The majority of men with germ cell tumours (GCTs) are cured with surgery, radiotherapy and conventional-dose chemotherapy appropriate to the location, histology, stage and biochemical markers of their tumour. For those patients who relapse or are refractory after optimal conventional chemotherapy, the two major salvage approaches are high-dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) or conventional-dose chemotherapy. There are no randomised controlled trials (RCTs) to establish efficacy in this setting, although considerable level III evidence supports the use of HDCT.rrr Prognostic factors for these patients include primary tumour location, response to first-line therapy, progression-free interval, and serum tumour markers.r Patients with relapse of primary mediastinal non-seminomatous GCTs represent a poorer prognosis subgroup in which there is limited evidence for the efficacy of HDCT.r
High-dose chemotherapy versus conventional-dose chemotherapy
A large retrospective analysis of 1435 evaluable patients compared the role of HDCT versus conventional-dose chemotherapy (CDCT).r Overall, 773 patients received CDCT, and 821 patients received HDCT. HDCT was associated with improved 2-year PFS (50% vs. 28%, p<0.001) and 5-year OS (53% vs. 41%, p<0.001). The authors conclude that the results suggest a benefit from HDCT but highlight the need for a large prospective randomised trial. A phase III multicentre European study prospectively compared CDCT using 4 cycles of VIP to a single HDCT after 3 cycles of VIP. This study failed to demonstrate statistically significant differences but has been criticised on methodological grounds.r A retrospective matched-pair analysis of CDCT vs HDCT favoured HDCT both for event-free and overall survival.r
Current salvage HDCT regimens can achieve durable remissions in 30-60% of patients, depending on patient selection and the timing of treatment (initial salvage vs. later in the disease course). Studies have demonstrated that sequential cycles with less intensive HDCT regimens are less toxic and possibly more effective than single-cycle more intensive regimens. A randomised trial conducted by the German Testicular Cancer Study Group compared the efficacy of sequential vs. single cycle HDCT in the salvage setting by randomising patients to either VIP x 3 followed by 1 cycle of HDCT consisting of carboplatin plus etoposide plus cyclophosphamide or VIP x1 followed by 3 cycles of HDCT, consisting of carboplatin plus etoposide.r Unfortunately, there was unacceptable toxicity in the single HDCT arm such that the trial closed prematurely and differences in efficacy, while similar, could not be properly assessed. This and other recent studies have established the standard-of-care for salvage HDCT to consist of two to three sequential cycles of carboplatin plus etoposide, administered 3-4 weeks apart.
The choice of conditioning agents for high-dose chemotherapy varies among institutions. While there have been no randomised studies addressing the optimal conditioning regimen for GCT patients undergoing HDCT, high-dose carboplatin and etoposide regimen is the conditioning regimen best supported by the available evidence.rr Limiting the regimen to two drugs may allow higher doses of the two most active agents (carboplatin and etoposide) to be administered. Attempts to incorporate other agents into the conditioning regimens have not lead to improved efficacy and may be more toxic.r
Conditioning with TICE
The TICE regimen was first established in the 1990s at the Memorial Sloan-Kettering Cancer Center. The dosing schedule and safety in 47 patients was first published in 2007.r The TICE regimen consists of 2 cycles of rapidly recycled conventional-dose paclitaxel plus ifosfamide and then G-CSF for stem cell mobilisation followed by 3 cycles of high-dose carboplatin and etoposide, with each high-dose cycle followed by an ASCT. Carboplatin is dosed by AUC. Efficacy and prognostic factor analysis on 107 patients was then published in 2010 by Feldman et al.r This protocol targeted patients predicted to have a poor outcome with salvage CDCT, including patients with extragonadal primary tumour site; progression after a prior salvage CDCT regimen; or an incomplete response or relapse within <6 months after first-line chemotherapy.
Note: there is a current actively recruiting randomised phase III study comparing the TICE regimen with conventional-dose chemotherapy using paclitaxel, ifosfamide and cisplatin (TIP) as first salvage treatment in relapsed or refractory germ cell tumours. Please see link for more information.
The efficacy and prognostic factor analysis on 107 patients that received the TICE conditioning protocol, was published in 2010 by Feldman et al.r There were 54 (50%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47%, and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal non-seminomatous GCTs are continuously disease-free.
Fig 1. Kaplan - Meier curves of (A) disease-free survival and (B) overall survival for patients treated with paclitaxel + ifosfamide and carboplatin + etoposide high-dose chemotherapy.
©Journal of Clinical Oncology 2007
The toxic effects of high-dose chemotherapy were primarily myelosuppression, mucositis, nausea, vomiting, dehydration, peripheral neuropathy, and otologic abnormalities. There were two (2%) treatment-related deaths, including one fatal cerebral haemorrhage and one fatal pulmonary haemorrhage. Ototoxicity, an important toxicity connected with high-dose carboplatin treatment that is especially relevant in a patient population previously treated with cisplatin-based therapy, was seen in some patients. Hearing loss was most significant at higher frequency levels, although moderate changes in hearing at the speech-range frequencies were seen.r
©Journal of Clinical Oncology 2007