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© 2000 American Society for Clinical Oncology Sequential Dose-Intensive Paclitaxel, Ifosfamide, Carboplatin, and Etoposide Salvage Therapy for Germ Cell Tumor PatientsFrom the Genitourinary Oncology, Nuclear Medicine, and Renal Services; Divisions of Solid Tumor Oncology, Thoracic Surgery, and Hematologic Oncology; and Departments of Medicine, Epidemiology and Biostatistics, Therapeutic Pharmacology, Urology, Surgery, and Radiology, Memorial Sloan-Kettering Cancer Center; and the Department of Medicine, Cornell University Medical College, New York, NY. Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email motzerr{at}mskcc.org
PURPOSE: To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood–derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison. PATIENTS AND METHODS: Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m2 plus ifosfamide 6 g/m2 were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1,200 mg/m2, and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC. RESULTS: Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula. CONCLUSION: Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.
DESPITE HIGH CURE rates for patients with advanced germ cell tumors (GCT), between 20% and 30% of patients with disseminated disease fail to achieve a durable complete response to chemotherapy regimens of cisplatin plus etoposide with or without bleomycin.1 In this setting, two treatment programs show curative potential. Approximately 25% of patients achieve a durable complete response when a regimen of ifosfamide and cisplatin plus vinblastine is given as second-line therapy.2,3 Two cycles of high-dose carboplatin plus etoposide with or without cyclophosphamide (or ifosfamide) followed by peripheral blood–derived stem-cell (PBSC) support given as third-line therapy resulted in durable complete responses in 15% to 25% of patients.4-6 Prognostic factors identify patients who are more likely to benefit and spare others the toxicity of a futile therapy. Patients with gonadal primary site who require salvage chemotherapy at the time of relapse after complete response to first-line therapy are most likely to achieve a complete response to conventional-dose cisplatin and ifosfamide salvage therapy.7,8 In contrast, patients with an incomplete response to first-line therapy or an extragonadal primary site rarely achieve a durable complete response to conventional-dose cisplatin plus ifosfamide salvage therapy.7 These patients are considered for clinical trials that include dose-intensive programs as second-line treatment.9 The Norton-Simon model10 predicts that multiple, rapidly recycled applications of chemotherapy are more likely to eradicate residual cancer cells than either single applications or multiple applications with long intervals between cycles. Therefore, to maximize the dose-intensity of chemotherapy, multiple large doses may be administered in as short an interval as is feasible. In this trial, patients with previously treated GCT and unfavorable prognostic features for achieving a favorable treatment outcome to conventional-dose salvage chemotherapy were treated with a dose-intensive program that consisted of rapid re-cycling of paclitaxel plus ifosfamide followed by carboplatin plus etoposide with PBSC support. The carboplatin dose was given according to the target area under the curve (AUC; in [milligrams per milliliter] x minutes), which was calculated by the Calvert formula11 according to the estimated glomerular filtration rate (GFR), and the target AUC was dose escalated among patient cohorts. Carboplatin concentrations were obtained in serum and the AUC was compared with the target AUC.
Eligibility Thirty-seven patients with advanced GCT were registered on this prospective, internal review board–approved trial between August 1994 and October 1997. All patients had histologically confirmed GCT, assessable disease, clinical resistance to cisplatin (established by failure to achieve a durable complete response to a cisplatin-based regimen), and one or more unfavorable prognostic features for treatment with conventional-dose salvage therapy. Unfavorable prognostic factors for achieving a complete response to cisplatin plus ifosfamide conventional-dose salvage therapy included the following: (1) extragonadal primary site, (2) progressive disease after an incomplete response to first-line therapy, or (3) poor or lack of response to prior treatment with cisplatin plus ifosfamide–containing conventional-dose therapy. Progressive GCT was documented by increasing values of serum alpha-fetoprotein (AFP) and/or and human chorionic gonadotropin (HCG). In the absence of elevated serum tumor marker(s), biopsy was performed to document the presence of active GCT (and exclude teratoma).
The intent of the trial was to restrict eligibility to patients with prior therapy
Additional eligibility criteria included WBC
Pretreatment Evaluation
Treatment Program
Commencing 6 hours after the completion of each cycle of paclitaxel/ifosfamide, patients received granulocyte colony-stimulating factor (G-CSF) 5 µg/kg twice daily by subcutaneous injection. Leukapheresis was performed on days 11 through 14, provided that the total leukocyte count had recovered to 1,000/mm3. Leukapheresis was performed daily for 3 consecutive days, and G-CSF was continued until the day before the last leukapheresis. Peripheral blood was processed and cryopreserved according to standard methods. Patients who mobilized less than a total of 8 x 106 CD34+ cells/kg underwent a second series of leukaphereses after the second cycle of paclitaxel/ifosfamide.
The criteria for treatment with cycle 2 and subsequent cycles was neutrophil count The Calvert formula11 (dose [mg] = target AUC x [glomerular filtration rate + 25]) was used to determine carboplatin dose according to the AUC in milligrams per milliliter per minute. The target AUC was escalated among cohorts of patients in group A for the phase I part of the trial. GFR was estimated using the radionuclide-labeled ligand technetium-99m diethylenetriamine penta-acetic acid (99MTc-DTPA).12 The ligand was injected via the IV route and the GFR was calculated by plasma clearance of the marker using a single-sample technique.12 The carboplatin dose range was from AUC of 12 to 32 mg/mL/min in patients with prior therapy restricted to six cycles or fewer (group A). More heavily pretreated patients (group B) were treated at a fixed target AUC of 24 mg/mL/min.
Six hours after each cycle of carboplatin/etoposide, G-CSF was commenced at a dose of 5 µg/kg twice daily subcutaneously. PBSC support was administered 48 hours after each carboplatin/etoposide cycle. The target cell number for each reinfusion was 2 x 106 CD34+ cells/kg of body weight. G-CSF was suspended on the morning of infusion, restarted 6 hours after infusion, and continued until granulocyte recovery to
Dose Escalation of Carboplatin Grade 4 hematologic toxicity was anticipated. Dose-limiting toxicity was defined as grade 3 neurotoxicity or grade 4 nonhematologic toxicity. Patient cohorts contained three patients unless dose-limiting toxicity was observed, whereby the number of patients was expanded to six for that and subsequent levels. The maximum-tolerated dose was defined as the level at which three of six patients experienced dose-limiting toxicity.
Supportive Care
Evaluation of Response and Toxicity Evaluation before carboplatin/etoposide administration and approximately 28 days after the first day of the last cycle of chemotherapy included physical examination, complete blood cell count, comprehensive chemistry panel, AFP and HCG, and computed tomography scan of chest, abdomen, and pelvis as required for assessment of tumor response. After completion of five cycles of chemotherapy and radiographic and marker assessment, surgical resection of all residual masses was considered. Responses were categorized as complete or incomplete. Response duration and survival were measured from the initiation of therapy. A complete response to chemotherapy alone was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease for at least 4 weeks; this included patients in whom surgical resection of residuum yielded necrotic debris, fibrosis, or mature teratoma but no evidence of viable malignant tumor. A complete response to chemotherapy plus surgery was defined as the complete excision of all masses, at least one of which contained viable tumor other than mature teratoma. An incomplete response was therefore observed in patients who failed to achieve a complete response to chemotherapy with or without surgery or who were observed to have failure of serum tumor marker normalization.
Pharmacology Studies Drug analysis was performed for carboplatin as previously described.14 In summary, the high-performance liquid chromatography analysis of carboplatin was performed with a modular system that consisted of an SP8775 autosampler, an SP8810 pump, and an SP8450 variable-wavelength ultraviolet/visible detector and recorded by a WINner chromatographic station (all by Spectra-Physics, San Jose, CA). The carboplatin assay was based on the method reported by Mulder et al.15 The fresh plasma was placed in a Centrifree ultrafiltration system (Amicon, Beverly, MA). The ultrafiltrate was collected, maintained at -20°, and analyzed within several weeks. Twenty microliters of the ultrafiltrate was analyzed by an Econosphere C18 5 µm 4.6 x 250 cartridge column (Alltech, Deerfield, IL) with a mobile phase consisting of 50 mmol/L of sodium dihydrogen phosphate and 10 mmol/L of sodium perchlorate adjusted to pH 8 with 0.5 mol/L of sodium hydroxide at a flow rate of 0.7 mL/min. The eluent was monitored at 230 nm at 0.01 absorbance unit full scale. The retention time of carboplatin was 18 minutes and the cycle time was 30 minutes. The limit of detection was 0.6 µg/mL, and an external standard method was used. The pretreatment plasma did not have interference for the drug of interest, and the AUC calculation by trapezoidal rule was performed with the Pharm/PCS program (Version 4.2).16
Patient Characteristics Thirty-three patients had nonseminoma and four had seminoma histology (Table 2). The primary site in the 35 male patients was testis in 25 patients, retroperitoneum in two, and mediastinum in eight. The primary sites of tumor in the two females were pelvis (extragonadal) and ovary (gonadal).
The prior number of cisplatin-containing regimens was one in 29 patients (78%), two in seven patients (19%), and three in one patient (3%). The first-line treatment was etoposide plus cisplatin for 10 patients; bleomycin and etoposide plus cisplatin for 22 patients; ifosfamide, cisplatin, and etoposide for three patients; etoposide plus carboplatin for one patient; and cisplatin, vinblastine, and bleomycin for one patient. Twelve patients (32%) had prior treatment with ifosfamide-containing chemotherapy. Prior best response to first-line therapy was complete response in six patients and incomplete response in 31 patients.
Treatment and Toxicity Treatment with paclitaxel/ifosfamide was relatively well tolerated; 10 patients were admitted for nadir fever. The median number of days of leukapheresis was 3 (range, 1 to 9 days), and the median number of CD34+ cells obtained per patient was 12.1 (range, 7.4 to 65.7) x 106. The median number of CD34+ cells infused per cycle of carboplatin/etoposide was 3.5 (range, 2.0 to 19) x 106. Myelosuppression was the major toxicity encountered with carboplatin/etoposide treatment. The median number of days from the start of carboplatin/etoposide until recovery of neutrophils to 1,000/mm3 for cycles 3, 4, and 5 were 14, 14, and 15 days, respectively. Sixty of 104 cycles of carboplatin/etoposide therapy were associated with hospitalization for nadir fever. Patients were treated successfully with antibiotics, and there were no deaths related to therapy. No patient required intensive care unit monitoring, four patients had culture-positive bacterial sepsis, and five nadir events were treated with amphotericin B. Carboplatin was administered to 36 of the 37 patients (as IV bolus for 21 group A patients and four group B patients and as prolonged infusion for 11 group A patients). Carboplatin dose given by 1-hour IV bolus was escalated in 21 group A patients from target AUC of 12 to 32 (mg/mL) x min without dose-limiting toxicity. An additional 11 patients were treated by prolonged 20-hour infusion of carboplatin. In these patients, gastrointestinal toxicity was more severe (see next paragraph). In all, six of the 37 patients experienced grade 3-4 nonhematologic toxicity. One patient had grade 3 neurosensory toxicity that was attributable to paclitaxel and prior cisplatin therapy. Two of four heavily pretreated patients (group B) experienced toxicity; one had grade 4 gastrointestinal hemorrhage plus grade 3 neuro-otic toxicity, and a second had grade 3 renal toxicity. Three patients treated with carboplatin by prolonged infusion, one at AUC 18 (mg/mL) x min and two at AUC 21 (mg/mL) x min, developed grade 3 gastrointestinal toxicity that was characterized by cramping and/or diarrhea.
Response and Survival
After completion of carboplatin/etoposide and surgical resection of residua, 21 patients (57%) achieved a complete response, and an additional two patients (5%) achieved a partial response with normal tumor markers. Therefore, 23 patients (62%) achieved a favorable response. Eighteen of the 21 patients who achieved a complete response required resection of residua; 14 had histologic findings of necrotic debris (complete response to chemotherapy alone), and four patients had residua containing viable GCT that was completely resected (complete response to chemotherapy plus surgery). The two patients who achieved a partial response with normal tumor markers did not undergo resection of residua and remain progression-free for 21+ and 31+ months.
Eight patients experienced relapse, and 15 (41%) of the favorable responses remain durable at a median follow-up of 31 months (range, 19 to 56 months). For the 33 patients in group A (prior cisplatin Three patients who experienced relapse or achieved an incomplete response were rendered disease-free by subsequent salvage therapy that consisted of other chemotherapy (one patient) and surgical resection of teratoma with malignant transformation (one patient) and yolk sac tumor (one patient). Eighteen patients (49%) are currently alive and free of progressive GCT (15 of 33 group A patients; 45%), two patients remain alive with progressive disease, and 17 have died of disease (Fig 1). The median follow-up period for the 20 survivors is 31 months (range, 18 to 56 months).
Measured AUC of Carboplatin Twenty-three of 25 patients (groups A and B) who were given carboplatin as a 1-hour bolus had samples obtained for pharmacology studies: the mean measured AUC was 16 (mg/mL) x min (range, 7 to 48 [mg/mL] x min) (Table 4). The mean target AUC in these patients based on the Calvert formula was 24 (mg/mL) x min (range, 12 to 32 [mg/mL] x min). The scatterplot of this data showed that the measured AUC did not reach the target AUC most of the time (Fig 2). The discrepancy was most pronounced for high target levels of 28 and 32 (mg/mL) x min. For example, for the target dose level AUC of 32 (mg/mL) x min, the three patients accrued had measured AUCs of 13, 22, and 23 (mg/mL) x min.
This prompted an inquiry into the effect of carboplatin delivery time on achieving the target AUC and the method of estimating the GFR. Nine of 11 patients treated with carboplatin by prolonged infusion were studied, and compared values of target and measured AUC were similar. Plasma clearance of 99MTc-DTPA was used in this study to estimate the GFR for calculation of the target AUC. Three other methods for estimating the GFR are Jaffe’s method (based on creatinine clearance),18 Cockcroft’s method (based on age, weight, and serum creatinine),19 and Jelliffe’s method (based on age, body surface area, and serum creatinine).20 The estimated GFR was compared according to the four methods. The mean values were 100 mL/min (99MTc-DTPA), 150 mL/min (Jaffe), 142 mL/min (Cockcroft), and 119 mL/min (Jelliffe), which indicates that the 99MTc-DTPA method resulted in the lowest estimation of the GFR. The measured AUC was compared with the target AUC for patients using the GFR rates obtained by each of the four methods. The correlation coefficients were 0.27 (99MTc-DTPA), 0.73 (Jaffe), 0.86 (Cockcroft), and 0.85 (Jelliffe).
Poor prognostic features were used to direct dose-intensive therapy as second-line treatment for patients predicted to be resistant to conventional-dose salvage programs. These predictive features included extragonadal primary site or best prior treatment outcome of incomplete response to cisplatin combination therapy. Nineteen (58%) of 33 patients with prior therapy limited to six cycles or fewer of cisplatin combination therapy achieved a complete response, and 12 (36%) remain in continuous complete response. In comparison, when 39 patients with extragonadal primary or best outcome of an incomplete response were treated with cisplatin, ifosfamide, and vinblastine or etoposide as first-line salvage therapy, 12 (31%) achieved a complete response, and six (15%) remain in durable complete response.2 Comparison with historical controls has recognized limitation, and selection factors are involved in selecting patients for a clinical trial of dose-intensive therapy. However, the high durable complete response proportion reported here supports recent recommendations for high-dose therapy with PBSC support to be given as second-line treatment to patients with testicular GCT after an incomplete response to cisplatin, etoposide, and bleomycin combination programs.1,21 This is based on the poor clinical outcome for patients with these features treated with conventional-dose salvage therapy.2,3 The treatment program comprised multiple cycles of sequential, dose-intensive therapy combined with PBSC support given over short time intervals. The median number of days between cycles of carboplatin/etoposide was 21. Patients were routinely followed-up as outpatients after carboplatin/etoposide chemotherapy and admitted as indicated for nadir fever, which infrequently required amphotericin B. Treatment was better tolerated when compared with the prior experience with high-dose carboplatin-containing chemotherapy with autologous bone marrow transplantation given to refractory patients as third-line therapy.4 In that program, patients were treated with one or two cycles of high-dose therapy, supportive care was formidable, and the median number of days between the two cycles in the program was 61 (range, 47 to 131 days).4 The results of three studies of high-dose therapy in heavily pretreated patients showed that the treatment-related death proportion was 10%, and the proportion of patients remaining in complete response was between 15% and 20%.4-6 The use of hematopoietic growth factors and PBSCs reduced the time to blood count recovery and allowed rapid recycling of therapy. Both paclitaxel and ifosfamide had antitumor activity as single agents in previously treated patients,22,23 and in vitro studies suggested synergy against cisplatin-resistant teratocarcinoma cell lines.24 Paclitaxel used in combination with ifosfamide and G-CSF was an effective regimen for procuring stem cells, and the antitumor effect was shown by the nearly one half of patients who experienced a 75% or greater reduction in markers compared with baseline levels after two cycles of paclitaxel plus ifosfamide.17 Paclitaxel has a broad range of effects on cellular processes that lead to apoptosis through the p53 pathway.25 Because the p53-dependent pathway has been implicated in GCT resistance to platinum,26 it is possible that pretreatment with paclitaxel enhanced the antitumor effect of carboplatin, given the high response rate that was seen in these cisplatin-resistant patients. Inclusion of carboplatin in high-dose programs for GCT is an essential component for achieving durable complete response against refractory GCT.27 Prior studies of high-dose therapy for GCT have determined carboplatin doses according to body surface area.27 The standard practice for determination of carboplatin doses in conventional-dose therapy uses the Calvert formula,11 generally in the range of AUC of 8 (mg/mL) x min or less. In our study, the dose of carboplatin was calculated using the Calvert formula11 for a target AUC that ranged from 12 to 32 (mg/mL) x min. The measured AUC was generally lower than the target AUC. The method of assessing GFR was likely a contributory factor, because estimation with 99MTc-DTPA was consistently lower than that achieved with the other methods, and 99MTc-DTPA has been cited in underestimating the GFR because of plasma protein binding.28,29 This method was chosen because the chromium-51–labeled EDTA ligand used by Calvert et al11 was not available in the United States. When examined retrospectively, correlation of measured AUC with predicted AUC according to the four methods of assessing renal clearance showed that the Jellife20 and Cockgroft19 methods resulted in the highest correlations. An ongoing study is prospectively studying the correlation between measured AUC and target AUC in high-dose carboplatin therapy using the Jelliffe formula20 in estimation of the GFR. Renal reabsorption of carboplatin has been reported,30 and it may be saturable if it is similar to cisplatin.31 One factor that could have resulted in lower reabsorption includes increased urine output from hydration, which was approximately 5 L/d during high-dose therapy. Also, if reabsorption is saturated, the net elimination at high-dose therapy could be higher than estimated, resulting in a lower AUC than predicted. In summary, dose-intensive therapy with sequential, accelerated chemotherapy cycles with paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was high for patients with unfavorable predictive prognostic features for achieving durable complete response to conventional-dose salvage programs. Because the AUC measured in blood was less than that which was predicted according to the Calvert formula,11 dosing of carboplatin in the high-dose setting is being further assessed in an ongoing trial.
Supported by a grant from the National Cancer Institute (grant no. CA 05826), Bethesda, MD, and by Bristol-Myers Squibb Co, Princeton, NJ. We thank Patricia Fischer for nursing care and Carol Pearce for review of the manuscript.
1. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242-253, 1997
2.
McCaffrey JA, Mazumdar M, Bajorin DF, et al: Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: Response and survival. J Clin Oncol 15:2559-2563, 1997 3. Loehrer PJ, 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]
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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 5. Linkesch W, Greinix HT, Hocker P, et al: Longterm follow up of phase I/II trial of ultra-high carboplatin, VP16, cyclophosphamide with ABMT in refractory or relapsed NSGCT. Proc Am Soc Clin Oncol 12:232, 1993 (abstr 717) 6. 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. Med 117:124-128, 1992 7. Motzer RJ, Geller NL, Tan CC, et al: Salvage chemotherapy for patients with germ cell tumors: The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer 67:1305-1310, 1991[Medline] 8. Motzer RJ, Green GA, McCaffrey JA, et al: Paclitaxel (T), ifosfamide (I), and cisplatin (P) as first-line salvage therapy for relapsed germ cell tumor (GCT) patients with favorable prognostic features. Proc Am Soc Clin Oncol 17:322a, 1998 (abstr 1241)
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Motzer RJ: Selecting patients with cisplatin-resistant germ cell tumors for high-dose chemotherapy. J Clin Oncol 14:2625-2626, 1997 10. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986[Medline] 11. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract]
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Fawdry RM, Gruenewald SM: Three-hour volume of distribution method: An accurate simplified method of glomerular filtration rate measurement. J Nucl Med 28:510-513, 1987
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Egorin MJ, Forrest A, Belani CP, et al: A limited sampling strategy for cyclophosphamide pharmacokinetics. Cancer Res 49:3129-3133, 1989
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Motzer RJ, Gulati SC, Tong WP, et al: Phase I trial with pharmacokinetic analyses of high-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in patients with refractory germ cell tumors. Cancer Res 53:3730-3735, 1993 15. Mulder PO, de Vries EG, Uges DR, et al: Pharmacokinetics of carboplatin at a dose of 750 mg/m2 divided over three consecutive days. Br J Cancer 61:460-464, 1990[Medline] 16. Tallarida RJ, Murray RB: Manual of Pharmacologic Calculations With Computer Programs. New York, NY,Springer-Verlag, 1990 17. Bokemeyer C, Gerl A, Schoffski P, et al: Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. Oncol 17:512-516, 1999 18. Rossignol B, Rossingnol D, Petitclerc C: Improvement of creatinine measurement of RA-1000. Clin Biochem 17:203-204, 1984 19. Cockgroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976[Medline] 20. Jelliffe RW: Creatinine clearance: Bedside estimate. Ann Intern Med 79:604-605, 1973 (letter) 21. NCCN Proceedings: NCCN practice guidelines for testicular cancer. Oncology 11:417-462, 1998
22.
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 23. Wheeler BM, Loehrer PJ, Williams SD, et al: Ifosfamide in refractory male germ cell tumors. J Clin Oncol 4:28-34, 1986[Abstract] 24. Motzer RJ, Chou TC, Schwartz L, et al: Paclitaxel in germ cell cancer. Semin Oncol 22:12-15, 1995 25. Ringel I, Horwitz SB: Paclitaxel affects microtubule dynamics and apoptosis. Adv Oncol 15:11-17, 1999 26. Houldsworth J, Xiao H, Murty VVV, et al: Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. Oncogene 16:2345-2349, 1999
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Carlsen JE, Moller ML, Lund JO, et al: Comparison of four commercial Tc-99m(Sn)DTPA preparations used for the measurement of glomerular filtration rate: Concise communication. J Nucl Med 21:126-129, 1980 30. Sorenson BT, Stromgren A, Jakobsen P, et al: Renal handling of carboplatin. Cancer Chemother Pharmacol 30:317-320, 1992[Medline] 31. Reece PA, Stafford I, Russell J, et al: Nonlinear renal clearance of ultrafilterable platinum in patients treated with cis-dichlorodiammineplatinum (II). Cancer Chemother Pharmacol 15:295-299, 1985[Medline] Submitted July 26, 1999; accepted November 16, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
six cycles of cisplatin combination therapy (group A) and, in this group of patients, to increase the carboplatin target AUC among patient cohorts in the manner of a phase I trial. After it was recognized that the therapy was relatively well tolerated when compared with a prior experience with high-dose chemotherapy given in a more conventional fashion,
3,000/mm3, platelets 
