Susan Burdette-Radoux

Phase I/II Trial of Adjuvant Dose-Dense Docetaxel/Epirubicin/Cyclophosphamide (TEC) in Stage II and III Breast Cancer

Abstract:  This phase I/II trial investigates the safety and feasibility of six cycles of concurrent taxane, anthracycline and cyclophosphamide on a dose dense schedule. Patients with stage II/III breast cancer were treated with docetaxel (T) 75 mg/m2, epirubicin (E) 75 mg/m2 (cohort 1, n = 3) or 100 mg/m2 (cohort 2, n = 12), and cyclophosphamide (C) 500 mg/m2 IV on day 1, with pegfilgrastim 6 mg subcutaneously on day 2, every 2 weeks for six cycles. Patients were assessed for toxicity every 2 weeks; cardiac function and response (if neoadjuvant) were assessed after six cycles. All patients in cohort 1 received 100% planned dose intensity; in cohort 2, five of twelve patients received 100% and 11/12 received >80%. There were no dose reductions or delays for day 1 myelotoxicity. Dose reductions as a result of febrile neutropenia (FN) occurred in cohort 2, with six of twelve patients experiencing FN in seven of sixty‐nine cycles. Six patients had anemia ≥grade 3; five received RBC transfusion and seven received an erythropoietic growth factor. Four patients required dose reductions for nonhematologic toxicity (two mucositis; one neurotoxicity; one diarrhea + cellulitis). Four patients developed thrombophlebitis, which was associated with FN in one of four. Two of fourteen evaluable patients had asymptomatic decreases in LVEF >10%; all remained within normal range. All four patients receiving neoadjuvant TEC had significant clinical responses (one CR, three PR). No pathologic CRs were seen. Conclusions: Dose dense TEC chemotherapy is feasible, has acceptable toxicity at doses equivalent to TAC (docetaxel 75 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2), and has moderate but manageable toxicity using a higher epirubicin dose of 100 mg/m2, with FN occurring in six of twelve patients at the higher dose.

A question of duration: Do patients with early-stage breast cancer need more than five years of Adjuvant endocrine therapy?

Women with hormone receptor-positive breast cancer continue to be at risk for recurrence and mortality for many years after diagnosis. Previous clinical trials established 5 years of endocrine therapy as a standard of care for both premenopausal and postmenopausal women, resulting in long-lasting benefit over shorter durations of treatment. Until recently, trials testing durations of tamoxifen longer than 5 years have not shown additional benefit, but the ATLAS (Adjuvant Tamoxifen, Longer Against Shorter) trial, reported in 2007, showed a small but significant reduction in risk of recurrence with 10 compared with 5 years of tamoxifen therapy. Aromatase inhibitors (AIs) improve relapse-free survival (RFS) in postmenopausal women when they are used sequentially with, or replace, tamoxifen for a total of 5 years of therapy. Extension of endocrine therapy to 10 years in the National Cancer Institute of Canada Clinical Trials Group MA.17 trial demonstrated that 5 years of letrozole therapy following 5 years of tamoxifen therapy results in an improvement in RFS, but not overall survival, in postmenopausal women. Trials testing durations of AI therapy for longer than 5 years are ongoing. Selection of candidates for extended endocrine therapy should balance recurrence risk, toxicity of treatment, and comorbidities that might impact life expectancy and risk of side effects.

A Phase II Study of Carboplatin, Etoposide, and Exisulind in Patients with Extensive Small Cell Lung Cancer: CALGB 30104

Purpose: To assess the efficacy and toxicity of carboplatin, etoposide, and exisulind as initial therapy for extensive stage small cell lung cancer. Patients and Methods: The Cancer and Leukemia Group B conducted a phase II study of carboplatin (area under the curve 6) day 1 and etoposide 80 mg/m2 days 1–3 administered intravenously every 21 days with exisulind 250 mg orally twice daily in 44 evaluable patients with previously untreated extensive stage small cell lung cancer. The hypothesis was the addition of a novel cytostatic agent to standard therapy may increase survival time. The primary end point of the study was to evaluate overall survival. The secondary end points were to characterize response rates and toxicity. Results: The majority of the patients were male (64%), Caucasian (95%), and had performance status 0 or 1 (77%). The median age was 61 (range 44–82) years. The percentage of patients alive at 1 year was 36.4% (95% [confidence interval] CI: 24.6–53.8%). The median overall survival was 10.6 months (95% CI: 9.1–14.7). The best overall response rate was 77% (95% CI: 62–89%) with 16% of the patients achieving complete response. The most frequent grade 3 or grade 4 hematological toxicities were neutropenia (64%), thrombocytopenia (36%), and febrile neutropenia (16%). The most common grade 3 or grade 4 nonhematological toxicities were gastrointestinal (30%) and electrolyte changes (23%). Conclusions: The addition of exisulind to a standard regimen of carboplatin and etoposide did not improve outcomes compared with historic controls treated with chemotherapy alone. Further evaluation of this regimen in small cell lung cancer is not warranted.

Low-dose metronomic cyclophosphamide/methotrexate (LDCM) and aspirin for patients without pathologic complete response (pCR) after neoadjuvant treatment for stage II-III breast cancer.

163 Background: Patients (pts) who fail to achieve pCR after neoadjuvant chemotherapy have a 20% risk of recurrence at two years. Data for effective postsurgical chemotherapy in this population is lacking. LDCM is an all-oral chemotherapy regimen with anti-angiogenic activity and acceptable toxicity in metastatic breast cancer. Aspirin is associated with a lower risk of breast cancer recurrence in retrospective studies and has anti-angiogenic activity. Here we combine LDCM and aspirin for high risk pts with poor response to neoadjuvant chemotherapy. METHODS Pts with stage II-III HER-2 negative breast cancer who had residual invasive cancer after neoadjuvant chemotherapy were eligible. Pts completed surgery and radiotherapy prior to enrolment and began study treatment within 180 days of surgery. Pts received four 28-day cycles of LDCM (cyclophosphamide 50 mg po daily, and methotrexate 2.5 mg po twice daily on days 1 and 2 each week ). Aspirin 325 mg daily was added on cycles 3 and 4. Pts were evaluated for the primary endpoint of toxicity and safety every 28 days. Secondary endpoint was 2 year relapse free survival. RESULTS 10 of 13 planned pts were evaluable for toxicity as of May 4, 2013. Pathologic stage ranged from T2N0 to T3N3. 70% of tumors were chemoresistant (stable or upstaged at time of surgery). 60% of pts had hormone receptor positive tumors and received concurrent hormonal therapy. Median age was 59 years (range 38-76). All pts completed 4 cycles of study treatment without dose reduction. There were no grade 3 or 4 related toxicities. Worst hematologic toxicity was grade 2 leukopenia. Worst nonhematologic toxicity was grade 2 fatigue; all other related toxicities were grade 1. 9 pts were evaluable for recurrence and one had recurred at a median followup of 16 months (range 10-26). CONCLUSIONS This antiangiogenic regimen is well tolerated in patients at high risk for recurrence after neoadjuvant chemotherapy, resulting in one recurrence at 16 months median followup, and it may be a candidate for future trials in this setting. Subsequent analyses will include longer term followup and biomarkers for angiogenesis. CLINICAL TRIAL INFORMATION NCT01612247.

Pathologic complete response after neoadjuvant paclitaxel and carboplatin chemotherapy for stage II-III breast cancer: A community cancer center experience.

43 Background: To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel in locally advanced breast cancer. METHODS In a retrospective study, 15 patients receiving neoadjuvant chemotherapy with carboplatin and paclitaxel from 2008 to 2013 were identified with breast cancer stages IIA to IIIB. Patients received carboplatin at 6 times the area under the curve (AUC 6) every 4 weeks and paclitaxel 80 mg/m2 weekly for 16 weeks. Weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) positive status. The primary endpoint was pathologic complete response (pCR) rate, defined as the absence of invasive cancer in breast and axillary lymph nodes. Partial response was defined as downstaging from clinical to pathologic stage. RESULTS 15 patients were identified. Median age was 57 years (range, 33 to 80 years). 6 women were African American, 3 Hispanic, 2 Asian and 3 Caucasian. 4 patients had stage IIIB disease, 5 had stage IIIA, 5 had Stage IIB and one had stage IIA. 2 patients had inflammatory cancer. 8 patients underwent modified radical mastectomy, 2 bilateral mastectomy and 4 lumpectomy. The tumor was estrogen receptor positive (ER+) in 8 patients, triple negative in 7 patients and HER2 positive in 2 patients. There were two episodes of febrile neutropenia and one death from sepsis. There was one episode of grade 4 thrombocytopenia requiring dose reduction of carboplatin to AUC 4. There were two instances of grade 3 peripheral neuropathy. One of these patients received a dose reduction of paclitaxel to 70 mg/m2. 10 patients received additional dose dense chemotherapy with doxorubicin and cyclophosphamide. Overall, the pCR rate was 0. Partial response was seen in 9 patients (60%). 14 patients received postoperative radiation; one patient declined radiation therapy. CONCLUSIONS In cooperative group trials, neoadjuvant carboplatin and paclitaxel has been shown to achieve high pCR rates in patients with triple negative and HER2 positive breast cancer without exposure to an anthracycline. In our ethnically diverse patient population at a community cancer center, no pathologic complete responses were seen.