Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5-fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2-positive disease) and to evaluate 5-year disease-free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21-day cycles of docetaxel (35 mg/m2  days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2-positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75-H →wTX-H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2-negative breast cancer and of 67% in patients with HER2-positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent-to-treat analysis, the pCR rate was 31% (37/118, 95% CI: 24-40%) in the HER2-negative patients, 24% (15/62, 95% CI: 14-37%) in ER-positive/HER2-negative patients, 39% (22/56, 95% CI: 27-53%) in the ER-negative/HER2-negative patients, and 46% (29/63, 95% CI: 34-48%) in the HER2-positive patients. The pCR rate in the 40 trastuzumab-treated patients was 53% (21/40, 95% CI: 38-67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand-foot skin reactions. One trastuzumab-treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1-2 decrements in left ventricular function; all five patients' cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease-free survival was 70% in the HER2-negative population (78% in ER-positive/HER2-negative and 62% in the ER-negative/HER2-negative patients) and 80% in the HER2-positive patients (87% in the trastuzumab-treated HER2-positive patients). At 5 years, overall survival was 80% in the HER2-negative population (88% in ER-positive/HER2-negative and 71% in the ER-negative/HER2-negative patients) and 86% in the HER2-positive patients (94.5% in the trastuzumab-treated HER2-positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5-year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Results of docetaxel plus oxaliplatin (DOCOX) ± cetuximab in patients with metastatic gastric and/or gastroesophageal junction adenocarcinoma: results of a randomised Phase 2 study.

BACKGROUND: Patients with advanced adenocarcinoma of the gastroesophageal junction/stomach are treated by combination chemotherapy, with minimal improvements in survival. We evaluated adding cetuximab to combination chemotherapy in these patients. METHODS: The primary objective was progression-free survival. Secondary objectives were response rate, time to response, duration of response and safety. Treatment Arm 1: docetaxel+oxaliplatin (DOCOX)=docetaxel 60 mg/m(2) plus oxaliplatin 130 mg/m(2) on Day 1 of each 21-day cycle. Arm 2: docetaxel+oxaliplatin+cetuximab (DOCOX+C)=DOCOX with C 400mg/m(2) first dose then 250 mg/m(2) weekly. The protocol was amended to allow collection of tissue to correlate responses with KRAS status. FINDINGS: One hundred fifty patients were enrolled (75/arm). DOCOX/DOCOX+C: gastric 44%/41%, gastroesophageal junction 51%/55%, both 5%/4%. Response rate/arm: 26.5%/38.0%. Median progression-free survival: 4.7/5.1 months (95% confidence interval (CI) 3.0-5.6/4.3-5.9); 1 year survival: 39.1%/33.0%, median overall survival: 8.5/9.4 months; median duration of response: 7.3/5.6months. Grade 3-4 treatment-related adverse events (%) included neutropenia (50%/44%), febrile neutropenia (13%/19%), diarrhoea (12%/17%), fatigue (12%/17%) and leukopenia (7%/14%). Discontinuation was due to progressive disease 39/32 and adverse events 21/34. KRAS was collected on some patients 2 years into the study because of new American Society of Clinical Oncology (ASCO) findings. INTERPRETATION: Cetuximab added to DOCOX may improve response rate minimally; there appears to be no improvement in progression-free survival, overall survival or 1-year survival. Cetuximab added to DOCOX did not produce clinically significant outcomes. Toxicities were consistent with the study drugs' known safety profiles. KRAS mutation was infrequent; no conclusions can be drawn from KRAS response data. ClinicalTrial.gov Identifier: NCT00517829.

Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer.

INTRODUCTION: Enzastaurin is an oral serine/threonine kinase inhibitor that targets protein kinase C-beta (PKC-ß) and the phosphatidylinositol-3-kinase/AKT pathway. This trial assessed pemetrexed-carboplatin ± enzastaurin to docetaxel-carboplatin in advanced non-small cell lung cancer. METHODS: Patients with stage IIIB (with pleural effusion) or IV non-small cell lung cancer and performance status 0 or 1 were randomized to one of the three arms: (A) pemetrexed 500 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles with a loading dose of enzastaurin 1125 or 1200 mg followed by 500 mg daily until disease progression, (B) the same regimen of pemetrexed-carboplatin without enzastaurin, or (C) docetaxel 75 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to six cycles. The primary end point was time to disease progression (TTP). RESULTS: Between March 2006 and May 2008, 218 patients were randomized. Median TTP was 4.6 months for pemetrexed-carboplatin-enzastaurin, 6.0 months for pemetrexed-carboplatin, and 4.1 months for docetaxel-carboplatin (differences not significant). Median survival was 7.2 months for pemetrexed-carboplatin-enzastaurin, 12.7 months for pemetrexed-carboplatin, and 9.2 months for docetaxel-carboplatin (log-rank p = 0.05). Compared with the other arms, docetaxel-carboplatin was associated with lower rates of grade 3 thrombocytopenia and anemia but a higher rate of grade 3 or 4 febrile neutropenia. CONCLUSION: There was no difference in TTP between the three arms, but survival was longer with pemetrexed-carboplatin compared with docetaxel-carboplatin. Enzastaurin did not add to the activity of pemetrexed-carboplatin.