TACE plus sorafenib for the treatment of hepatocellular carcinoma: results of the multicenter, phase II SOCRATES trial.

PURPOSE: The present multicenter phase II trial investigated the combination of TACE and sorafenib for the treatment of HCC. PATIENTS AND METHODS: Eligibility criteria included histologically confirmed, unresectable HCC beyond Milan criteria, no extrahepatic spread, Child-Pugh score ≤ 8 and ECOG PS 0-2. Patients had received no prior therapy for HCC. Sorafenib was given at a dose of 400 mg/bid (interrupted only around TACE). TACE with lipiodol, 50 mg doxorubicin and polyvinyl alcohol (PVA) particles was repeated q6w as long as there was no overall disease progression. Tumor assessment by MRI was performed q6w according to EASL criteria. The primary endpoint was time to progression (TTP). RESULTS: Patients (n = 43) received a mean of 2.6 ± 2.2 TACE interventions (range 0-10). Median TTP was 16.4 months (95 % CI 10.7-∞). Median overall survival (OS) was 20.1 months (95 % CI 17.6-28.2). Disease control rate according to EASL criteria was 74.4 % (7 % complete responses [CRs] + 41.8 % partial responses [PRs] + 25.6 % stable diseases [SDs]). Four patients (9 %) became amenable to either radiofrequency ablation or liver transplantation; 5 (12 %) patients died during the trial. Overall, there were 360 AEs, including 56 grade 3/4 AEs and 39 SAEs. CONCLUSIONS: Combination treatment of TACE and sorafenib in the present trial was tolerable and associated with an interesting response rate, TTP and OS. Combination therapies will probably close gaps in the present mono therapy driven treatment guidelines for locally advanced HCC.

Phase II study on combined intravenous and intra-arterial chemotherapy with gemcitabine and mitomycin C in patients with advanced pancreatic cancer.

BACKGROUND/AIMS: This prospective phase II study on a combination of intraarterial (i.a.) and systemic chemotherapy was performed to test whether regional chemotherapy may overcome the chemoresistance of pancreatic cancer. METHODOLOGY: One treatment cycle consisted of an i.a. infusion through an angiographic catheter into the celiac artery of 8.5mg/m2 mitomycin C (MMC) and 500 mg/m2 gemcitabine on days 1 and 22, and intravenous infusions of 500 mg/m2 gemcitabine on days 8 and 15. Study-endpoints were overall survival and tumor response as measured by computed tomography (CT). Treatment was continued until disease progression or complete remission on CT. RESULTS: Thirty-seven treatment cycles were performed in 17 patients. The most frequent side effects were hematological with 18 episodes of grade III/IV toxicities. According to radiographic and tumor marker criteria, four (24%) and seven patients (41%), respectively, demonstrated an objective response. The median actual progression-free and overall survivals were 4.6 and 9.1 months, respectively. Patients without distant metastases had a longer median survival (15 months) than those with distant metastases (7.1 months, p = 0.037). CONCLUSIONS: This combination treatment was well tolerated and resulted in tumor response rates, median overall- and progression-free survival times superior to systemic gemcitabine chemotherapy, and comparable to the more toxic FOLFIRINOX regimen.

A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study.

PURPOSE: To investigate whether infusional high-dose 5-flurouracil (HD-FU) provides a significant improvement in recurrence-free survival (RFS) and overall survival (OS) compared with a standard bolus 5-FU regimen (Mayo Clinic) in patients with curatively resectable stage III colon cancer. METHODS: Patients (n=1601) were randomised to receive either the Mayo Clinic regimen or one of the three HD-FU regimens; LV5FU2, the Arbeitsgemeinschaft Internistische Onkologie (AIO) or the Grupo Espanol para el Tratamiento Digestivos (TTD), the data from which were combined to provide the HD-FU arm for final analysis. RESULTS: Patients were evenly balanced for age, TMN, tumor grade and vascular and lymphatic invasion. Median follow-up was approximately 42months, RFS (hazard ratio [HR]=0.997) and OS (HR=0.96) (primary end-point) were not statistically different between the two treatment arms. Infusional HD-FU was generally better tolerated than bolus 5-FU regimen. CONCLUSIONS: Infusional HD-FU does not improve RFS and OS in curatively resected stage III colon cancer patients compared to the Mayo Clinic regimen, but is less toxic.

Prospective pilot study of neoadjuvant chemotherapy with 5-fluorouracil, folinic acid and oxaliplatin in resectable liver metastases of colorectal cancer. Analysis of 42 neoadjuvant chemotherapies.

PURPOSE: Since there are currently no data available from a prospective trial, the primary objective of this prospective study was to investigate whether the rate of R0-liver resections without morbidity would be at least 50 % in patients with neoadjuvant chemotherapy for colorectal liver metastases. PATIENTS AND METHODS: 42 patients were treated with a biweekly FOLFOX regimen. Chemotherapy consisted of a 2-hour infusion of folinic acid (FOL) 500 mg/m2, followed by a 24-hour infusion of 5- fluorouracil (F) 2000 mg/m2 daily for two days. Oxaliplatin (OX) 85 mg/m 2 was given simultaneously with FOL. Treatment allocation was randomized with either 3 or 6 cycles for the final 30 patients. A liver resection was performed 2 to 5 weeks after the final infusion. RESULTS: An objective response was observed in 20 of 42 patients (response rate was 27 % higher after 6 cycles). Liver resection (R0) could be performed in 34 patients. Postoperative complications were reported in 14 patients (13 occurring within 30 days after resection) and severe complications in 5 cases (including two deaths after extended resection). Liver failure and persistent biliary fistula were the most frequently documented complications. There was no relevant difference in safety criteria between 3 and 6 applications. CONCLUSION: The use of neoadjuvant chemotherapy in resectable liver metastases induced significant remissions without increasing morbidity. The rate of severe complications and cases of no R0-resection in this study was 31 % and was with that significantly lower than 50 % (95 % CI 17.6 %-47.1 %). The risk to the patient is therefore acceptable when undergoing neoadjuvant treatment in a prospective intergroup trial.

Technical complications of continuous intra-arterial chemotherapy with 5-fluorodeoxyuridine and 5-fluorouracil for colorectal liver metastases.

BACKGROUND: Intra-arterial chemotherapy is an effective modality to treat unresectable hepatic metastases from colorectal primaries if systemic chemotherapy has failed. Response rates of more than 40% and a median survival of 15 to 25 months have been reported from randomized trials. In this retrospective study, we analyzed specific technical complications associated with continuous intra-arterial chemotherapy for colorectal liver metastases. METHODS: From 1982 to 1995, single-center clinical data from 180 patients with colorectal liver metastases were evaluated. Continuous intra-arterial chemotherapy was administered using either an implanted infusion pump or an intra-arterial port with an external infusion pump. The intra-arterial catheter was implanted according to the Watkins' technique. The treatment protocols consisted of 5-fluorouracil- or 5-fluorodeoxyuridine-based regimens. RESULTS: A total of 70 patients (39%) received an intra-arterial infusion pump and 110 patients (61%) an intra-arterial port. Sixty-eight technical complications affected port systems (62%), whereas 29 patients with pumps (41%) were affected by technical complications. Therapy-relevant complications were observed in 47% of the ports and 30% of the infusion pumps. The median complication-free survival was 12.2 months for infusion pumps and 7.3 months for ports (P =.0016). CONCLUSIONS: Our data demonstrate that pumps are superior to ports in terms of complication rate and complication-free survival. On the basis of our results, pumps have a potential for a longer treatment, which may result in a prolonged median survival.