Is high-dose chemotherapy based on carboplatin, a late dose-intensification of a cisplatin-based salvage chemotherapy in germ cell tumour patients?

Abstract

I read with great interest a recent paper by Pico et al. [1.Pico J.L. Rosti G. Kramar A. et al.A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.Ann Oncol. 2005; 16: 1152-1159Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar] reporting the first results of the IT94 phase III randomised trial. This trial compared four courses of PEI (cisplatin, etoposide, ifosfamide) or VeIP (vinblastine, ifosfamide, cisplatin) with three courses of PEI/VeIP followed by a single shot of high-dose chemotherapy (HDCT) with CarboPEC (carboplatin, etoposide, cyclophosphamide) in germ cell tumour (GCT) patients with incomplete remission or relapse from the first-line chemotherapy. Results showed similar overall response rates (ORRs) in both arms, while 3-year event-free survival was 35% in the standard-dose and 42% in the HDCT arm (P = 0.16) with no difference in 3-year overall survival. Patients with complete response (CR) after CarboPEC had a significant advantage in the 3-year disease-free survival (75% versus 55%, P < 0.04), even if this subgroup analysis was not planned in advance. The authors concluded that results clearly demonstrated that ‘late dose-intensification’ of a salvage regimen provides no clinical benefit in these patients.I have some concerns regarding the article. Other authors consider GCT patients who did not fall into the partial response with negative marker (PRm-) and CR categories after chemotherapy to have failed treatment [2.Hartmann J.T. Einhorn L. Nichols C.R. et al.Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an International multicenter analysis.J Clin Oncol. 2001; 19: 1641-1648Crossref PubMed Scopus (91) Google Scholar, 3.De Giorgi U. Demirer T. Wandt H. et al.Second-line high-dose chemotherapy in patients with mediastinal and retroperitoneal primary non-seminomatous germ cell tumors: the EBMT experience.Ann Oncol. 2005; 16: 146-151Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 4.Bhatia S. Abonour R. Porcu P. et al.High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.J Clin Oncol. 2000; 18: 3346-3351Crossref PubMed Scopus (131) Google Scholar]. In this manner, in the IT94 trial, ‘late dose-intensification’ was given only to patients with PRm- or CR after three courses of PEI/VeIP. Regarding the Results section, the authors have not particularly reported the outcome of patients with PRm- or CR after three courses of PEI/VeIP, but it is easy to believe that these patients were most of those obtaining a CR status after the last course of the treatment with a significant advantage in the 3-year disease-free survival [1.Pico J.L. Rosti G. Kramar A. et al.A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.Ann Oncol. 2005; 16: 1152-1159Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. Also, patients having achieved stable disease or partial response with positive markers after three courses of conventional chemotherapy received CarboPEC as third-line salvage treatment, but not as second-line ‘late dose-intensification’. The activity of just one course of HDCT versus one course of PEI/VeIP in these patients seems questionable as demonstrated by the similar ORRs observed in both treatment arms.Furthermore, the last course of CarboPEC should be considered a different chemotherapeutic regimen in all cases. Tandem HDCT based on carboplatin and etoposide showed impressive results in patients with cisplatin-refractory GCTs with 37% of 2-year failure-free survival [5.Vaena D.A. Abonour R. Einhorn L.H. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables.J Clin Oncol. 2003; 21: 4100-4104Crossref PubMed Scopus (76) Google Scholar, 6.Einhorn L.H. Curing metastatic testicular cancer.Proc Natl Acad Sci USA. 2002; 99: 4592-4595Crossref PubMed Scopus (305) Google Scholar]. In the past, carboplatin was considered equivalent to cisplatin in most tumours, but every tentative attempt to change cisplatin with carboplatin failed in GCT. Despite the fact that these results did not support the use of conventional dose carboplatin, carboplatin was incorporated into high-dose salvage protocols in GCTs, due to the better toxicity profile [7.De Giorgi U. Rosti G. Papiani G. et al.The status of high-dose chemotherapy with hematopoietic stem cell transplantation in patients with germ cell tumor.Haematologica. 2002; 87: 95-104PubMed Google Scholar]. Importantly, another platinum analogue, oxaliplatin, is an active agent in patients with cisplatin-refractory GCT [8.Kollmannsberger C. Rick O. Derigs H.G. et al.Activity of oxaliplatin in patients with relapsed or cisplatin-refractory germ cell cancer: a study of the German Testicular Cancer Study Group.J Clin Oncol. 2002; 20: 2031-2037Crossref PubMed Scopus (99) Google Scholar]. It is time to consider carboplatin as a drug different from cisplatin in GCTs. Therefore, HDCT based on carboplatin should not be considered a ‘late dose-intensification’ of a cisplatin-based regimen, but simply another chemotherapeutic regimen.Preliminary results of the IT94 trial showed a potential role for one single course of CarboPEC to eradicate the minimal residual disease, possibly in patients with PRm- or CR status after three courses of PEI/VeIP, that is absolutely not repeatable in prospective randomised studies due to the paucity of this patient population. This effect could explain both the significant advantage for the HDCT arm in 3-year disease-free survival (75% versus 55%, P < 0.04) in patients with CR after CarboPEC and the trend towards a 3-year event-free survival advantage (35% versus 42%, P = 0.16) for the HDCT arm without any impact on ORRs.In cisplatin-refractory non-mediastinal primary GCT, tandem HDCT based on carboplatin and etoposide is recommended based only on a large retrospective series [5.Vaena D.A. Abonour R. Einhorn L.H. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables.J Clin Oncol. 2003; 21: 4100-4104Crossref PubMed Scopus (76) Google Scholar, 6.Einhorn L.H. Curing metastatic testicular cancer.Proc Natl Acad Sci USA. 2002; 99: 4592-4595Crossref PubMed Scopus (305) Google Scholar]. Mature results of the IT-94 trial, including outcome of patients with PRm- or CR after three courses of PEI/VeIP, could carry a new indication of CarboPEC in a further subset of relapse GCT. I read with great interest a recent paper by Pico et al. [1.Pico J.L. Rosti G. Kramar A. et al.A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.Ann Oncol. 2005; 16: 1152-1159Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar] reporting the first results of the IT94 phase III randomised trial. This trial compared four courses of PEI (cisplatin, etoposide, ifosfamide) or VeIP (vinblastine, ifosfamide, cisplatin) with three courses of PEI/VeIP followed by a single shot of high-dose chemotherapy (HDCT) with CarboPEC (carboplatin, etoposide, cyclophosphamide) in germ cell tumour (GCT) patients with incomplete remission or relapse from the first-line chemotherapy. Results showed similar overall response rates (ORRs) in both arms, while 3-year event-free survival was 35% in the standard-dose and 42% in the HDCT arm (P = 0.16) with no difference in 3-year overall survival. Patients with complete response (CR) after CarboPEC had a significant advantage in the 3-year disease-free survival (75% versus 55%, P < 0.04), even if this subgroup analysis was not planned in advance. The authors concluded that results clearly demonstrated that ‘late dose-intensification’ of a salvage regimen provides no clinical benefit in these patients. I have some concerns regarding the article. Other authors consider GCT patients who did not fall into the partial response with negative marker (PRm-) and CR categories after chemotherapy to have failed treatment [2.Hartmann J.T. Einhorn L. Nichols C.R. et al.Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an International multicenter analysis.J Clin Oncol. 2001; 19: 1641-1648Crossref PubMed Scopus (91) Google Scholar, 3.De Giorgi U. Demirer T. Wandt H. et al.Second-line high-dose chemotherapy in patients with mediastinal and retroperitoneal primary non-seminomatous germ cell tumors: the EBMT experience.Ann Oncol. 2005; 16: 146-151Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 4.Bhatia S. Abonour R. Porcu P. et al.High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.J Clin Oncol. 2000; 18: 3346-3351Crossref PubMed Scopus (131) Google Scholar]. In this manner, in the IT94 trial, ‘late dose-intensification’ was given only to patients with PRm- or CR after three courses of PEI/VeIP. Regarding the Results section, the authors have not particularly reported the outcome of patients with PRm- or CR after three courses of PEI/VeIP, but it is easy to believe that these patients were most of those obtaining a CR status after the last course of the treatment with a significant advantage in the 3-year disease-free survival [1.Pico J.L. Rosti G. Kramar A. et al.A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.Ann Oncol. 2005; 16: 1152-1159Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. Also, patients having achieved stable disease or partial response with positive markers after three courses of conventional chemotherapy received CarboPEC as third-line salvage treatment, but not as second-line ‘late dose-intensification’. The activity of just one course of HDCT versus one course of PEI/VeIP in these patients seems questionable as demonstrated by the similar ORRs observed in both treatment arms. Furthermore, the last course of CarboPEC should be considered a different chemotherapeutic regimen in all cases. Tandem HDCT based on carboplatin and etoposide showed impressive results in patients with cisplatin-refractory GCTs with 37% of 2-year failure-free survival [5.Vaena D.A. Abonour R. Einhorn L.H. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables.J Clin Oncol. 2003; 21: 4100-4104Crossref PubMed Scopus (76) Google Scholar, 6.Einhorn L.H. Curing metastatic testicular cancer.Proc Natl Acad Sci USA. 2002; 99: 4592-4595Crossref PubMed Scopus (305) Google Scholar]. In the past, carboplatin was considered equivalent to cisplatin in most tumours, but every tentative attempt to change cisplatin with carboplatin failed in GCT. Despite the fact that these results did not support the use of conventional dose carboplatin, carboplatin was incorporated into high-dose salvage protocols in GCTs, due to the better toxicity profile [7.De Giorgi U. Rosti G. Papiani G. et al.The status of high-dose chemotherapy with hematopoietic stem cell transplantation in patients with germ cell tumor.Haematologica. 2002; 87: 95-104PubMed Google Scholar]. Importantly, another platinum analogue, oxaliplatin, is an active agent in patients with cisplatin-refractory GCT [8.Kollmannsberger C. Rick O. Derigs H.G. et al.Activity of oxaliplatin in patients with relapsed or cisplatin-refractory germ cell cancer: a study of the German Testicular Cancer Study Group.J Clin Oncol. 2002; 20: 2031-2037Crossref PubMed Scopus (99) Google Scholar]. It is time to consider carboplatin as a drug different from cisplatin in GCTs. Therefore, HDCT based on carboplatin should not be considered a ‘late dose-intensification’ of a cisplatin-based regimen, but simply another chemotherapeutic regimen. Preliminary results of the IT94 trial showed a potential role for one single course of CarboPEC to eradicate the minimal residual disease, possibly in patients with PRm- or CR status after three courses of PEI/VeIP, that is absolutely not repeatable in prospective randomised studies due to the paucity of this patient population. This effect could explain both the significant advantage for the HDCT arm in 3-year disease-free survival (75% versus 55%, P < 0.04) in patients with CR after CarboPEC and the trend towards a 3-year event-free survival advantage (35% versus 42%, P = 0.16) for the HDCT arm without any impact on ORRs. In cisplatin-refractory non-mediastinal primary GCT, tandem HDCT based on carboplatin and etoposide is recommended based only on a large retrospective series [5.Vaena D.A. Abonour R. Einhorn L.H. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables.J Clin Oncol. 2003; 21: 4100-4104Crossref PubMed Scopus (76) Google Scholar, 6.Einhorn L.H. Curing metastatic testicular cancer.Proc Natl Acad Sci USA. 2002; 99: 4592-4595Crossref PubMed Scopus (305) Google Scholar]. Mature results of the IT-94 trial, including outcome of patients with PRm- or CR after three courses of PEI/VeIP, could carry a new indication of CarboPEC in a further subset of relapse GCT.