Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer (OGSG 0802).

BACKGROUND: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients. METHODS: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths. CONCLUSION: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Selective TACE with irinotecan-loaded 40 µm microspheres and FOLFIRI for colorectal liver metastases: phase I dose escalation pharmacokinetic study.

BACKGROUND: Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 µm microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen. METHODS: The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration. RESULTS: Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and Cmax of plasma SN-38 per 1 mg injected irinotecan dose were significantly higher in irinotecan-loaded microspheres compared with FOLFIRI (P = 0.009 and P <  0.001, respectively). CONCLUSION: Selective TACE using 40 µm irinotecan-loaded microspheres combined with systemic FOLFIRI was feasible and safe even when a high dose of irinotecan was loaded. Irinotecan-loaded microspheres resulted in a higher plasma concentration and AUC of SN-38 than treatment with FOLFIRI. Further large scale trials to evaluate the efficacy are mandatory. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, Registration number; UMIN000015367 ; Registered date; 08,10,2014.

Capecitabine and oxaliplatin combined with bevacizumab are feasible for treating selected Japanese patients at least 75 years of age with metastatic colorectal cancer.

BACKGROUND: Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥ 75 years with mCRC. METHODS: This prospective, open-label phase II trial recruited patients aged ≥ 75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m(2) of oxaliplatin on day 1 of each cycle combined with 2000 mg/m(2) of oral capecitabine per day on days 1-14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival. RESULTS: Thirty-six patients (male 58%; median age 78 years; colon cancer 67%) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0 months. Twelve patients (33.3%) experienced adverse effects (AEs) ≥ grade 3 and frequent AEs ≥ grade 3, including neutropenia (22.2%) and neuropathy (13.9%). Hypertension was the most frequent AE ≥ grade 3 associated with bevacizumab (11.1%). Low baseline creatinine clearance associated significantly with the incidence of AEs ≥ grade 3. Response and disease control rates were 55.6 and 91.7%, respectively. Median progression-free and overall survival times were 11.7 months (95% confidence interval, 8.0-13.4 months) and 22.9 months, respectively. CONCLUSION: XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥ 75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit.

Transcatheter arterial chemoembolization using cisplatin powder mixed with degradable starch microspheres for colorectal liver metastases after FOLFOX failure: results of a phase I/II study.

PURPOSE: To report the results of a phase I/II study of a transcatheter arterial chemoembolization protocol using cisplatin powder and degradable starch microspheres (DSM) for unresectable colorectal liver metastases after failure of FOLFOX (5-flourouracil, leucovorin plus oxaliplatin) chemotherapy conducted to determine the recommended dose of cisplatin powder and to assess the efficacy and safety of the protocol. MATERIALS AND METHODS: A fine-powder formulation of cisplatin was mixed with DSM and administered via the hepatic artery every 4 weeks. In phase I, three cohorts of patients received escalating doses of cisplatin powder: 50 mg/m(2), 65 mg/m(2), and 80 mg/m(2). In phase II, tumor response, toxicity, and survival times were assessed. RESULTS: The study enrolled 24 patients. Previously, FOLFOX had been administered to all patients, an irinotecan-containing regimen had been administered to 12 patients, and bevacizumab or cetuximab or both had been administered to 14 patients. In phase I, dose-limiting toxicity did not appear at any level, and the recommended dose of cisplatin powder was determined to be 80 mg/m(2). In phase II, a tumor response rate of 61.1% was achieved. The median hepatic progression-free survival and overall survival were 8.8 months (95% confidence interval [CI], 4.06-13.5 mo) and 21.1 months (95% CI, 8.37-33.8 mo). The following grade 3 toxicities were observed: thrombocytopenia (12.5%), aspartate transaminase elevation (33.3%), alanine transaminase elevation (12.5%), hyponatremia (8.3%), and cholecystitis (4.2%). CONCLUSIONS: This study shows that transcatheter arterial chemoembolization with cisplatin powder at a dose of 80 mg/m(2) mixed with DSM is well tolerated and can produce a high response rate with a long survival time for patients with unresectable colorectal liver metastases after failure of FOLFOX.

[A surgical (right lobectomy) case of liver metastasis of colon cancer after chemotherapy using mFOLFIRI and cetuximab].

A man in his early seventies underwent low anterior resection and partial resection of the liver for the rectal cancer and liver metastasis. However, 4 months after the surgery, he was found to have a liver tumor at S5 and S7 by abdominal CT scan. Then, he underwent chemotherapy (mFOLFOX6), but the metastatic tumor was progressive. We selected FOLFIRI + cetuximab regimen for second-line therapy to resect the metastatic tumor. As the metastatic lesion was become smaller after 4-course of the regimen including cetuximab, we decided to perform a radical resection. We conducted a right lobectomy of the liver, and the tumor was completely resected.

[A surgical (pancreatoduodenectomy) case of lymph node metastatic recurrence of colon cancer after chemotherapy].

A woman in her fifties underwent a right hemicolectomy (D3) for cancer of the ascending colon in October 2007, definitively and pathologically diagnosed as papillary adenocarcinoma invading to the subserosa, and no metastasis was detected to lymph node. But 13 months after the surgery, she was found to have a mass near the anastomosis by an abdominal CT scan. Colonoscopy showed an evaluating lesion with ulcer in the anal side of the anastomosis. We tried to resect the metastasis, but it was not resectable because of the invasion to the pancreas. The mFOLFOX regimen was effective. After the chemotherapy (6 courses), we decided to perform a radical resection. We conducted pancreatoduodenectomy in May 2009. She is still alive 12 months after surgery.

[The introduction of the clinical study in the general hospital].

Our hospital fights against a clinical study clearly. However, our hospital did not participate in a clinical study here. When I widened a clinical study in cooperation with the staff, I make a progress report. I started a clinical study only with a doctor first. Therefore it was recognized many problems happened and to promote a clinical study without cooperation of the work of many kinds. I studied with the staff to promote a clinical study and deepened understanding. Thereafter the clinical study was led by a nurse of the chemotherapy room; , in addition, was able to get various cooperation from a skiagrapher. When OGSG0603 began, the nurse and the pharmacist served to become the key than a doctor. I was able to promote a clinical study by cooperation of much staff. In addition, I was able to carry out the system improvement of each section by performing a clinical study.

A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer.

PURPOSE: Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) enhances antitumor activity. LV is thus often added to 5-FU-based regimens for the treatment of metastatic colorectal cancer (mCRC). A combination of S-1, oxaliplatin, and LV (SOL) was shown to be feasible, effective, and safe in a previous phase I trial. We therefore conducted a randomized phase II trial to evaluate efficacy and safety of SOL compared with mFOLFOX6. METHODS: Patients with mCRC and no prior chemotherapy were randomly assigned to receive either SOL or mFOLFOX6. SOL consisted of S-1 (40-60 mg bid) plus oral LV (25 mg bid) for 1 week and oxaliplatin (85 mg/m(2)) on day 1, repeated every 2 weeks. RESULTS: Among 107 patients enrolled from July 2008 through July 2009, 105 (56 in the SOL group and 49 in the mFOLFOX6 group) were eligible and evaluated. The median progression-free survival was 9.6 months in the SOL group and 6.9 months in the mFOLFOX6 group [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.49-1.40]. The median overall survival was 29.9 and 25.9 months, respectively (HR 0.91, 95 % CI 0.55-1.49). The response rate was 55 % in both groups. Grade 3 or 4 adverse drug reactions were neutropenia (20 % with SOL vs 41 % with mFOLFOX6), sensory neuropathy (20 vs 2.0 %), anorexia (13 vs 7.8 %), fatigue (11 vs 5.9 %), and diarrhea (11 vs 3.9 %). CONCLUSIONS: SOL demonstrated promising efficacy and acceptable toxicity as first-line chemotherapy for mCRC. Further studies of SOL combined with molecular target agents are warranted.

Phase II study of S-1 monotherapy in patients over 75 years of age with advanced gastric cancer (OGSG0404).

BACKGROUND: S-1+cisplatin (CDDP) is the standard treatment for advanced gastric cancer (AGC) in Japan and Korea. However, the usefulness of S-1 based chemotherapy for elderly patients is unclear. Therefore, we conducted a multicenter phase II study of S-1 monotherapy for AGC in elderly patients. MATERIALS AND METHODS: Chemotherapy-naïve patients aged over 75 years with AGC were enrolled. The starting dose of S-1 was determined on the basis of body surface area and modified according to the creatinine clearance value. S-1 was administered twice a day during a 4-week period followed by a 2-week rest period. RESULTS: Thirty-five patients were enrolled. The response rate (RR) was 14.3% and the median overall survival was 14.6 months. Grade 3 or more severe adverse events consisted of anaemia (3%), neutropaenia (3%), anorexia (3%), and fatigue (6%). There were no treatment-related deaths. CONCLUSION: Our study indicates that S-1 monotherapy is safe and well tolerated in chemotherapy-naïve elderly patients with AGC, but exerts limited activity when given using a tailor-made dosing strategy based on renal function.

Hepatic arterial infusion of 5-fluorouracil for patients with liver metastases from colorectal cancer refractory to standard systemic chemotherapy: a multicenter, retrospective analysis.

INTRODUCTION: This retrospective study evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU) for patients with liver metastases from colorectal cancer refractory to standard systemic chemotherapy. PATIENTS AND METHODS: Fifty-five patients who had shown disease progression during the prior standard systemic chemotherapy with oxaliplatin, irinotecan, and 5-FU were enrolled. The treatment was weekly HAIC with 5-FU 1000 mg/m2/5 hours through an indwelling catheter-port system. RESULTS: No major adverse reaction was observed other than grade 3 leukocytopenia (3.6%) and hyperbilirubinemia (1.8%). The overall response rate and disease control rate were 18.2% and 70.9%, respectively. The median progression-free survival and median overall survival (OS) were 2.8 months, and 6.7 months, respectively. The initial sites of disease progression were liver in 14, other than liver in 27, and both in 6. Multivariate analysis identified Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 and number of extrahepatic metastatic sites (NMS) ≤ 1 as favorable prognostic factors for OS (hazard ratio [HR], 8.277; 95% CI, 3.60-19.0; P = .000 for ECOG PS; and HR, 2.456; 95% CI, 1.30-4.61; P = .005 for NMS). CONCLUSION: HAIC with 5-FU may be a safe and effective treatment for patients with colorectal liver metastases refractory to standard systemic chemotherapy.

Early detection of therapeutic response to hepatic arterial infusion chemotherapy of liver metastases from colorectal cancer using diffusion-weighted MR imaging.

The purpose of this study was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) is useful for early detection of the response of hepatic colorectal metastases to hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU). The subjects were 12 patients with hepatic colorectal metastases. The indwelling catheter for HAIC was placed in the hepatic artery, and 1000 mg/m(2) 5-FU was given repeatedly once a week. DWI was performed before and 9 days after HAIC. The minimum and mean apparent diffusion coefficient (ADC) values (minADC and meanADC) were measured. The relative change in ADC values (%ADC) and the relative change in tumor size on follow-up CT after 3 months (reduction ratio) were determined. Liver metastases were divided into two groups, responder and nonresponder. The correlation between %ADC and reduction ratio was determined, and %ADC was compared between the two groups. Eleven patients successfully completed HAIC over the 3-month period; 48 metastatic lesions were evaluated. Positive correlations were observed for relative change between %minADC and reduction ratio (r = 0.709) and between %meanADC and reduction ratio (r = 0.536). Both %minADC and %meanADC were significantly greater in the responder group than in the nonresponder group. With the threshold determined as < 3.5%, the receiver-operating curve analysis showed higher sensitivity and specificity values for %minADC (100% and 92.6%, respectively) than for %meanADC (66.7% and 74.1%, respectively). In conclusion, the relative change in minimum ADC values on DWI may be useful for early detection of the response of liver metastases to HAIC with 5-FU.