Cisplatin, Ifosfamide, and Vinblastine or Etoposide

In the mid 1980s, ifosfamide was found to have efficacy in patients with refractory GCT. One trial using single-agent ifosfamide in heavily pretreated refractory patients reported an objective response rate (RR) of 23%. However, the median duration of the response was short and the median overall survival (OS) was only 3.5 months. Several groups subsequently combined ifosfamide and cisplatin with either etoposide (VIP) or vinblastine (VeIP) to treat refractory disease.

Initial reports from American and European groups included mixed populations receiving VIP or VeIP in the second-line, third-line, or later setting. These trials established a 5-day regimen of cisplatin (100 mg/m ² daily for 5 days) and ifosfamide (1.2 g/m ² daily for 5 days) with either etoposide (75 mg/m ² daily for 5 days) or vinblastine (0.11 mg/kg for 2 days) administered every 3 weeks as standard salvage chemotherapy, with CR rates in 25% to 36% of patients and median response durations between 3.5 and 34 months. Nephrotoxicity and myelosuppression were the main toxicities with these regimens.

Building on these reports, investigators evaluated these regimens in the initial salvage setting ( Table 1 ). In 1 series, 56 patients with advanced GCT resistant to 1 prior cisplatin-containing regimen were treated with 4 cycles of either VIP or VeIP. The reported CR rate was 36%. An additional 15% of patients who did not undergo resection of the residual disease achieved marker-negative partial response (PR). With a median follow-up of 52 months, sustained CRs were seen in 23% of patients and the median OS was 18 months. French investigators from the Institut Gustave Roussy retrospectively reported their experience with second-line VIP/VeIP in 54 patients. The CR rate after VIP/VeIP was 44%, with sustained CR in 19% of treated patients. However, nearly one-third of responders received consolidation with HDCT, making it difficult to interpret the durability of remissions to VIP/VeIP alone. With a 30-month median follow-up, sustained CRs were observed in 63% of those who attained a CR and then received HDCT versus 26% of those with CR without subsequent consolidative treatment. Toxicity profiles were similar for VIP and VeIP; 2 treatment-associated deaths occurred in patients receiving subsequent HDCT. A series from Italy documented 36 patients who failed first-line therapy with either PVB or BEP (a combination of bleomycin, etoposide, cisplatin) and went on to receive second-line treatment with modified versions of VIP or VeIP. In an attempt to reduce renal toxicity, the dosing schedule was altered to avoid simultaneous administration of platinum and ifosfamide; dosages of ifosfamide and etoposide were also slightly reduced, whereas that of cisplatin was increased. The CR rate for all evaluable patients was 56%, and the sustained CR rates were 42%. Remission rates were higher for patients with prior PVB treatment who received modified VIP than for those receiving modified VeIP for progressive disease after prior BEP treatment. This result was not surprising given the known superiority of BEP over PVB in the first-line setting. Renal toxicity was less pronounced than in previous reports of patients receiving heavier pretreatment.

No prospective trial has compared the efficacy of VIP with that of VeIP in the second-line setting. Although PVB was the previous standard first-line regimen for disseminated GCT, VIP had generally been used more frequently for initial salvage because vinblastine was part of PVB. In 1987, a pivotal randomized trial by the Southeastern Cancer Study Group comparing BEP with PVB in the first-line treatment of disseminated GCT demonstrated superiority in the advanced disease subgroup and overall significantly less toxicity for BEP. This study not only established this regimen as the standard of care for first-line treatment but also made VeIP the second-line therapy of choice because vinblastine had been replaced by etoposide in the first-line setting. The first prospective study to exclusively evaluate VeIP in the second-line setting was reported by Loehrer and colleagues in 1998 and included 135 patients who were treated after failing to respond to a cisplatin/etoposide-based first-line regimen, mostly standard BEP (88%). Of 135 assessable patients, 67 (50%) achieved disease-free status; 32 (24%) patients remained in sustained CR with a minimum follow-up of 6 years. In this single-center study, the 2-, 3-, and 7-year survival rates were 38%, 35%, and 32%, respectively. Prospective data for second-line VIP/VeIP are available from the European multicenter randomized phase 3 IT-94 trial, which compared CDCT (VIP or VeIP) with 3 cycles of CDCT consolidated with 1 cycle of HDCT. The VIP/VeIP arm treated 136 patients and yielded a CR rate of 42% with sustained CRs in 26% at a median follow-up of 45 months. The trial’s findings comparing CDCT with HDCT are discussed in detail later.

Paclitaxel-Containing Regimen

Early trials of paclitaxel in metastatic GCT were conducted after antitumor activity was seen in other malignancies, including breast and ovarian cancers, and the efficacy of this regimen was demonstrated in platinum-refractory ovarian cancer, making paclitaxel an attractive option for salvage therapy for disseminated GCT. Several small phase 2 trials of single-agent paclitaxel were reported. A study from Memorial Sloan-Kettering Cancer Center (MSKCC) treated 31 patients with limited prior therapy (second- and third-line settings) and poor prognostic features, such as incomplete response (IR) to prior therapy (76%) or extragonadal primaries (29%). The results showed an overall response rate (ORR) of 26% including 3 CRs (10%); all responders remained disease free at the time of report. Of 8 patients with treatment response, 3 had primary mediastinal (PM) nonseminomatous (NS) GCT (PMNSGCT). Similarly, a German phase 2 trial treated 24 patients with a median of 7 prior cycles of platinum-containing therapy. The ORR was 25%, including PR in 2 patients who had previously received HDCT and in 1 patient with PMNSGCT. A CR rate of 8% was reported for this trial; the median response duration was 8 months. Additional early-phase trials in more heavily pretreated patients demonstrated slightly lower RRs but confirmed single agent activity for paclitaxel.

Following these encouraging results, combination regimens containing paclitaxel were undertaken. Preclinical data showing synergy with cisplatin led to the TIP regimen, which combined paclitaxel, ifosfamide, and cisplatin. Several phase 2 trials evaluated TIP in the initial salvage setting ( Table 2 ). The original report was a combined phase 1 and 2 study of 30 patients who received 1 prior platinum-containing regimen. In the phase I portion, patients received escalating doses of paclitaxel, with 250 mg/m ² as a 24-hour continuous infusion established as the maximum tolerated dose for the phase 2 portion of the trial. Paclitaxel was combined with ifosfamide, 6 g/m ² , plus mesna and cisplatin, 100 mg/m ² per 21-day cycle, each administered over 4 to 5 days after completion of paclitaxel infusion. All patients received prophylactic growth factor support with granulocyte colony-stimulating factor on days 7 to 18. Recognizing earlier reports of low RRs to CDCT salvage therapy in patients with poor-risk features, and hypothesizing that such patients would likely benefit from more aggressive salvage therapy upfront, enrollment was limited to patients with favorable features, requiring all of the following: (1) prior treatment limited to 1 program, or 6 or less prior cycles of cisplatin, (2) gonadal primary site, and (3) best prior response to first-line chemotherapy of CR of any duration or marker-negative PR lasting 6 months or longer. After encouraging results with the first 30 patients, additional subjects were accrued to the phase 2 portion of this trial, and in 2005, the updated analysis of 46 patients with second-line TIP was published. With a median follow-up of nearly 6 years, 32 (70%) of 46 patients achieved CR and 29 (63%) were continuously disease free. Myelosuppression, the major toxicity, was managed with growth factor support, whereas nephrotoxicity and neurotoxicity were not more severe than that described with other ifosfamide-based salvage CDCT regimens.

A second phase 2 study of second-line TIP was conducted as a multicenter trial through the British Medical Research Council (MRC). Patients received paclitaxel, 175 mg/m ² ; ifosfamide, 5 g/m ² ; and cisplatin, 100 mg/m ² per cycle, without prophylactic growth factor support. A total of 51 patients were included, all had received first-line therapy with BEP, and risk stratification was not part of the eligibility assessment (ie, patients with PMNSGCT as well as those with late relapse were included). The CR rate was 31%. With a median follow-up of 26 months, the 1-year failure-free survival (FFS) and OS were 38% (95% confidence interval [CI], 23%–53%) and 70% (95% CI, 56%–84%), respectively. Less-favorable features in this patient population (compared with those in the MSKCC study) may account for the lower CR rate. However, a subgroup analysis of the MRC trial demonstrated that patients with good-risk features had a CR rate of 35% with 1-year FFS and OS of 43% (95% CI, 23%–63%) and 81% (95% CI, 64%–98%), respectively. Similarly, a small phase 2 trial from Slovakia treated 17 patients after failure to respond to cisplatin-based first-line therapy (mostly BEP [88%]) with 4 to 6 cycles of second-line dose-attenuated TIP (paclitaxel, 175 mg/m ² ; ifosfamide, 6 g/m ² ; and cisplatin 100 mg/m ² per cycle). The CR rate, 2-year disease-free survival (DFS), and 2-year OS were 41%, 47% (95% CI, 23%–71%), and 64% (95% CI, 37%–91%), respectively. The investigators identified the lower dose of paclitaxel as the primary reason for the inferior RRs and survival compared with the original report from MSKCC, and this may similarly explain the more modest outcomes to TIP in the MRC study.

On the basis of phase 2 data for TIP and VeIP, a randomized phase 3 trial compared these regimens in the second-line setting, but terminated early because of poor accrual. Hence, both VeIP and TIP continue to be considered standard conventional-dose regimens in the salvage setting, although the single-arm series of TIP suggests this is the more active regimen.

Salvage HDCT

Following success with autologous bone marrow in relapsed hematologic malignancies during the 1970s, studies were undertaken in several solid malignancies in the early 1980s. This treatment was investigated in GCT because of known chemosensitivity, the dose-response phenomena of individual drugs with synergistic action, the rare occurrence of bone marrow metastasis, and a young patient population with low incidence of significant comorbidities. Characteristics of the drugs chosen for these studies included (1) antitumor activity in conventional doses without evidence that the dose-effect plateau had been reached and (2) myelosuppression, even at high doses, being the dominant adverse effect, a toxicity that could be modulated by autologous bone marrow infusion. In the case of GCT, carboplatin, etoposide, and cyclophosphamide fulfilled these requirements. Carboplatin was chosen over cisplatin because its predominant toxicity is myelosuppression but other adverse effects such as neurotoxicity and nephrotoxicity were not seen. Early phase 1 studies established safety for high-dose carboplatin and etoposide as single agents with and without the use of stem cell rescue.

One noteworthy study of HDCT in GCT was a combined phase 1 and 2 trial reported in 1989. The phase 1 portion established a regimen of etoposide, 1200 mg/m ² , and carboplatin, 1500 mg/m ² per cycle, as the recommended dose. A total of 33 treatment-refractory patients received 1 to 2 cycles of HDCT followed by autologous stem cell rescue. Toxicities were significant, all patients developed severe myelosuppression and 7 treatment-related deaths (21%) were reported. However, the CR rate was 25% despite heavy pretreatment, and a subsequent publication of long-term follow-up (including additional patients treated on this program) reported sustained CR rates of 15%. These results prompted further study of this treatment program in a multi-institutional phase 2 protocol sponsored by the Eastern Cooperative Oncology Group. Similar results were achieved (ORR 44%, CR sustained >1 year 13%, treatment-related deaths 13%). Together, these studies demonstrated that HDCT could be curative, even in the third-line setting. They established the combination of high-dose (HD) carboplatin and etoposide as the basis for subsequent high-dose protocols.

Later efforts focused on confirming activity, increasing the number of patients who achieved durable responses, and reducing toxicity. Better tolerability has largely been achieved through the routine use of growth factor support as well as peripheral blood stem cells in lieu of autologous bone marrow rescue. General improvements in supportive care and antibiotics also diminished the toxicity associated with HDCT, and with all the abovementioned measures treatment-related mortality has improved from greater than 20% initially to typically less than 3%. Strategies to improve efficacy have included intensification of HD carboplatin/etoposide as well as addition of other agents. In 2007, an Indiana University group published a retrospective evaluation of 184 patients treated between 1996 and 2004, 73% of whom were in the initial salvage setting. The HD regimen consisted of 2 cycles of carboplatin, 2100 mg/m ² , and etoposide, 2250 mg/m ² , both administered over 3 days and supported by autologous stem cell reinfusion, given in some patients after 1 to 2 cycles of VeIP. After a median follow-up of 4 years, 63% of patients were continuously disease free. PMNSGCTs and late relapses were not included in this trial because of previously observed poor outcomes with HDCT in these subgroups. Other investigators have incorporated additional agents with carboplatin and etoposide into HDCT programs. This incorporation has been tolerable in the case of ifosfamide, cyclophosphamide, and paclitaxel but has resulted in excessive toxicity for other combinations such as the addition of thiotepa.

HDCT in the Second-Line Setting

The choice of CDCT versus HDCT is controversial in the initial salvage setting because there are limited data for guidance. A point made in favor of HDCT was its better tolerability in patients with less prior therapy. In 1998, a large single-center series of 150 patients published by Rick and colleagues retrospectively reported a heterogeneous population with respect to the timing of HDCT (first-line treatment vs initial salvage vs later salvage). A program of 3 cycles of CDCT followed by 1 cycle of HD VIP was used. For patients with good-risk Beyer scores (see section on Prognostic Factors), the 2-year OS declined significantly depending on whether HDCT was used as first-line, first-salvage, or subsequent salvage treatment (78%, 66%, and 47%, respectively; P <.05). In a retrospective report from the Indiana University, 65 patients who received 2 cycles of HD carboplatin and etoposide with autologous stem cell rescue as initial salvage following relapse after standard cisplatin-based first-line therapy, demonstrated a continuous DFS rate of 57% with or without surgery at a median follow-up of more than 3 years. All patients on this trial had one or more favorable features such as gonadal primary tumor and CR or marker-negative PR to first-line therapy.

Following these encouraging early results, European investigators retrospectively analyzed 193 patients treated with CDCT (119) versus HDCT (74) for first salvage treatment at several centers. A matched-pair analysis between the 2 groups was undertaken using prognostic factors recognized in prior studies, including primary site, response to first-line therapy, relapse-free interval, and tumor marker levels. A total of 38 pairs of patients from both groups were fully matched (all 5 criteria), and an additional 17 pairs were partly matched (4 of 5 criteria including primary site and response to first-line therapy). For these 55 pairs, multivariate analyses examined event-free survival and OS as primary end points. Hazard ratios for OS favoring HDCT ranged between 0.77 and 0.83 (95% CI, 0.60%–0.99%), whereas those for event-free survival showed a trend ranging between 0.72 and 0.84 (95% CI, 0.59%–1.01%). Of note, salvage regimens in the CDCT group contained ifosfamide and etoposide in 36% and 63% of patients, respectively, whereas all patients in the HDCT group were treated with 3 cycles of VIP followed by 1 cycle of HD carboplatin/ifosfamide/etoposide.

The only prospective, randomized study to address the question of the optimal initial salvage approach was the IT-94 trial, a randomized phase 3 trial comparing HDCT with CDCT for second-line therapy. This European multicenter study enrolled 280 patients from 43 institutions in 11 countries between 1994 and 2001. Through 1:1 randomization, the trial compared the efficacy of 4 cycles of CDCT using VIP/VeIP with 3 cycles of the same CDCT followed by 1 cycle of CarboPEC (HDCT using carboplatin [200–550 mg/m ² ], etoposide [1800 mg/m ² ], and cyclophosphamide [200 mg/kg]) with stem cell rescue in patients who failed first-line cisplatin-based therapy (85% standard BEP or EP regimens). Response to salvage treatment was similar in both groups, with CR rates for CDCT and HDCT of 42% and 43%, respectively; treatment-related mortality was 3% and 7%. With a median follow-up of 45 months, the sustained CR rates were 26% and 35%. No survival benefit was seen for the HDCT arm. This study has recognized the following limitations: (1) only 1 cycle of HDCT was given, whereas 2 to 3 cycles of HDCT are widely accepted as the standard of care; (2) in the HDCT group, only 81% of patients actually proceeded to receive CarboPEC following 3 cycles of CDCT; (3) patients refractory to first-line platinum-containing chemotherapy were excluded; and (4) many centers recruited as few as 1 to 3 patients in the trial, which may have compromised the safety and efficacy of HDCT.

An unplanned subgroup analysis from IT-94 demonstrated that among those patients who achieved a CR to salvage chemotherapy, the 2-year DFS was superior in the HDCT arm. The investigators concluded that future strategies for optimizing HDCT should include multivariate prognostic analyses to identify those patients who were likely to benefit from this approach. A large, more recent international study took this approach. A retrospective analysis of initial salvage chemotherapy in almost 1600 subjects treated at multiple centers worldwide was performed to identify prognostic factors. Approximately equal numbers of patients were treated with CDCT and HDCT. The use of modern first-line and salvage regimens was required for inclusion in the report. On multivariate analysis, prognostic factors that allowed patient stratification into 5 well-defined categories were identified. These data have been further developed and through inclusion of additional patients, have been used to develop a prognostic model for initial salvage therapy regardless of the treatment intensity (see section on Prognostic Models). There was a similar distribution among the 5 prognostic categories for CDCT and HDCT. Despite this, superior progression-free survival (PFS) and OS were seen for HDCT in each category with the exception of OS in the low-risk group. Because of the retrospective nature of this analysis, selection bias is likely a factor behind the favorable outcomes in patients treated with HDCT. A prospective trial comparing sequential HDCT with CDCT as initial salvage is planned.

Choosing second-line therapy for relapsed or recurrent GCT varies. HDCT is considered a standard approach by some investigators, whereas others favor reserving HDCT for the third-line setting to avoid unnecessary toxicity in patients who might potentially be cured with CDCT. The approach at MSKCC is to base initial salvage chemotherapy decisions on prognostic models for CDCT and HDCT.

Prognostic Factors

Although prognostic factors at the initiation of first-line chemotherapy for disseminated GCT are universally accepted, there has previously been no agreement on risk stratification after failure of first-line therapy. Clinical variables that could help predict response to salvage therapy had largely been based on relatively small or single-center retrospective series and early-phase clinical trials. The unresolved question of CDCT versus HDCT has further complicated stratification because prognostic factors had typically been analyzed separately for each entity and could not be readily applied to each other. Lastly, patient populations are heterogeneous as to the extent of prior therapy as well as the first-line and salvage regimens used, making the development of a practical model challenging. Although several groups have systematically applied their findings in selecting patients for subsequent trials and determining whether to opt for CDCT or HDCT, agreement had not been reached on a universal model until recently.

For CDCT salvage regimens, earlier retrospective series and phase 2 trials identified best response to first-line therapy and location of primary tumor as predictors of response to second- and third-line therapies. The authors’ group retrospectively reviewed 124 patients who had been treated on 4 prospective trials and failed to achieve a sustained CR, 94 of whom went on to receive second-line therapy. It was determined that response to salvage therapy was significantly enhanced in patients with a prior CR to first-line chemotherapy, testis primary site, normal l -lactate dehydrogenase levels, normal human chorionic gonadotropin (HCG) levels, and 1 site of metastasis. Similarly, a European multicenter retrospective analysis of 164 patients treated in the initial salvage setting reported 3 independent variables of prognostic significance, including progression-free interval, response to induction treatment, and levels of serum markers (HCG and α fetoprotein [AFP]) at relapse. Multivariate analysis from a German report of 60 patients treated with initial salvage chemotherapy identified age less than 35 years, CR to primary treatment, and relapse-free interval greater than 3 months as independent predictors for successful salvage treatment.

For salvage HDCT, several specific variables predictive of a poor outcome have been reported, including pretreatment levels of HCG, PMNSGCT, and absolute refractory disease (defined as no marker response to initial treatment). In addition to individual factors, several prognostic models have been developed to help stratify patients in consideration of HDCT. In 1996, Beyer and colleagues retrospectively performed a multivariate analysis of 310 patients treated with at least 1 cycle of salvage HDCT at 4 centers in the United States and Europe. Progressive disease (PD) before HDCT, PMNSGCT, refractory or absolute refractory disease to conventional-dose cisplatin, and HCG levels greater than 1000 U/L were identified as independent adverse prognostic indicators of survival after HDCT. A scoring system based on these risk factors, referred to as the Beyer score, was established to categorize patients as having good (0 points), intermediate (up to 2 points), or poor prognosis (>2 points), with reliable discrimination in regard to RR, proportion of patients in whom the condition relapsed, FFS, and OS (all with P <.001). Of note, more than 90% of the patients treated in this European series received a single HDCT course and most were treated with 2 or more regimens before HDCT.

These findings could not be reproduced in a later report from Indiana University evaluating patients with less-extensive prior therapy. Subsequently, investigators from the Indiana University developed a separate prognostic model for HDCT based on 184 patients with testicular GCT treated between 1996 and 2004. Patients with late relapse (>2 years) and PMNSGCT were not included in this analysis because of poor results seen previously in this population. Multivariate analysis identified 3 significant predictors of adverse DFS: (1) IGCCCG poor-risk classification at initial diagnosis, (2) platinum-refractory disease defined as tumor progression within 4 weeks after the most recent cisplatin-based chemotherapy, and (3) receipt of HDCT as third-line or subsequent chemotherapy. Based on these factors, patients were classified into 3 prognostic groups based on their total score (referred to as the Einhorn score). Sustained DFS was approximately 80%, 60%, and 40% for patients with low-, intermediate-, and high-risk Einhorn scores, respectively. The Beyer score did not reliably predict DFS in this patient population ( P = .25).

The authors’ group evaluated prognostic factors in a series of 107 patients treated with 2 courses of rapidly recycled (every 14 days) conventional-dose paclitaxel and ifosfamide for stem cell mobilization, followed by 3 cycles of HD carboplatin and etoposide (TI-CE) plus stem cell support. This HDCT trial targeted patients predicted for a poor prognosis to conventional salvage therapy by requiring at least 1 unfavorable prognostic feature for enrollment, including extragonadal primary site, PD following an IR to first-line chemotherapy, and PD after cisplatin plus ifosfamide–based CDCT salvage. Nearly half of patients (47%) achieved 5-year DFS. Factors predicting unfavorable DFS or OS to TI-CE included mediastinal primary tumor site, HCG levels of 1000 U/mL or more, 2 or more lines of prior therapy, 3 or more metastatic sites, and IGCCCG intermediate- or poor-risk classification at diagnosis. The study also tested both the Einhorn and Beyer prognostic models for their ability to predict DFS. Whereas findings were partially reproduced, the 2 models could not be fully applied because of the differences in eligibility criteria. The lack of complete reproducibility of the Einhorn and Beyer models in the TI-CE series demonstrates the limitations of these prediction rules, each developed in specific patient populations with varying clinical features, prior management, and HDCT regimens.

The International Prognostic Factor Study Group recently presented their prognostic model for initial salvage therapy independent of regimen intensity ( Table 3 ). This series comprised a total of 1984 patients from 38 centers throughout 14 countries in Europe and North America. Seven factors were significant for PFS on multivariate analysis, including histology (seminoma vs nonseminoma), primary tumor site (mediastinal vs retroperitoneal vs gonadal), response to first-line chemotherapy (CR vs PR vs other), progression-free interval after first-line chemotherapy, AFP levels at salvage, HCG levels at salvage, and the presence of nonpulmonary visceral metastases. Each factor was assigned a point value, and a sum score was calculated for each patient. Depending on the scores, the patients were divided into 5 risk groups (very low, low, intermediate, high, and very high) with distinct PFS and OS rates regardless of the treatment intensity. The large international and multicenter population in this study, the strict definition of inclusion criteria and salvage regimen, as well as this model’s ability to predict outcomes to both HDCT and CDCT initial salvage approaches allows wider applicability than prior prognostic systems. This scoring system is regarded as the new standard predictive model in the relapsed/refractory setting.

Table 3

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