S-1 is an oral anticancer agent composed of tegafur (FT),S -1 (Taiho Pharmaceutical, Tokyo, Japan) is an oral anticancer agent. This anticancer drug is currently one of the most widely prescribed agents for treatment of gastric cancer in Japan, as a standard option for chemotherapy.(1-3) S-1 is a formulation of FT, CDHP, and Oxo in a molar ratio of 1:0.4:1. (4) FT is a pro-drug for cytotoxic 5-FU. The biotransformation of FT to 5-FU is demonstrated to be catalyzed by the liver drug-metabolizing enzyme CYP2A6.(5,6) The addition of CDHP increases the plasma level of 5-FU, as CDHP prevents degradation of 5-FU by competitively inhibiting DPD, (7) which is a rate-limiting enzyme responsible for 5-FU detoxification.(8) Oxo reduces the gastrointestinal toxicity caused by the active 5-FU by blocking the orotate phosphoribosyltransferase pathway, which relates to further activation of 5-FU. (9,10) CYP2A6 is a polymorphic enzyme that shows considerable interindividual variability in its activity.(11-18) CYP2A6*1 is defined as the wild-type allele. CYP2A6*4 is a complete deletion of the CYP2A6 gene.(11-13) Among the CYP2A6*4 variants, CYP2A6*4A is a major variant seen in the Japanese population.(12,13) CYP2A6*7 is a single nucleotide polymorphism (1412T>C) causing an amino acid change (I471T) that decreases enzymatic activity.(14) CYP2A6*9 has a -48T>G nucleotide substitution in the TATA box of the 5′ flanking region of the CYP2A6 gene, which reduces the expression levels of CYP2A6 mRNA and protein in human livers.(15,16) These CYP2A6 polymorphisms are seen frequently in Japanese people with allele frequencies of approximately 20% for CYP2A6*4A, 6% for CYP2A6*7, and 20% for CYP2A6*9. (13,17,18) Thus, it was postulated that these CYP2A6 genetic polymorphisms in Japanese people influenced the PK variability of FT and 5-FU and susceptibility to adverse effects as well as S-1 anticancer activity. The results obtained by Daigo et al. partly support this hypothesis. (19) They found that the four-fold higher AUC of FT seen in one patient compared with four other patients was attributed to the simultaneous presence of CYP2A6*4A and CYP2A6*11 (S224P), causing reduced catalytic activity in the patient. This implies that CYP2A6 genetic polymorphisms alter the PK of FT.Because CDHP has been reported to be predominantly excreted in the urine, (20) interindividual variability of the plasma level of CDHP caused by renal function was expected to occur. The variability in the plasma concentration of CDHP that thus occurred was assumed to affect the PK of 5-FU. Ikeda et al. have suggested this point with data obtained from four patients. (21) Taking these considerations into account, the PK of 5-FU were expected to be influenced by polymorphisms in the CYP2A6 gene, (11)(12)(13)(14)(15)(16)(17)(18) and the PK of CDHP. Therefore, in the present study, the effects of CYP2A6 genotype and plasma

Pulmonary resection for colorectal metastases is well accepted. However, the main cause of death after pulmonary resection is recurrence in the lung. The aim of this study was to clarify whether a repeat pulmonary resection was warranted in patients with recurrent lung metastases. The records of 76 patients undergoing initial pulmonary resection, including 14 patients undergoing a repeat operation for lung metastases, were reviewed for survival, operative morbidity, and mortality. Overall, pulmonary resection was performed 96 times in this group of patients. The operative mortality was 0%, morbidity involved only one case of major postoperative hemorrhage associated with the first operation. The cumulative 5-year survival rate for the 76 patients was 32%. After the second pulmonary operation, recurrence was identified in 79% (11 of 14) of the patients. In 10 patients with isolated lung recurrence after a first pulmonary resection, who showed no extrapulmonary disease before or at the time of first thoracotomy, the 3-year, and 5-year-survival rate after the second pulmonary resection was 67%, and 33%, respectively, comparing favorably with the survival rate in those who underwent primary pulmonary resection. In contrast, all 4 patients with extrapulmonary disease before or at the time of thoracotomy had poor prognosis. Repeat pulmonary operation for isolated recurrent colorectal metastases to the lung yielded results comparable to those after the first pulmonary resection in terms of operative mortality and survival in the absence of hilar/mediastinal lymph node or extrathoracic involvement.

ABSTRACT:This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) <20 ml/min] who were undergoing dialysis and received 100 mg/m 2 irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr >60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDPglucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, IntroductionSeveral lines of evidence have demonstrated that severe renal failure differentially affects drug uptake or efflux transporters and drug-metabolizing enzymes in the liver. Even drugs that are predominantly eliminated by hepatic transport and metabolism can be affected by severe renal failure, leading to unexpected consequences, such as atypical pharmacokinetics and an increased risk of adverse drug reactions. High levels of uremic toxins in such patients are partially implicated in these effects (Nolin et al., 2008).Irinotecan is extensively metabolized in the liver to an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by carboxylesterase, which is then conjugated predominantly by liver UDPglucuronosyltransferase (UGT) 1A1 to form inactive SN-38 glucuronide (SN-38G) (chemical structures; http://www.pharmgkb.org/ search/pathway/irinotecan/metabolites.html). Polymorphisms in UGT1A1 gene, such as UGT1A1*28 and *6, can cause reduced glucuronidation of SN-38, thus resulting in severe irinotecaninduced toxicity. UGT1A1*6/*6, *28/*28, and *6/*28 genotypes have been linked to significantly decreased conversion of SN-38 to SN-38G and severe neutropenia in Asians (Minami et al., 2007).Transporters expressed in the liver are also implicated in the pharmacokinetics of irinotecan and its metabolites. The uptake of SN-38 from the systemic circulation by hepatocytes is mediated by organic anion transporter peptide 1B1 (OATP1B1) (Nozawa et al., 2005). ATP-binding cassette transporters such as ABCC2, ABCB1, and ABCG2 govern the biliary excretion of irinotecan and its metabolites (http://www.pharmgkb.org/do/serve?objId ϭ PA2001&objCls ϭ Pathway).Because irinotecan is extensively metabolized and transported in the liver, attention has been focused on the hepatic factors underlying interpatient variability in pharmacokinetics of irinotecan. Studies examining the pharmacokinetics of irinotecan in renally impaired patients are scant. The pharmacokinetics of irinotecan in patients with mild renal impairment who had a creatinine clearance (Ccr) of 35 to 66 ml/min were similar to those in patients with normal renal function (de Jong et al., 2008). Although several case reports have examined the effects of more severe renal dysfunction requiring dialysis on the pharmacokinetics or toxicity of irinotecan (Venat-Bouvet et al., 2007;Czock et al., 2009), no prospective study has been per...

ImportanceFor patients with RAS wild-type metastatic colorectal cancer, adding anti–epidermal growth factor receptor (anti-EGFR) or anti–vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined.ObjectiveTo evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer.Design, Setting, and ParticipantsRandomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015–January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022).InterventionsPanitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days.Main Outcomes and MeasuresThe primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate.ResultsIn the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).Conclusions and RelevanceAmong patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population.Trial RegistrationClinicalTrials.gov Identifier: NCT02394795

We found that multiple concomitant medicines were significantly associated with severe irinotecan-related toxicity, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions in patients with cancer who received irinotecan-based chemotherapy.