High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed or refractory testicular cancer: a systematic review and meta-analysis

Abstract

Background: The role of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in the management of patients with relapsed/refractory germ-cell tumors has not been established in prospective studies. Our aim was to estimate the benefits and harm of this treatment in men with relapsed/refractory germ-cell tumors.

Methods: Electronic databases, conference proceedings, and trial registers until April 30, 2023, were searched. Randomized and non-randomized prospective controlled trials were included. Risk of bias assessments were performed using either RoB2 or ROBINS-I tools. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Time-to-event data were analyzed using the hazard ratio. The primary outcome was overall survival, and a meta-analysis was not conducted to assess it because non-randomized trials were judged to have a critical risk of bias. Categorical data were analyzed using a risk ratio. All results are presented with the corresponding 95% confidence interval.

Results: Four out of 3,824 records met the inclusion criteria, and three out of four were used to assess primary and secondary outcomes. Based on the IT94 study (N = 263 participants), single high-dose chemotherapy followed by autologous hematopoietic cell transplantation may have little to no effect on overall survival [hazard ratio (HR) 0.98, 95%CI 0.68 to 1.42; p = 0.916]. Non-randomized trials (N = 43 participants) showed contrasting results, which may be explained by the number of cycles of high-dose chemotherapy administered in each study. Regarding secondary outcomes, information was only provided for event-free survival, response rate, and acute toxicities.

Conclusions: Based on prospective data, there is insufficient evidence to support or refute the proposal that high-dose chemotherapy with autologous hematopoietic cell transplantation improves survival in men with relapsed/refractory germ-cell tumors. If this treatment is considered essential, the choice should be made by experienced clinicians at high-volume cancer centers.

Keywords: adverse (side) effects; chemotherapy; high dose chemotherapy with autologous stem cell transplantation; refractory germ cell tumors; relapsed germ cell tumor; survival.

Figure 1

PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2

RoB2 risk of bias assessment of randomized controlled trials (intention-to-treat analysis). Risk of bias was separately assessed for each outcome.

Figure 3

RoB2 risk of bias assessment of randomized controlled trials (per-protocol analysis). Risk of bias was only assessed for toxicity.

Figure 4

ROBINS-I risk of bias assessment of non-randomized controlled trials. Risk of bias was separately assessed for each outcome. Faure-Conter et al. (ITT analysis): overall survival. Mardiak et al. (ITT analysis): overall survival. Mardiak et al. (1) (ITT analysis): response rate. Mardiak et al. (2) (ITT analysis): toxicity. Mardiak et al. (3) (per-protocol analysis): toxicity. ITT, intention-to-treat.

Figure 5

HDCT vs. CDCT: overall survival. HDCT, high-dose chemotherapy; CDCT, conventional-dose chemotherapy.

Figure 6

Meta-analysis of pooled estimates of complete response.

Figure 7

Meta-analysis of pooled estimates of overall response rate.

Figure 8

Meta-analysis of pooled estimates of failure.

Figure 9

Meta-analysis of pooled estimates of febrile neutropenia ≥ G3.

Figure 10

Meta-analysis of pooled estimates of thrombocytopenia ≥ G3.