Taxane therapy

RTOG 9602 evaluated weekly paclitaxel and conventional radiotherapy for patients with GBM. Previous studies had shown taxanes to be potent radiosensitizers. Thirty-five evaluable patients were reported (49). With a median follow-up of 20 mo the overall median survival was 9.7 mo with median survival times for RPA classes II, IV, V, and VI being 16.3, 10.2, 9.5, and 2.5 mo, respectively. Median survival by RPA class with brief taxane therapy was comparable to RTOG historical controls treated with standard EBRT and BCNU (1-yr BCNU). Clinicopathologic evaluation did not disclose any cor-... 

Rizzo R, Spaggiari F, Indelli M et al (2010) Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients. Breast Cancer Res Treat 124 593-598... 

A364 -> T [116]. BMS-247550 has a potent tubulin polymerisation capacity (2,5 fold more potent as Taxol), a broad cytotoxicity (mean IC50 of 3.9 nM) and is efficacious in vivo after i.v. and p.o application [115]. A MTD with neutropenia as DLT (without G-CSF co-treatment) was determined and objective responses in breast and cervical cancer patients refractory to prior taxane therapy were observed [117]. In a clinical trial, the formation of microtubule bundles in peripheral blood mononuclear cells (PBMCs) was monitored and cell death occurred after peak microtubule bundle formation [118]. 

Capecitabine is a tumor-selective oral fluoropyrimidine. It has been approved by the FDA and NICE for the treatment of colorectal cancer in both the adjuvant and metastatic settings and for patients with breast cancer after anthracycline and taxane therapy [93 ,94 ]. It has also been approved by NICE for advanced gastric cancer as part of platinum-based therapy [95 ]. In a randomized phase III study of adjuvant capecitabine versus fluorouracil -I- leucovorin, efficacy was similar between the groups but grade 3/4 adverse reactions were significantly less common in those who were given capecitabine [96 ]. The starting dose is usually 1000-1250 m m bd for 14 days, followed by 7 days rest. 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-line therapy for MBC. Single agent capecitabine, vinorelbine, or gemcitabine have response rates of 20% to 25% when used after an anthracycline and a taxane (see Table 61-1). 

Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to progression were increased with combination therapy as compared with capecitabine alone. Adverse effects include myelosuppression, peripheral neuropathy, and myalgias/arthralgias. 

Caponigro F, Willemse P, Sorio R, Floquet A, van Belle S, Demol J, Tambaro R, Comandini A, Capriati A, Adank S, Wanders J. (2005) A phase II study of sabarubicin (MEN-10755) as second line therapy in patients with locally advanced or metastatic platinum/taxane resistant ovarian cancer. Invest New Drugs 23 85-89. 

Although taxanes bind to p-tubulin promoting microtubule polymerization and stabilization of the spindle complex, they serve to cause a sustained mitotic block at the metaphase/anaphase boundary. This block will occur at a lower concentration than that which is required to increase the microtubule mass (10). However, it is not completely clear how this interaction with microtubules translates into cell death. Morphologic features and the characteristic DNA fragmentation patterns seen in the setting of apoptosis have been documented in tumor cells after therapy with taxanes (10). These observations are accompanied by the phosphorylation of Bcl-2, an anti-apoptotic protein, changing the cellular balance between Bax and Bcl-2 to a status that favors apoptosis (11). 

Concurrent therapy for the treatment of more than three brain metastases using paclitaxel and radiation has been explored in a phase III trial (144). The hypothesis here being that high-dose paclitaxel in combination with cranial radiation should improve local control while providing systemically active amounts of chemotherapy. Unfortunately, there was no statically significant improvement in survival seen. There is certainly a place to further explore the benefits and toxicides experienced with concurrent taxane-based therapy with radiation in metastatic disease. The role of the taxanes in concurrent chemoradiotherapy with sarcomas and pediatric tumors has not been explored at this time. 

The success of taxane-based therapy in cancer treatment has stimulated interest in further improving its efficacy profile and in identifying new tubulin-active agents. Two taxane analogs, BMS-184476 and BMS-188797, demonstrate greater activity than paclitaxel or docetaxel in a number of human tumor cell lines as well as in rodent solid tumors and human xenografts (4,145). BMS-184476 was discovered to be more potent... 

The initial experience with the taxanes and especially with paclitaxel in the realm of combined modality therapy has had a substantial impact on the treatment of cancers both in the United States and worldwide. Paclitaxel delivered in concert with radiation provides a classical model of the development of clinically applicable treatment strategies from laboratory-based studies. The initial in vitro works of Tishler (39) and Choy (40) have translated in a very tangible way into approaches that are clinically applicable and in the next generation of randomized clinical trials their efficacy will be compared to more traditional chemotherapies in the combined modality setting. While the experience to date with both paclitaxel and docetaxel has been largely positive, the mortality rates in many of the solid tumor types remind us that much more needs to be done. 

Choy H. Taxanes in combined modality therapy for solid tumors. Crit Rev Oncol Hematol 2001 37(3) 237-247. 

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