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© 2003 American Society for Clinical Oncology Long-Term Survival After High-Dose Salvage Chemotherapy for Germ Cell Malignancies With Adverse Prognostic Variables
From the Division of Hematology-Oncology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, IN. Address reprint requests to Lawrence H. Einhorn, MD, Indiana University Cancer Center, 535 Barnhill Dr, Rm 473, Indianapolis, IN 46202; e-mail: leinhorn{at}iupui.edu.
Purpose: Independent prognostic variables for patients undergoing high-dose chemotherapy (HDCT) as salvage modality for germ cell tumors (GCT) were previously described, and a score was created. Patients with more than 2 points had a poor prognosis. However, these data were from patients treated from 1984 to 1993, and most received a single HDCT course. In this study, we evaluated outcomes at Indiana University and determined the applicability of the Beyer score to contemporary poor-risk patients.
Patients and Methods: We performed a retrospective analysis of patients who received salvage HDCT between 1988 and 2001 and had at least one of the following characteristics: platinum-refractory or absolutely platinum-refractory GCT, primary mediastinal nonseminomatous GCT (PMNSGCT), human chorionic gonadotropin (HCG)
Results: Eighty patients were identified. Fifty-six were platinum refractory, 23 had a Beyer score greater than 2, and 13 had PMNSGCT. Fifty-six patients received two HDCT courses. HDCT included carboplatin and etoposide. Forty-three patients received HDCT as first salvage modality. Median overall survival was 14.7 months. The 2-year FFS was 32%. No relapses have occurred after 2 years from HDCT. Patients with greater than 2 points in the Beyer score, platinum-refractory patients, and patients with HCG Conclusion: Results with PMNSGCT remained poor. However, other patients with poor prognosis should not be denied an attempt at curative salvage HDCT.
SINCE THE introduction of cisplatin in the early 1970s, testicular cancer has been the prototype of a highly curable malignancy.1 Approximately 70% of metastatic testicular cancer patients will be cured with their initial cisplatin-based combination. Thus, 30% become candidates for salvage therapy. High-dose chemotherapy (HDCT) with autologous bone marrow transplantation, or more recently peripheral-blood stem-cell transplantation (PBSCT), has been used increasingly as an effective salvage modality. Most centers currently administer two courses of HDCT (tandem transplantation) as initial or subsequent salvage chemotherapy.
In 1996, Beyer et al2 published the results of a multivariate analysis of factors predictive of outcome after HDCT. Participants were from three centers in Europe and one center from Indiana University (Indianapolis, IN). This study revealed that platinum refractoriness, absolute platinum refractoriness, primary mediastinal nonseminomatous germ cell tumor (PMNSGCT), progressive disease before HDCT, and human chorionic gonadotrophin (HCG) greater than 1,000 mU/mL before HDCT were independent adverse prognostic factors. These variables allowed the creation of a prognostic score (Table 1
However, this study involved patients treated between 1984 and 1993. More than 90% of patients treated in Europe received a single HDCT course, and the majority received two or more regimens before HDCT. Because the above results might not represent current outcomes with HDCT, which at present in the United States is more often used in tandem fashion as first salvage modality with the use of peripheral-blood stem cells (PBSCs) rather than with autologous bone marrow, we reviewed the recent Indiana University experience for patients with poor prognostic features before transplantation.
We conducted a retrospective review of consecutive patients that received HDCT followed by autologous bone marrow transplantation or PBSCT between 1988 and 2001 at Indiana University, using medical charts and electronic medical records. Follow-up related to survival information was obtained from referring community physicians as necessary. Patients were identified using the Bone Marrow Transplant Germ-Cell Tumors database at Indiana University. Patients were included if they had HDCT performed as salvage modality and when any of the following criteria were satisfied: platinum refractoriness (progressive disease with increasing serum markers within 4 weeks after the last cycle of cisplatin-based chemotherapy, after an initial response or stable disease); absolute platinum refractoriness (increasing serum markers while receiving initial chemotherapy); HCG  1,000 mU/mL or alpha-fetoprotein (AFP) 1,000 ng/mL before the first HDCT course; or PMNSGCT. The study was approved by the Indiana University Institutional Review Board.
Stem-Cell Collection, HDCT, and Transplantation As a result of ongoing dose-escalation trials before 1993, 33 patients (41%) received HDCT with carboplatin doses ranging from 500 to 700 mg/m2/d for 3 days and etoposide doses ranging from 400 to 550 mg/m2/d for 3 days. In the earliest of these trials, chemotherapy was given on alternating days. Forty-seven patients (59%) received HDCT consisting of carboplatin 700 mg/m2 intravenously (IV) infused during 15 to 30 minutes daily for 3 days and etoposide 750 mg/m2 IV infused during 2 hours daily for 3 days, both given on days -6, -5, and -4 before transplantation. In addition to carboplatin and etoposide, eight patients also received ifosfamide 2 g/m2/d for 5 days or 3.3 g/m2/d for 3 days, given under different clinical trials enrolling patients at the time. Autologous bone marrow or PBSCs were infused on day 0 through a free-flowing IV central catheter after premedication with diphenhydramine 50 mg IV. After hematologic recovery, patients were restaged with serum markers and imaging studies of involved sites of disease. Appropriate patients then proceeded to receive a second identical HDCT course followed by infusion of marrow or PBSCs (see Results). Patients were treated in a dedicated unit, in either laminar air flow or HEPA-filtered private rooms. Fifteen patients were initially managed as outpatients and were only admitted if complications occurred. Antimicrobial prophylaxis was used routinely and included acyclovir, fluconazole, oral quinolones, and either penicillin or vancomycin starting at day -1. Neutropenic fever episodes were treated empirically with broad-spectrum antibiotics according to established guidelines. After filgrastim became available, patients received granulocyte colony-stimulating factor 5 µg/kg/d beginning on day 0 and continuing until they had achieved an absolute granulocyte count of 2,000/µL for 2 days.
Definitions and Statistical Analysis Complete remission (CR) was defined as the absence of clinically and radiographically detectable disease, including normalization of HCG and AFP levels for at least 1 month. The term no evidence of disease-teratoma [NED(T)] was used to describe patients in whom complete surgical resection of residual masses yielded teratoma. A negative partial response marker (negative PRm) was defined as the presence of negative markers and radiographic disease that was stable or decreasing on serial radiographic studies. Postchemotherapy resection of residual disease was performed in selected patients with an incomplete radiographic response associated with normalization of serum markers. All other responses were classified as nonresponders or transplant-related mortality, if death occurred during the transplantation admission. The main end points were FFS and OS. Calculation of survival started at the first day of the first HDCT course. FFS events included lack of response to HDCT, transplant-related mortality, or relapse after HDCT. For 16 patients, all of whom died within 2 years after HDCT, death was considered the FFS event given the absence of detailed dates of relapse or unknown response to transplantation. One patient had normalized serum markers with HDCT and had a post-PBSCT resection of a residual mass that contained viable cancer. He was considered to have FFS. The Kaplan-Meier method3 was used for calculation of FFS and overall survival.
Eighty patients were identified. Median age was 30 years (range, 17 to 56 years). Patient characteristics are described in Table 2  . Thirty-three percent of patients fulfilled more than one inclusion criteria for entry into the study. Of patients with a single inclusion characteristic, six were PMNSGCT, four had AFP 1,000 ng/mL, 11 had HCG 1,000 mU/mL, and 32 were cisplatin refractory. The median follow-up for patients last reported alive was 56 months (range, 11 to 166 months).
Prior Chemotherapy Regimens and Number of HDCT Courses Fifty-seven patients (71%) received bleomycin, etoposide, and cisplatin as initial treatment for systemic disease. Forty-three patients (54%) received HDCT as the first salvage regimen. Of these patients, 26 also received one or two cycles of another regimen as an attempt at cytoreduction while transplantation was being arranged. This regimen was vinblastine, ifosfamide, and cisplatin in 21 patients or other cisplatin-containing regimens in the remaining patients. Table 2  illustrates the prior number of chemotherapy regimens given.
After hematologic recovery from the first transplantation, 56 patients (70%) immediately proceeded to the second HDCT course. Twenty-four patients did not receive a second transplantation. The reasons included progressive disease or excessive toxicity after the first HDCT course, or enrollment onto a specific clinical trial. Figure 1
Response to HDCT and Posttransplant Therapies Sixty-three patients were assessable for response to HDCT. A complete remission was achieved in 25 of 80 patients (31%). Eleven additional patients (14%) had a partial remission with negative markers; four of these patients had resection of residual masses, showing teratoma in three patients and teratoma plus residual yolk sac tumor in one patient. Twenty-two patients (27.5%) did not respond to HDCT and five patients died from transplant-related complications before discharge from the bone marrow transplantation unit. All deaths happened before 1994 and were related to sepsis, which was complicated by acute renal failure in two patients. Of patients assessable for response, 21 received oral etoposide 50 mg/m2/d for 21 consecutive days every 4 weeks for 3 months, beginning at the time of hematologic recovery after transplantation. Fourteen of these patients had a CR, negative PRm, or NED(T) after HDCT, and three patients experienced relapse in this group. Among 22 patients who also achieved CR, had negative PRm, or had NED(T) but did not receive oral etoposide, nine relapses were observed.
Survival
Patients with HCG 1,000 mU/mL before HDCT had a 2-year FFS of 26% (95% CI, 8% to 44%), whereas patients with AFP 1,000 ng/mL before HDCT had a 2-year FFS of 18% (95% CI, 0% to 37%). Of the four patients showing AFP 1,000 ng/mL as the only adverse characteristic, two had a CR with HDCT but only one remained continuously with NED at last follow-up. Platinum-refractory patients (including the one absolutely platinum-refractory patient) had a 2-year FFS of 37% (95% CI, 24% to 50%). The group of patients with PMNSGCT had no failure-free survivors at 2 years. This subset contained the only patient in the whole series who currently has NED without having responded to HDCT (follow-up, 140 months). This patient experienced disease progression immediately after transplantation. He seems to have been cured with desperation resection of the mediastinal mass (which contained yolk sac tumor), followed by oral etoposide.
According to the predictive score derived from the study of Beyer et al,2 patients with a score
According to number of HDCT courses received, the 2-year FFS for patients receiving one HDCT course was 21% (95% CI, 5% to 37%), whereas patients receiving two HDCT courses had a 2-year FFS of 37% (95% CI, 24% to 49%). According to number of prior standard-dose chemotherapy regimens received, the 2-year FFS for a single previous regimen was 32.5% (95% CI, 18% to 46%), whereas patients receiving more than one prior regimen had a 2-year FFS of 31.5% (95% CI, 16% to 46%). According to the HDCT regimen used, the 2-year FFS was 38% (95% CI, 23% to 51%) for patients receiving the currently used regimen of carboplatin 700 mg/m2/d IV for 3 days and etoposide 750 mg/m2/d IV daily for 3 days, and was 24% (95% CI, 10% to 39%) for patients receiving lower doses (see Patients and Methods). According to the source of stem cells, patients receiving autologous marrow had a 2-year FFS of 23% (95% CI, 12% to 34%); when the source was PBSCs, the 2-year FFS was 49% (95% CI, 30% to 67%).
In this retrospective analysis, we were able to demonstrate superior outcomes to the prior study of Beyer et al2 with the use of HDCT for relapsed GCT in patients with the worst combination of adverse prognostic features, namely a high Beyer score. The results in patients with HCG 1,000 mU/mL before transplantation also seem to have improved (Table 3). In the study of Beyer et al,2 even though a subset of patients were from Indiana University (where tandem transplantations have been performed since 1989), the majority of patients were treated in Europe and received a single HDCT course. Furthermore, HDCT was primarily used as second or third salvage modality in that study, with more than 85% of patients having received at least two prior regimens, as opposed to the current series in which only 46% received at least two prior regimens. It is likely that the differences in number of HDCT courses administered and patient selection account for the survival seen with patients treated at Indiana University between 1988 and 2001, as opposed to the Beyer study. The ability to deliver safely two cycles of HDCT in this patient population (with the second cycle usually given within 4 weeks from the first cycle) is in part related to the use of hematopoietic growth factors and faster engraftment with PBSCT, resulting in decreased toxicity. The difference in FFS seen with our patients who received one versus two HDCT courses (2-year FFS 21% v 37%, respectively) is probably related to worse baseline patient characteristics in the first group (such as a greater incidence of toxicities or more progressive disease cases after the first HDCT course) because for most patients, the initial intention was to deliver tandem transplants.
We showed similar results to the historical control group in patients with elevated AFP (Table 3 From this and previous studies, it is clear that achieving a CR or partial remission with negative markers after HDCT is a prerequisite for freedom from relapse and long-term survival in the overwhelming majority of patients. In addition, in this series the only PRm-negative long-term survivors are those who had post-HDCT resection of residual masses. Even though this may represent underlying patient characteristics biases, we recommend that such surgery be done whenever feasible. The extent to which oral etoposide maintenance contributes to long-term survival is unclear. The rationale of oral etoposide maintenance therapy involves eradication of any residual microscopic disease after achieving CR or negative PRm with HDCT. It has been proven to be safe, without treatment-related mortality or increased incidence of secondary leukemias. In a previous phase II study of oral etoposide maintenance for patients with GCT in remission after any type of salvage therapy,9 74% of patients remained disease free with a median follow-up time of 36 months. Oral etoposide was given to 14 patients in our series who achieved CR or negative PRm after HDCT. Three of those patients have experienced relapse after treatment. In contrast, long-term survival with oral etoposide for patients who experienced treatment failure with salvage HDCT is rare,10 and happened to only one patient in this series (after surgical resection of a mediastinal mass and oral etoposide). The biologic mechanisms that mediate cisplatin refractoriness in germ cell tumors (defined on the basis of response to conventional chemotherapy) are not well understood. For patients who were cured in our series, the germ cell malignancy still remained sensitive to platinum HDCT, which required stem-cell support to be practically feasible. For the remainder of our cisplatin-refractory patients, who died as a result of the disease, it is possible that factors such as bulk of disease, other comorbidities affecting transplantation outcome, and true cisplatin resistance at the cellular and molecular level explain the outcomes. The potential role of salvage HDCT followed by PBSCT for germ cell tumors was recently evaluated in a phase III clinical trial performed by the European Group for Blood and Marrow Transplantation (IT-94).11 However, this trial excluded cisplatin-refractory patients. Patients in the transplantation arm received three cycles of either vinblastine or etoposide plus cisplatin plus ifosfamide (with mesna) chemotherapy followed by a single course of HDCT. Motzer et al8 previously reported their experience with tandem HDCT in the salvage setting using carboplatin, etoposide, and cyclophosphamide. Six of 33 cisplatin-refractory patients were long-term survivors. Rick et al12 conducted a study of salvage paclitaxel, ifosfamide, and cisplatin followed by a single HDCT course with carboplatin, etoposide, and thiotepa. Nineteen patients were cisplatin refractory, and there were no long-term survivors for patients with Beyer score greater than 2. A third study, which evaluated the role of sequential paclitaxel and ifosfamide followed by three cycles of HDCT with carboplatin and etoposide in patients who had not achieved prior durable responses to cisplatin, yielded a long-term survival rate of 49% (18 of 37 patients), but the patient population was not necessarily comparable to those in our series.13 In summary, at present a substantial proportion of patients with relapsed germ-cell malignancies and adverse prognostic features before HDCT can be treated with salvage therapy when HDCT is used as the first salvage modality and tandem transplants are used. Given that alternative options for survival for such patients are extremely limited or nonexistent at present, we recommend that clinicians consider early tandem HDCT with PBSCT in all such patients, with the exception of those with PMNSGCT.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Lawrence H. Einhorn, Bristol-Myers Squibb.
We thank Lisa Wood and Patty Fredenburgh, Indiana University Bone Marrow Transplant Program, for assistance with the Germ-Cell Tumors Database, and Constantin Yiannoutsos, PhD, Indiana University Department of Statistics, for reviewing the manuscript.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31–June 3, 2003.
1. Einhorn LH: Treatment of testicular cancer: A new and improved model. J Clin Oncol 8:1777–1781, 1990[Abstract]
2. Beyer J, Kramar A, Mandanas R, et al: High-dose chemotherapy as salvage treatment in germ cell tumors: A multivariate analysis of prognostic variables. J Clin Oncol 14:2638–2645, 1996 3. Kaplan EL, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc 53:457–481, 1958[CrossRef]
4. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers—International Germ Cell Cancer Collaborative Group. J Clin Oncol 15:594–603, 1997
5. Hartmann JT, Einhorn L, Nichols CR, et al: Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: Results of an international multicenter analysis. J Clin Oncol 19:1641–1648, 2001 6. Broun ER, Nichols CR, Einhorn LH, et al: Salvage therapy with high-dose chemotherapy and autologous bone marrow support in the treatment of primary nonseminomatous mediastinal germ cell tumors. Cancer 68:1513–1515, 1991[CrossRef][Medline] 7. 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]
8. 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 9. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 13:1167–1169, 1995[Abstract]
10. 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 11. Rosti G, Pico JL, Wandt H, et al: High-dose chemotherapy (HDC) in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors (GCT); first results of a prospective randomised trial of the European Group for Blood and Marrow Transplantation (EBMT): IT-94 study. Proc Am Soc Clin Oncol 21:180a, 2002 (abstr 716)
12. Rick O, Bokemeyer C, Beyer J, et al: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19:81–88, 2001
13. 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 Submitted June 17, 2003; accepted August 20, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 had a 2-year FFS of 35% (95% CI, 22% to 50%), whereas patients with a score greater than 2 had a 2-year FFS of 30% (95% CI, 11% to 49%). Table 3
