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Paclitaxel is the prototype of a new class of chemotherapeutic agents with an antimitotic effect that is related to its ability to interfere with the microtubule system. It causes peripheral neurological toxicity by means of its activity on the axonal microtubules. To define the clinical and neurophysiological characteristics of paclitaxel neuropathy 23 patients undergoing paclitaxel therapy at a dose of 175 mg/m2 were studied. The patients were divided into two groups, with only one group receiving pretreatment with potentially neurotoxic drugs such as cisplatin and carboplatin. The results showed a high incidence of mild neurotoxicity in both groups. Treatment was discontinued due to severe neurotoxicity in only one patient pretreated with platinum-compounds. The clinical and neurophysiological data make it possible to define paclitaxel neurotoxicity as a distal axonal neuropathy with a summatory effect in patients pretreated with cisplatin; the possible reversibility of paclitaxel neurotoxicity requires further confirmation.

Background: The aim of this study was to perform an independent review of the efficacy data and to determine whether the efficacy difference observed in a phase III randomised clinical trial that compared doxorubicin plus paclitaxel (AT) versus fluorouracil/doxorubicin/cyclophosphamide (FAC) in first-line chemotherapy of metastatic breast cancer was maintained after a longer follow-up period. Material and Methods: A blinded independent review of original radiological images and original case report forms (CRFs) was conducted by an expert radiologist and an expert medical oncologist, respectively. The analysis of the updated data included time to progression (TTP) and overall survival (OS). Results: CRFs for all 267 patients randomised in the study were available for medical review. The results of the independent review were consistent with the original analysis. At a median follow-up of 69 months, the difference in median TTP and OS in favour of the AT arm remained significant (median TTP 8.1 vs. 6.2 months, (p = 0.036); OS 23.0 vs. 18.3 months, (p = 0.005), respectively). Conclusions: This blinded independent review and analysis of updated data confirmed the advantage for AT over FAC with regard to TTP and OS in patients with metastatic breast cancer.

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Patients with CML in lymphoid blast crisis (LBC-CML) or advanced Ph+ ALL have an unsatisfactory and only brief response to imatinib mesylate (IM). Moreover, treatment options in pts who failed IM are extremely limited. Dasatinib (BMS-354825) is a novel, oral kinase inhibitor that targets BCR-ABL and SRC kinases, and has shown promising clinical activity in a Phase I dose escalating study in patients with BCR-ABL-positive leukemias. Between January 2005 and June 2005, 77 pts (42 CML-LBC and 35 Ph+ ALL) who had failed IM-based therapy were enrolled in this multinational Phase II study investigating the safety and efficacy of dasatinib. This preliminary analysis summarizes data on the first 28 pts accrued (13 CML-LBC and 15 Ph+ ALL) who were accrued prior to March 20, 2005. Dasatinib was administered orally at 70 mg twice daily (BID) on a continuous daily dosing schedule; dose escalation to 100 mg BID or dose reduction to 50 mg and 40 mg BID were allowed for poor initial response or persistent toxicity, respectively. Complete blood counts were performed weekly and bone marrow evaluation, including cytogenetic analysis, was scheduled every month. Mutation analyses were performed in all pts. 27 pts were IM resistant and 1 was IM intolerant; 17 (61%) pts had received prior IM doses >600 mg/day, 13 (46%) pts received IM for <1 year and 12 pts (43%) previously underwent stem cell transplantation. Response on prior IM regimen included complete hematologic response (CHR) in 19 (68%) pts and major cytogenetic response (MCyR) in 11 (39%) pts. Median time from leukemia diagnosis was 16.6 months (range 4.9–101.6). Median age was 44 years (range 20–84) and 61% of pts were male. At baseline, median platelet count was 37 x 103/mm3 (range 7–360) with median peripheral blood blasts of 35% (range 0–90) and median blasts in bone marrow of 81% (1–100). Dasatinib doses were escalated in 8 (29%) pts and 3 (11%) pts required dose reduction. 13 pts had a major hematologic response (7 CHR and 6 no evidence of leukemia, [CHR without complete recovery of PMN or platelets]) and 12 pts had a cytogenetic response within 1–3 months (11 complete and 1 minor). 9/13 pts (69% of responding pts) maintained their response after a median follow-up of 14+ weeks (range 10+ - 24+). Complete clearing of extramedullary sites was documented. Analysis of molecular response is ongoing. The majority of pts had grade 3 or 4 myelosuppression, which was pre-existing in most cases (63% with grade 3–4 neutropenia and 58% with grade 3–4 thrombocytopenia had the same grade at study entry); PMN <500/mm3 in 64% of pts and platelets <25 x 103/mm3 in 71% of pts. Non-hematologic toxicities included grade 1 and 2 peripheral edema (3 pts) and grade 1 facial edema (2 pts). GI intolerance was infrequent. In conclusion, dasatinib has significant and clinically meaningful efficacy in this heavily pretreated population of LBC-CML and Ph+ ALL pts with acquired resistance to imatinib. Updated data on all 77 patients with a minimum of 6 months’ follow-up will be presented.