Constance Cirrincione

PURPOSE: Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. PATIENTS AND METHODS: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. RESULTS: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. CONCLUSION: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

PURPOSE: This study was designed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a standard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival. PATIENTS AND METHODS: After surgical treatment, 3,121 women with operable breast cancer and involved lymph nodes were randomly assigned to receive a combination of cyclophosphamide (C), 600 mg/m(2), with one of three doses of doxorubicin (A), 60, 75, or 90 mg/m(2), for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2). Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. RESULTS: There was no evidence of a doxorubicin dose effect. At 5 years, disease-free survival was 69%, 66%, and 67% for patients randomly assigned to 60, 75, and 90 mg/m(2), respectively. The hazard reductions from adding paclitaxel to CA were 17% for recurrence (adjusted Wald chi(2) P =.0023; unadjusted Wilcoxon P =.0011) and 18% for death (adjusted P =.0064; unadjusted P =.0098). At 5 years, the disease-free survival (+/- SE) was 65% (+/- 1) and 70% (+/- 1), and overall survival was 77% (+/- 1) and 80% (+/- 1) after CA alone or CA plus paclitaxel, respectively. The effects of adding paclitaxel were not significantly different in subsets defined by the protocol, but in an unplanned subset analysis, the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 (95% confidence interval, 0.59 to 0.86) for those with estrogen receptor-negative tumors and only 0.91 (95% confidence interval, 0.78 to 1.07) for patients with estrogen receptor-positive tumors, almost all of whom received adjuvant tamoxifen. The additional toxicity from adding four cycles of paclitaxel was generally modest. CONCLUSION: The addition of four cycles of paclitaxel after the completion of a standard course of CA improves the disease-free and overall survival of patients with early breast cancer.

PURPOSE: To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer. PATIENTS AND METHODS: Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) -positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastasis, and overall survival (OS). RESULTS: Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer-specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. CONCLUSION: With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.

BACKGROUND: In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. METHODS: Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival. RESULTS: The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone. CONCLUSIONS: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer.

PURPOSE: One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. PATIENTS AND METHODS: Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. RESULTS: Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. CONCLUSION: In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.