Hematopoietic Cell Transplantation for Germ-Cell Tumors and Other Adult Solid Tumors

Introduction to Germ-Cell Tumors

Germ-cell tumors (GCT) are the most common malignancy in young men ages 15 to 35 years. These tumors have great response rates to cisplatin-based chemotherapy, with cure rates for metastatic disease as high as 70% to 80%. In 2020, there were 9610 estimated new cases of GCT and 440 estimated deaths because of GCT, reflecting a 5-year survival rate of approximately 95%.

Prognosis may be predicted by the classification system developed by the International Germ Cell Cancer Consensus Group (IGCCCG), which stratifies patients into good-, intermediate-, and poor-risk groups based on disease characteristics and serum tumor markers. First-line therapy with bleomycin, etoposide, and cisplatin (BEP) in patients with advance disease yields long-term event-free survival (EFS) rates of 90% in good-risk patients. This decreases to 80% for intermediate-risk GCT and 50% for poor-risk patients ( Table 28.1 ).

In patients with relapsed or refractory disease, the best approach to therapy includes salvage regimens based on ifosfamide and cisplatin, plus either vinblastine (VeIP), etoposide (VIP), or paclitaxel (TIP), which result in complete response (CR) rates of 50% to 60%. Long-term EFS of 20% to 30% has been reported in patients in first relapse with a CR rate of 70% to 80% and a 2-year progression-free survival (PFS) of 50% to 60%. However, patients in second relapse are largely incurable with current standard treatment. High-dose chemotherapy (HDC) followed by an autologous hematopoietic cell transplant (HCT) is an alternative approach for second-line treatment and is preferred as a third-line option optimization of HDC with autologous HCT; for example, the widespread adoption of using peripheral blood progenitor cells instead of bone marrow graft sources has increased the safety and decreased current treatment-related mortality (TRM) rates to below 5%. The dose escalation of chemotherapy up to 10-fold, thus exploiting the dose-response effect of alkylators and other drugs, drives the benefit from this approach.

Clinical Results in Refractory or Relapsed Nonseminomatous Germ-Cell Tumor

In the mid-1980s, investigators at Indiana University began studying the use of tandem cycles of HDC with carboplatin and etoposide (CE) followed by autologous HCT as salvage treatment for patients with refractory GCT. These initial studies showed this treatment resulted in long-term EFS rates of 15% for patients in second relapse and 38% for those transplanted in first relapse.

In their initial retrospective review of 184 patients with relapsed or refractory metastatic GCT treated with two courses of HD CE, each followed by autologous HCT, 116 patients had a CR of disease without relapse during a follow-up period of 4 years. For patients that received the treatment as second-line therapy, 70% were disease-free during the follow-up, and 45% who received the treatment as third line or later remained disease-free as well.

In a follow-up retrospective analysis conducted by Indiana University, a total of 364 patients with relapsed metastatic GCT treated with HDC (CE) followed by autologous HCT for two cycles demonstrated similar results. For patients receiving HDC as second-line treatment (n = 303), 2-year PFS was 63%, and 61 patients received HDC as a third-line or subsequent therapy with a 2-year PFS of 49% ; however, no patients with late relapses or primary mediastinal tumors were included.

Similarly, an alternative HDC regimen pioneered by Feldman et al. may be considered for treatment of these patients. The TICE regimen (paclitaxel and ifosfamide for two cycles followed by high-dose CE with autologous HCT for three cycles) yielded a 47% disease-free survival (DFS) at 5 years in 107 patients with relapsed disease and unfavorable prognostic features.

Motzer et al. evaluated the use of a triplet of high-dose carboplatin, etoposide, and cyclophosphamide in patients with cisplatin-refractory GCT. Fifty-eight patients were treated; 40% (n = 23) achieving a CR, and 21% (n = 12) were free of disease at a median follow-up of 28 months. In cisplatin-sensitive GCT, two cycles of high-dose ifosfamide, carboplatin, and etoposide followed by autologous HCT were then evaluated, and 9 of 20 patients (45%) were alive and disease-free at a median follow-up of 45 months.

A phase II study with relapsed/refractory cisplatin-sensitive GCT (n = 80) used conventional-dose chemotherapy with three cycles of paclitaxel, ifosfamide, and cisplatin followed by one cycle of HDC with carboplatin, etoposide, and thiotepa. Only 62 (78%) patients received HDC, and 41 of 62 patients (66%) responded to therapy, with a 3-year EFS of 25%.

At MD Anderson Cancer Center, other HDC regimens have been explored utilizing different mechanisms of synergy in patients with very poor prognostic features. Vascular endothelial growth factor (VEGF) expression is involved in tumor development, angiogenesis, and metastasis in GCT. As a result, we investigated whether the addition of bevacizumab (an anti-VEGF monoclonal antibody) to HDC followed by autologous HCT for two cycles (gemcitabine, docetaxel, melphalan, carboplatin [GemDMC] for one cycle, followed by ifosfamide, carboplatin, and etoposide [ICE] for the second cycle) in patients with intermediate/high-risk relapsed or refractory GCT improved outcomes. Forty-two patients were initially enrolled in a phase II trial with a median of three prior relapses and four prior lines of therapy. The majority of patients had unresponsive disease before enrollment, and 87% of them were cisplatin refractory. At a median follow-up of 46 months, the relapse-free survival (RFS) and overall survival (OS) rates were 56% and 58%, respectively. Adverse side effects primarily included mucositis and renal dysfunction, and the addition of bevacizumab increased mucositis after GemDMC substantially (Grade 3, 75%). With the aforementioned side effect profile in mind, bevacizumab was subsequently omitted from GemDMC and ICE in a second cohort of 28 patients. This combination has shown impressive outcomes including a 26-month EFS of 71% and OS of 74% but with less mucositis. The results of this trial reflected the benefit of the synergistic interaction between gemcitabine and the other agents based on deoxyribonucleic acid damage repair inhibition through suppression of nucleotide excision repair, a major mechanism of cisplatin resistance in GCT cells.

Clinical Results in Front-Line High-Risk Nonseminomatous Germ-Cell Tumor

In patients who showed a prolonged half-life of tumor markers during SDC, Motzer and colleagues at Memorial Sloan Kettering Cancer Center developed a strategy of switching to HDC, which resulted in CR rate of 57%, 50% EFS at a median follow-up of 30 months, and significantly longer OS than historical controls.

The role of HDC in first-line therapy was further evaluated in three randomized studies. An early European randomized trial in the 1980s failed to show a therapeutic benefit for HDC in 115 untreated poor-risk patients who were randomized to receive three to four cycles of SDC or two cycles followed by one cycle of a stem cell-supported high-dose cisplatin-containing regimen. A later European study compared SDC with BEP for four cycles to one cycle of VIP followed by three cycles of high-dose VIP with autologous HCT in patients with poor-risk feature. This study closed prematurely after slowly enrolling only 137 of the 222 planned patients. At its first analysis with 4.4-year median follow-up, the 2-year EFS (45% vs. 58%, P = .06) and 2-year OS (66% vs. 73%, P > .05) differences did not reach statistical significance.

In a U.S. Intergroup trial, 219 patients with newly diagnosed disease with intermediate or poor risk features according to the IGCCCG criteria were randomized to receive four cycles of BEP or two cycles of BEP followed by two cycles of HDC with CEC. This trial, conducted by Motzer et al., resulted in 1-year durable CR rates that did not differ significantly between the transplant and control arms (48% vs. 52%, P = .5). There were no significant differences in EFS ( P = .4) or OS ( P = .9). A subset analysis according to early tumor marker clearance suggested a significant benefit of HDC among those patients experiencing a slow marker decline (61% vs. 34% 1-year EFS, P = .03).

To summarize, the available data from all randomized trials performed thus far do not advocate for a standard role for HDC in first-line treatment of GCT.