Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as “state-of-the art” treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLC D-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials. [ONCOLOGY 13(5):647-658:1999]
Breast cancer is the most frequently diagnosed cancer in American women, and the second most common cause of cancer death. Over the past several decades, there has been a fairly steady increase in the incidence of the disease. Epidemiologic data from the United States analyzed between 1988 and 1990 indicate that the lifetime risk of developing breast cancer is 12.2%, or, stated in another way, one in eight women will develop the disease at some point during her life.
Although approximately 80% of breast cancer patients present with disease limited to the breast and/or axillary lymph nodes, almost half of these patients later develop metastatic disease and eventually succumb to it. Metastatic breast cancer represents a historically incurable condition despite the judicious use of various hormonal manipulations, as well as surgical and radiotherapeutic interventions, and the application of active cytotoxic chemotherapeutic agents for hormone-refractory disease. For most patients with metastatic disease, treatment provides only temporary control of cancer growth. Outside of experimental protocols, the goals of management, therefore, are to palliate symptoms with as little treatment-related toxicity as possible and to extend the duration of high-quality life.
Metastatic breast cancer is moderately sensitive to chemotherapy, with 25% to 40% of patients achieving a partial or, less commonly, complete response to single-agent therapy; the duration of such responses averages 6 months. Historically, the most commonly used cytotoxic agents in the management of metastatic breast cancer have been cyclophosphamide (Cytoxan, Neosar), methotrexate, fluorouracil, doxorubicin, and, more recently, the taxanes. When the disease progresses further, vinorelbine (Navelbine) and other vinca alkaloids, mitomycin (Mutamycin), mitoxantrone (Novantrone), gemcitabine (Gemzar), etoposide, and cisplatin (Platinol) represent some of the other frequently used cytotoxic drugs.
Combinations of two, three, or more chemotherapeutic agents are occasionally employed based on preclinical data suggesting improved antitumor activity (ie, additive or synergistic effects); many of these combinations are derived empirically, however. Although combination regimens may sometimes yield higher response proportions than single-agent therapy, this can occur at the cost of greater toxicity, perhaps resulting in an overall lower therapeutic index. This issue was specifically addressed by two studies presented at the 34th annual meeting of the American Society of Clinical Oncology (ASCO) in 1998.
The first study, conducted by the Finnish Breast Cancer Group, randomized 303 breast cancer patients with distant metastases to one of two regimens: (1) single-agent chemotherapy with epirubicin (20 mg/m² weekly until disease progression or a cumulative dose of 1,000 mg/m²), followed by mitomycin (8 mg/m² every 4 weeks) as second-line therapy; or (2) the CEF polychemotherapy regimen, consisting of cyclophosphamide (500 mg/m²), epirubicin (60 mg/m²), and fluorouracil (500 mg/m²) every 3 weeks, followed by mitomycin (8 mg/m²) and vinblastine (6 mg/m²) every 4 weeks. Although responses to CEF tended to last modestly longer than responses to epirubicin alone (median duration, 12 vs 10.5 months; P = .07), no significant difference in time to progression (P =.28) or overall survival (P = .65) was found between the two arms.
Moreover, no difference in survival was seen when only the patients who received both the first- and second-line treatments were compared (P = .96), or when survival was calculated from the beginning of second-line therapy (P = .56). Single-agent therapy was also associated with less toxicity and better quality of life.
The second report, presented by the International Taxotere 304 Study Group, described the results of a phase III study comparing single-agent docetaxel (Taxotere) therapy vs the combination of mitomycin and vinblastine in patients with metastatic breast cancer whose disease had progressed following an anthracycline-containing regimen. In this experience, single-agent docetaxel therapy proved more effective than mitomycin plus vinblastine, not only with respect to response rate and time to treatment failure, but, most gratifyingly, with regard to survival. Median survival duration was 11.4 months in the docetaxel group vs 8.7 months in the mitomycin-vinblastine group (P = .0097).
In this context, the experience of Sledge and colleagues, reported at the 1997 ASCO meeting, should be considered. In that study, Eastern Cooperative Oncology Group Study (ECOG) 1193, single-agent therapy with either doxorubicin or paclitaxel (Taxol) was compared with the combination of doxorubicin and paclitaxel as first-line therapy in 739 patients with metastatic breast cancer. Patients receiving single-agent therapy were crossed over to the other agent at the time of disease progression.
Monotherapy with either doxorubicin or paclitaxel had equivalent therapeutic activity; the combination of the two drugs resulted in superior overall response rate and time to treatment failure. Despite this, combination therapy was not superior to sequential single-agent therapy with regard to overall survival and quality of life.
Taken together, these trials should prompt a reconsideration of the conventional wisdom that combination chemotherapy is the “gold standard” for the treatment of metastatic breast cancer.
Ultimately, the treatment of stage IV breast cancer often represents an attempt to reach an equilibrium between the palliation conferred by response to therapy, on the one hand, and treatment-related toxicity, on the other.
Thus, the issue of the value of dose intensification is of utmost importance, since increased doses are commonly associated with greater toxicity.
A trial of the Italian group Gruppo Oncologico Nord-Ouest (GONO), reported at ASCO 1998 by Lionetto et al, is instructive in this regard. This trial randomized patients to receive either standard doses of CEF or the same regimen in an intensified manner with growth factor support; patients in the “intensified CEF” arm actually received an 80% increase in dose intensity compared to those in the standard CEF arm. Quality of life was also assessed.
In the 151 randomized patients, no differences between the two arms were observed with respect to response rates or progression-free survival. However, the intensified regimen was associated with more toxicity. Grade 3 and 4 events were more frequent with intensified CEF than with the standard regimen (anemia, 18% vs 3%; leukopenia, 26% vs 6%; thrombocytopenia, 8% vs 2%; and mucositis, 13% vs 3%).
High-Dose Chemotherapy With Stem-Cell Support
Regarding dose escalation, the potential role of high-dose chemotherapy with stem-cell rescue still awaits definition. Although some authors have reported 5-year disease-free survival proportions of approximately 20% in selected patients treated with such regimens,[9,10] to date there has been no demonstration of clear superiority of high-dose consolidation over other strategies in the management of stage IV breast cancer.
Most studies of high-dose chemotherapy have been uncontrolled phase I and II trials, often accompanied by the irresistible, but problematic and unfortunate, comparisons with historical controls. Moreover, the inherent bias of patient selection for these trials has also been an issue. The first reported randomized trial of standard chemotherapy vs high-dose chemotherapy with either autologous bone marrow or peripheral blood stem-cell support, conducted by Bezwoda et al, showed that high-dose therapy significantly extended the durations of response and survival. However, the median follow-up was only 72 weeks, the study was small, and the standard-dose chemotherapy arm has been criticized for being suboptimal.
At the 1998 ASCO meeting, several presentations evaluated different transplant modalities, ie, single vs tandem high-dose chemotherapy, tandem vs triple high-dose chemotherapy, and purging of tumor cells from peripheral blood stem cells.[12,13] The exploratory nature of these trials and preliminary results underscore the need for large, prospective clinical trials to address these questions.
On the basis of the limited data available to date from randomized, prospective trials, high-dose chemotherapy cannot yet be considered “state-of-the-art” treatment for advanced breast cancer and should be offered only to patients in the setting of clinical trials. The final results of such large prospective trials are eagerly awaited (Table 1).
If multiagent chemotherapy and dose escalation prove to be suboptimal in conferring a consistent survival advantage in metastatic breast cancer, other strategies must be pursued. These include the development of newer active drugs, or the exploration of different alternatives, for example, biological therapies.
The taxanes, ie, paclitaxel and docetaxel, are a relatively new addition to the chemotherapeutic arsenal against breast cancer. Their mechanism of action involves the formation of polymerized microtubules and their stabilization against the forces that lead to depolymerization. Proapoptotic effects, as well as antiangiogenic actions, may also be clinically relevant.[14,15]
The determination of optimal dosing and scheduling of taxanes has been an important objective during their development. While the clinical development of docetaxel has largely involved a single administration schedule (1-hour infusion) and a narrow dose range (60 to 100 mg/m²), the range of paclitaxel doses and schedules has been broader (varying from 80 to 250 mg/m² infused over 1 hour weekly to 3-, 24-, or even 96-hour infusions every 3 weeks).
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