***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: BACKGROUND Right- and left-sided colon cancers ( RC , LC ) differ with respect to biology , pathology and epidemiology . Previous data suggest a mortality difference between RC and LC . We examined if primary tumour side also predicts for outcome in chemotherapy refractory , metastatic colon cancer ( MCC ) . We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor ( EGFR ) inhibition with cetuximab . METHODS Reanalyzing NCIC CO.17 trial ( cetuximab versus best supportive care [ BSC ] )  , we coded the primary tumour side as RC ( caecum to transverse colon ) or LC ( splenic flexure to rectosigmoid ) . The association between tumour side and baseline characteristics was assessed . Cox regression models determined factors affecting overall survival ( OS ) and progression free survival ( PFS ) . RESULTS Patients with RC ( 150/399 ) had more poorly differentiated , mutant KRAS , mutated PIK3CA and wild-type BRAF tumours , fewer liver and lung metastases , and shorter interval between diagnosis and study entry . Among BSC patients , tumour side was not prognostic for PFS ( hazard ratios ( HR ) 1.07 [ 0.79 - 1.44 ] , p = 0.67 ) or OS ( HR 0.96 [ 0.70 - 1.31 ] , p = 0.78 ) . Among wild-type KRAS patients , those with LC had significantly improved PFS when treated with cetuximab compared to BSC ( median 5.4 versus 1.8 months , HR 0.28 [ 0.18 - 0.45 ] , p < 0.0001 ) , whereas those with RC did not ( median 1.9 versus 1.9 months , HR 0.73 [ 0.42 - 1.27 ] , p = 0.26 ) , [ interaction p = 0.002 ] . CONCLUSION In refractory MCC , tumour location within the colon is not prognostic , but is strongly predictive of PFS benefit from cetuximab therapy . Additional research is needed to underst and the molecular differences between RC and LC and their interaction with EGFR inhibition BACKGROUND No evidence -based treatment options are available for patients with advanced colorectal cancer ( CRC ) progressing after st and ard therapies . MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide . The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation , after failure of approved treatments . PATIENTS AND METHODS Patients were enrolled in a monocentre , open-label , phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles . The treatment was continued for at least six cycles or until progressive disease . RESULTS Thirty-two patients were enrolled from August 2012 to July 2013 . Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade ≥3 toxicities . No complete response occurred . The objective response rate was 12 % , reaching the pre-specified level for promising activity . Median progression-free survival and overall survival were 1.8 and 8.4 months , respectively . Patients with KRAS , BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation ( 44 % versus 0 % ; P=0.004 ) . TP53 status had no influence on the primary end point . CONCLUSIONS Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation . Further studies in biomolecularly enriched population s or in a r and omized setting are necessary to demonstrate the efficacy of temozolomide after failure of st and ard treatments Purpose Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a st and ard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer . However , in some cases , it is difficult to administer irinotecan after third-line treatment . Therefore , we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan , oxaliplatin , and fluoropyrimidines .  Methods The study was design ed as a phase II , non-r and omized , open-label , multicenter trial . Cetuximab was initially administered at 400 mg/m2 , followed by weekly infusion at 250 mg/m2 . S-1 was administered at a fixed dose of 80 mg/m2 orally twice daily for 28 days followed by a 14-day break , result ing in a 6-week treatment course . The primary endpoint was progression-free survival ( PFS ) . The secondary endpoints were the overall response rate ( ORR ) , overall survival ( OS ) , disease control rate ( DCR ) , time to treatment failure , dose intensity , safety , and BRAF mutation status . Results Thirty-seven patients were eligible . The median PFS was 5.5 months , the median OS was 13.5 months , the ORR was 29.7 % , and the DCR was 73.0 % . The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1 . Grade 3–4 adverse events that occurred in > 10 % of the patient population included rash , dry skin , diarrhea , paronychia , anorexia , fatigue , mucositis , and neutropenia . Conclusions Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan- , oxaliplatin- , and fluoropyrimidine-refractory metastatic colorectal cancer Background The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to st and ard chemotherapy has not been verified . We performed a single-arm , open-label , Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin . Methods Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy .  The primary endpoint was the disease control rate ( DCR ) after 12 weeks of treatment starting . The DCR was defined as the sum of patients with complete response , partial response , and stable disease . Results Thirty-three patients were enrolled . The median age was 62 ( range : 35–77 ) years and the male/female ratio was 19/14 . Eastern Cooperative Oncology Group performance status was 0 in 84.8 % . Fourteen primary tumors were in the colon and 19 were in the rectum . All patients received modified FOLFOX6 as the protocol treatment . After 12 weeks of treatment starting , the DCR was 39.4 % ( 95 % confidence interval 21.8–57.0 ) and the response rate ( complete response and partial response ) was 6.1 % . The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2 . Median progression-free survival time was 98 days and median overall survival was 300 days . The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1 % and 3.1 % , respectively . The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1 % and 0 % , respectively . There were no other severe adverse events and no treatment-related deaths . Conclusion Reintroducing oxaliplatin can be both safe and effective . This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior oxaliplatin-based therapy PURPOSE We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies , cetuximab and bevacizumab , in patients with metastatic colorectal cancer . PATIENTS AND METHODS This was a r and omized phase II study in patients with irinotecan-refractory colorectal cancer . All patients were naïve to both bevacizumab and cetuximab .  Patients in arm A received irinotecan at the same dose and schedule as last received before study entry , plus cetuximab 400 mg/m2 loading dose , then weekly cetuximab 250 mg/m2 , plus bevacizumab 5 mg/kg administered every other week . Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan . RESULTS Forty-three patients received cetuximab , bevacizumab , and irinotecan ( CBI ) and 40 patients received cetuximab and bevacizumab  alone ( CB ) . Toxicities were as would have been expected from the single agents . For the CBI arm , time to tumor progression ( TTP ) was 7.3 months and the response rate was 37 % ; for the CB arm , TTP was 4.9 months and the response rate was 20 % . The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months . CONCLUSION Cetuximab and bevacizumab can be administered concurrently , with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone . This combination plus irinotecan also seems to be feasible . The activity seen with the addition of bevacizumab to cetuximab , or to cetuximab plus irinotecan , seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naïve to bevacizumab The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost . Evidence for clinical benefit from new treatment options is derived from clinical research , in particular phase III r and omised trials , which generate unbiased data regarding the efficacy , benefit and safety of new therapeutic approaches . To date , there is no st and ard tool for grading the magnitude of clinical benefit of cancer therapies , which may range from trivial ( median progression-free survival advantage of only a few weeks ) to substantial ( improved long-term survival ) . Indeed , in the absence of a st and ardised approach for grading the magnitude of clinical benefit , conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented , discussed and promoted as major advances or ' breakthroughs ' . Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high- quality clinical trials , the European Society for Medical Oncology ( ESMO ) has developed a vali date d and reproducible tool to assess the magnitude of clinical benefit for cancer medicines , the ESMO Magnitude of Clinical Benefit Scale ( ESMO-MCBS ) . This tool uses a rational , structured and consistent approach to derive a relative ranking of the magnitude of clinical ly meaningful benefit that can be expected from a new anti-cancer treatment . The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care , helping to frame the appropriate use of limited public and personal re sources to deliver cost-effective and affordable cancer care . The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis Aims and Background We evaluated the activity in terms of time to progression ( TTP ) of mitomycin C and capecitabine in patients with advanced colorectal cancer who progressed after 2 lines of chemotherapy . Methods Patients with advanced colorectal cancer undergoing third-line chemotherapy after failure of 5-FU with CPT-11 or oxaliplatin-based chemotherapy regimens  were treated with capecitabine and mitomycin C. Results Sixty-one patients were enrolled in this study . The median age was 55 years ( range , 26 - 78 years ) and the male : female ratio 21 : 40 . We observed partial remissions in 5 patients ( 8 % ) , stable disease in 25 patients ( 40 % ) and progression of disease in 31 patients ( 52 % ) . Median TTP was 3 months and median survival was 6 months . Global toxicity was mild and entirely acceptable . Grade 3 - 4 hematological toxicity occurred in 12 patients and grade 3 - 4 nonhematological toxicity in 5 patients . Conclusions The combination of capecitabine and mitomycin C could represent an effective and manageable treatment option for colorectal cancer patients failing previous chemotherapy regimens BACKGROUND Cetuximab ( C ) , alone or with irinotecan , demonstrates activity in irinotecan-refractory colorectal cancer ( CRC ) . Activity of 5-fluorouracil ( 5-FU ) , leucovorin ( L ) , and bevacizumab ( B ) , and preliminary data of cetuximab + bevacizumab , and toxicity profiles suggests that FOLF-CB ( 5-FU , L , C+B ) may have activity with a favorable toxicity profile as first-line therapy . METHODS Eligible patients were r and omized at registration to either 
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There was limited evidence to support rechallenge with chemotherapy , targeted therapy or both .
Compared with placebo , an overall survival benefit for trifluridine/tipiracil ( also known as TAS-102 ) or regorafenib has been shown for patients previously treated with conventional chemotherapy and targeted therapy .
There was no evidence to suggest a difference in efficacy between these treatments .
Conclusions These findings support the introduction of an approved agent such as trifluridine/tipiracil or regorafenib beyond the second line before any rechallenge in patients with mCRC who have failed second-line treatment