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Dose intense triplet chemotherapy with gemcitabine, carboplatin, paclitaxel with peripheral blood progenitor cell support for six cycles in advanced epithelial ovarian cancer.

ABSTRACT: The interval required for haematological reconstitution following myelosuppressive chemotherapy can be reduced by the infusion of autologous peripheral blood progenitor cells (PBPCs). When carboplatin (C) and paclitaxel (P) are followed by granulocyte colony-stimulating factor (GCSF), multiple courses can be given at 10-day intervals with the autologous PBPCs from a unit of whole blood with each cycle. We extended this approach and defined the dose-limiting toxicity and maximum-tolerated dose for the addition of gemcitabine (G) to CP for patients (pts) with EOC in a phase I-II study of increasing doses of G (0, 800, 1000 and 1250 mg x m(-2)) over four cohorts with C at area under curve (AUC) 6, plus P at 175 mg x m(-2) 3 h(-1) every 10 days for six cycles. Granulocyte colony-stimulating factor 5 microg x kg(-1) day(-1) was given s.c. days 1-10 and 450 ml whole blood was venesected before each treatment, stored untreated at 4 degrees C and reinfused 24 h later. In all, 17 patients with EOC either bulky stage IV or recurrent after treatment-free interval >12 months were treated over 30 months. Of the 17 patients, 13 completed six cycles (one patient stopped early with PD, three with toxicity), interdose interval 9-28 (median 10) days. Delays occurred in four patients due to infection or malaise, and there were no dose reductions. Haematological toxicity was not considered to be dose limiting. Febrile neutropenia was uncommon (2 patients), but grade III/IV thrombocytopenia was seen across all cohorts. Treatment was not delayed for thrombocytopenia and no bleeding complications occurred. Grade III transaminitis was seen in all patients in cohort 4 and grade IV toxicity, considered to be dose limiting, occurred in one. Responses were observed at all dose levels with six CR, seven PR, three SD and one PD. Dose intense GCP was deliverable over six cycles with manageable haematological toxicity, but with dose-limiting hepatic toxicity in cohort 4. The MTD was gemcitabine 1000 mg x m(-2), carboplatin AUC 6, paclitaxel 175 mg x m(-2) given every 10 days for six cycles.

SUBMITTER: Barlow C

PROVIDER: S-EPMC2409688 | biostudies-other | 2004 Apr

REPOSITORIES: biostudies-other

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Project description:Background: Lung cancers represent the main cause of cancer related-death in the world. Recently, immunotherapy alone or in combination with chemotherapies have deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatments so far. The development of new therapies based on comprehension of mechanisms of resistance is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hampers to clearly understand the consequence of these molecules on tumor cells and then, to identify adapted second line therapies. Methods: To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts (Human Foreskin Fibroblasts-2, HFF2). MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinic schedule of administration consisting on three repetitions of treatments (one combination and two single treatments (paclitaxel or gemcitabine)). The impact of treatments was studied using cell viability assay, histology, 3’RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. Results: We showed that treatments induced a decrease of cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damages repair and the cell cycle. Interestingly, we also observed a modification of the expression of genes considered as hallmarks of response/resistance to immune check point inhibitors and immunogenicity and particularly an increase of CD274 gene expression, coding for PD-L1. This result was validated at the protein level and showed to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed on an additional cell line, expressing low basal level of CD274. These results are consistent with previous observations on patients showing higher PD-L1 tumoral expression after chemotherapy exposure. Conclusions: This study shows that MCTS could be interesting models to study the impact of first line therapies using conditions close to the clinical practice and then, to identify more adapted second line or concomitant therapies for the treatment of lung cancers.

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Dose intense triplet chemotherapy with gemcitabine, carboplatin, paclitaxel with peripheral blood progenitor cell support for six cycles in advanced epithelial ovarian cancer.

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