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Incidence of Late-Relapse Germ Cell Tumor and Outcome to Salvage Chemotherapy
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     the Departments of Medicine and Epidemiology and Biostatistics, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York

    the Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University, Ithaca, NY

    ABSTRACT

    PURPOSE: To define the incidence, clinical features, and outcome to salvage chemotherapy in patients with late-relapse germ cell tumor (GCT) after a complete response to first-line chemotherapy.

    PATIENTS AND METHODS: Two patient populations were examined. First, retrospective analysis of 246 patients treated on a clinical trial with salvage chemotherapy was performed; 29 patients with late-relapse GCT were identified and evaluated for treatment outcome and survival. Salvage regimens included paclitaxel, ifosfamide, and cisplatin, single agents, or a high-dose chemotherapy program. Second, the incidence of late relapse was assessed by retrospective analysis of 551 patients after a complete response (CR) to first-line chemotherapy.

    RESULTS: Twenty-nine patients received salvage chemotherapy on a clinical trial for late relapse GCT. The median survival was 23.9 months. At a median follow-up of 50.6 months, there were nine survivors. The chemotherapy regimens varied, but the only CRs were observed in patients treated with paclitaxel, ifosfamide, and cisplatin. Seven (50%) of 14 patients treated with paclitaxel, ifosfamide, and cisplatin achieved a continuous CR. Among the second population of 551 patients who had previously achieved a CR to a first-line chemotherapy trial, 17 were identified as having a late relapse (3%). The median time to relapse for these 17 patients was 7.8 years.

    CONCLUSION: Late-relapse GCT is uncommon and is associated with a poor prognosis resulting from a high degree of resistance to chemotherapy. Chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by surgery may be effective in patients with late-relapse GCT who are not considered candidates for primary surgery.

    INTRODUCTION

    Between 70% and 80% of patients with advanced metastatic germ cell tumor (GCT) are cured with combination chemotherapy comprised of cisplatin and etoposide with (BEP) or without (EP) bleomycin. For patients who fail to achieve a complete response (CR) or who relapse, potentially curative chemotherapy options include vinblastine, ifosfamide, and cisplatin combination chemotherapy or high-dose carboplatin and etoposide with peripheral blood stem cell rescue.1-3 We have recently reported a high degree of efficacy in a phase I/II trial of paclitaxel, ifosfamide, and cisplatin in relapsed GCT. In this study, 46 patients were treated, with 32 (70%) patients achieving a CR to therapy and 35 patients alive at a median follow-up of 51 months.4,5

    Until recently, relapse from metastatic GCT was believed to occur within 2 years of completing chemotherapy, with relapse rates of 5% and 10% after a CR.6,7 First reported in case series format, then detailed in a larger series by Baniel et al,10 late relapse was defined as a relapse occurring after 2 years of chemotherapy or surgical treatment.8-10 Late-relapse disease has been reported to occur in 1% to 4% of patients who have had a CR to first-line chemotherapy for advanced disease. Clinical features associated with late-relapse GCT include predominance of yolk sac histology, elevated serum alpha-fetoprotein levels, and presence of malignant transformation of teratoma to somatic malignancies.10-12

    Standard salvage treatment regimens in patients with late-relapse disease are nearly always associated with a poor outcome.10,11,13,14 Therefore, surgical resection of late-relapse metastasis associated with elevated serum tumor markers, referred to as "surgical salvage," is the standard approach to patients with a solitary site of metastasis.

    The Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) experience with chemotherapy for late-relapse disease is examined from two perspectives. First, patient outcome and survival after treatment on nine salvage chemotherapy trials were examined. Second, the frequency of late-relapse GCT after first-line chemotherapy treatment was examined by accessing a database of patients treated with first-line chemotherapy trials at MSKCC. We describe clinical features and outcome to salvage chemotherapy, and the incidence of late-relapse GCT after first-line chemotherapy.

    PATIENTS AND METHODS

    Patient Selection and Eligibility

    Two populations were examined in this retrospective study to identify patients with late-relapse germ cell tumor. Late relapse was defined as (1) relapse occurring more than 2 years after completion of initial chemotherapy for metastatic GCT, and (2) no evidence of second primary at the time of recurrence. All patients included in this study were treated on an MSKCC institutional review board-approved trial with informed consent. In addition, to update follow-up for this analysis, permission to contact patients was obtained from the institutional review board.

    We reviewed clinical data from nine clinical trials of salvage chemotherapy conducted at MSKCC from 1989 to 2001.4,5,15-20 Patients entered onto more than one clinical trial at MSKCC were evaluated at the time of entry on their first trial. Eligibility for all trials except the paclitaxel, ifosfamide, and cisplatin trial allowed previous salvage therapy. Twenty-nine (11.8%) of 246 patients met criteria for late-relapse GCT. All 29 patients had pathologic or serologic evidence of cancer. Eight patients (7%) were identified from 114 treated on salvage chemotherapy trials between 1989 and 1995, and 21 (16%) of 132 patients were identified from 1995 to 2004. Information was recorded from first chemotherapy treatment through completion of salvage chemotherapy. Salvage chemotherapy on the clinical trial included paclitaxel, ifosfamide, and cisplatin, single agents, or a high-dose chemotherapy program. The MSKCC salvage chemotherapy programs, toxicities, and treatment results of the trials have been previously reported.

    To assess the incidence of late relapse after first-line chemotherapy, follow-up data was reviewed from 551 patients who had been treated on clinical trials of first-line chemotherapy at MSKCC and who had achieved a CR. All were treated in first-line chemotherapy clinical trials at MSKCC from 1978 to 2001, had more than 2 years of follow-up without recurrence, and had a CR. Clinical features at initial chemotherapy treatment and median time to relapse for the late relapses were also determined.

    Response Assessment and Statistical Analysis

    Responses were classified as either CR or incomplete response (IR) according to MSKCC criteria. A CR to chemotherapy was defined as the disappearance of all clinical, radiographic, and biochemical evidence of disease; this included patients in whom surgical resection of residual disease yielded only necrotic debris, fibrosis, or mature teratoma. A CR to chemotherapy and surgery was defined as the complete excision of all masses that contained viable GCT. Any response less than a CR was considered to be an IR. Relapse time was measured from the completion of initial chemotherapy to the date of relapse. Survival time was measured from the date of MSKCC salvage chemotherapy trial initiation to date of death or last follow-up. Patients were considered to be continuously disease free if, at their last follow-up, they had not recurred since their initial therapy for late relapse. Currently no-evidence-of-disease (NED) patients include the continuously disease-free patients and those who, after successful treatment for progression after late relapse, had NED at time of last followup. Survival distributions were estimated using the Kaplan-Meier method.21 Incidence was measured per 1,000 person-years of follow-up starting at the point at which patients are at risk for late relapse, namely 2 years from the completion of chemotherapy.

    RESULTS

    Characteristics of Patients Treated With Salvage Chemotherapy

    All 29 patients treated on a clinical trial of salvage chemotherapy for late-relapse GCT had a testis primary site (Table 1) . The most common site of metastasis at time of first-line chemotherapy was the retroperitoneum (25 patients; 86%). Twenty-seven (93%) received cisplatin combination chemotherapy, one patient received carboplatin plus etoposide, and one patient received a nonplatinum combination program. Eighteen patients (62%) underwent surgery other than orchiectomy in addition to chemotherapy as a part of initial management, which included a retroperitoneal lymph node dissection (RPLND) in 17 patients (58%). Six patients had an RPLND before chemotherapy and 11 had postchemotherapy RPLND. Pathology from the postchemotherapy RPLND contained viable GCT in two patients and teratoma alone in five patients; one additional patient had teratoma resected from a residual lung nodule.

    Median time to late relapse in the 29 patients was 10.5 years (range, 2.6 to 25.1 years). Twenty-three patients (79%) experienced relapse more than 5 years after initial therapy, with 15 patients (52%) relapsing more than 10 years after initial therapy. Late relapse was initially detected by the presence of symptoms in 21 patients (72%) and by elevated markers in eight patients (28%). All 29 patients had nonseminomatous GCT, which included four patients with malignant transformation. The retroperitoneum was the most commonly involved site, with 24 patients (83%) having retroperitoneal involvement.

    There were 15 patients who received salvage chemotherapy before entry into an MSKCC clinical trial. Of these, 11 patients were treated with conventional-dose cisplatin and ifosfamide regimens and three patients were treated with high-dose chemotherapy with autologous stem cell rescue programs after experiencing treatment failure with a prior salvage regimen. Nine of the 15 patients received one prior salvage regimen, three patients received two, and three patients received three or more. Only one patient who was treated with etoposide and ifosfamide plus cisplatin achieved a brief CR, but subsequently relapsed. The remaining 14 patients achieved an IR to all prior salvage chemotherapies.

    Response to MSKCC Salvage Chemotherapy Trial

    Outcome by salvage chemotherapy regimen is shown in Table 2. Eight patients had a favorable response to salvage chemotherapy (Table 3). Seven of 14 patients treated with paclitaxel and ifosfamide plus cisplatin achieved a continuous CR: three to chemotherapy with resection of residual masses showing necrosis or teratoma, three to chemotherapy plus resection of viable GCT, and one to chemotherapy without additional surgery. No other salvage regimen resulted in a favorable clinical response, except for sequential treatment with paclitaxel/ifosfamide followed by carboplatin/etoposide therapy and stem cell rescue, which resulted in one patient’s achieving a partial response (residual mass) with normalized serum tumor markers.

    Nine of 29 patients (31%) were alive at time of last follow-up, and eight had NED. This included seven patients who were continuously disease free after paclitaxel, ifosfamide, and cisplatin, and one patient who had a partial response to paclitaxel, ifosfamide, and cisplatin, but progressed and was rendered NED by desperation surgery. The ninth patient was treated with paclitaxel and ifosfamide followed by carboplatin and etoposide, and achieved a partial response with negative markers. Eight of the nine survivors had received no prior salvage chemotherapy. Five additional patients had desperation surgery after a salvage chemotherapy clinical trial, but none were rendered disease free. The median survival for the 29 patients was 23.9 months (95% CI, 10.8 to 27.5), with a median follow-up of 50.6 months (range, 6.6 to 88.9 months) for the nine survivors (Fig 1).

    Late Relapse After First-Line Chemotherapy Trial

    Five hundred fifty-one patients who were treated with first-line chemotherapy, achieved a CR, and were recurrence free more than 2 years after the completion of initial therapy was assessed. The median follow-up, defined from start of initial therapy to date of last follow-up for all patients, was 11.4 years (range, 2.2 to 25.5 years). Seventeen patients (3%) were identified with late relapse disease (Table 4), for an incidence of 3.1 per 1,000 person-years of follow-up. First-line chemotherapy included etoposide for seven of the 17 patients; the remaining 10 received a vinblastine combination regimen. At initial diagnosis, International Germ Cell Cancer Collaborative Group classification of the 17 patients revealed six patients with good-risk disease, six patients with intermediate-risk disease, four patients with poor-risk disease, and one patient with unknown classification. Most (94%) had retroperitoneal disease at time of first-line chemotherapy. Twelve patients (70%) had undergone an RPLND after completion of first-line chemotherapy. Median time to late relapse for the 17 patients was 7.8 years (range, 2.7 to 18.7 years). Late relapse was detected by symptoms in nine patients, a rising marker in three patients, routine chest x-ray in two patients, and unknown in three patients. Although the focus of this study was to identify the frequency of late-relapse viable GCT, four additional patients were identified with late-relapse teratoma.

    DISCUSSION

    Late-relapse GCT is associated with a poor prognosis, based on an advanced-stage presentation and resistance to chemotherapy, including standard programs such as cisplatin, vinblastine, and ifosfamide.10,13 For the 29 patients evaluated on clinical trials, entry was based on a requirement for salvage chemotherapy. Therefore, our patient population comprised of patients not rendered disease free by surgery nor considered surgical candidates because of extensive disease or multiple sites.

    In this poor-prognosis group, several patients were rendered continuously disease free with chemotherapy followed by surgical resection. Treatment with paclitaxel, ifosfamide, and cisplatin resulted in a CR in seven of 14 patients with late-relapse GCT (regimen summarized in Table 5). 4,5 One patient also achieved a partial response with normalized markers to paclitaxel and ifosfamide in combination with dose-intensive carboplatin and etoposide. Although the number of responders was small, the favorable outcome of several patients is encouraging, given the poor response rate previously reported for this patient population. Paclitaxel may be important in combination therapy in overcoming resistance for late relapse GCT.22 This may reflect the different biology of late relapse versus de novo GCT.23 Further studies to better delineate the unique molecular profile of late relapse GCT are warranted.

    Late relapse GCT comprised a minority of patients (12%) treated on salvage clinical trials at our center. In our series, the proportion of patients with late relapse GCT after treatment with first-line chemotherapy was 3%, for an incidence of 3.1 per 1,000 years of follow-up. Two other relatively large series have reported this proportion to be 4% and 3%.10,13 Increased tumor burden at the time of primary therapy, the absence of primary RPLND, and the presence of teratoma after primary therapy have been associated with the development of late-relapse disease.10,11,13,24,25

    The aforementioned factors and the poor prognosis associated with late relapse emphasize the importance of adequate management at initial diagnosis of GCT. Adequate RPLND at the time of initial therapy has been raised as a possible means to prevent late relapse.26,27 We could not address this issue in our series, but feel strongly that surgery to resect teratoma, malignant transformation, and chemotherapy resistant, viable GCT remains an integral part of the management of GCT. The data also support long-term surveillance after successful GCT management.28,29 Periodic abdominal computed tomography scans might detect late relapse earlier and increase the likelihood of effective surgical resection.

    In summary, late-relapse GCT is relatively uncommon. Its existence and grave consequences emphasize the critical role for adequate initial management of GCT and for long-term follow-up of patients after treatment. Chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by surgery may be effective in patients with late-relapse GCT who are not considered candidates for primary surgery. Experience in a larger series of patients is warranted to better define a degree of efficacy.

    Authors’ Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Acknowledgment

    We thank Carol Pearce for her review of this manuscript.

    NOTES

    Supported by the Craig D. Tifford Foundation.

    Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 12-17, 2005.

    Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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