IU/L). Eleven patients had values greater than 1,000 IU/L. Seventy-five percent of the patients had previously received two or more platinum-containing regimens (Table 3). Ten patients had prior HDCT with stem-cell support. Those patients treated with a single platinum-containing regimen had primary mediastinal nonseminomatous tumors or were platinum-refractory (progression within 4 weeks of the last course of platinum combination chemotherapy). Ten patients were overtly platinum-refractory.
The median number of cycles of paclitaxel and gemcitabine administered was two (range, one to six). Four patients (14%) completed all six cycles. Twenty-one patients (75%) stopped therapy because of progressive disease, and an additional two stopped therapy because of rising markers, although technically the increase did not meet the definition of progressive disease. One patient was still on treatment after three cycles of therapy. The combination of paclitaxel and gemcitabine was well tolerated, despite this being a heavily pretreated population. Table 4 lists the grade 3 and grade 4 toxicities. There were no grade 5 toxicities. Hematologic toxicity, especially leukopenia/neutropenia, was the most prevalent toxicity. However, only one case of febrile neutropenia was seen and there were no cases of bleeding. No patients terminated therapy because of toxicity.
Six (21.4%) of 28 patients were coded as responders, including three CRs (95% confidence interval, 11.9% to 49.2%). One additional patient remains on therapy and has had a greater than 50% reduction in the size of two pulmonary lesions and a decrease in the hCG from over 5,000 IU/L to less than 100 IU/L. This patient will likely be the seventh responder. Seven patients (25%) had stable disease and 14 (50%) had progressive disease. The durations of the PRs were 2, 3, and 6.5 months, and all three patients have subsequently progressed. Their overall survival times were 2, 11, and 17.5+ months; only the patient with an overall survival time of 17.5+ months is still alive at the time of this writing. One patient with CR remained progression-free for 8 months but subsequently relapsed. He is currently disease-free after two subsequent surgeries for resection of germ cell cancer. The two other CR patients are continuously disease-free at 15+ and 25+ months. The patient now 15+ months disease-free had radiographic resolution of two pulmonary nodules, the largest being 2.5 x 1.8 cm, and normalization of his serum AFP, which was 4,514.1 ng/mL at the beginning of treatment with paclitaxel plus gemcitabine. In the patient now disease-free at 25+ months, the disease was absolutely cisplatin-refractory to BEP therapy; this patient also progressed on oral etoposide. Paclitaxel plus gemcitabine achieved resolution of supraclavicular and retroperitoneal lymph nodes and normalization of the serum hCG that was 2,377 IU/L at the start of therapy. Among the 10 patients with cisplatin-refractory disease (progression within 4 weeks of prior cisplatin chemotherapy), three (30%) responded (one CR, two PRs). One (10%) of the 10 patients for whom previous HDCT had failed responded (CR with subsequent relapse). The median overall survival time was 8.3 months (range, 2 to 25+ months). Two patients are continuously disease-free at 15+ and 25+ months (95% confidence interval, 4.3 to 11.0 months).
The discovery of new active agents in germ cell tumors and their subsequent incorporation into first-line and salvage regimens is well known. Significant advances in the postcisplatin era have included etoposide and ifosfamide, which first demonstrated activity as single agents and then as part of active salvage regimens.1 A phase III trial of cisplatin and bleomycin plus either vinblastine or etoposide established the superiority of the etoposide-containing arm on the basis of improved survival and toxicity.17 Ifosfamide remains a crucial component of salvage therapy; however, a phase III trial comparing cisplatin plus etoposide and either bleomycin or ifosfamide in patients with poor-risk metastatic germ cell tumors failed to show a survival benefit for the ifosfamide-containing arm. BEP remains the standard first-line chemotherapy regimen because of less myelosuppression.18,19 There is no standard treatment for patients believed to be incurable after cisplatin combination chemotherapy or carboplatin-based HDCT. A phase II trial of daily oral etoposide in refractory germ cell patients demonstrated activity with three (14%) of 21 PRs and another three patients with more than 90% decrease in serologic disease but stable radiographic disease.8 Unfortunately, attempts to combine oral etoposide with other agents have not led to an effective salvage regimen. Oral etoposide remains primarily a palliative option for these patients. Paclitaxel and gemcitabine as single agents also represent options for this refractory germ cell population. The single-agent response rates for paclitaxel (11% to 26%) and gemcitabine (15% to 19%) do not seem different than the combination of paclitaxel and gemcitabine reported here (21.4%); however, this study represents a more heavily pretreated population than others.9-14 Although there is no proof that the combination of paclitaxel plus gemcitabine is superior to the single agents given sequentially, we have seen some durable remissions which have rarely, if ever, been seen with the single agents. Again, the two patients continuously disease-free have a reasonable chance of cure with this chemotherapy regimen alone. Previously, new active agents (ie, etoposide and ifosfamide) have been combined with cisplatin in hopes of developing curative salvage regimens or improved induction therapy in previously untreated patients. Paclitaxel and gemcitabine have already been investigated as part of combination regimens. Memorial Sloan-Kettering Cancer Center has used paclitaxel 200 mg/m2 plus ifosfamide 6 g/m2 for two cycles given 2 weeks apart with leukapheresis followed by high-dose carboplatin and etoposide for three cycles with autologous peripheral-blood stem-cell transplants.20 Results are encouraging, with 23 (62%) of 37 patients with cisplatin-resistant germ cell tumors with unfavorable prognostic features achieving favorable responses and 15 (41%) persisting for a median period of 30 months. Investigators at Memorial Sloan-Kettering Cancer Center have also used four cycles of paclitaxel 175 to 250 mg/m2, ifosfamide 5 g/m2, and cisplatin 100 mg/m2 as initial salvage in a risk-adapted strategy to deliver less intensive therapy to patients with a better prognosis (testis primary tumor site and prior CR to first-line chemotherapy).21 Twenty-four (80%) of 30 patients achieved favorable responses, with 22 (73%) durable responses with a median follow-up of 33 months. Toxicity was primarily hematologic, with only two cases of grade 3 neurotoxicity. Italian investigators used paclitaxel (80 mg/m2), cisplatin (50 mg/m2), and gemcitabine (800 mg/m2) given IV on days 1 and 8 of a 3-week cycle for four cycles as third-line salvage therapy. They achieved a 50% major response rate (10 of 20 patients), including four pathologically documented CRs maintained from 3+ to 19+ months.22 Paclitaxel is also being evaluated as part of first-line therapy in selected patients. The German Testicular Cancer Study Group examined a high-dose etoposide, ifosfamide, and cisplatin plus paclitaxel regimen in patients with poor-risk germ cell tumors in a phase I/II study; they found it to be a feasible regimen.23 Romanian investigators have used a combination of paclitaxel, ifosfamide, and cisplatin in first-line treatment of high-risk germ cell tumors.24 The success of paclitaxel plus gemcitabine in these refractory patients is encouraging, especially for the two patients continuously disease-free with chemotherapy alone. Therapy with paclitaxel plus gemcitabine represents a viable treatment regimen for this cohort of patients, with some probability for long-term disease-free survival.
Supported in part by Public Health Service grant nos. CA23318, CA66636, CA21115, CA49883, CA17145, CA15488, and CA21076 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, and the Department of Health and Human Services, Washington, DC.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
1. Einhorn EH: Testicular cancer: An oncological success story. Clin Cancer Res 3: 2630-2632, 1997
2.
Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337: 242-253, 1997 3. Loehrer PJ Sr, Gonin R, Nichols CR, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16: 2500-2504, 1998[Abstract] 4. Nichols CR, Tricot G, Williams SD, et al: Dose-intensive chemotherapy in refractory germ cell cancer: A phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 7: 932-939, 1989[Abstract]
5.
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
6.
Pont J, Bokemeyer C, Harstrick A, et al: Chemotherapy for germ cell tumors relapsing after high-dose chemotherapy and stem cell support: A retrospective multicenter study of the Austrian Study Group on Urologic Oncology. Ann Oncol 8: 1229-1234, 1997
7.
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 8. Miller JC, Einhorn LH: Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol 17: 36-39, 1990[Medline]
9.
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 10. Nazario A, Amato R, Hutchinson L, et al: Paclitaxel in extensively pretreated nonseminomatous germ cell tumors. Urol Oncol 1: 184-187, 1995[CrossRef]
11.
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 12. 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]
13.
Einhorn LH, Stender MJ, Williams SD: Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 17: 509-511, 1999
14.
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 15. Einhorn L, Raghavan D, Kindler H, et al: A phase I trial of gemcitabine plus paclitaxel combination therapy in patients with refractory solid tumors. Proc Am Soc Clin Oncol 17: 207a, 1998 (abstr 796) 16. Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clin Trials 10: 1-10, 1989[Medline] 17. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316: 1435-1440, 1987[Abstract] 18. Loehrer PJ Sr, Lauer R, Roth BJ, et al: Salvage therapy in recurrent germ cell cancer: Ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109: 540-546, 1988
19.
Nichols CR, Catalano PJ, Crawford ED, et al: Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 16: 1287-1293, 1998
20.
Motzer RJ, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18: 1173-1180, 2000
21.
Motzer RJ, Sheinfeld J, Mazumdar M, et al: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18: 2413-2418, 2000 22. Pizzocaro G, Nicolai N, Salvioni R, et al: Paclitaxel, cisplatin, gemcitabine (TPG) third line therapy in metastatic germ cell tumors (GCT) of the testis. Proc Am Soc Clin Oncol 20: 194a, 2001 (abstr 773) 23. Hartmann J, Schleucher N, Metzner B, et al: Phase I/II study of sequential high dose VIP plus paclitaxel (T) in patients (pts) with ’poor prognosis’ germ cell tumor (GCT). Proc Am Soc Clin Oncol 20: 173a, 2001 (abstr 691) 24. Cebotaru C, Todor N, Iancu D, et al: Phase II paclitaxel, ifosfamide and cisplatin as first-line chemotherapy in high risk germ cell tumours. Proc Am Soc Clin Oncol 20: 194a, 2001 (abstr 775) Submitted June 26, 2001; accepted December 17, 2001.
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Copyright © 2002 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 increase in AFP or hCG. 
four times normal and bilirubin 
