(UroToday.com) The 2025 GU ASCO annual meeting featured a session on emerging trends in germ cell tumors and a presentation by Dr. Nabil Adra discussing the current evidence and indications for high-dose chemotherapy in testicular cancer. Dr. Adra highlighted that 20% of patients with metastatic germ cell tumor will progress after first line therapy: 11% for good risk disease, 25% for intermediate risk disease, and 46% for poor risk disease. Progression is defined by serology and radiography, and we should use caution with initiating salvage therapy with borderline AFP and hCG. Options to treat relapsed germ cell tumors include salvage surgery, standard-dose chemotherapy, and high-dose chemotherapy. The International Prognostic Factors Study Group previously established prognostic variables as:
- Response to first line therapy
- PFI post first line therapy
- AFP salvage
- hCG salvage
- Non-pulmonary visceral metastasis
- Histology
In 2011, Lorch et al.1 published an international retrospective assessment of conventional-dose versus high-dose chemotherapy as first salvage treatment in patients with metastatic germ cell tumors. Among 1,984 patients, 773 patients received conventional-dose chemotherapy, and 821 patients received high-dose chemotherapy. The hazard ratio for progression free survival was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for overall survival was 0.65 (95% CI, 0.56 to 0.75), favoring high-dose chemotherapy:
High-dose chemotherapy was also beneficial compared to conventional dose chemotherapy with regards to progression free survival across all risk groups:
There are several high-dose chemotherapy regimens available, including carboplatin etoposide regimen x 2:
Another regimen used for high-dose chemotherapy is the TI-CE regimen:
Both Indiana University and Memorial Sloan Kettering Cancer Center (MSKCC) have published their series’ of salvage high-dose chemotherapy, Indiana using the carboplatin + etoposide regimen and MSKCC using the TI-CE regimen, with comparable results:
In 2017, Dr. Adra and colleagues published the Indiana University experience (2004-2014) of high-dose chemotherapy and autologous peripheral-blood stem-cell transplantation for relapsed metastatic germ cell tumors.2 There were 364 patients included in this retrospective assessment, of which 341 received two consecutive courses of high-dose chemotherapy consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by peripheral-blood stem-cell transplantation. There were 23 patients received only a single course of high-dose chemotherapy because of progressive disease or toxicity. Over a median follow-up of 3.3 years, the 2-year progression free survival was 60% (95% CI, 55% to 65%) and the 2 year overall survival was 66% (95% CI, 60% to 70%):
Dr. Adra notes that there are many unsettled issues regarding high-dose chemotherapy, including:
- Which patients should receive high-dose chemotherapy?
- Should high-dose chemotherapy be used as initial salvage?
- How to treat primary mediastinal non-seminoma?
- Progressive brain metastasis
- Late relapse
- Short term and long term toxicity from high-dose chemotherapy
- What is the role of biomarkers to detect minimal residual disease?
- Maintenance strategies post high-dose chemotherapy
In 2005, Pico et al.3 published a randomized trial of high-dose chemotherapy in the salvage treatment of patients failing first line platinum chemotherapy, with randomization to VIP or VeIP x 4 (Arm A) versus VIP or VeIP x 3 followed by high dose chemotherapy x 1 (carboplatin, etoposide, cyclophosphamide; Arm B):
Among 280 patients randomized, there were similar complete and partial response rates observed in both treatment arms (56%, 95% CI 50% to 62%). Of note, there were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with VeIP x 3 followed by high dose chemotherapy x 1 were observed in either 3-year event-free survival (35% versus 42%, p = 0.16) or overall survival (53%; 95% CI 46% to 59%).
In 2012, Lorch et al.4 reported results of sequential versus single high-dose chemotherapy in patients with relapsed or refractory germ cell tumors. Patients were randomized to VIP x 1 followed by high-dose chemotherapy x 3 (carboplatin, etoposide; Arm A) versus VIP x 3 followed by high-dose chemotherapy x 1 (carboplatin, etoposide, cyclophosphamide; Arm B):
In this study, there was no difference progression free survival (p = 0.456) or overall survival (p = 0.57), however, treatment related death was noted in 14% of patients receiving VIP x 3 followed by high-dose chemotherapy x 1, compared to 4% for VIP x 1 followed by high-dose chemotherapy x 3:
Recently, Seidel et al.5 performed a retrospective, international multicenter analysis (1996-2022) to assess the efficacy and safety of high-dose chemotherapy as the first or subsequent salvage treatment line in patients with relapsed or refractory germ cell cancer. This included heterogeneous high-dose chemotherapy regimens, including carboplatin etoposide, carboplatin etoposide cyclophosphamide, carboplatin etoposide thiotepa, carboplatin etoposide ifosfamide. There were 159 patients that received high-dose chemotherapy as first salvage, and 124 patients that received high-dose chemotherapy as subsequent salvage. Patients that received first salvage high-dose chemotherapy had significantly improved overall survival (p = 0.00027):
Grade 3+ non-hematologic adverse events included 78% in the first salvage group versus 97% in the subsequent salvage group (p < 0.001), and treatment-related deaths included 2% in the first salvage versus 7% in the subsequent salvage group (p = 0.08). Similarly, in the Indiana experience [2], earlier lines of high-dose chemotherapy had improved progression free survival:
The ongoing A031102 trial is a phase III trial comparing TIP versus TI-CE as initial salvage relapsed germ cell tumor:
With regards to salvage high-dose chemotherapy in primary mediastinal non-seminoma, Richardson et al.6 reported the Indiana University experience. This included 32 patients between 2006-2021 that included two consecutive courses of high-dose chemotherapy consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by peripheral blood stem cell transplantation. With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression free survival rate was 31% (95% CI 16%-47%), and the 2-year overall survival rate was 35% (95% CI 19%-52%). At the last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy; there were three treatment-related deaths.
Certainly, there is short term and long term toxicity with high dose chemotherapy. Short term non-hematologic toxicity includes gastrointestinal, hepatic, pulmonary, renal, and neurologic. Cumulative dose of etoposide is associated with increased risk of leukemia: doses >2 g/m2 are associated with 2-3% risk of leukemia. Treatment-related mortality is ~3%, and most survivors have reported general adverse health outcomes:
Dr. Adra finished his presentation by highlighting two trials: the randomized phase 2 trial of maintenance oral etoposide or observation following high-dose chemotherapy for relapsed metastatic germ cell tumor:
Secondly, the phase I/II trial of zanzalintinib with oral etoposide following high-dose chemotherapy in patients with relapsed metastatic germ cell tumor:
Dr. Adra concluded his presentation by discussing the current evidence and indications for high-dose chemotherapy in testicular cancer with the following take-home points:
- High dose chemotherapy is effective salvage therapy for patients with relapsed germ cell tumors
- Cures can be achieved in patients with platinum-refractory disease, mediastinal non-seminoma, >=3 line therapy, and progressive brain metastases
- We should exercise caution with borderline conventional tumor markers and sanctuary sites (testis, brain)
- Optimal patient selection of high-dose chemotherapy versus standard-dose chemotherapy is currently being studied in a randomized phase III trial (NCT02375204)
- Minimal residual disease post high-dose chemotherapy needs further evaluation (biomarkers, maintenance)
Presented by: Nabil Adra, MD, Indiana University Health Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:
- Lorch A, Bascoul-Mollevi C, Kramer A, et al. Conventional-dose versus high-dose chemotherapy as first salvage treatment in male patients with metastatic germ cell tumors: Evidence from a large international database. J Clin Oncol. 2011 Jun 1;29(16):2178-2184.
- Adra N, Abonour R, Althouse SK, et al. High-dose chemotherapy and autologous peripheral-blood stem-cell transplantation for relapsed metastatic germ cell tumors: The Indiana University Experience. J Clin Oncol. 2017 Apr 1;35(10):1096-1102.
- Pico J-L, Rosti G, Kramar A, et al. A randomized trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol. 2005 Jul;16(7):1152-1159.
- Lorch A, Kleinhans A, Kramar A, et al. Sequential versus single high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: long-term results of a prospective randomized trial. J Clin Oncol. 2012 Mar 10;30(8):800-805.
- Seidel C, Schaefers C, Connolly EA, et al. Efficacy and safety of high-dose chemotherapy as the first or subsequent salvage treatment line in patients with relapsed or refractory germ cell cancer: An international multicentric analysis. ESMO Open. 2024 May;9(5):103449.
- Richardson NH, Taza F, Abonour R, et al. High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University Experience.