Jean-Marc Nabholtz

Responsiveness of the EuroQol in breast cancer patients undergoing high dose chemotherapy

Objective: To assess the responsiveness of the EuroQol (EQ-5D) by comparing it with the Functional Living Index-Cancer (FLIC) and a self-reported rating of health-related quality of life (HRQL). Methods: HRQL was measured four times during the course of high dose chemotherapy (HDC) and bone marrow transplantation in 40 patients with stage II and III breast cancer. Measurements were at baseline (T1), pre-HDC (T2), 3 weeks post-HDC (T3), and 3 months post-HDC (T4). Results: Effect size ranged from 1.16 (T1–T3) to 0.66 (T3–T4) for the EQ-5D and 0.85–0.91 respectively for the FLIC. No significant differences in effect sizes between the EQ-5D and the FLIC were found. Repeated measures ANOVA yielded a significant change for all measures, with HRQL decreasing post-HDC and returning to baseline levels by 3 m post-HDC. EQ-5D dimensions changed significantly over time for mobility, self-care, and usual activities. EQ-5D index scores at T3 had a bimodal distribution. Interpretation of psychological changes was facilitated by an analysis of FLIC items. Conclusions: The EQ-5D is responsive to the clinically large changes associated with HDC in breast cancer patients. The bimodal distribution of the EQ-5D index has implications for the interpretation of EQ-5D change scores.

Docetaxel–Anthracycline Combinations in Metastatic Breast Cancer

The taxanes and anthracyclines have emerged as the most active agents for treating women with advanced breast cancer. As such, investigation of the two drug classes in combination regimens has been eagerly pursued. The rationale for combining docetaxel with an anthracycline includes high clinical activity of each individual agent, lack of complete clinical cross resistance, and non-overlapping toxicity profiles. Phase II trials of the docetaxel combinations with either doxorubicin or epirubicin showed high activity, with acceptable tolerability in patients with metastatic breast cancer. Consequently, three randomized trials have compared docetaxel–anthracycline-based regimens with standard anthracycline-based polychemotherapies as first-line therapy for women with advanced breast cancer. Improved outcome was reported in favor of the docetaxel–anthracycline combinations, with manageable hematologic toxicity and favorable non-hematologic safety profiles. Therefore, docetaxel–anthracycline combinations represent a validated option in first-line treatment for women with advanced breast cancer, and are further evaluated as adjuvant treatment for early stage breast cancer, with already promising prospects and the potential to change the natural history of breast cancer.

New adjuvant strategies for breast cancer: Meeting the challenge of integrating chemotherapy and trastuzumab (Herceptin)

Improvements in breast cancer treatment will arrive with better understanding of its biology and through biologically oriented therapeutic interventions as well as better identification of patient populations susceptible to benefit from classical therapies (endocrine and chemotherapy). Among the new chemotherapies, the taxanes have emerged as powerful agents in the treatment of metastatic breast cancer and a strong emphasis has been pursued into their development in the adjuvant setting. Two generations of adjuvant pivotal trials with taxanes have been developed. The first generation compared taxane/anthracycline regimens to nontaxane combinations or sequence regimens. The second generation of trials is presently being performed and contains taxanes in both arms, comparing their use in combination or in sequence. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is the first biologic modifier with significant activity in advanced breast cancer patients amplifying the HER2 gene. As a consequence of these results, including improved survival in the metastatic setting, this agent has been very quickly considered for adjuvant development. However, the significant cardiac toxicity observed with trastuzumab/anthracycline combinations has led to two main strategies for integrating trastuzumab in the adjuvant setting: (1) addition of trastuzumab to mostly anthracycline-based programs (sequential approach); and (2) biology-oriented strategy based on synergism between trastuzumab and chemotherapy agents. Large-scale clinical research programs are presently being developed and will create a challenge for clinical researchers. The adequate scientific hypothesis, related to the pivotal studies of trastuzumab in the adjuvant setting, require large sample sizes (several thousand patients) and a very strict selection of the patient population (tumors amplifying the HER2 gene). Success in a timely fashion requires global collaboration, dedication to high-standard clinical research, and awareness of all available protocols by oncologists and patients with breast cancer.

Combination chemotherapy for metastatic breast cancer

Despite more than four decades of effort, the improvement in survival in metastatic breast cancer has been modest. Recently, however, new drugs such as the taxanes have emerged as pivotal agents in the treatment of metastatic disease and they are now being investigated in the adjuvant setting. In addition, the introduction of molecularly targeted therapies such as trastuzumab provides a new paradigm for the development of biologic treatments. The incorporation of trastuzumab into new combination regimens based on potential molecular synergies is a focus of current research.