***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose : Inherited variations in drug metabolizing enzymes may influence drug efficacy . This phase II study assesses the impact of second-line weekly irinotecan (CPT-11)/docetaxel in non-small cell lung cancer ( NSCLC ) patients , and gauges the uridine diphosphate glucuronosyl transferase ( UGT1A1 ) polymorphism influence in toxicity and antitumor activity . Experimental Design : Fifty-one patients with NSCLC treated with at least one prior chemotherapy regimen were enrolled . Patients received irinotecan 70 mg/m2 followed by docetaxel 25 mg/m2 . Both drugs were given on days 1 , 8 , and 15 every 28 days . UGT1A1 polymorphism were analyzed in blood sample s of 47 patients . The UGT1A1 polymorphism are classified according to the number of TA repeats in the promoter region of this gene . Results : Three patients ( 6 % ) achieved a partial response and nineteen patients ( 37 % ) had stable disease . Median survival was 8 months ( 95 % CI : 4.8–11.2 ) and 1-year survival 30 % . Grade 3–4 hematologic toxicity was low ( less than 10 % of patients ) ; 15 % of patients had grade 3 asthenia and 25 % of patients had grade 3/4 diarrhea . The frequency of UGT1A1 genotypes was as follows : 6/6 49 % , 6/7 36 % , and 7/7 15 % . No differences in toxicity were observed according to UGT1A1 polymorphism . A nonsignificant improvement in time to progression ( 4 vs. 3 months ) and median survival ( 11 vs. 8 months ) was detected in patients with the variant alleles ( 6/7 and 7/7 ) . Conclusions : This weekly irinotecan/docetaxel regimen has shown an acceptable toxicity profile while encouraging median and 1-year survival in heavily pretreated NSCLC patients . The tendency to better prognosis in patients carrying the variant genotypes 6/7 and 7/7 of UGT1A1 gene requires further validation Background : The impact of thymidylate synthase ( TYMS ) and UDP-glucoronosyltransferase 1A ( UGT1A ) germline polymorphisms on the outcome of colorectal cancer ( CRC ) patients treated with irinotecan plus 5-fluorouracil ( irinotecan/5FU )  is still controversial . Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU . Methods : Genotyping of TYMS ( 5′TRP and 3′UTR ) , UGT1A1 * 28 , UGT1A9 * 22 and UGT1A7 * 3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a r and omised phase 3 study . Their association with response , toxicity and survival was investigated by univariate and multivariate statistical analysis . Results : TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response ( OR=5.87 , 95 % confidence interval (CI)=1.68–20.45 ; P=0.005 ) . UGT1A1 * 28/*28 was predictive for haematologic toxicity ( OR=6.27 , 95 % CI=1.09–36.12 ; P=0.04 ) , specifically for neutropenia alone ( OR=6.40 , 95 % CI=1.11–37.03 ; P=0.038 ) or together with diarrhoea ( OR=18.87 , 95 % CI=2.14–166.67 ; P=0.008 ) . UGT1A9 * 1/*1 was associated with non-haematologic toxicity ( OR=2.70 , 95 % CI=1.07–6.82 ; P=0.035 ) . Haplotype VII ( all non-favourable alleles ) was associated with non-haematologic toxicity ( OR=2.11 , 95 % CI=1.12–3.98 ; P=0.02 ) . Conclusion : TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients . A genetic-based algorithm to optimise treatment individualisation is proposed Oxaliplatin and irinotecan have proven effective in the treatment of gastric cancer . We attempted to determine whether single nucleotide polymorphisms in ERCC1 , GST , TS and UGT1A1 predicted overall survival in gastric cancer patients receiving FOLFOX and /or FOLFIRI chemotherapy .  Total genomic DNA was extracted from the whole blood of patients . The PCR-restriction fragment length polymorphism technique was applied in order to detect the known variant sites of ERCC1 , GST , TS and UGT1A1 . The response rate of FOLFOX  ( N=75 ) was 24 % . Grade 3 - 4 neutropenia and neurotoxicity were observed at frequencies of 34.7 and 16 % , respectively . TTP and OS of first-line administration of FOLFOX ( N=35 ) were 3.1 months ( 95 % CI , 0.1 - 6.1 months ) and 13.9 months ( 95 % CI , 12.2 - 15.6 months ) , respectively . Only the GSTM1 positive genotype exhibited a significantly better time to progression ( P=0.023 ) . However , significant genotypic variation of TS , GST and ERCC1 , which was assumed to affect the activity of oxaliplatin , was not observed to affect RR , toxicity and overall survival . The response rate of FOLFIRI ( N=74 ) was 23 % . Grade 3 - 4 neutropenia and diarrhea were observed in 55.4 and 9.5 % of cases , respectively . TTP and OS of first-line administration of FOLFIRI ( N=33 ) was 4.9 months ( 95 % CI , 3.5 - 6.4 months ) and 19.0 months ( 95 % CI , 8.5 - 29.5 months ) . The low expression type ( 2R/2R , 2R/3C and 3C/3C ) of TS was associated with a high incidence of grade > or=3 neutropenia . However , significant genotypic variation of UGT1A1 , which was assumed to affect irinotecan toxicity , was not observed to affect RR , toxicity or survival . In this study , the GSTM1 positive genotype evidence d a significantly better time to progression in cases of advanced gastric cancer being treated with FOLFOX . The low expression type ( 2R/2R , 2R/3C and 3C/3C ) of TS was associated with a high incidence of grade > or=3 neutropenia in cases of advanced gastric cancer treated with FOLFIRI PURPOSE Irinotecan plus cisplatin ( IP ) improved survival over etoposide plus cisplatin ( EP ) in Japanese patients with extensive-stage small-cell lung cancer ( E-SCLC ) . To confirm those results and discern the potential role of population -related pharmacogenomics ( PG ) in outcomes , we conducted a large r and omized trial of identical design to the Japanese trial in North American patients with E-SCLC . PATIENTS AND METHODS Patients were r and omly assigned to IP ( irinotecan 60 mg/m(2 ) on days 1 , 8 , and 15 ; cisplatin 60 mg/m(2 ) day 1 , every 4 weeks ) or EP ( etoposide 100 mg/m(2 ) on days 1 through 3 ; cisplatin 80 mg/m(2 ) day 1 , every 3 weeks ) . Blood specimens for genomic DNA analysis were collected before r and om assignment in 169 patients . RESULTS Of 671 patients , 651 were eligible ( 324 and 327 patients in the IP and EP arms , respectively ) . Response rates with IP and EP were 60 % and 57 % , respectively ( P = .56 ) . Median progression-free survival for IP and EP was 5.8 and 5.2 months , respectively ( P = .07 ) . Median overall survival for IP and EP was 9.9 and 9.1 months , respectively ( P = .71 ) . Severe diarrhea was more common with IP ( 19 % v 3 % ) ; severe neutropenia and thrombocytopenia were higher with EP versus IP ( 68 % v 33 % and 15 % v 4 % , respectively ) . PG analysis showed that ABCB1 (C3435T)T/T ( membrane transport ) was associated with IP-related diarrhea ; UGT1A1 (G-3156A)A/A ( drug metabolism ) was associated with IP-related neutropenia . CONCLUSION This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients . Both regimens produced comparable efficacy , with less hematologic and greater gastrointestinal toxicity with IP . These results emphasize the potential importance of PG in interpreting trials of cancer therapy BACKGROUND The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined . Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer . METHODS In this open-label , r and omised , phase 3 trial , we r and omly assigned patients ( 1:1 ratio ) with advanced , measurable , non-resectable colorectal cancer and WHO performance status 0 - 2 to receive either first-line treatment with bolus ( 400 mg/m(2 ) ) and infusional ( 2400 mg/m(2 ) ) fluorouracil plus leucovorin ( 400 mg/m(2 ) ) ( simplified LV5FU2 regimen ) , second-line LV5FU2 plus oxaliplatin ( 100 mg/m(2 ) ) ( FOLFOX6 ) , and third-line LV5FU2 plus irinotecan ( 180 mg/m(2 ) ) ( FOLFIRI ) or first-line FOLFOX6 and second-line FOLFIRI . Chemotherapy was administered every 2 weeks . R and omisation was done central ly using minimisation ( minimisation factors were WHO performance status , previous adjuvant chemotherapy , number of disease sites , and centre ) . The primary endpoint was progression-free survival after two lines of treatment . Analyses were by intention-to-treat . This trial is registered at Clinical Trials.gov , NCT00126256 . FINDINGS 205 patients were r and omly assigned to the sequential group and 205 to the combination group . 161 ( 79 % ) patients in the sequential group and 161 ( 79 % ) in the combination group died during the study . Median progression-free survival after two lines was 10·5 months ( 95 % CI 9·6 - 11·5 ) in the sequential group and 10·3 months ( 9·0 - 11·9 ) in the combination group ( hazard ratio 0·95 , 95 % CI 0·77 - 1·16 ; p=0·61 ) . All six deaths caused by toxic effects of treatment occurred in the combination group . During first-line chemotherapy , significantly fewer severe ( grade 3 - 4 ) haematological adverse events ( 12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group ; p<0·0001 ) and non-haematological adverse events ( 26 events vs 186 events ; p<0·0001 ) occurred in the sequential group than in the combination group . INTERPRETATION Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced , non-resectable colorectal cancer . FUNDING Sanofi-Aventis France The primary end point of the study was the analysis of associations between polymorphisms with putative influence on  5-fluorouracil/irinotecan activity and progression-free survival ( PFS ) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy .  Peripheral blood sample s from 146 prospect ively enrolled patients were used for genotyping polymorphisms in thymidylate synthase ( TS ) , methylenetetrahydrofolate reductase ( MTHFR ) , excision repair cross-complementation group-1 ( ERCC 1 ) xeroderma pigmentosum group-D ( XPD ) , X-ray cross-complementing-1 ( XRCC 1 ) , X-ray cross-complementing-3 ( XRCC 3 ) and uridine diphosphate-glucuronosyltransferases-A1 ( UGT1 A1 ) . TS 3′-UTR 6+/6 + and XRCC3 - 241 C/C genotypes were associated with adverse PFS . Hazard ratio for PFS achieved 2.89 ( 95 % confidence interval=1.56–5.80 ; P=0.002 ) in 30 patients ( 20 % ) with both risk genotypes . Risk for Grade III – IV neutropenia was significantly associated with UGT1A1 * 28 7/7 genotype . These promising findings deserve further investigations and their validation 
    Output:
    
There was also no evidence of irinotecan dose , regimen or line of therapy having an impact on this association