Danika Lew

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

BACKGROUND Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. METHODS We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. FINDINGS Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. INTERPRETATION Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. FUNDING National Cancer Institute (US National Institutes of Health).The most common presentation of breast cancer is an estrogen receptor-positive (ER+) tumor in postmenopausal women, for whom tamoxifen is the gold standard against which other systemic adjuvant treatments are compared.(1–4) Whether to add chemotherapy to endocrine therapy is attractive in theory(5), but there is no consensus regarding such treatment in postmenopausal women with tamoxifen-responsive disease.(3,4) Individual phase III trials that compared chemotherapy plus tamoxifen versus tamoxifen alone did not show a significant survival benefit in older women.(6–9) A recent meta-analysis of all existing trials based on individual patient data found that the addition of chemotherapy to tamoxifen is only marginally beneficial in older women, in contrast to major survival improvements in premenopausal populations (see Figure 4, reference 10 for the EBCTCG metaanalysis) Figure 4 Southwest Oncology Group trial SWOG-8814 (North American Breast Intergroup 0100) forest plots of hazard ratios and 95% confidence intervals for major subsets for disease-free survival. Panel A describes the disease-free survival advantage for chemotherapy ... Most individual trials in postmenopausal women tested the addition of regimens based on cyclophosphamide, methotrexate and 5-fluorouracil (CMF) to tamoxifen(3,4, 6–8, 10), but in certain breast cancer study populations, CMF may be inferior to anthracycline-based regimens(11–16). No clinical trials have shown, however, that anthracycline-based therapy adds to the benefit of tamoxifen specifically in postmenopausal patients with ER+ disease. Moreover, interference with drug-induced cytotoxicity has been found in vitro when tamoxifen is added to cancer cell lines concurrently with chemotherapy(17–20), yet concurrent tamoxifen and CMF has been a common practice in clinical trials. Our two objectives were to determine if chemotherapy, consisting of 6 months of cyclophosphamide, doxorubicin (AdriamycinR), and 5-fluorouracil (CAF) plus 5 years of tamoxifen, was superior to tamoxifen alone; and to assess if CAF followed by tamoxifen was better than CAF plus concurrent tamoxifen. The CAF program we used was the most dose-intense combination among the commonly used regimens when this trial was designed.(11) This report presents 10-year outcomes for both objectives.

Southwest Oncology Group Study of Paclitaxel and Carboplatin for Advanced Transitional-Cell Carcinoma: The Importance of Survival as a Clinical Trial End Point

PURPOSE The combination of paclitaxel and carboplatin for the treatment of advanced transitional-cell carcinoma (TCC) of the urothelium has promising activity and acceptable toxicity. The purpose of this trial was to evaluate the efficacy of this regimen in a cooperative group setting. PATIENTS AND METHODS Twenty-nine patients with advanced TCC were treated every 21 days with paclitaxel 200 mg/m(2), administered as a 3-hour infusion, followed by carboplatin dosed to an area under the curve of 5. Prior systemic adjuvant or neoadjuvant platinum-based therapy was not permitted unless completed at least 1 year before enrollment. Patients were evaluated for response every three cycles, and follow-up was conducted to determine survival. RESULTS Twenty-nine patients were enrolled and were assessable. Four (14%) had received prior adjuvant or neoadjuvant therapy. Node-only disease was present in 24%, and 76% of patients had extranodal disease. The median number of cycles received was five. Grade 4 toxicity consisted primarily of neutropenia (38% of patients). Neurologic toxicity was noted in 16 patients (grade 1 in four patients, grade 2 in five patients, grade 3 in six patients, and grade 4 in one patient). Six partial responses and no complete responses were noted, for a response proportion of 20.7% (95% confidence interval, 8% to 40%). Median progression-free survival time was 4 months, and overall survival time was 9 months. CONCLUSION The combination of paclitaxel and carboplatin for the treatment of advanced TCC is reasonably well tolerated. However, a response proportion considerably lower than that previously reported was noted. In addition, the median survival time of 9 months was less than the survival time previously reported for patients treated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. Although our results may reflect enrollment of patients with poor prognostic features, they also call into question the utility of this regimen.

Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil With and Without Tamoxifen for High-Risk, Node-Negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102

PURPOSE We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status. PATIENTS AND METHODS Node-negative patients identified by tumor size (> 2 cm), negative HR, or high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF + TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned comparisons were calculated. RESULTS Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for HR-negative patients (DFS, HR = 0.81 for no TAM v TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05). CONCLUSION CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive disease, but not in HR-negative disease.

Phase III Comparison of Standard Doxorubicin and Cyclophosphamide Versus Weekly Doxorubicin and Daily Oral Cyclophosphamide Plus Granulocyte Colony-Stimulating Factor As Neoadjuvant Therapy for Inflammatory and Locally Advanced Breast Cancer: SWOG 0012

PURPOSE Patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC) were randomly assigned to 21-day doxorubicin and cyclophosphamide administered for five cycles (standard arm) versus weekly doxorubicin and daily oral cyclophosphamide administered with granulocyte colony-stimulating factor support for 15 weeks (continuous arm). All patients had subsequent weekly paclitaxel for 12 weeks before surgery. PATIENTS AND METHODS Patients (n = 372) were randomly assigned to the standard arm (n = 186) or the continuous arm (n = 186) stratified by disease type (LABC, n = 256; IBC, n = 116). The primary outcome was microscopic pathologic complete response (pCR) at surgery. Secondary outcomes included disease-free survival, overall survival, and toxicity. RESULTS More patients in the standard arm had grade 3 to 4 leukopenia and neutropenia, but there were more instances of stomatitis/pharyngitis and hand-foot skin reaction in the continuous arm. Assessed among 356 eligible patients, pCR was not different between the treatment groups stratified by disease type (P = .42). In subset analysis, higher pCR rates were observed in the continuous arm versus the standard arm only for stage IIIB disease (P = .0057) and in IBC (P = .06). Comparison of overall survival and disease-free survival showed no difference between treatment groups (P = .37 and P = .87, respectively). CONCLUSION No significant clinical benefit was seen for the investigational arm in this trial overall.

Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis From INT-0137 (S9313)

PURPOSE We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). PATIENTS AND METHODS High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. RESULTS Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar. CONCLUSION The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

A Phase II Study of Imatinib Mesylate and Capecitabine in Metastatic Breast Cancer: Southwest Oncology Group Study 0338

BACKGROUND Imatinib mesylate is a potent inhibitor of the Bcr-Abl, c-Kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. On the basis of variable expression of c-Kit and PDGFR in breast cancer and of in vitro data supporting synergy between imatinib and capecitabine, the Southwest Oncology Group conducted a phase II trial of the combination in metastatic breast cancer. PATIENTS AND METHODS Eligible patients had progressive, measurable metastatic breast cancer and received<or=2 previous chemotherapy regimens for metastatic disease. Previous 5-fluorouracil or capecitabine for metastatic disease was not allowed. Patients were accrued on a 2-stage design and received imatinib mesylate 400 mg by mouth daily and capecitabine at 1000 mg/m2 by mouth twice daily for 14 days of a 21-day cycle. The primary endpoint was the confirmed response rate (RR). Tumors were evaluated for c-Kit, PDGFR-beta, and hormone receptor expression. RESULTS Nineteen fully evaluable patients were enrolled, with a confirmed RR of 11% (95% CI, 1%-33%). Eleven percent had unconfirmed partial responses, and 42% had stable disease. The trial did not accrue to the second stage. The estimated 6-month progression-free survival was 16% (95% CI, 0%-32%), and the median overall survival was 14 months (95% CI, 7-15 months). The combination was well tolerated. Of 8 available tumor samples, 2 stained for c-Kit, and all had stromal staining for PDGFR-beta. CONCLUSION In unselected patients, the combination of imatinib mesylate and capecitabine was well tolerated but did not result in improved RRs compared to those reported with capecitabine alone.

Abstract S5-07: SWOG S0500 – A randomized phase III trial to test the strategy of changing therapy versus maintaining therapy for metastatic breast cancer patients who have elevated circulating tumor cell (CTC) levels at first follow-up assessment

Introduction: CTC are detectable in approximately 75% of patients with metastatic breast cancer (MBC), and are elevated (≥5CTC/7.5 ml whole blood (WB)) in about half. Elevated CTC at baseline are associated with a worse prognosis, and a decline in CTC levels suggests response to therapy. We initiated a prospective randomized clinical trial (SWOG S0500) to test whether a change in chemotherapy after failure to clear CTC after one cycle of first line chemotherapy would improve outcomes of patients starting first line cytotoxic chemotherapy for MBC. Methods: Patients initiating first-line chemotherapy for MBC were enrolled. All patients had measurable or evaluable disease that included bone metastases. Patients with elevated CTC at baseline and who continued to have elevated CTC after 21 days of therapy were randomly assigned to either continue initial therapy until progression or to change to a second line chemotherapy (physician choice) immediately at cycle 2. Patients with elevated CTC at baseline, which were not elevated at the 21-day follow-up were maintained on their initial therapy. Patients without elevated CTC at baseline were followed in an observation arm. The primary endpoint was overall survival, and progression-free survival was a secondary endpoint. It was expected that approximately 500-650 patients would have to be screened to enroll 120 patients in the randomized trial. Power was 81% with 2-sided α = 0.05 to detect a 70% increase in median overall survival for patients randomized to change therapy. Three interim analyses were planned during the course of the trial. Results: From 10/1/2006 until 3/15/2012, 624 patients were registered of whom 612 were eligible. A baseline CTC was obtained in 593 (97%) eligible patients of whom 317 (53%) had elevated CTC at baseline. Thirty-one patients (10%) with elevated baseline CTC did not complete the follow-up CTC due to death, progression, withdrawal, or assay failure. Of the 286 remaining patients, 123 patients (43%) continued to have elevated CTCs after the first cycle of chemotherapy and were randomly assigned to either maintain original chemotherapy (n = 64) or switched to new chemotherapy (n = 59). Final outcome results will be analyzed in October 2013 and will be reported if released by the SWOG Data Safety Monitoring Board. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-07.

S1-1: A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226.

Background: Anastrozole inhibits the aromatase enzyme-induced estrogen synthesis, and fulvestrant down-regulates estrogen receptors in hormone receptor-positive breast cancer. We hypothesized that the simultaneous disruption of the ligand-receptor axis with concurrent use of these agents may be potentially additive or synergistic in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women. Materials and Methods: A total of 707 patients were randomized to either 1 mg anastrozole P.O. daily (Arm 1) or to the combination of anastrozole and fulvestrant (Arm 2). Fulvestrant was given as an intramuscular injection as follows: loading dose of 500 mg on day 0, followed by 250 mg on days 14, 28 and 250 mg maintenance monthly thereafter. The primary endpoint was progression-free survival (PFS), with a power of 90% and one-sided alpha of 0.025 to detect an expected median PFS of 10 months in Arm 1 versus 13 months in Arm 2. Randomization was stratified by adjuvant tamoxifen use with the possibility of differential benefit of fulvestrant in the two strata. Patients were encouraged to crossover to fulvestrant after progression on the anastrozole alone arm (40% did), if they were not candidates for immediate chemotherapy. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Two interim analyses were performed with the final analysis using a 2-sided p-value of 0.04. Results: There were 548 events (287 and 261 by arms, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for anastrozole and 15.0 months for the combination of fulvestrant and anastrozole (log-rank p=0.0145; HR=0.81 (95% CI 0.68−0.96). In a subset analysis of tamoxifen-naive women (60%, n=414), median PFS was 12.6 months and 17.0 months for Arms 1 and 2, respectively (log-rank p=0.0069; HR=0.74 (95% CI 0.60−0.92)), and 14.1 months and 13.5 months for Arms 1 and 2, respectively, in the 40% of tamoxifen-pretreated women (log-rank p = 0.56; HR=0.93 (95% CI 0.71−1.20)). A trend for improved overall survival (OS) in the combination arm was seen (median OS was 42 and 48.6 months based on 152 and 137 deaths respectively, log-rank p = 0.094; HR=0.82 (95% CI 0.65−1.03)). On the combination arm, three treatment-related deaths occurred: due to pulmonary embolism (2) or cerebrovascular ischemia (1); one Grade 4 thrombosis/embolism and one Grade 4 neutropenia and lymphopenia were reported. On the anastrozole arm, four patients experienced Grade 4 toxicities: thrombosis/embolism, arthralgia, thrombocytopenia, and dyspnea. In general, Grade 3 or higher toxicity was rare (12.7% vs. 14.5% for Arms 1 and 2, respectively) and did not differ significantly. Discussion: The combination of anastrozole and fulvestrant was associated with improved PFS compared to anastrozole alone as well as a trend in OS despite substantial crossover, thus offering a new standard in the first-line treatment of hormone receptor-positive breast cancer in postmenopausal women, specifically in tamoxifen-naive patients. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI CA32102, CA38926 and AstraZeneca. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-1.

S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer.

CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1) the weekly AC+G regimen is superior to ddAC x 6 and 2) 12 weeks of weekly paclitaxel (wP) is superior to q 2 week paclitaxel x 6 (ddP). METHODS Between December 2003 and November 2010, 2,716 patients were randomized in a 2 x 2 factorial design to 1) AC+G vs ddAC and 2) P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. At the first interim analysis, the AC randomization was halted for futility, and S0221 was closed to accrual 10 November 2010. S0221 reopened 15 December 2010, after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued. Accrual halted at a total of 3,294 in January 2012. RESULTS By September 7, 2012, 487 events and 340 deaths had occurred, prompting the third planned interim analysis. The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed. A Cox model adjusting for the AC arms had a HR = 1.08 (95% CI 0.90-1.28; p=0.42), with the 99.5% CI excluding the original alternative hypothesis that the HR=0.82. There was no significant interaction of the two factors. Estimated 5-year progression-free survivals were 82% for weekly P and 81% for ddP. Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P. Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P. Percent grade 3-4 toxicity per arm are shown in the Table. CONCLUSIONS Either ddPx6 or weekly P x 12 are acceptable schedules of P administration. The differences in leukopenia likely reflect ascertainment bias against weekly P. If this is accepted, weekly P x 12 produces less overall toxicity than 6 cycles of ddP. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. CLINICAL TRIAL INFORMATION NCT00070564. [Table: see text].

Phase II trial of edatrexate in relapsed or refractory germ cell tumors : A Southwest Oncology Group Study (SWOG 9124)

Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast, lung, and head and neck cancers, as well as in non-Hodgkins lymphomas. A phase II trial of edatrexate in relapsed or refractory malignant germ cell tumors was conducted by the Southwest Oncology Group (SWOG). Twenty-five patients were enrolled in the trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for four weeks followed by a one-week rest period. The treatment course was repeated every five weeks. Among the 23 patients evaluable for response, there were no objective responses with all patients developing progressive disease. Thirteen patients (56%) developed Grade 3–4 toxicities, predominantly stomatitis and malaise/fatigue/lethargy. One patient developed Grade 4 anemia while another developed grade 4 anemia and thrombocytopenia. No patients discontinued treatment due to toxicity nor were there any toxic deaths. Edatrexate administered in this dose and schedule has no antitumor activity and has substantial toxicity in patients with relapsed or refractory germ cell tumors.