Date Published: March 15, 2018
Author(s): Deaglan J. McHugh, Darren R. Feldman.
The majority of metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy, but 20–30% of patients will relapse after first-line chemotherapy and require additional salvage strategies. The two major salvage approaches in this scenario are high-dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) or conventional-dose chemotherapy (CDCT). Both CDCT and HDCT have curative potential in the management of relapsed/refractory GCT. However, due to a lack of conclusive randomized trials, it remains unknown whether sequential HDCT or CDCT represents the optimal initial salvage approach, with practice varying between tertiary institutions. This represents the most pressing question remaining for defining GCT treatment standards and optimizing outcomes. The authors review prognostic factors in the initial salvage setting as well as the major studies assessing the efficacy of CDCT, HDCT, or both, describing the strengths and weaknesses that formed the rationale behind the ongoing international phase III “TIGER” trial.
Germ cell tumors (GCTs), comprising 1% of male cancers and 5% of male genitourinary malignancies, are the most common tumor in young men. Most patients with advanced disease are cured with platinum-based chemotherapy; however, 20–30% patients will fail to achieve a durable response and require salvage treatment . Unfortunately, the majority of patients requiring salvage chemotherapy will ultimately die, with death from GCT accounting for the greatest number of average life years lost of any non-childhood malignancy . Presently, the two major salvage approaches include conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT).
For patients with metastatic GCT, prognostic factors at initial diagnosis are universally accepted with the International Germ Cell Cancer Cooperative Group (IGCCCG) classification used to guide first-line chemotherapy. Patients experiencing treatment failure with cisplatin-based first-line chemotherapy, however, represent a highly heterogeneous population. Traditionally, separate prognostic factor analyses were performed for patients undergoing CDCT and HDCT, respectively. Factors consistently associated with favorable outcome to salvage CDCT regimens across multiple series included gonadal primary tumor site, complete response (CR) to first-line chemotherapy, and disease-free interval after first-line chemotherapy of at least several months, whereas burden of disease and tumor marker levels at the time of salvage chemotherapy demonstrated prognostic importance in some but not all series [3–6].
Cisplatin plus ifosfamide-containing regimens form the backbone of salvage CDCT, with studies testing a variety of third drugs to add to this combination. In the 1980s when the combination of cisplatin, vinblastine, and bleomycin (PVB) was the standard first-line regimen, the combination of etoposide, ifosfamide, and cisplatin (VIP) was the most common salvage regimen since it included two drugs not administered in the first-line setting. Once etoposide plus cisplatin (EP) and bleomycin plus EP (BEP) supplanted PVB as standard first-line treatment regimens, vinblastine, ifosfamide, and cisplatin (VeIP) became the most popular salvage regimen. Numerous studies reported on salvage VIP, VeIP, or both used in heterogeneous populations of patients including in the second-, third-, and even later-line setting. CR rates approximated 25–35% with durable remission rates of 5–15% [11–13]. Once activity was demonstrated, VeIP and VIP were moved forward for evaluation in the initial salvage setting with improvement in CR rates to approximately 40–50% and durable remission rates to approximately 25% (Table 1) [4, 5]. In the largest study evaluating VeIP as initial salvage treatment, Loehrer and colleagues treated 135 patients who experienced progressive GCT after first-line chemotherapy but who had remained disease-free for at least 3 weeks from their last chemotherapy dose and observed a CR rate of 50% and durable remission rate of 24% .
The concept of HDCT stemmed from work in the 1980s, demonstrating that tumor cell resistance acquired after therapy with alkylating agents could be overcome by dose intensification (e.g., increase in dose by multiples of 5–10). To avoid the need for direct bone marrow harvest, growth factor support, typically G-CSF with or without chemotherapy, is used to disrupt adhesions between hematopoietic stem cells (HSCs) and stromal cells in the bone marrow, releasing HSCs into the vasculature for collection.
Given the efficacy of both CDCT and HDCT in the salvage setting and in particular, the excellent outcomes with HDCT for patients with unfavorable features, several studies have attempted to compare these two strategies to establish the optimal initial salvage approach (Table 3). In the first study to address this question, Beyer et al. conducted a retrospective, matched pair analysis comparing initial salvage HDCT and CDCT . Fifty-five pairs of patients with relapsed/refractory NSGCT treated with either initial salvage CDCT or HDCT between 1981 and 1995 had full matches on at least 4 of 5 selected prognostic factors (primary tumor location, response to first-line treatment, duration of response, and serum AFP and serum HCG). Hazard ratios favored HDCT for both event-free survival (EFS; 0.72–0.84) and OS (0.77–0.83). Results remained consistent when restricting analysis to those who received both etoposide and cisplatin as initial therapy. Limitations were acknowledged, including the fact that CDCT patients were treated at multiple institutions as part of a cooperative group trial and from earlier time points, in contrast to HDCT, where patients were treated at a single center and more recently. These differences were previously demonstrated to be of prognostic significance [22, 23]. Furthermore, 18% of CDCT patients did not receive etoposide in their first-line regimen and not all patients received ifosfamide during salvage CDCT. Finally, selection bias leading to patients with better performance status or fewer comorbidities receiving initial salvage HDCT could not be excluded. Collectively, these weaknesses may overinflate the differences favoring HDCT.
The TIGER trial (A031102, E1407) is an international collaboration among many centers in North America, Europe, and Australia with the goal of determining the optimal initial salvage chemotherapy approach in patients with advanced GCT. Patients with unequivocal disease progression after a minimum of 3 and no more than 6 cisplatin-based chemotherapy cycles, administered in the first-line setting, are randomized 1:1 to receive CDCT with TIP (control arm) or HDCT using TI-CE (experimental arm) as illustrated in Figure 1. The primary endpoint is OS, with secondary endpoints including PFS, favorable response rate, toxicity, quality of life, and biological correlates. Patients will be stratified by a modification of their IPFSG category into low-, intermediate-, and high-risk groups, with prospective evaluation of outcomes by risk group. With a target accrual of 420 patients, the study is powered to detect a 29% difference in OS between the two arms. The study is ongoing and as of 11/1/2017 has accrued 67 (16%) patients. Results are anxiously awaited and will hopefully definitively establish either HDCT or CDCT as the standard of care in the initial salvage setting.
Both CDCT and HDCT have curative potential in the salvage management of relapsed/refractory GCT. Common salvage CDCT regimens include VeIP, TIP, and GIP, with no randomized data establishing one clearly superior regimen, although the best results reported to date are with TIP, albeit in a favorably selected patient population. Salvage HDCT regimens can achieve durable remissions even in patients with unfavorable characteristics with low TRM. As a result of conflicting data from retrospective series suggesting improved outcomes with HDCT and the IT-94 randomized study demonstrating no benefit to HDCT over CDCT, the optimal initial salvage approach remains unclear with practices varying widely around the world. The global cooperative group-led TIGER trial (A031102, E1407) is testing TIP versus TI-CE in this setting and seeks to definitively answer this important question.