Phase II study of combination chemotherapy with irinotecan and cetuximab for pretreated metastatic colorectal cancer harboring wild-type KRAS.

The aim of this study was to prospectively evaluate the efficacy of combination irinotecan and cetuximab chemotherapy in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. KRAS status was evaluated using the Cycleave PCR method; only patients without KRAS mutations were included. Cetuximab was administered initially at 400 mg/m² followed by weekly 250 mg/m² infusions. Irinotecan was administered biweekly. From October 2008 to April 2009, a total of 30 patients were enrolled. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 80.0% (95% CI, 61.4-92.3%). Among the 15 patients with stable disease, 11 patients experienced >10% tumor shrinkage. Median progression-free survival was 5.8 months (95% CI, 4.1-7.6). Median overall survival was not reached at a median follow-up of 10.1 months. Grade 2 skin toxicity was observed in 23 patients, while no grade 3 skin toxicity was observed. Combined irinotecan and cetuximab is effective for pretreated metastatic wild-type KRAS colorectal cancer.

Prognostic factors for metastatic colorectal cancer patients undergoing irinotecan-based second-line chemotherapy.

BACKGROUND: No reports about factors that predict prognosis after second-line chemotherapy for metastatic colorectal cancer have been published. METHODS: We retrospectively analyzed 124 patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy after first-line folinic acid/5-fluorouracil (5-FU)/oxaliplatin (FOLFOX) with or without bevacizumab. RESULTS: A multivariate Cox model revealed 5 prognostic factors for worse survival: ECOG performance status 2, pathologically poorly differentiated adenocarcinoma, peritoneal metastasis, progression-free survival of first-line FOLFOX < 6 months, and lactate dehydrogenase ≥ 400 IU/L. When patients were categorized into 3 risk groups-patients without any prognostic factors (low-risk, n = 55), patients with one prognostic factor (intermediate-risk, n = 32), and patients with 2 or more prognostic factors (high-risk, n = 37)-overall survival from initiation of second-line chemotherapy was 23.5, 14.6, and 5.5 months, respectively. The proportion of patients who were eligible to receive further chemotherapy after disease progression was significantly lower in the high-risk group (41%) than in the intermediate- (67%) and low-risk (95%) groups. CONCLUSION: Several prognostic factors for survival after second-line therapy and probability of receiving third-line chemotherapy were identified. This risk classification system might be useful for determining which patients should receive cetuximab in the second-line setting rather than the third-line setting.

Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301).

OBJECTIVES: No established therapy exists for unresectable intrahepatic cholangiocarcinoma (ICC). We conducted a phase I/II study to ascertain the recommended dose (RD) of hepatic arterial infusion using gemcitabine (GEM) for ICC and to assess the efficacy and safety. METHODS: For patients with unresectable ICC, GEM was administered through the hepatic artery via the port system as a 30-minute infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. In phase I, dosage for levels 1, 2, and 3 was set at 600, 800, and 1000 mg/m, respectively, and was increased in 3 to 6 patients at a time. Maximum tolerated dose was defined as a dosage resulting in dose-limiting toxicity in 2 of 3 patients or 3 of 6 patients, and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response and toxicity. RESULTS: During the phase I, 16 patients were enrolled. Maximum tolerated dose was not reached. Assuming RD at 1000 mg/m, the phase II enrolled a total of 13 patients. The following Grade 3 toxicities were observed: neutropenia 20%, increased gamma-glutamyl transpeptidase 8%, increased aspartate aminotransferase 4%, increased alanine aminotransferase 4%, increased bilirubin 4%, nausea 4%, and fatigue 4%. The tumor response rate was 7.7% (complete response 0, partial response 1, stable disease 8, and progressive disease 4). CONCLUSION: Whereas the toxicity of hepatic arterial infusion with 1000 mg/m GEM for ICC was tolerable, expected efficacy could not be obtained, thus suggesting only minimal activity.

Neutropaenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX.

We retrospectively analysed 153 patients with metastatic colorectal cancer who received FOLFOX with or without bevacizumab as first-line chemotherapy. Several background characteristics and chemotherapy features (grade of neutropaenia, use of bevacizumab or irinotecan, re-introduction of FOLFOX, and tumour progression) as time-varying covariates were analysed as potential prognostic factors. Of the 153 patients, mild neutropaenia (grade 1-2) occurred in 60 patients (39%) and severe neutropaenia (grade 3-4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropaenia. According to a multivariate Cox model with time-varying covariates, hazard ratios (HRs) of death were 0.55 (95% confidence interval (CI), 0.31-0.98; P=0.044) for patients with mild neutropaenia and 0.35 (95% CI, 0.18-0.66; P=0.002) for those with severe neutropaenia. Both mild and severe neutropaenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropaenia may improve chemotherapy efficacy.

A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer.

PURPOSE: Gemcitabine monotherapy or gemcitabine-containing combination chemotherapy is the standard first-line therapy for advanced pancreatic cancer. After disease progression, there is no standard regimen available. In a previous phase II trial, S-1 has been reported to show considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. This study evaluated the efficacy and toxicity of S-1 in patients with gemcitabine-refractory metastatic pancreatic cancer. METHODS: Eligibility criteria were histologically proven pancreatic adenocarcinoma with confirmation of progressive disease while receiving gemcitabine-based first-line chemotherapy, 20-74 years of age, Karnofsky performance status of 80-100 points, with measurable metastatic lesions, adequate hematological, renal and liver functions, and written informed consent. S-1 was administered orally at 40 mg/m(2) twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. The primary endpoint of this study was an objective response, and secondary endpoints included toxicity, progression-free survival (PFS) and overall survival, as well as clinical benefit response in symptomatic patients. RESULTS: Forty patients from two institutions were enrolled between September 2004 and November 2005. The most common adverse reactions were fatigue and anorexia, although most of those adverse reactions were tolerable and reversible. One patient developed grade 3 pneumonitis without neutropenia and recovered with appropriate antibiotic treatment. Although no complete response was seen, partial response was obtained in six patients (15, 95% confidence interval, 3.9-26%). Stable disease was noted in 17 patients (43%), and progressive disease in 15 patients (38%). Out of 19 evaluable patients, a clinical benefit response was observed in four patients (21%). The median PFS was 2.0 months, and the median survival time was 4.5 months with a 1-year survival rate of 14.1%. CONCLUSION: S-1 as monotherapy had marginal anti-tumor activity with tolerable toxicity in patients with gemcitabine refractory metastatic pancreatic cancer.

Phase II study of cisplatin, epirubicin and continuous infusion of 5-fluorouracil in patients with advanced intrahepatic cholangiocellular carcinoma (ICC).

BACKGROUND/AIMS: To clarify the efficacy and toxicity of cisplatin, epirubicin, and continuous infusion of 5-FU (CEF therapy) in patients with advanced intrahepatic cholangiocellular carcinoma (ICC). METHODOLOGY: Chemo-naïve patients with advanced ICC were treated with cisplatin at 80 mg/m2 and epirubicin at 50 mg/m2 on day 1, and continuous infusion of 5-FU at 500 mg/m2/day on days 1 through 5. If there was no evidence of tumor progression or unacceptable toxicity, the treatment was repeated every 4 weeks, up to a maximum of 6 courses. RESULTS: Thirty-nine patients were enrolled in this study. The median number of courses was 2 (range, 1-6). A partial response was obtained in 4 patients (10%) with a median duration of 2.3 months. Twenty-seven patients (69%) showed no change, and 7 patients (18%) had progressive disease. The median survival time was 9.1 months and the 1-year survival rate was 23%. The progression-free survival time was 5.1 months. Grade 3 to 4 adverse effects were leukocytopenia (51%), neutropenia (74%), thrombocytopenia (23%), and nausea/vomiting (10%). Most of the toxicities were reversible, but 2 patients died of neutropenic sepsis. CONCLUSIONS: CEF therapy has marginal antitumor activity against advanced ICC, although hematological toxicity is the major and most frequent toxicity.

Central venous access port-related complications in outpatient chemotherapy for colorectal cancer.

BACKGROUND: The current standard chemotherapy for advanced or metastatic colorectal cancer in Japan is FOLFOX or FOLFIRI therapy. Although both therapies include continuous infusion of 5-fluorouracil (5-FU), outpatient home chemotherapy is possible by placing a central venous access port (CV-port) and using a portable disposable pump. The port system has been placed more frequently since the approval of FOLFOX. Consequently, more complications involving ports and pumps have been encountered. METHODS: At our hospital, 232 patients with colorectal cancer underwent outpatient home chemotherapy by placing a CV-port and using a portable disposable pump for continuous infusion of 5-FU between 1998 and 2005. Incidence and contents of complications involving ports and pumps were investigated retrospectively. RESULTS: A total of 54 incidents of complications involving ports and pumps were identified in 3142 treatments (1.72%) from among 34 of the 232 patients (14.7%). In 2005, when FOLFOX was introduced, 31 incidents occurred in 1903 treatments (1.63%) for 19 of 149 patients (12.8%). Incidents involved port placement (n = 6), catheter and port system-related complications (n = 15), puncture needle-related complications (n = 3), skin complications related to tape fixation (n = 20) and pump-related complications (n = 10). In 10 patients (4.3%), system-related complications made therapy difficult to continue and system exchange was required. CONCLUSIONS: Technical troubles involving ports and pumps occurred at a certain rate, and skin incision was required for system exchange in some cases. When performing outpatient chemotherapy using ports and pumps, thorough prior guidance and double-checking must be implemented, and proper countermeasures must be established.

Bilateral pneumothorax after unilateral transthoracic puncture.

Pneumothorax is a common complication following transthoracic interventional procedures. Most often, this occurs unilaterally on the side of the intervention. Bilateral pneumothorax following unilateral puncture is rare, but may mandate emergent chest tube insertion. We describe two cases in which bilateral pneumothorax occurred after unilateral thoracic puncture. One patient had a history of esophageal resection, while the other had no history of thoracic surgery.

[Tumor markers for pancreatic and biliary tract cancer].

There are a variety of tumor markers used for diagnosis of pancreatic and biliary tract cancer including carbohydrate antigens such as CA19-9, DUPAN-2, CA50 and Span-1, the carcinoembryonic antigen and pancreatic enzymes such as elastase 1. The tumor marker kinetics in serum help to predict survival in patients receiving surgical and/or non-surgical treatment. Since each of those tumor markers remains at a low sensitivity and specificity in the early stage, none are useful for detecting early cancer. In spite of the development of various diagnostic techniques, pancreas and biliary tract cancer is usually diagnosed at an incurable stage, and the 5-year survival rate is extremely low. Therefore, improvements in survival may well result from screening for early-stage pancreatic and biliary cancer. The development of tumor markers with higher sensitivity and specificity should have the highest priority.