Annals of Oncology Advance Access originally published online on November 9, 2005
Annals of Oncology 2006 17(3):530-531; doi:10.1093/annonc/mdj027
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© 2005 European Society for Medical Oncology
letter to the editor |
Is high-dose chemotherapy based on carboplatin, a late dose-intensification of a cisplatin-based salvage chemotherapy in germ cell tumour patients?
I read with great interest a recent paper by Pico et al. [1
] 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 [2–4]. 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]. 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, 6]. 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]. Importantly, another platinum analogue, oxaliplatin, is an active agent in patients with cisplatin-refractory GCT [8]. 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, 6]. 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.
Istituto Toscano Tumori-Department of Oncology, San Giuseppe Hospital, Empoli, Florence, Italy
* (E-mail: ugo_degiorgi{at}yahoo.com)
References
1. Pico JL, 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: 1152–1159.
2. Hartmann JT, Einhorn L, Nichols CR 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: 1641–1648.
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: 146–151.
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: 3346–3351.
5. Vaena DA, Abonour R, Einhorn LH. Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables. J Clin Oncol 2003; 21: 4100–4104.
6. Einhorn LH. Curing metastatic testicular cancer. Proc Natl Acad Sci USA 2002; 99: 4592–4595.
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: 95–104.
8. Kollmannsberger C, Rick O, Derigs HG 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: 2031–2037.
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