ORIGINAL ARTICLE Post-operative sequential high-dose chemotherapy with haematopoietic stem cell support as front-line treatment in advanced ovarian cancer: a phase II multicentre study A Gonc ¸alves 1 , R Delva 2 , M Fabbro 3 , L Gladieff 4 , J-P Lotz 5 , J-M Ferrero 6 , C Linassier 7 , P-H Cottu 8 , P Viens 1 and J-M Extra 9 1 Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France; 2 Department of Medical Oncology, Centre Paul Papin, Angers, France; 3 Department of Medical Oncology, Centre Val d’Aurelle, Montpellier, France; 4 Department of Medical Oncology, Institut Claudius Regaud, Toulouse, France; 5 Department of Medical Oncology, Hoˆpital Tenon, Paris, France; 6 Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France; 7 Department of Medical Oncology, Hoˆpital Bretonneau, Tours, France; 8 Department of Medical Oncology, Hoˆpital Saint-Louis, Paris, France and 9 Department of Medical Oncology, Institut Curie, Paris, France In spite of multimodal management including aggressive surgery and chemotherapy, the prognosis of advanced ovarian cancer (AOC) remains poor. Multicycle high-dose chemotherapy (HDC) with haematopoietic stem cell (HSC) support has been shown to be a promising proce- dure in various cancers including AOC. We conducted a phase II multicentre study to evaluate feasibility, toxicity and efficacy of post-operative front-line sequential HDC withHSCsupportinAOC.Thirtyfourpatientswithstage IIIC/IV received a post-operative sequential combination of high-dose cyclophosphamide/epirubicin (D1, D21) with HSC harvesting, high-dose carboplatin (D42, D98) followed by HSC infusion, and dose-dense paclitaxel (D63, D77, D119, D133). Rh-G-CSF (filgrastim) was administered following all cycles. Primary endpoint was pathologicalcompleteresponserate(pCR).Thirtypatients received at least 7 of the scheduled 8 cycles. Haemato- logical toxicity was significant but manageable. Grade 3/4 extra-haematopoietic toxicities were relatively uncommon and reversible. No toxicity-related death was observed. The observed pCR was 37% and did not reach the initial endpoint. Post-operative front-line sequential HDC in AOC is feasible and safe in a multicentre setting. The observed pCR does not support a clear advantage over conventional treatment. This approach remains an experi- mental strategy to further optimise and validate. Bone Marrow Transplantation (2006) 37, 651–659. doi:10.1038/sj.bmt.1705302; published online 27 February 2006 Keywords: advanced ovarian cancer; haematopoietic stem cell support; high-dose chemotherapy; phase II trial Introduction In spite of multidisciplinary management including aggres- sive surgical cytoreduction and post-operative chemother- apy, five-year survival rates in advanced ovarian cancer (AOC) do not exceed 30%. 1 In these patients, current standard chemotherapeutic agents include platinum com- pounds and taxanes, the combination of which allows a high clinical response rate to be obtained (70 to 80%), including 30 to 40% of pathological complete response, with a median progression-free survival of 15 to 18 months and a median overall survival of 35 to 38 months. 2,3 Ovarian cancer was considered early on as a good model for high-dose chemotherapy (HDC): it is a chemosensitive disease with a documented dose-response effect for alkylating agents and platinum compounds, 4,5 although no significant clinical benefit has been shown for modest increases in dose of platinum compounds. In recurrent or refractory disease, such a therapeutic approach was shown to induce significant response rates, but duration of response was short and long term progression-free survival was uncommon. 6,7 Recently, some evidence suggested that HDC administered as consolidation after conventional chemotherapy, in surgically verified responding patients might significantly improve long term outcome. 8–10 How- ever, this putative benefit is restricted by definition to a selected patient population, i.e. responding patients, while excluding patients initially resistant to conventional dose. In addition, administration of a single HDC cycle, although very effective in a low burden setting, might not be sufficient to eradicate the ‘last cell’ and prevent the disease relapse. An alternative method of manipulating the dose-effect concept may be to deliver HDC as front-line treatment and as dose-dense and rapidly cycled sequential drug combina- tions. Using sequential administration of HDC regimen based on various anti-tumour agents with different action mechanisms may combine dose-density and dose-intensity concepts while limiting the development of drug resistance. 11 Received 5 October 2005; revised 11 January 2006; accepted 14 January 2006; published online 27 February 2006 Correspondence: Dr A Gonc ¸alves, Department of Medical Oncology, Institut Paoli-Calmettes, 232 Boulevard Sainte-Marguerite, 13273 Cedex 9, Marseille, France. E-mail: goncalvesa@marseille.fnclcc.fr Bone Marrow Transplantation (2006) 37, 651–659 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt