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Journal of Clinical Oncology, Vol 25, No 1 (January 1), 2007: pp. 85-90 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9401 Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin Plus Etoposide in Previously Treated Germ Cell Tumors
From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Departments of Epidemiology and Biostatistics, Urology, Surgery, and Audiology, and Division of Thoracic Surgery, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University Medical College, New York, NY Address reprint requests to G. Varuni Kondagunta, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: kondaguv{at}mskcc.org
Purpose To evaluate the optimal dose of carboplatin as well as the efficacy and tolerability of sequential, dose-intense chemotherapy with paclitaxel and ifosfamide followed by carboplatin and etoposide (TICE) plus peripheral-blood stem-cell (PBSC) support in patients with germ cell tumors (GCT) who are likely to experience treatment failure with conventional-dose salvage treatment. This prospective trial followed a similarly designed report of TICE, which used a different means of carboplatin dosing. Patients and Methods The 48 patients entered onto this trial had progressive GCT and unfavorable prognostic features after chemotherapy. Two cycles of paclitaxel plus ifosfamide were administered with leukapheresis, followed by three cycles of carboplatin plus etoposide with reinfusion of PBSC. Results Twenty-three (49%) of 47 assessable patients achieved a complete response (CR) to chemotherapy. An additional three patients (6%) achieved a CR to chemotherapy and surgery. The CR rate was 55%. Six patients experienced relapse, but 24 patients (51%) are alive and free of disease at a median follow-up time of 40 months. Four patients who experienced relapse or achieved an incomplete response were rendered disease free by salvage surgical resection. When combined with results of the prior trial of similar design, TICE chemotherapy yielded an overall CR of 56% (n = 84), with 50% of patients alive with no evidence of disease. Conclusion TICE is an effective and tolerable dose-intense treatment for patients with previously treated metastatic GCT who have a poor predicted outcome to conventional-dose salvage chemotherapy.
The majority of patients with advanced germ cell tumors (GCT) achieve a continuous complete response (CR) to first-line cisplatin-containing combination chemotherapy.1 Effective salvage therapy is needed for the remaining 20% to 30% of patients with progressive or relapsed GCT. Earlier high-dose studies reported long-term survival in 15% to 25% of patients, but treatment-related toxicity was formidable, and treatment-related deaths occurred in approximately 10% of patients.2-4 Toxicity has subsequently been reduced by substituting peripheral-blood stem cells (PBSC) for bone marrow, using hematopoietic growth factors, and selecting patients with a history of less prior therapy, thereby reducing cumulative toxicity. Conventional doses of vinblastine, ifosfamide, and cisplatin as second-line therapy have been shown to achieve a durable CR in approximately 25% to 50% of these patients. Studies of high-dose carboplatin plus etoposide chemotherapy with autologous bone marrow transplantation when administered as third-line therapy showed CR in 30% to 50% of patients.2,3,5 These varied high-dose regimens usually included two cycles of carboplatin and etoposide chemotherapy, with timing of the second cycle depending on blood count recovery.2-4 Prognostic factors are used to direct conventional and high-dose salvage programs in second-line therapy. Patients who do not achieve a CR to first-line therapy (best outcome of incomplete response [IR]) and patients with extragonadal primary site (nonseminoma histology arising from the mediastinum) rarely experience long-term survival from treatment with vinblastine, ifosfamide, and cisplatin.6 Clinical trials of dose-intense chemotherapy are offered to these patients, as well as to patients who experience progression after vinblastine, ifosfamide, and cisplatin second-line chemotherapy. We previously reported on a phase I and II trial of a high-dose regimen that involved rapid recycling of paclitaxel plus ifosfamide followed by carboplatin plus etoposide (TICE) with stem-cell support.7 This trial was performed in previously treated GCT patients who had unfavorable prognostic features. In this trial, the carboplatin dose was determined by target area under the curve [AUC; in (mg/mL)–min]. The AUC was calculated using the Calvert formula8 according to estimated glomerular filtration rate (GFR) and was dose escalated among patient cohorts. GFR was calculated based on plasma clearance of the radionuclide-labeled ligand diethylenetriamine penta-acetic acid ([99M]Tc-DTPA).9 The results of this trial showed a high durable CR rate and long survival in the 37 patients, with relative tolerance for the high-dose regimen.7 In the first TICE study, we measured levels of carboplatin in serum and correlated measured AUC with predicted AUC (target AUC). However, the measured levels of carboplatin were lower than predicted by the Calvert formula using the radionuclide-labeled ligand [99M]Tc-DTPA to assess GFR.9 We performed a retrospective analysis showing that AUC using the Jelliffe formula to predict GFR produced better correlation, and that Calvert's formula is not as accurate when used at higher target AUCs.10 The current study of similar design was conducted to confirm efficacy and feasibility of our approach, with the dose of carboplatin based on target AUC using the Jelliffe formula11 to predict GFR. In this second trial, patients with previously treated GCT and unfavorable prognostic features were treated with rapid recycling of TICE with stem-cell support. Carboplatin dose was administered according to target AUC, and target AUC was dose escalated among patient cohorts.
Eligibility Between January 1998 and May 2003, 48 patients with advanced metastatic GCT were accrued to this prospective trial approved by the institutional review board at Memorial Sloan-Kettering Cancer Center (New York, NY). All patients had histologically confirmed GCT and assessable disease; clinical resistance to cisplatin established by failure to achieve a durable CR 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 CR to conventional-dose salvage therapy included: extragonadal primary site; progressive disease after an IR to first-line therapy; and poor or lack of response to prior treatment with cisplatin plus ifosfamide conventional-dose therapy. Progressive GCT was documented by increasing values of serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (HCG). In the absence of elevated serum tumor marker(s), a biopsy was performed to document the presence of active GCT (and to exclude teratoma). The intent of this trial was to restrict eligibility to patients with prior therapy of six or more cycles of cisplatin combination therapy (group A) and, in this group of patients, to increase the carboplatin target AUC in the manner of a phase I trial. Once the maximum-tolerated dose (MTD) was established, additional patients would be treated at the MTD. Because this program was relatively well tolerated and to accumulate additional pharmacologic data, more heavily pretreated patients were enrolled at a fixed dose level of carboplatin AUC of 21 (mg/mL)–min (group B).
Additional eligibility criteria included WBC count
Study Design Treatment program. Treatment consisted of two cycles of paclitaxel plus ifosfamide administered 14 days apart followed by three cycles of carboplatin and etoposide with PBSC support administered at 14- to 21-day intervals (Table 1). Treatment was administered as described previously.1 Carboplatin was dosed according to target AUC and administered with etoposide at a dose of 400 mg/m2/d intravenously on days 1 through 3 of cycles 3 to 5 (total dose per cycle, 1,200 mg/m2).
For group A patients, the planned phase I carboplatin doses were AUC of 21, 24, 28, and 32 (mg/mL)–min, infused as a 1-hour bolus each day, with the total dose divided over 3 days. Grade 4 hematologic toxicity was anticipated. Dose-limiting toxicity (DLT) was defined as grade 3 neurotoxicity or grade 4 nonhematologic toxicity. Patient cohorts consisted of three patients unless one DLT was observed, whereupon the number of patients was expanded to six for that and subsequent levels. The MTD was defined as the level at which three of six patients experienced DLT. Once the MTD was established, additional group A patients were enrolled at the MTD for the phase II portion of the study. Group B patients were treated similarly with carboplatin but at a fixed AUC of 21 (mg/mL)–min bolus (Jelliffe formula).
The Calvert formula8 [dose (mg) = target AUC x (GFR + 25)] was used to dose carboplatin according to AUC (mg/mL)–min. The target AUC was escalated among cohorts of three or six patients. GFR was estimated using Jelliffe's method based on age, body-surface area, and serum creatinine.11 The following formula was used:
Evaluation of response and toxicity. Physical examination was performed, and vital signs were taken weekly between cycles, or more frequently as indicated. A CBC was performed, and AFP, HCG, and LDH were measured before each cycle. Weekly serum tumor markers (AFP, HCG, and LDH) were obtained during therapy if they were previously elevated. A 12-hour urine collection for creatinine clearance was performed before treatment with carboplatin/etoposide. Evaluation before carboplatin/etoposide and approximately 28 days from the start of the last cycle of chemotherapy included physical examination, CBC, comprehensive chemistry panel, AFP and HCG, and computed tomography scan of the chest, abdomen, and pelvis to assess tumor response. After five chemotherapy cycles and radiographic and marker assessment, surgical resection of all residual masses was considered. Responses were categorized as CR or IR. Response duration and survival were measured from the initiation of therapy. A CR 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 who underwent surgical resection of residual disease that yielded necrotic debris, fibrosis, or mature teratoma but no evidence of viable malignant tumor. A CR 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 IR was observed in patients who did not achieve CR to chemotherapy with or without surgery or whose serum tumor markers failed to normalize. Pharmacology studies. In this study, the dose of carboplatin was calculated using the Calvert formula8 for a target AUC ranging from 12 to 28 (mg/mL)–min. Pharmacokinetic studies of carboplatin were performed to assess the relationship between target and measured AUC as described previously.7
Audiometry.
Audiometry information was obtained from 19 patients who had audiograms performed before and after high-dose chemotherapy. The hearing assessment included otologic history, air and bone conduction testing using the Hughson-Westlake method, speech audiometry, impedance audiometry, and distortion product otoacoustic emissions. Testing was performed in a double-walled audiometric testing suite (IAC 1400 Series[Industrial Acoustics Company, Bronx, NY]). Masking was used if indicated. Bone and air conduction thresholds (250 to 4,000 Hz and 250 to 8,000 Hz, respectively) were obtained using a Grason-Stadler (model GSI 61) clinical audiometer (Grason-Stadler Inc, Madison, WI) with TDH-50 earphones and MX-51 ear cushions. Hearing loss from both pre- and postchemotherapy audiograms was graded on a scale from 0 to 5, with 0 indicating no loss and 5 indicating profound loss. At each frequency level for each ear, the change in hearing loss between the pre–and post–high-dose chemotherapy audiograms was calculated by subtracting the prechemotherapy grade from the postchemotherapy grade. Change in hearing loss was then collapsed into the following three categories: no change; intermediate loss (1 to 2 degrees of change); and severe loss (
Patient Characteristics Forty-eight patients were enrolled onto this study. One patient withdrew from the study within 3 days of enrollment and received no treatment; this patient is not included in the results. Forty-two patients had nonseminoma histology, and five had seminoma histology (Table 2).
Determination of Phase II Dose A cohort of three group A patients was initially enrolled at a carboplatin AUC of 21 (mg/mL)–min, with no DLTs experienced. The dose was then escalated, with a second cohort of six patients enrolled at an AUC of 24 (mg/mL)–min. The DLT noted at this dose level was grade 4 febrile neutropenia in one patient. Escalation to an AUC of 28 (mg/mL)–min required enrollment of six patients and resulted in three DLTs. One patient had grade 3 neuropathic auditory disturbance, and two patients had grade 4 colitis, diarrhea, and anorexia; grade 4 electrolyte abnormality was also seen in one patient who had diarrhea. Therefore, the MTD for group A patients was determined to be an AUC of 24 (mg/mL)–min, and all subsequent group A patients were treated at this dose level. As previously described, a fixed dose of AUC 21 (mg/mL)–min was used for group B patients. The following data on patients at all dose levels are reported together.
Treatment and Toxicity
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/µL for cycles 3, 4, and 5 were 14 (range, 12 to 16 days), 14 (range, 12 to 18 days), and 14 days (range, 12 to 17 days), respectively. Eighty-two of 121 cycles of carboplatin/etoposide therapy were associated with hospitalization for neutropenic fever. There were no deaths related to therapy.
Response and Survival
Measured AUC of Carboplatin We obtained pharmacology samples for 37 patients. The measured AUCs are listed in Table 4.
Audiometry Nineteen patients had hearing assessments before and after chemotherapy. The degree of hearing loss was more severe at higher frequency levels (Fig 3). There was moderate hearing loss at the hertz range of speech (2,000 to 4,000 Hz). Hearing aids were recommended to four patients based on symptoms. Because of the small sample size, it was not possible to determine whether the number of total chemotherapy cycles or ototoxic antibiotics (aminoglycosides or vancomycin) administered during episodes of hospitalization for neutropenic fever played a role in the hearing loss.
This study confirms the efficacy and tolerability of TICE chemotherapy in patients with metastatic, progressive GCT after cisplatin chemotherapy. Selection of patients for this program was based on clinical evidence of resistance to first-line cisplatin combination chemotherapy and unfavorable prognostic features associated with highly resistant GCT. These unfavorable features included extragonadal primary site or best prior treatment outcome of IR to cisplatin combination therapy. The conduct of this trial followed a previously reported study of the TICE program with identical eligibility.7 However, this regimen differed in the dosing method of carboplatin, which was performed by an improved means of assessing GFR using the Calvert formula. In both trials, the TICE treatment program comprised multiple cycles of sequential, dose-intense therapy combined with PBSC and hematopoietic growth factor support administered over short intervals. In this second TICE trial, the proportion of patients with a CR was 55%, with 43% of the patients continuously disease free and 51% of the patients alive without evidence of disease at time of last follow-up. When combining these results with the cohort of patients previously reported, a total of 84 patients have been treated with the TICE regimen (Table 5). 7 Summarizing the results from both series yields a CR rate of 56% (95% CI, 45% to 67%), with 39% of patients continuously disease free and 50% alive without evidence of disease after a median follow-up time of more than 58 months. The results are highly promising given the lower response rates previously reported with high-dose carboplatin, etoposide, and cyclophosphamide from studies by our center and elsewhere.12
When treatment outcome with TICE was categorized by primary site, 60% of 58 patients with a gonadal primary site achieved a CR. Mediastinal nonseminoma is recognized as showing a high degree of resistance to all salvage chemotherapy.13,14 Given the generally poor outcome to salvage chemotherapy, surgical resection of mediastinal GCT is recommended after first-line bleomycin, etoposide, and cisplatin therapy in patients with elevated markers and resectable tumors. In our experience with TICE, however, several patients with mediastinal nonseminoma who could not be managed by surgery were rendered continuously disease free with this regimen. However, the number of patients with mediastinal GCT was small (17 patients). A larger series is needed to define the utility of this approach in patients with mediastinal nonseminoma, as well as to compare conventional-dose salvage therapy with paclitaxel, ifosfamide, and cisplatin, which shows a high response rate in relapsed testicular GCT.15 Inclusion of carboplatin in high-dose regimens for GCT is essential for achieving durable CR against refractory GCT.12 One of the unique aspects of the TICE regimen as a high-dose treatment for GCT was dosing based on target AUC according to the Calvert formula, rather than by body-surface area (used in many of the GCT high-dose regimens). There was a better correlation between target and measured AUC for carboplatin dosing using the Jelliffe formula to calculate GFR. Also, the demonstrated safety and efficacy of this approach suggest that this dosing method should be studied further in high-dose chemotherapy for GCT. TICE chemotherapy is an intensive program that is administered to patients who would likely not be cured by conventional treatment programs. The risk for severe toxicity is recognized, but the primary objective in this patient population is cure. Given these circumstances, the toxicity profile can be considered acceptable. Subsequent to the acute toxicity associated with the high-dose part of the program, the long-term toxicities experienced are neurotoxicity and otic toxicity. A recent report cited otic toxicity associated with TICE chemotherapy.16 Ototoxicity, an important toxicity connected with high-dose carboplatin treatment that is especially relevant in a patient population previously treated with cisplatin-based therapy, was seen in some patients. Hearing loss was most significant at higher frequency levels, although moderate changes in hearing at the speech-range frequencies were seen. To minimize otic toxicity, we recommend avoiding aminoglycosides in treating neutropenic fever after high-dose carboplatin. Formal data on otic toxicity in this setting is minimal, necessitating further study in high-dose chemotherapy trials. In summary, dose-intense therapy of sequential, accelerated TICE administered with PBSC support resulted in a high, continuous CR rate in patients with a poor predicted outcome to conventional-dose salvage chemotherapy. The treatment was well tolerated, with carboplatin dosed by AUC using the Calvert formula and GFR calculated using the Jelliffe formula, and is considered one approach for patients with refractory disease. This method of calculating carboplatin dosing yielded better correlation to measured AUC than historic methods, but further study is needed to determine the optimal regimen and timing of high-dose carboplatin in resistant GCT.
The authors indicated no potential conflicts of interest.
Conception and design: Jennifer Bacik, Dean Bajorin, Lillian Reich, Madhu Mazumdar, George J. Bosl, Robert J. Motzer Financial support: Dean Bajorin, George J. Bosl, Robert J. Motzer Administrative support: Dean Bajorin, George J. Bosl, Robert J. Motzer Provision of study materials or patients: G. Varuni Kondagunta, Joel Sheinfeld, Dean Bajorin, Manjit Bains, Lillian Reich, Amy Budnick, George J. Bosl, Robert J. Motzer Collection and assembly of data: G. Varuni Kondagunta, Jennifer Bacik, Dean Bajorin, John Deluca, Nicole Ishill, Madhu Mazumdar, George J. Bosl, Robert J. Motzer Data analysis and interpretation: G. Varuni Kondagunta, Jennifer Bacik, Dean Bajorin, Nicole Ishill, Madhu Mazumdar, George J. Bosl, Robert J. Motzer Manuscript writing: G. Varuni Kondagunta, Jennifer Bacik, Dean Bajorin, Madhu Mazumdar, George J. Bosl, Robert J. Motzer Final approval of manuscript: G. Varuni Kondagunta, Jennifer Bacik, Joel Sheinfeld, Dean Bajorin, Manjit Bains, Lillian Reich, John Deluca, Amy Budnick, Nicole Ishill, Madhu Mazumdar, George J. Bosl, Robert J. Motzer
We thank Patricia Fischer for nursing care and Carol Pearce, MFA, Writer/Editor in the Memorial Sloan-Kettering Cancer Center Department of Medicine Editorial Unit, for her review of the manuscript.
Supported by Grants No. CA 05826 and NIH K24 CA82431 from the National Cancer Institute and by the Craig D. Tifford Foundation. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242-253, 1997 2. 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 3. Motzer RJ: High-dose chemotherapy for germ cell tumors (GCT): Memorial Sloan-Kettering Cancer Center. Bone Marrow Transplant 18:S53-S54, 1996 (suppl 1)[Medline] 4. Linkesch W, Greinix HT, Hocker P, et al: Longterm follow up of phase I/II trial of ultra-high carboplatin, VP-16, cyclophosphamide with ABMT in refractory or relapsed NSGCT. Proc Am Soc Clin Oncol 12:232, 1993 (abstr) 5. Siegert W, Beyer J, Strohscheer I, et al: High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: A phase I/II study—The German Testicular Cancer Cooperative Study Group. J Clin Oncol 12:1223-1231, 1994 6. 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[CrossRef][Medline] 7. 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 8. 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] 9. 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 10. Mazumdar M, Smith A, Tong WP, et al: Calvert's formula for dosing carboplatin: Overview and concerns of applicability in high-dose setting. J Natl Cancer Inst 92:1434-1436, 2000 11. Jelliffe RW: Letter: Creatinine clearance—Bedside estimate. Ann Intern Med 79:604-605, 1973[CrossRef][Medline] 12. Motzer RJ, Bosl GJ: High-dose chemotherapy for resistant germ cell tumors: Recent advances and future directions. J Natl Cancer Inst 84:1703-1709, 1992 13. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University experience. J Clin Oncol 12:1390-1393, 1994[Abstract] 14. Vuky J, Bains M, Bacik J, et al: Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 19:682-688, 2001 15. 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 16. Dubs A, Jacky E, Stahel R, et al: Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ cell tumors. J Clin Oncol 22:1158, 2004 Submitted May 11, 2006; accepted October 6, 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
3,000/µL, platelets 
