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Paclitaxel, Vinorelbine and 5-Fluorouracil in Breast Cancer Patients Pretreated with Adjuvant Anthracyclines

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Paclitaxel, Vinorelbine and 5-Fluorouracil in Breast Cancer Patients Pretreated with Adjuvant Anthracyclines British Journal of Cancer (2005) 92, 634 – 638 & 2005 Cancer Research UK All rights reserved 0007 – 0920/05 $30.00 www.bjcancer.com Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines Clinical Studies 1 1 1 2 2 2 3 3 A Berruti , R Bitossi , G Gorzegno , A Bottini , D Generali , M Milani , D Katsaros , IA Rigault de la Longrais , 3 4 4 4 5 6 6 7 R Bellino , M Donadio , M Ardine , O Bertetto , S Danese , MG Sarobba , A Farris , V Lorusso and ,1 L Dogliotti* 1Oncologia Medica, Azienda Ospedaliera San Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy; 2Breast Unit, Azienda Ospedaliera Istituti Ospitalieri, largo Priori, 26100 Cremona, Italy; 3Ginecologia Oncologica, Azienda Ospedaliera OIRM Sant’Anna, via Ventimiglia 3, 10126 Torino, Italy; 4 Oncologia Medica, Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera San Giovanni Battista Molinette, corso Bramante 88, 10126 Torino, 5 6 Italy; Ginecologia Divisione A, Azienda Ospedaliera OIRM Sant’Anna, corso Spezia 60, 10126 Torino, Italy; Oncologia Medica, Istituto Clinica Medica 7 Universitaria, via San Pietro 8, 07100 Sassari, Italy; Oncologia Medica, Istituto Oncologico, via Amendola 209, 70126 Bari, Italy We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant À2 À2 anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m on days 1 and 15, PTX 60 mg m on days 1, 8 À2 and 15 and continuous infusion of 5-FU at 200 mg m every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable. British Journal of Cancer (2005) 92, 634–638. doi:10.1038/sj.bjc.6602335 www.bjcancer.com Published online 25 January 2005 & 2005 Cancer Research UK Keywords: breast cancer; metastatic disease; paclitaxel; vinorelbine; 5-fluorouracil Breast cancer is the most commonly diagnosed cancer and remains blocking the cells in the G2/M phase of the cell cycle (Manfredi and the first cause of cancer-related death in women in Italy (Negri Horwitz, 1984). The combination of vinorelbine and paclitaxel is et al, 2001). In the management of patients with metastatic disease, thought to create a total microtubule poison that offers theoretical chemotherapy may offer effective palliation, and anthracyclines advantages deriving from the potential synergy between the two are widely recognised as the most active drugs (Esteva et al, 2001; drugs when given together. Preclinical data have shown that Crown et al, 2002). The widespread use of these agents in the paclitaxel and vinorelbine were synergistic in vitro (Photiou et al, adjuvant setting, however, limits their employment in disease 1997; Budman et al, 2000), while in vivo their combination recurrence, thus demanding the testing of new effective regimens. produced a significantly greater proportion of cell kill of In the past decade, vinorelbine and taxanes have been shown to transplanted p388 murine leukaemia cells than either agent alone generate a consistent level of activity in advanced breast cancer, (Knick et al, 1995). The combination of paclitaxel and vinorelbine yielding as single agents overall response rates between 30.0 and has been evaluated in a number of phase I and II trials. As a whole, 50.0% along with acceptable toxicity profiles. Both drugs were the results have been encouraging, with an overall response rate demonstrated to be relatively non-crossresistant to anthracyclines between 47.4 and 67.0% (Martin et al, 1998; Tortoriello et al, 1998; (Esteva et al, 2001; Crown et al, 2002). Culine et al, 1999; Ellis et al, 1999; Romero Acuna et al, 1999; Vici Vinorelbine blocks the formation of the mitotic spindle et al, 2000; Ibrahim et al, 2001; Ballestrero et al, 2003). apparatus at the metaphase by inhibiting microtubule assembly Fluoropyrimidines, and 5-fluorouracil (5-FU) in particular, have (Fellous et al, 1989). Conversely, paclitaxel promotes and stabilises been employed for over 40 years to treat numerous solid tumours polymerised tubulin into nonfunctional microtubule bundles, thus including breast cancer (Venturini, 2002). Fluorouracil is an S- phase-specific agent with a short serum half-life of 10–20 min, making it active only against a small proportion of tumour cells in *Correspondence: Professor L Dogliotti; E-mail: [email protected] the S phase when administered via short intravenous bolus Received 20 July 2004; revised 22 November 2004; accepted 25 injection. When it is given over an extended period of time, the November 2004; published online 25 January 2005 resulting greater number of actively dividing cells exposed to the Chemotherapy in metastatic breast cancer A Berruti et al 635 drug warrants the administration of 5-FU as a continuous infusion patients had a central venous access. All drugs were administered (Cameron et al, 1994; Regazzoni et al, 1996). In addition, due to on an outpatient basis. Since preclinical data suggested that the the modified plasma concentration profile, large cumulative sequence of administration of paclitaxel and vinorelbine was fluorouracil doses administered via continuous infusion are better predictive for treatment efficacy (Photiou et al, 1997; Budman et al, tolerated than bolus injection (Cameron et al, 1994; Regazzoni et al, 2000), vinorelbine infusion preceded paclitaxel infusion. Dose 1996). The moderate myelotoxicity of infusional 5-FU allows its modifications were performed as follows: in case of myelosuppres- combination with other myelotoxic agents. The theoretical sion, if the WBC count was p2500 mlÀ1 and/or the platelet count advantages of the association of infusional 5-FU with paclitaxel was less than 100 000 mlÀ1, then 5-FU was continued but both and vinorelbine include (1) 5-FU has a different mechanism of paclitaxel and vinorelbine at that day were omitted. If the blood cytotoxicity, (2) its proposed mechanism of resistance is different count had recovered after 1 week, full-dose vinorelbine and and (3) it possesses relatively nonoverlapping toxicity. The paclitaxel were then administered. If the blood count had not therapeutic activity of fluorouracil combined with vinorelbine or recovered, then both vinorelbine and paclitaxel were further paclitaxel in metastatic breast cancer has been widely tested, and omitted, and the drug dose was subsequently reduced by 25%. In high response rates (up to 70.0% as a first-line approach) have the event of hand and foot syndrome, for mild to moderate been reported (Vredenburgh et al, 1998). To our knowledge, the palmoplantar erythema (dryness and erythema with pain), patients association of protracted infusion of 5-FU with both vinorelbine continued 5-FU; for severe palmoplantar erythema with blistering and paclitaxel has never been tested. In a phase II trial we and desquamation, 5-FU was interrupted until the erythema had conducted, biweekly vinorelbine associated with protracted 5-FU returned to grade 1 or less, and afterwards 5-FU was restarted at infusion was found to be extremely active as a second- or third-line full doses. For WHO grade 1 or 2 diarrhoea, antidiarrhoeal agents approach in advanced breast cancer patients previously treated were prescribed; for persistent diarrhoea, 5-FU, but not vinor- with anthracyclines (Berruti et al, 2000). In view of these elbine or paclitaxel, was discontinued for 1 week. In case of Clinical Studies encouraging results, we tested this combination in association resolution, 5-FU was restarted at full doses; if symptoms persisted, with paclitaxel as first-line treatment in advanced breast cancer a 25% dose reduction was performed. For grade 3 or 4 diarrhoea, patients pretreated in adjuvant setting with anthracycline-contain- 5-FU was withdrawn until the diarrhoea had returned to grade 1 or ing regimens. The primary aim of the study was to evaluate the less, and afterwards 5-FU was restarted with a 50% reduction in activity of the combination regimen; the secondary aim was to dosage. In patients with grade 2 mucositis, infusional 5-FU was assess toxicity, time to progression (TTP) and overall survival stopped for 1 week, then restarted at full doses; if symptoms (OS). recurred, a 25% dose reduction was performed. For grade 3 or 4 mucositis, 5-FU was withdrawn until complete resolution (grade 0) and restarted with a 25% reduction in dosage. Vinorelbine and PATIENTS AND METHODS paclitaxel doses were delayed for 1 week in case of grade 2 neurotoxicity; in the event of grade 3 neurotoxicity, vinorelbine Patients was reduced by 50% in subsequent cycles, whereas paclitaxel was withdrawn. Women, 18 years of age or older, were eligible for the study if they Relative dose intensity was defined as the actual weekly doses of had histologically confirmed advanced breast cancer and disease vinorelbine, paclitaxel and 5-FU at the end of treatment divided by assessable according to the World Health Organization (WHO) the planned weekly dose. Supportive care could include blood criteria of disease response (22). Other eligibility criteria included transfusion and administration of analgesics, antiemetics and good performance status (WHO grade 0–1), adequate bone growth factors as appropriate.
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