The Emerging Role of Paclitaxel in Breast Cancer Therapy1
Total Page：16
File Type：pdf, Size：1020Kb
Vol. 1, 247-256, March 1995 Clinical Cancer Research 247 Minireview The Emerging Role of Paclitaxel in Breast Cancer Therapy1 Andrew D. Seidman2 overexpressing subline of MCF-7 cells appears to result in the Breast and Gynecological Oncology Service, Memorial Sloan- development of 4.4-fold less resistance (6). Furthermore, in Kettering Cancer Center, New York, New York 10021 paclitaxel-resistant cells, the ratio of soluble to polymerized tubulin is greater than that observed in sensitive cells (7). Introduction Ongoing investigation should clarify the relationship between Multiple chemotherapeutic agents and regimens exist with tubulin alterations and resistance to taxanes. documented antitumor activity against breast cancer; however, In parallel with the development of clinical trials of paclitaxel- less than one in five patients with stage IV breast cancer are alive based combination regimens, in vivo and in vitro studies have 5 years from the first detection of distant metastases (1). Although examined combinations for cytotoxicity in several systems. In vitro improved response proportions have been observed, overall sur- studies in human MCF-7 breast carcinoma cells exposed to a LD vival for patients with metastatic breast cancer has not been sig- of paclitaxel for 24 h followed by a 1-h incubation with varying nificantly improved by the progress of the past three decades. Furthermore, despite the proven magnitude of benefit of adjuvant concentrations of doxorubicin showed less than additive cytotox- icity for the combination of paclitaxel and doxorubicin (8). On the systemic therapy in reducing the risk of recurrence (2), a significant fraction of patients with early stage breast cancer still will relapse other hand, when an AlT cell viability assay was used, others have and ultimately die of metastatic disease. Clearly new active agents shown the combination of paclitaxel and doxorubicin to be partly and strategies are needed to improve upon this situation. synergistic in vitro (82). Clonogenic cell survival assays have The development of paclitaxel (Taxol#{174}), the prototype demonstrated maximum cytotoxicity in MCF-7 cells when expo- taxane, as an anticancer agent accelerated after the elucidation sure to alkylating agents precedes paclitaxel (9). In SKBR-3 human of its unique mechanism of action (3) and by the initial dem- breast adenocarcinoma cells, pretreatment with edatrexate, a new onstration of its activity in refractory advanced ovarian carci- dihydrofolate reductase inhibitor, before paclitaxel showed marked noma (4). Multidisciplinary efforts to procure sufficient quan- synergism in inhibiting cell growth, while the reverse schedule tities of this agent have allowed a rapid expansion of clinical showed antagonism (10). Synergy has also been reported in trials. This review will address the development of paclitaxel for MDA-MB 435 human breast cancer cells when gallium nitrate, a use in breast cancer, the clinical results noted thus far in the ribonucleotide reductase inhibitor, preceded paclitaxel (1 1), and treatment of metastatic disease, the design of presently ongoing similarly when tiazofurin, a C-nucleoside, was applied prior to trials, and examine avenues of future investigation. paclitaxel in the same cells (12). Others have reported preliminarily on similar sequence and schedule-dependent effects between pa- Predlinical Activity of Paditaxel against Breast Cancer clitaxel and fluorouracil (77), navelbine (78, 79), and estramustine Paclitaxel was chosen for development in part because of (80). While Phase I clinical trials of cytotoxic combinations are significant activity against the subrenally implanted human often empiric or based on in vitro studies such as those mentioned MX-1 mammary tumor xenograft (5). In this model, following above (76), computerized quantitation of synergism and antago- subrenal implantation in athymic mice, s.c. administration of nism of paclitaxel, topotecan, and cisplatin against human terato- paclitaxel (200 mg/kg) on days 1-10 resulted in mammary carcinoma cells may offer a rational alternative to clinical protocol tumor regression. In vitro studies suggest that phenotypic resis- design (81). This approach uses the combination index-isobolo- tance may relate in part to the duration of paclitaxel exposure (6, gram method and is based on the median effect principle which 27, 83). In in vitro studies using paclitaxel in DMSO, CHO and considers the potencies of each drug and combinations of drugs, as human A2780 cells were more responsive to increased exposure well as the shape of their dose-effect curves (81). time than to increased dose above plateau concentrations of With a greater understanding of autocrine and paracrine 0.8-1.6 sWml and 0.01 jig/ml, respectively. However, in four regulation of breast cancer cell proliferation and growth, novel human ovarian carcinoma cell lines treated with paclitaxel in treatment strategies are emerging (13). Synergistic cytotoxicity Cremophor EL, prolonging the duration of paclitaxel exposure has also been demonstrated for the combination of paclitaxel did not appear to increase cell kill or the fraction of cells in and mAbs directed against the her-2/neu receptor in BT-474 G2-M, suggesting that intracellular binding of paclitaxel to cells (which overexpress this receptor) and with the anti-EGFr3 microtubules is stable (84). In this study, there was a suggestion 528 in MDA-468 cells, which overexpress EGFr (14). that Cremophor EL at high concentrations may contribute to the cytotoxic response. With regard to breast carcinoma, prolonga- tion of paclitaxel exposure from 3 to 24 h in a P-glycoprotein 3 The abbreviations used are: EGFr, epidermal growth factor receptor; MSKCC, Memorial Sloan-Kettering Cancer Center; rhG-CSF, recombinant Received 1 1/14/94; accepted 12/22/94. human granulocyte-colony-stimulating factor; CR, complete response; G- t was supported by the American Society of Clinical Oncology Research CSF, granulocyte-colony-stimulating factor; EORTC, European Organiza- Career Development Award. tion for Research on Treatment of Cancer; ECOG, Eastern Cooperative 2 To whom requests for reprints should be addressed, at Breast and Oncology Group; mdr, multidrug resistant; CMFP, Cyclophosphamide- Gynecologic Oncology Service, Memorial Sloan-Kettering Cancer Cen- methotrexate-5-fluorouradil-prednizone; AFM, Adnamycin-5-fluoroura- ter, 1275 York Avenue, New York, NY 10021. cil-methotrexate. Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 1995 American Association for Cancer Research. 248 Emerging Role of Paclitaxel in Breast Cancer Therapy Paclitaxel in Patients with Minimal Prior progression or relapse within 6 months of prior chemotherapy. Chemotherapy Approximately one-third of patients had received only adjuvant chemotherapy, one-third had been treated with one regimen for Phase II Trials. Two initial Phase II clinical trials demon- metastatic disease only, and another third of patients had received strated the significant antitumor activity of paclitaxel in patients both. With 471 patients entered and 454 evaluable for response, who had received minimal prior chemotherapy. In 1991, Holmes et 29% of patients (65/225) responded at the higher dose level, with a!. (15) at M. D. Anderson Cancer Center reported a 56% (95% a 22% response rate (51/229) at the lower dose level (P = 0.108). confidence interval, 35-76%) response proportion in women re- The median time to progression for patients treated with 175 ceiving 200-250-mg/m2 doses via 24-h i.v. infusion every 3 weeks mg/m2 was 4.2 months versus 3.0 months with 135 mg/m2 (ad- as a second chemotherapy regimen (1 1 patients had prior chemo- justed relative risk, 1.34, P = 0.003, log rank P = 0.02). Treatment therapy for metastatic disease, 14 as adjuvant therapy). The median was well tolerated at both dose levels; with 175 mg/rn2, grade 4 response duration was 9 months, with a median time to progression neutropenia of short duration occurred in 27% of patients. Overall for all patients of 10 months. Granulocytopenia was dose limiting, the safety of 3-h pacitaxel infusions in this dose range was firmly but febrile neutropenia occurred in only 5% of 232 courses. A established in more than 2500 cycles of therapy, with a very low confirmatory trial at MSKCC studied the drug as first chemother- incidence of febrile neutropenia (<5% of patients), and a less than apy for stage IV disease in 28 patients (16, 17). rhG-CSF was 10% incidence of any grade 3-4 nonhematological toxicity. Sub- administered daily at 5 p.gfkg/day s.c. on days 3-10 to ameliorate sequent to this trial, in April 1994 the U.S. Food and Drug Ad- anticipated myelosuppression. Three complete and 13 partial re- ministration approved paclitaxel for use in metastatic breast cancer sponses were noted in 26 evaluable patients (62%; 95% confidence at 175 mg/m2 via 3-h infusion after failure of chemotherapy or interval, 41-80%) who received paclitaxel at 250 mg/m2 via 24-h relapse within 6 months of adjuvant chemotherapy. continuous i.v. infusion every 21 days. Responses were observed in visceral, osseous, and nodal/soft tissue sites of disease, including a Paclitaxel in Patients with Extensive Prior Therapy pathologically documented CR in recurrent disease in a previously After the observation of significant antitumor activity of irradiated chest wall site. Treatment was generally well tolerated, paclitaxel in women with stage IV breast cancer with minimal with only 4% of 178 treatment cycles resulting