Volume 11, Issue 11 , Pages 903-911, November 2005
Paclitaxel-Based High-Dose Chemotherapy with Autologous Stem Cell Rescue for Relapsed Germ Cell Cancer
Article Outline
Abstract
We evaluated the antitumor activity of tandem cycles of high-dose chemotherapy with autologous peripheral stem cell transplantation (aPSCT) in relapsed germ cell tumors by using high-dose paclitaxel, carboplatin, etoposide, and ifosfamide. Thirty-three patients were entered, and 31 underwent protocol therapy. Paclitaxel 350 mg/m2 (5 patients) or 425 mg/m2 (26 patients) by 24-hour continuous intravenous infusion was followed by 3 daily doses of carboplatin and either etoposide (cycle 1) or ifosfamide/mesna (cycle 2). The carboplatin dose had a calculated area under the curve of 7 mg-min/mL, and the daily dose of etoposide was 20 mg/kg (cycle 1). Ifosfamide 3 g/m2/d for 3 days (with mesna uroprotection) was substituted for etoposide in cycle 2. Each cycle was supported by granulocyte colony-stimulating factor–mobilized peripheral blood stem cells. Thirty-one patients were evaluable for response, toxicity, and long-term disease control. Two patients did not undergo aPSCT because of rapid disease progression. Nineteen patients received both cycles of aPSCT, 8 progressed after cycle 1, 3 refused the second cycle, and 1 died of fungal infection during cycle 1. Twelve patients remain relapse free at a median of 67 months from the initiation of therapy. Whereas the International Germ Cell Cancer Collaborative Group category at the time of initial diagnosis did not seem to predict outcome, the patient’s probability of achieving durable remission was significantly associated with the Beyer prognostic score at the time of protocol entry. Regimens containing the most active agents in relapsed nonseminomatous germ cell tumors, including high-dose paclitaxel, are well tolerated and have promising activity even in patients with poor-risk features who do not achieve durable remissions with standard therapy. The Beyer prognostic system is a valuable predictor for patients undergoing aPSCT.
Key words: High-dose chemotherapy , Autologous peripheral stem cell support , Germ cell tumors , Paclitaxel
Introduction
The treatment of advanced germ cell tumors (GCTs) with cisplatin-based combination chemotherapy with or without surgery results in a cure for 70% to 80% of unselected patients. Approximately half of the patients who do not achieve remission with first-line therapy have a complete marker response to second-line therapy at standard doses; however, less than half of these patients are cured [1]. Although autologous peripheral stem cell transplantation (aPSCT) is frequently used in the United States for patients in first or subsequent relapse [2, 3], the precise indications for this modality remain ill defined. Important unanswered questions include identification of the most active agents, the selection of patients most likely to benefit from aPSCT, and the potential superiority of tandem cycles over single cycles of high-dose chemotherapy.
The prognostic system developed by the International Germ Cell Cancer Collaborative Group (IGCCCG) [4] provides important information regarding initial characteristics that have been widely accepted and applied in the design of phase II and III trials for initial therapy of GCT. To date, a comparable system for patients in relapse or with an incomplete response to initial chemotherapy has not been routinely applied. A series of phase II studies in the United States have led to the widespread use of tandem cycles of high-dose carboplatin and etoposide with or without cyclophosphamide or ifosfamide (see review [3)], but this approach has not yet been evaluated in a phase III randomized trial for patients with refractory or relapsed GCT. It is common in the United States to treat patients in a “favorable” relapse (low-volume, low-marker disease after a complete response to first-line chemotherapy) with second-line therapy consisting of standard doses of cisplatin-based chemotherapy, whereas patients with less favorable characteristics or subsequent relapse are more often referred for aPSCT, by which time the durable remission rate from tandem aPSCT is only 20% to 40% [3].
Because GCT is typically a disease of young patients with favorable organ function, an important consideration is to develop regimens that incorporate newer agents with proven activity that have acceptable safety and toxicity profiles. On the basis of a series of recent studies documenting the activity of paclitaxel as a single agent [5] in GCT and our own studies and those of others regarding dose escalation of paclitaxel in aPSCT [6, 7, 8], we designed a regimen of tandem cycles of aPSCT that incorporated the 2 most active classes of agent (paclitaxel and carboplatin) while still including etoposide, ifosfamide, and carboplatin, as we previously evaluated in patients with advanced GCT [9]. Because we proposed to administer tandem cycles of aPSCT, each containing high-dose paclitaxel, we used data from our own experience and others’ experiences regarding the dose-limiting toxicity of paclitaxel with aPSCT; this toxicity consists of peripheral neuropathy at the maximum tolerated dose of 775 mg/m2 administered as a 24-hour continuous intravenous (IV) infusion after doxorubicin and high-dose cyclophosphamide [7] or in combination with high-dose cisplatin and high-dose cyclophosphamide [8]. When we combined escalating doses of paclitaxel with high-dose ifosfamide, carboplatin, and etoposide, dose-limiting stomatitis and diarrhea were observed at a paclitaxel dose of 275 mg/m2 over 24 hours. When etoposide was omitted from the regimen, the paclitaxel could be escalated to a maximum dose of 575 mg/m2 over 24 hours, and the dose-limiting toxicity was neuropathy [8].
With these considerations about the safety of high-dose paclitaxel and our intent to use the drug in combination with carboplatin (both cycles) and etoposide (1 cycle), we incorporated an abbreviated dose escalation of paclitaxel for both cycles. The starting dose of paclitaxel for each cycle was 350 mg/m2, and 2 additional dose levels, 425 and 500 mg/m2, were planned, with 5 patients in each cohort to be observed through the first cycle before dose escalation in the next cohort of patients. The rationale for administering tandem cycles of high-dose therapy was a general principle of chemotherapy: a single cycle would be inadequate to provide optimal cell kill. The specific justifications for tandem cycles of the regimen we studied were an effort to avoid the severe neurotoxicity related to a single high dose of paclitaxel [10] and a desire to combine the paclitaxel and carboplatin “backbone” with a different third drug in each cycle (etoposide in cycle 1 and ifosfamide in cycle 2).
Patients and methods
Patients
To be eligible for the trial, patients older than the age of 15 years with a Karnofsky performance status ≥70% were required to have biopsy-proven, measurable (by radiographic study or serum tumor marker elevation), and relapsed or refractory GCT judged to be incurable by standard salvage therapy; patients in relapse who had intermediate- or high-risk disease at initial diagnosis [4] were included. Because of their particularly unfavorable prognosis, patients with mediastinal primary GCT in first relapse and those patients who had received prior paclitaxel (maximum cumulative exposure of ≤600 mg/m2) as third-line treatment were required to be responsive to salvage therapy. Patients with a history of central nervous system metastases were required to have completed therapy with surgery, radiation, or both and to be neurologically stable off of corticosteroids before protocol enrollment.
There was no limit on prior cisplatin; peripheral neuropathy was not considered an exclusion criterion. Patients were required to have a calculated creatinine clearance of ≥70 mL/min before cycle 1 and ≥60 mL/min before cycle 2. Before stem cell collections and each cycle of aPSCT, serum bilirubin had to be ≤1.6 mg/dL, and aspartate aminotransferase and alanine aminotransferase had to be ≤2 times the institutional upper limit of normal. Patients with positive serology for hepatitis B or C were to undergo liver biopsy to rule out chronic active hepatitis or cirrhosis; patients with positive human immunodeficiency virus serology were excluded. Before beginning granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral stem cell collections and before each treatment cycle, patients were required to have an absolute neutrophil count ≥1500/μL, platelets ≥120000/μL, and hemoglobin ≥10 g/dL. Patients were required to have a normal radionuclide-determined left ventricular ejection fraction and no evidence of arrhythmias or ischemia on electrocardiogram. Requirements for pulmonary function included a room air arterial oxygen concentration ≥70 mm Hg, a forced expiratory volume in 1 second of ≥2.0 L or ≥75% of the predicted lower limit of normal, and no history of bleomycin-induced pulmonary toxicity. All patients provided their voluntary, written informed consent after protocol approval by the institutional review board, in accordance with an assurance filed with and approved by the Department of Health and Human Services.
Treatment Protocol
Stem cell mobilizationAll patients received G-CSF 10 μg/kg/d subcutaneously for 4 days before the initiation of leukapheresis, followed by daily G-CSF during collections until the total collected product exceeded 4 × 106 CD34+ cells per kilogram. G-CSF was withheld if the total white blood count was >80000/μL.
Chemotherapy regimensCycle 1 chemotherapy consisted of paclitaxel, etoposide, and carboplatin. Premedication for paclitaxel consisted of 2 doses of dexamethasone 20 mg orally given at 12 and 6 hours before the initiation of paclitaxel, which was given as a 24 hour continuous IV infusion at 350 mg/m2 (first 5 patients) or 425 mg/m2 (all other patients) on day −7. Immediately before the infusion, patients also received diphenhydramine 50 mg orally and cimetidine 300 mg orally. On days −6, −5, and −4, each patient received etoposide 20 mg/kg IV over 2 hours and carboplatin at a calculated area under the curve [11] of 7 mg-min/mL IV over 30 minutes. Premedication for etoposide consisted of hydrocortisone 50 mg IV and diphenhydramine 50 mg IV, which were repeated halfway through the etoposide infusion. Premedication for carboplatin included dexamethasone, lorazepam, and a 5-hydroxytryptamine-3 antiemetic agent.
Patients with increasing serum tumor markers or other clinical or radiographic evidence of tumor progression before cycle 2 were taken off protocol therapy. Otherwise, all patients who had recovered from the acute toxicities associated with cycle 1 were permitted to begin cycle 2 at 2 to 4 weeks after hospital discharge. All of the pretreatment tests detailed previously were required before cycle 2, with the exception of brain magnetic resonance imaging, viral serologic tests, and cardiac and pulmonary function testing.
Cycle 2 chemotherapy consisted of paclitaxel, ifosfamide, and carboplatin. Paclitaxel and carboplatin were administered exactly as in cycle 1. Ifosfamide 3 g/m2 was given daily IV over 30 minutes on days −6, −5, and −4. Allopurinol 300 mg orally was administered daily on day −7 through day 0, and alkaline hydration and diuresis were established before ifosfamide and continued throughout its administration. Mesna was given as an initial 1 g/m2 IV bolus immediately before the first dose of ifosfamide, followed by a 10 g/m2 continuous IV infusion over 72 hours (24 hours beyond the final ifosfamide dose). All patients had a urinalysis daily on days −6 through −3. If the patient developed hematuria (>50 red blood cells per high-power field), ifosfamide was to be withheld, mesna was to be continued, and additional hydration was to be provided; ifosfamide was to be resumed upon the resolution of hematuria.
Stem cell reinfusion and supportive careCell infusions and protocol-specific supportive care were identical for the 2 cycles. Because we had previously demonstrated earlier granulocyte recovery by splitting the infusion of autologous peripheral stem cells [12], all patients received 12.5% of the total CD34+ stem cell product on day −2 of each cycle and 37.5% of the product on day 0 of each cycle. Premedication for each stem cell infusion consisted of diphenhydramine 50 mg IV and acetaminophen 650 or 1000 mg orally. Continuous oximetry and frequent vital sign measurements were required during and for at least 4 hours after each infusion, and symptom management consisted of meperidine for chills and oxygen for hypoxia or dyspnea in association with the cell infusions. All patients received G-CSF 5 μg/kg/d IV starting on day −2 and continuing until the absolute neutrophil count exceeded 1000/μL for 3 consecutive days. Platelet transfusion support was provided to keep the platelet count ≥20000/μL, and red blood cell transfusions were provided to keep the hemoglobin >9 g/dL. Antimicrobial prophylaxis consisted of levofloxacin 500 mg/d orally or IV and amphotericin B 10 mg/d IV. Patients who became febrile were treated with additional broad-spectrum antibiotics, and antimicrobial agents were adjusted as indicated by the clinical condition and culture results. All patients with positive herpes simplex serology received acyclovir 250 mg/m2 intravenously every 8 hours during the period of neutropenia and until the resolution of stomatitis. Patients were treated in single rooms equipped with positive-pressure air flow during the period of neutropenia.
Clinical and data monitoringFrom the initiation of chemotherapy until recovery of blood counts and adequate oral intake, all patients had daily laboratory testing consisting of a complete blood cell count (with a differential white blood cell count when the total white blood cell count was ≥500/μL) and a serum chemistry panel that included electrolytes, blood urea nitrogen, creatinine, and glucose. A comprehensive serum chemistry panel including hepatic transaminases, bilirubin, alkaline phosphatase, lactate dehydrogenase, uric acid, albumin, calcium, phosphorus, and magnesium was performed at least 3 times weekly, and coagulation studies were performed twice weekly. Serum tumor markers (alfa fetoprotein [AFP] and β-human chorionic gonadotropin [HCG]) were measured weekly, starting at the time of protocol enrollment. A chest radiograph was performed at least weekly. After recovery from cycle 2, patients whose serum tumor markers had normalized and who had residual masses were referred for surgical resection.
The National Cancer Institute Common Toxicity Criteria, version 2.0 (http://ctep.info.nih.gov/reporting/ctc-3test.html), were used to assess toxicities. Patients were evaluated as often as necessary to confirm recovery from acute toxicities and then underwent clinical and laboratory evaluation at monthly intervals for the first year. Evaluations were performed every 2 months during the second year, every 4 months during the third year, twice during the fourth year, and then yearly. Radiographic evaluations for tumor assessment were required with every second clinical evaluation until 5 years after treatment and then at the discretion of the physician.
Statistical Methods
Overall survival and progression-free survival, based on intention to treat, were calculated from the initiation of protocol procedures (G-CSF mobilization before stem cell collection) to the time of death from any cause or tumor marker progression. Standard Kaplan-Meier methods were used for survival analysis by using S-Plus software (S-Plus 6.0; Insightful, Seattle, WA). All significance testing was 2 sided (log-rank test).
Results
Patient Characteristics and Treatment Details
Thirty-three patients were initially enrolled and met the eligibility criteria before protocol procedures were initiated. Two of these patients had rapidly progressive disease, and 1 also had poor stem cell mobilization that precluded protocol therapy. The patient characteristics are listed in Table 1. Patients included 32 men and 1 woman, with a median age of 30 years (range, 17-49 years). Twenty-four patients were classified as having had poor-risk GCT at initial diagnosis, on the basis of 1 or more of the criteria established by the IGCCCG [4]. The criteria by which these patients fell into the poor-risk category included lactate dehydrogenase ≥10 times the institutional upper limit of normal (1 patient; initial values were not available in 6 patients), metastatic disease in 1 or more visceral (brain, bone, or liver) sites (all 24 patients), mediastinal-primary nonseminomatous GCT (3 patients), serum β-HCG >50000 U/L (8 patients), and AFP >10000 ng/mL (7 patients). The median duration of response to first-line therapy was 4 months (range, 0-128 months). Twelve patients had normalized serum tumor markers in response to salvage therapy, and 21 had increasing markers. Two patients had responded to paclitaxel-containing salvage therapy. The tumor histologic results were choriocarcinoma (n = 8), embryonal carcinoma/teratocarcinoma (including yolk sac and endodermal sinus and including the 1 female patient; n = 18), mediastinal germ cell syndrome with poorly differentiated carcinoma (n = 1), mixed GCT (n = 1), and pure seminoma (n = 5). The numbers of prior treatment regimens were 1 (3 patients), 2 (27 patients), or 3 (3 patients). Eleven patients had prognostic scores of ≤2 by the system of Beyer et al., and 22 patients had scores >2 by these criteria [13].
Table 1. Patient Characteristics
| Variable | Data |
|---|---|
| Disease | |
 Poor risk at diagnosis, in first relapse | 24 |
| β-HCG >50 000 U/L | 8 |
| AFP >10 000 ng/mL | 7 |
| LDH >10 times upper limit of normal | 1 (unknown in 6) |
| Mediastinal primary tumor | 3 |
| Visceral metastasis | 22 |
| Histologic characteristics | |
| Choriocarcinoma | 8 |
| Embryonal/yolk sac | 17 male, 1 female |
| Mixed nonseminometous GCT | 1 |
| Pure seminoma | 5 |
| Mediastinal germ cell syndrome with poorly differentiated carcinoma | 1 |
| Demographics | |
| Male/female | 32/1 |
| Age range, y (median) | 17–49 (30) |
| No. of prior regimens | |
| 1 | 3 |
| 2 | 27 |
| 3 | 3 |
| Response status immediately before protocol therapy | |
| Responsive disease (markers normal) | 12 |
| Progressive disease (markers increasing) | 21 |
Two patients did not proceed to aPSCT because they had rapidly progressive disease. Twelve patients received only the first cycle of aPSCT, for the following reasons: 8 had progressive GCT after cycle 1, 3 refused a second cycle (2 patients developed severe peripheral neuropathy, and 1, with a history of supraventricular tachycardia, developed a symptomatic episode during the first cycle), and 1, a heavy smoker, died during cycle 1 as a result of fungal pneumonia. Nineteen patients completed both cycles of protocol therapy. The median interval between day 1 of cycle 1 and day 1 of cycle 2 was 58 days (range, 41-155 days), and the median interval between hospital discharge after cycle 1 and admission for cycle 2 was 32 days (range, 12-134 days).
Toxicities of aPSCT
The grade 3 and 4 toxicities of therapy for the 31 patients who began the aPSCT regimen are listed in Table 2. Severe stomatitis was predominantly limited to cycle 1 at the paclitaxel dose of 425 mg/m2. One of 5 patients at the lower paclitaxel dose of 350 mg/m2 and 5 of 19 patients who underwent the second cycle of aPSCT experienced grade 3 or 4 stomatitis. Because dose-limiting mucositis occurred in the first cycle at the second dose level of paclitaxel (425 mg/m2), we did not further escalate the paclitaxel dose during the first cycle. Although the mucositis in the second cycle of therapy was only mild and was not dose limiting, we elected not to escalate the paclitaxel dose in that cycle because of the concern that patients might develop irreversible cumulative neurotoxicity. Other gastrointestinal toxicities were similar in both cycles. All patients developed a subacute sensory neuropathy characterized by generally painless hypesthesias in a stocking-glove distribution that began within several days to 1 week after the cycle 1 dose of paclitaxel, peaked after the second cycle, and subsided in most patients over several weeks to months after the last exposure to paclitaxel. No patient experienced grade 3 or 4 nephrotoxicity in either cycle. The characteristics for stem cell mobilization and the results of hematopoietic reconstitution were similar to those that we reported previously in our study of tandem cycles of ifosfamide, carboplatin, and etoposide [9].
Table 2. Grade 3/4 Acute Regimen-Related Toxicities of Protocol Therapy⁎
| Variable | Cycle 1 (n = 31)† | Cycle 2 (n = 19)‡ |
|---|---|---|
| Stomatitis | 21 | 6 |
| Nausea/vomiting | 9 | 3 |
| Hepatic | ||
| Bilirubin alone | 3 | 2 |
| Bilirubin and transaminase | 1 | 1 |
| Transaminase alone | 7 | 6 |
| Diarrhea | 2 | 3 |
| Dermatitis | 2 | 0 |
| Regimen-related mortality | 1 | 0 |
⁎ National Cancer Institute Common Toxicity Criteria, version 2—Bone Marrow Transplantation scale. |
† Paclitaxel, etoposide, and carboplatin. |
‡ Paclitaxel, ifosfamide, and carboplatin. |
Therapeutic Outcomes
Twelve patients (36% of all patients who were registered) were alive and progression free at a median of 67 months (Figure 1). Two of these patients did not receive cycle 2 because of refusal or toxicities that did not meet off-protocol criteria. Of the other 21 patients, 1 died of therapy-related infection, and the remaining patients relapsed and died as a result of GCT. Eight patients who achieved normalization of serum tumor markers underwent surgical excision of residual masses at a median of 6 months after study entry. One patient had progressive disease before surgery, and the other patients had surgery for residual radiographic masses and normalized serum tumor markers. Of the 5 who had no pathologic evidence of tumor (4 with necrosis/fibrosis and 1 with mature teratoma), 4 (including the patient with mature teratoma) remain disease free after protocol therapy; all 3 patients with viable GCT (all with embryonal or yolk sac histologic results) have died of progressive disease. Of the 24 patients whose initial prognostic category was poor risk by the IGCCCG criteria, the outcome after protocol therapy was similar to those of the entire patient population (Figure 2).
Figure 1.
Progression-free (PFS) and overall (OS) survival for all 33 patients entered onto the protocol (Kaplan-Meier analysis).
Figure 2.
A, Progression-free survival by IGCCCG risk group at diagnosis. B, Overall survival by IGCCCG risk group at diagnosis.
Patients were classified by the system of Beyer et al. according to their prognostic factors just before aPSCT. This system assigns a score of 2 for β-HCG levels >1000 U/L, 2 for tumor that is absolutely refractory to cisplatin-based therapy for relapse (progressing on therapy), and 1 each for a mediastinal primary tumor, a tumor that is refractory to cisplatin-based therapy (progressing within 4 weeks of the last exposure), and disease progression immediately before aPSCT [13]. Of 22 patients with favorable prognostic scores (≤2), 10 (45%) achieved remission and remain progression free, whereas only 2 (18%) of 11 with unfavorable prognostic scores (>2) remain progression free after aPSCT (P = .05; Figure 3A). Overall survivals paralleled disease-free survivals (P = .03; Figures 1, 2B, and 3B).
Figure 3.
A, Progression-free survival by Beyer risk group at the time of protocol entry. B, Overall survival by Beyer risk group at the time of protocol entry.
Discussion
The last 3 decades have witnessed the evolution of therapy (from palliative to curative) for advanced germ cell cancer in the vast majority of patients. Furthermore, most of the acute toxicities of standard chemotherapy regimens for GCT are now readily manageable with appropriate supportive care interventions, and the long-term toxicities of curative therapy are modest, consisting mainly of reversible neuropathy and restrictive lung disease, possible accelerated cardiovascular events, sexual dysfunction and diminished fertility, and a slightly increased risk of second malignancies (see review [14]). Thus, although the number of patients for whom major improvements in therapy are still needed is modest, they are predominantly young men for whom the individual effect of a curative therapy is enormous. It is unknown at present whether improvements in aPSCT regimens will lead to a higher fraction of cured patients or whether this need can be met only with the discovery of improved agents for first-line therapy that will be based on a better understanding of the molecular genetics of these malignancies and the individuals who develop them.
When our study was developed, there was general agreement that a substantial fraction of patients with advanced disease whose initial therapy failed could be cured with aPSCT. In the United States, this was addressed with the use of tandem cycles containing carboplatin and etoposide with or without a third agent, generally an alkylating agent such as ifosfamide or cyclophosphamide. Data in support of the use of paclitaxel originated from the report of Motzer et al [5].
Because there was, at the time of this study’s inception in 1995, no widely used accepted prognostic system for classifying patients in relapse or for predicting their response to therapy, we accepted a heterogeneous group of patients for treatment in this study. Because the IGCCCG system for classifying patients at the time of diagnosis has been widely incorporated in recent protocols for patients receiving first-line therapy, we initially analyzed the entire study population and the subsets of patients whose initial characteristics in the IGCCCG fell into the poor-risk category on the basis of serum lactate dehydrogenase, AFP, β-HCG, sites of metastasis (visceral [including bone, liver, and brain] versus nonvisceral), and site of primary tumor (testis or retroperitoneal versus mediastinal). In our heterogeneous study population, the initial presenting characteristics did not seem to predict the outcome of protocol therapy. This observation is not surprising, because many other factors, especially the rate of decline of serum tumor markers during therapy, probably influence the outcome of first-line therapy [15, 16, 17, 18]. The use of such predictive factors to tailor therapy is currently undergoing evaluation in a large US Intergroup study and has been incorporated into smaller studies as well.
The prognostic system for patients in relapse was also derived from an international database of patients in relapse from initial therapy who were then treated with aPSCT [13]. In multivariate analysis, the most important prognostic factors for long-term relapse-free survival were progressive disease before aPSCT, refractory or absolutely refractory disease, and an HCG level >1000 U/L. After this study was completed, we assigned a prognostic score to each patient according to these characteristics (mediastinal versus nonmediastinal primary tumor, progression just before aPSCT, degree of refractoriness to prior cisplatin-based therapy, and level of β-HCG). Although the accuracy of this system as applied to our patients may have been limited by missing marker data between the last chemotherapeutic regimen and the time of protocol entry, we found a strong association between this score and the outcome of protocol therapy, particularly for patients with a high score. These patients may be better served by participating in studies of novel agents than by undergoing aPSCT. The Beyer prognostic score should also be considered as a prestratification criterion in future phase III studies. For patients with favorable scores in this system, it may be of greater value to explore the effect of variables such as drug, dose, single (most common in European centers) versus tandem (used in most US centers) versus multiple cycles of high-dose therapy supported by hematopoietic stem cells. An example of the latter is the TICE regimen, consisting of 2 cycles of paclitaxel and ifosfamide for cytoreduction and stem cell mobilization, followed by 3 cycles of high-dose carboplatin and etoposide, each supported by stem cells. The recent report of this regimen, piloted by Motzer [19] and updated by Kondagunta [20] showed that >75% of patients with poor-prognosis nonseminomatous GCT (incomplete serum tumor marker response to first-line chemotherapy, relapsed extragonadal primary tumor, or second relapse) achieved a durable complete remission with chemotherapy with or without surgery. This novel regimen consists of 2 cycles of paclitaxel and ifosfamide to cytoreduce the tumor and mobilize autologous peripheral blood hematopoietic cells, followed by 3 cycles of cell-supported chemotherapy consisting of high-dose carboplatin and etoposide [19, 20].
Among the most important questions that remain to be answered in this field is the true power of aPSCT strategies to overcome drug resistance and, thus, cure patients in relapse after 1 or more prior regimens. Until recently, the literature was composed of uncontrolled trials of small to moderate size featuring patients with heterogeneous characteristics who were treated with aPSCT regimens containing 2 or 3 drugs (carboplatin and etoposide with or without cyclophosphamide or ifosfamide) [3]. The preliminary results of an important European multicenter trial to compare aPSCT with standard-dose second-line therapy regimens were recently published [21]. Patients in this trial had advanced GCT in first relapse but were not platinum refractory (their disease had not progressed or relapsed within 1 month of prior exposure to cisplatin-containing chemotherapy). Those who were randomized to standard-dose chemotherapy received 4 cycles of VIP or VeIP (etoposide or vinblastine with ifosfamide and cisplatin), and those who were randomized to aPSCT received 3 cycles of standard-dose chemotherapy followed by a single cycle of high-dose carboplatin, etoposide, and cyclophosphamide with stem cell support. The results of this trial demonstrated no statistically significant difference in overall survival between the 2 groups. The treatment mortality in the aPSCT arm was higher than that in the standard-dose arm, and all other outcome parameters were the same in the 2 groups (response rate, 1-year event-free survival, and overall survival). Although the authors reported that patients in the standard-therapy arm did not often cross over to receive aPSCT, there were other potential explanations for this negative result. Two different reinduction regimens were available, and only a single cycle of non–taxane-based aPSCT was administered. The dose of carboplatin (1-2.2 g/m2) is similar to that which is used in each cycle in the ongoing US Intergroup and previous and current Memorial Sloan-Kettering trials and is comparable to the range of carboplatin doses used in this study. Furthermore, the patients enrolled in that trial had an unusually poor prognosis (65% of patients in both arms had an incomplete response to initial therapy) but were not stratified by IGCCCG or Beyer risk group.
We have shown that aPSCT using tandem cycles containing high-dose paclitaxel in combination with etoposide plus carboplatin and with ifosfamide plus carboplatin can be given safely and possesses encouraging activity in patients with poor-prognosis GCT. In view of the excellent activity of paclitaxel and its synergy with the other agents used in this regimen, we believe that it should undergo further testing, particularly in comparison with other regimens commonly used in this setting, such as tandem cycles of etoposide plus carboplatin. Many questions remain to be addressed as we attempt to identify the ideal treatment of patients with recurrent GCT. These include the use of other agents directed at molecular targets specific to GCT and the design of disease-specific strategies that do not depend on the modest dose response achievable with currently available drugs. A better understanding of the biology and unique susceptibilities of these tumors will then allow investigators to narrow the gap between cure and death in advanced GCT.
Acknowledgments
Supported by City of Hope Cancer Center Support Grant CA 33572.
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PII: S1083-8791(05)00459-3
doi:10.1016/j.bbmt.2005.07.010
© 2005 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 11, Issue 11 , Pages 903-911, November 2005
