Hideki Isobe

Phase II Trial of Cetuximab plus Irinotecan for Oxaliplatin- and Irinotecan-Based Chemotherapy-Refractory Patients with Advanced and/or Metastatic Colorectal Cancer: Evaluation of Efficacy and Safety Based on KRAS Mutation Status (T-CORE0801)

Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. Methods: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. Results:KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. Conclusion: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.

Hyperbaric Oxygen Therapy for Pancreatic and Gastrointestinal Disease

We report the results of hyperbaric oxygen therapy (HBO) for pancreatic and gastrointestinal disease. Thirty-nine patients received 100% oxygen at 2 atmospheres absolute pressure for 60 min. Results: In all four patients with liver abscess, feverishness subsided within 2.7 days after the start of HBO. All of three patients with infection after hepatic resection were relieved of systemic inflammatory response system (SIRS) and showed reduced CRP levels after HBO. In all of seven patients with acute appendicitis, pyrexia was relieved at 1.8 days after HBO introduction, and further surgery was not necessary. Among five patients with colorectal disease, HBO was effective in four, but ineffective in one. Five of six cases of infection after pancreatic resection were cured immediately after HBO. There were no complications such as middle ear inflammation, oxygen intoxication or pneumothorax. Conclusions: HBO is sometimes effective for treatment of refractory gastro enteric infections, especially those for which drainage is difficult. Pyrexia improved within 2.3 days after the start of HBO in most cases. If infection is refractory to standard antibiotics or drainage, HBO should be considered as an additional treatment. Since HBO is safe and generally cost-effective, it should be considered as an adjunct therapy for all gastro enteric infections.

Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.

Phase II intermittent (or stop and go) l-OHP administration of first-line bevacizumab (BV) plus mFOLFOX6 or CapeOX therapies in Japanese patients with mCRC: The interim report of T-CORE0901.

664 Background: Cumulative sensory neurotoxicity of l-OHP used in standard 1st-line FOLFOX / CapeOX +/- BV therapies in mCRC results in impairment of patients quality of life (QoL) and discontinuation of the treatment. CONcePT trial revealed that intermittent l-OHP use in BV plus FOLFOX7 is safe, keeping efficacy comparing with BV plus FOLFOX7 in which l-OHP is administered until time to treatment failure. But it is unknown that intermittent l-OHP administration is also safe and effective in Japanese pts with mCRC Methods: This trial aims to enroll 65 of Japanese pts with mCRC. Either BV+FOLFOX or BV+CapeOX is selected by decision of physician in charge. In BV+FOLFOX arm, pts receive 6 cycles of BV plus mFOLFOX6 (5 mg/kg of BV, 85 mg/m2 of l-OHP, 200 mg/m2 of I-LV, 400 mg/m2 of 5-FU by rapid IV infusion on day1, and 2,400 mg/m2 of 5-FU 46 hr by continuous IV infusion as a 2 weeks course) and 6 cycles of BV plus sLV5FU2. In BV+CapeOX arm, pts recieve 4 cycles of BV plus CapeOX (7.5 mg/kg of BV, 120 mg/m2 of l-OHP and capecitabine 1,000mg/m2 twice daily, day1 to 14 as a 3weeks course) and 4 cycles of BV+capecitabine. The primary endpoint is progression free survival (PFS) and secondary endpoints are tumor response (RR), overall survival (OS), time to treatment failure (TTF) and frequency of neurotoxicity. RESULTS According the protocol, interim analysis about efficacy and safety was performed at the time the 13th pts was received the treatment for 7 months. Median progression free survival is 290+ days (95% CI 119 - 558 days) and PFS of 9 cases were more than 7 months, which is threshold value. No serious adverse effects were observed in 13 cases. The efficacy and safety evaluation committee recommended continuing the study and the current accrual is 47 cases. CONCLUSIONS This is the interim report of T-CORE0901 trial and the study remains open to accrual with projected enrollment completion in 2012.