Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5-13+ months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%-76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no allergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).
Background:We recently reported that the GHI Recurrence score (GHI-RS) provided additional information regarding distant recurrence beyond that obtained from classical clinical factors (age, nodal status, tumour size, grade, randomised treatment) in 1231 patients with ER+ primary breast cancer in the ATAC trial who did not receive chemotherapy and were randomized between anastrozole vs. tamoxifen (Dowsett et al, SABCS 2008). Here we develop a score based on 4 standard laboratory assays (IHC4 score) and compare its prognostic value to that of the GHI-RS.Methods:Quantitative IHC scores were obtained for ER, PgR, and Ki67, and HER2 was scored as positive/negative in 1125 of those women from TransATAC for whom the GHI-RS and sections were available; 793 of those women were node negative. An IHC4 score was obtained by a proportional hazards regression using classical variables and the 4 IHC values. This was done separately for all patients and node negative patients for recurrence (TTR) and distant recurrence (TTDR), but the scores were very similar (pairwise correlation ρ > 0.93). The data set was then split at random into two equal parts. Models were created on each half with the classical and IHC4 variables to create an IHC4 score, which was then applied to the other half (validation) and compared with the GHI-RS. Results were summarized by likelihood ratio (LR) χ2 test which combined results from the two halves. This was repeated for 100 random splits of the data.Results: Each of the 4 IHC variables added significantly to a model containing the classical variables and the overall model was highly significant (χ2(4df)=34.9, P < 0.0001, for TTDR on all pts). Of the 4 variables PgR was the most predictive for all patients. When restricted to node negative patients, ER and HER2 were jointly the strongest predictors.The IHC4 score was modestly correlated with GHI-RS (ρ=0.70), and in sample splitting evaluations provided a similar amount of information as the GHI-RS score (GHI-RS slightly more for TTR and IHC4 slightly more for TTDR, see Table).Mean change in LR χ2 for addition of IHC4 or GHI-RS or both to classic model (C) in the validation halves of 100 random splits of the data. Higher values indicate more information. TTRTTDRModelAll PatientsNode Neg.All PatientsNode Neg.C+IHC4 vs C (1df)19.721.226.926.6C+GHI-RS vs C (1df)26.725.625.619.4C+IHC4+GHI-RS vs C (2df)30.029.932.529.7The predicted 9y distant recurrence proportion for an No, T<2cm, poorly differentiated tumour receiving anastrozole at either the 25th or 75th percentile of each score was 6.7% vs 12.3% for IHC4 and 7.8% vs 11.2% for GHI-RS.None of these variables provided predictive information regarding the choice between tamoxifen or anastrozole.Conclusion:These data suggest that 4 standard IHC assays performed in a high quality laboratory can provide similar amounts of prognostic information for endocrine treated ER+ breast cancer patients as the GHI-RS. External validation in another data set is needed to confirm these results.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 74.
The combination of paclitaxel/24 hours with doxorubicin/48 hours is an effective antineoplastic treatment for metastatic breast cancer. However, the incidence of complete response, the median overall survival, and time to progression were not greater than for standard doxorubicin-based combinations. Additionally, a sequence-dependent interaction between paclitaxel and doxorubicin, given in the schedule described here, was defined. Other strategies and schedules should be evaluated to maximize the antineoplastic efficacy of these two potent agents.
To test the hypothesis of whether high doses of chemotherapy in combination achieve higher response rates and longer durations of response and survival, we treated 33 pre- and perimenopausal patients with good performance status in a prospective trial with escalating doses of fluorouracil, doxorubicin and cyclophosphamide (FAC). Patients were randomly assigned to be treated within a protected environment (laminar air flow room), with prophylactic antibiotics, or in a standard hospital room. Important patient characteristics were equally distributed in the two treatment arms. A major objective response was observed in 27 of the 32 evaluable patients (84%), and 11 (34%) achieved a complete remission (CR). There was no significant difference in overall and complete response rates between the two treatment arms, nor was there a substantial difference in times to progression or survival between the groups treated in or out of the protected environment. Comparison of the results of this study with previously reported programs of FAC chemotherapy in patients with metastatic breast cancer shows that this study achieved higher overall and complete response rates. However, neither the time to progression, nor the survival of responders or the entire patient group was different from our previous experience with standard FAC chemotherapy. When the study was initiated in 1976, the proposed dose escalation represented high-dose chemotherapy. In retrospect, even the "high" doses used in this study represent only a modest increase over standard doses of chemotherapy. Much steeper dose escalations will be needed to evaluate the efficacy of high-dose chemotherapy in breast cancer, as well as the protective value of the protected environment and prophylactic antibiotics in metastatic breast cancer.
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