The use of leucovorin to modulate 5-fluorouracil (FUra)-mediated inhibition of thymidylate synthase has been shown both in vitro and in vivo to improve the antitumor activity of FUra. Based on the activity of this combination in previously untreated patients, we performed a study of FUra and high-dose leucovorin (HDFA) in patients with metastatic breast cancer and minimal prior chemotherapy. Patients were stratified by prior chemotherapy (or relapse within 12 months of completing adjuvant chemotherapy) versus no prior chemotherapy (or relapse at greater than 12 months since completion of adjuvant chemotherapy). FUra was given daily for 5 days at 370 mg/m2/day with HDFA, 500 mg/m2/day, beginning 24 hours before and continuing 12 hours beyond the first and last FUra doses, respectively. Two objective responses occurred among 21 patients in the pretreated group (10%; 95% confidence interval: 1–30%). Four of 36 eligible patients (11%) in the “no prior therapy group” had complete responses (95% confidence interval: 3–26%). The major toxicities were moderate leucopenia and mucositis. We conclude that FUra plus leucovorin has modest antitumor activity in metastatic breast cancer.
Purpose To improve treatment outcome for patients presenting with inflammatory breast cancer (IBC), we have sequentially developed and tested single and tandem dose-intense chemotherapy regimens (DICT). Tumor- and treatment-related factors were analyzed to generate a prognostic model. Patients and Methods Between May 1989 and April 2002, 120 patients received conventional-dose chemotherapy, surgery, and sequentially developed single- or tandem-cycle DICT. Disease- and treatment-specific features were subjected to univariate and multivariate analysis to correlate with outcome. Results At a median follow-up of 61 months (range, 21 to 161 months), estimated 5-year relapse-free survival (RFS) and overall survival (OS) were 44% (95% CI, 34% to 53%) and 64% (95% CI, 55% to 73%), respectively. In an age-adjusted multivariate analysis, RFS was better in patients with estrogen receptor (ER)/progesterone receptor (PR)–positive tumors (P = .002), for patients with fewer than four involved axillary nodes before DICT (P = .01), and in patients treated with radiation therapy (P = .001) and tandem DICT (P = .049). OS was improved in patients with ER/PR-positive tumors (P = .002), in those with fewer than four involved axillary nodes before DICT (P = .03), and in patients treated with radiation therapy (P = .002). Conclusion This retrospective analysis suggests that either single or tandem DICT can be administered safely and may benefit selected patients with stage IIIB IBC. Those with receptor-negative IBC and with four or more involved axillary nodes before DICT need improved neoadjuvant and postadjuvant intensification therapy. A prospective randomized trial of single versus tandem DICT would be required to confirm the potential benefit of tandem DICT in the setting of IBC.
Objectives: Report the feasibility, toxicities, and long-term results of a Phase I/II trial of 90Y-labeled anticarcinoembryonic antigen (anti-CEA) (cT84.66) radioimmunotherapy (RIT), gemcitabine, and hepatic arterial infusion (HAI) of fluorodeoxyuridine (FUdR) after maximal hepatic resection of metastatic colorectal cancer to the liver. Methods: Patients with metastatic colorectal cancer to the liver postresection or ablation to minimum disease were eligible. Each cohort received HAI of FUdR for 14 days on a dose escalation schedule. The maximum HAI FUdR dose level planned was 0.2 mg/kg/day, which is the standard dose for HAI FUdR alone. On day 9, 90Y-cT84.66 anti-CEA at 16.6 mCi/m2 as an i.v. bolus infusion and on days 9–11 i.v. gemcitabine at 105 mg/m2 were given. Patients could receive up to three cycles every 6 weeks of protocol therapy. Four additional cycles of HAI FUdR were allowed after RIT. Results: Sixteen patients were treated on this study. A maximum tolerated dose of 0.20 mg/kg/day of HAI FUdR combined with RIT at 16.6 mCi/m2 and gemcitabine at 105 mg/m2 was achieved with only 1 patient experiencing grade 3 reversible toxicity (mucositis). After surgery, 10 patients had no evidence of visible disease and remained without evidence of disease after completion of protocol therapy. The remaining 6 patients demonstrated radiological visible disease after surgery and after protocol therapy 2 patients had a CR, 1 patient had PR, 2 had stable disease, and 1 had progression. With a median follow-up of 41.8 months (18.7–114.6), median progression free survival was 9.6 months. Two patients demonstrated long-term disease control out to 45+ and 113+ months. Conclusion: This study demonstrates the safety, feasibility, and potential utility of HAI FUdR, RIT, and systemic gemcitabine. The trimodality approach does not have higher hematologic toxicities than seen in prior RIT-alone studies. Future efforts evaluating RIT in colorectal cancer should integrate RIT with systemic and regional therapies in the minimal tumor burden setting.
Abstract BACKGROUND: Cancer of the pancreas is the fourth leading cause of cancer-related death in the United States with less than 5% living for more than 5 years. These dismal statistics reflect the early metastasis of cancer cells. Overexpression or activation of Src and STAT3 are commonly detected in pancreas cancer leading to increased cell proliferation and migration. Dasatinib is a broad spectrum ATP competitive inhibitor of protein tyrosine kinases including the SRC family of kinases. We conducted a pilot trial of single agent dasatinib in patients with metastatic pancreas cancer. METHODS: Patients with metastatic pancreatic cancer were enrolled and treated with dasatinib 70 mg twice per day. Due to the difficulty of obtaining serial biopsies on pancreas cancer patients correlative studies were performed on peripheral blood mononuclear cells as a surrogate. Peripheral blood mononuclear cells were collected at baseline, 6 hours after the first dose and at the beginning of the next cycle. Western blots were performed to evaluate Src and STAT3 protein levels. RESULTS: Seven patients were enrolled in the trial with two patients completing two cycles of chemotherapy. Two patients withdrew for toxicity with one patient having grade 4 diarrhea and grade 3 vomiting. The second patient withdraw for grade 3 fatigue and grade 2 diarrhea. Two patients completed 2 cycles and had minor grade 1-2 toxicities attributable to dasatinib but had progressive disease upon restaging. Three patients did not want to continue on study and were removed in the first cycle. Western blots performed on peripheral blood mononuclear cells showed a rapid decrease of phosphorylated STAT3 (p-STAT3) six hours after treatment in three patients but only one patient had a corresponding decrease in phosphorylated Src (p-Src). For two patients the p-STAT3 levels remained low after completion of the first cycle. These patients had an overall survival of 50 weeks and 61 weeks. The overall survival for the other patients ranged from 8-12 weeks. CONCLUSION: Because pancreatic cancer remains resistant to current therapies despite recent advances in the development of molecular targeted therapies, there is an urgency to understand these pathways. Our patient with a rapid decrease in p-STAT3 and p-Src six hours after treatment had an overall survival of 61 weeks which reflects the biology of the tumor but also suggests the importance of simultaneously inhibiting these pathways. Since STAT is a target of Janus kinase, additional studies evaluating JAK activity are being done. Future clinical trials combining molecular targeted therapies in addition to traditional cytotoxics are warranted as we strive to improve the survival of our patients with this deadly disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2525.
