Downstaging Without Complete Pathologic Response After Neoadjuvant Treatment Improves Cancer Outcomes for cIII but not cII Rectal Cancers Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer Decreases Distant Recurrence and Could Eradicate Local Recurrence KRAS and BRAF mutations and PTEN expression do not predict efficacy of cetuximab-based chemoradiotherapy in locally advanced rectal cancer. Effect of neoadjuvant cetuximab, capecitabine, and radiotherapy for locally advanced rectal cancer: results of a phase II study Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with locally advanced resectable rectal cancer: a multicenter Phase II study. Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years' follow-Up. A road map for efficient and reliable human genome epidemiology Neoadjuvant therapy of rectal carcinoma with UFT-leucovorin plus radiotherapy. Identification of a Biomarker Profile Associated With Resistance to Neoadjuvant Chemoradiation Therapy in Rectal Cancer Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 to T4 rectal cancer A Pathologic Complete Response of Rectal Cancer to Preoperative Combined-Modality Therapy Results in Improved Oncological Outcome Compared With Those Who Achieve No Downstaging on the Basis of Preoperative Endorectal Ultrasonography Quantitative Synthesis in Systematic Reviews Long-term Oncologic Outcome Following Preoperative Combined Modality Therapy and Total Mesorectal Excision of Locally Advanced Rectal Cancer Preoperative radiochemotherapy in rectal cancer: long-term results of a phase II trial.
Background The aim of this study was to evaluate whether downstaging impacts prognosis in patients with cII versus cIII rectal cancer . Material s and Methods We identified from our colorectal cancer data base 295 patients with primary cII and cIII rectal cancer staged by CT and ERUS/MRI who received 5-FU-based chemoradiation followed by R0 surgery after a median interval of 7 weeks during 1997–2007 . The median radiotherapy dose was 5040 cGy . We excluded 58 patients with pathologic complete response ( pCR ) and compared among the remaining 162 patients pathologic downstaging ( cII to ypI , cIII to ypII or ypI ) versus no pathologic downstaging ( c stage ≤ yp stage ) . Outcomes evaluated were 5-year overall survival , 3-year cancer-specific survival , disease-free survival , overall recurrence , local recurrence , and distant recurrence . Results The median age was 58 years and median follow-up was 48 months . Patients with downstaging versus no downstaging were statistically comparable with respect to demographics , chemoradiation regimen , interval time between neoadjuvant chemoradiation and surgery , tumor distance from anal verge , surgical procedures performed , and follow-up time . With the exception of local recurrence rates , downstaging result ed in significantly improved cancer outcomes for cIII but not cII . Conclusions Downstaging without pCR is a significant prognostic factor for patients with stage cIII rectal cancer . Tumor response to neoadjuvant chemoradiation should be taken into account when defining the optimal adjuvant chemotherapy regimen for patients with cIII rectal cancer Background The aim of this study was to evaluate the clinical implication s of pathologic complete response ( pCR ) ( i.e. , T0N0M0 ) after neoadjuvant chemoradiation and radical surgery in patients with locally advanced rectal cancer . Material s and Methods A single-center , prospect ively maintained colorectal cancer data base was queried for patients with primary cII and cIII rectal cancer staged by CT and ERUS/MRI undergoing long-course neoadjuvant chemoradiation followed by proctectomy with curative intent between 1997 and 2007 . Patients were stratified into pCR and no-pCR groups and compared with respect to demographics , tumor and treatment characteristics , and oncologic outcomes . Outcomes evaluated were 5-year overall survival , disease-free survival , disease-specific mortality , local recurrence , and distant recurrence . Results The query returned 238 patients ( 73 % male ) , with a median age of 57 years and median follow-up of 54 months . Of these , 58 patients achieved pCR . Patients with pCR vs no-pCR were statistically comparable with respect to demographics , chemoradiation regimens , tumor distance from anal verge , clinical stage , surgical procedures performed , and follow-up time . No patient with pCR had local recurrence . Overall survival and distant recurrence were also significantly improved for patients achieving pCR . Conclusions Achievement of pCR after neoadjuvant chemoradiation is associated with greatly improved cancer outcomes in locally advanced rectal cancer . Future studies should evaluate the relationship between increases in pCR rates and improvements in cancer outcomes in this population PURPOSE Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog ( PTEN ) ( deleted on chromosome 10 ) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer . The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer ( LARC ) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown . METHODS AND MATERIAL S We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy ( 45 Gy plus 5.4 Gy ) in patients with LARC ( stage uT3/4 or uN+ ) . The status of KRAS and BRAF mutations was determined with direct sequencing , and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies . Tumor regression was evaluated by using st and ardized regression grading , and disease-free survival ( DFS ) was calculated according to the Kaplan-Meier method . RESULTS A total of 57 patients were available for analyses . A total of 31.6 % of patients carried mutations in the KRAS genes . No BRAF mutations were found , while the loss of PTEN expression was observed in 9.6 % of patients . Six patients achieved complete remission , and the 3-year DFS rate was 73 % . No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers . CONCLUSIONS In the present series , no BRAF mutation was detected . The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS Purpose The aim of this study was to investigate the efficacy and safety of neoadjuvant cetuximab , capecitabine , and radiotherapy for patients with locally advanced rectal cancer . Methods Sixty-three eligible patients were selectively enrolled in this study . Neoadjuvant treatment consisted of cetuximab and capecitabine for 6 weeks and radiotherapy for 5 weeks . Surgical resection was performed 6–8 weeks after the completion of neoadjuvant treatment . KRAS mutation statuses were analyzed retrospectively after the cetuximab treatment . All the patients underwent a st and ardized postoperative follow-up for at least 3 years . Results A pathological complete response ( pCR ) was achieved in eight patients ( 12.7 % ) . Overall down-staging was found in 49 patients ( 77.8 % ) . The 3-year disease-free survival ( DFS ) rate and overall survival ( OS ) rate was 76.2 % and 81.0 % , respectively . The most common adverse events during neoadjuvant treatment were acneiform skin rash ( 82.5 % ) , radiodermatitis ( 46.0 % ) , and diarrhea ( 36.5 % ) . KRAS mutations were detected in 19 of 63 ( 31.2 % ) tumors . The down-staging rate in patients with KRAS wild-type ( WT ) was significantly higher than patients with KRAS mutation ( P = 0.020 ) . There was no significant difference in the pCR rate , 3-year DFS rate or 3-year OS rate between KRAS WT patients and KRAS-mutated patients . Conclusion Neoadjuvant treatment with cetuximab and capecitabine-based chemoradiotherapy is safe and well tolerated . The pCR rate , 3-year DFS rate and OS rate are not superior to the rate of neoadjuvant chemoradiotherapy using two or more cytotoxic agents . The KRAS WT is highly associated with tumor down-staging to cetuximab plus capecitabine-based CRT in patients with LARC PURPOSE To evaluate the efficacy and safety of preoperative chemoradiation with cetuximab , irinotecan , and capecitabine in patients with rectal cancer . METHODS AND MATERIAL S Forty patients with locally advanced , nonmetastatic , and mid- to lower rectal cancer were enrolled .  Radiotherapy was delivered at a dose of 50.4 Gy/28 fractions . Concurrent chemotherapy consisted of an initial dose of cetuximab of 400 mg/m(2 ) 1 week before radiotherapy , and then cetuximab 250 mg/m(2)/week , irinotecan 40 mg/m(2)/week for 5 consecutive weeks and capecitabine 1,650 mg/m(2)/day for 5 days a week ( weekdays only ) from the first day during radiotherapy . Total mesorectal excision was performed within 6 ± 2 weeks . The pathologic responses and survival outcomes were evaluated as study endpoints , and an additional KRAS mutation analysis was performed . RESULTS In total , 39 patients completed their planned preoperative chemoradiation and underwent R0 resection . The pathologic complete response rate was 23.1 % ( 9/39 ) , and 3 patients ( 7.7 % ) showed near total regression of tumor . The 3-year disease-free and overall survival rates were 80.0 % and 94.7 % , respectively . Grade 3/4 toxicities included leukopenia ( 4 , 10.3 % ) , neutropenia ( 2 , 5.1 % ) , anemia ( 1 , 2.6 % ) , diarrhea ( 2 , 5.1 % ) , fatigue ( 1 , 2.6 % ) , skin rash ( 1 , 2.6 % ) , and ileus ( 1 , 2.6 % ) . KRAS mutations were found in 5 ( 13.2 % ) of 38 patients who had available tissue for testing . Clinical outcomes were not significantly correlated with KRAS mutation status . CONCLUSIONS Preoperative chemoradiation with cetuximab , irinotecan , and capecitabine was active and well tolerated . KRAS mutation status was not a predictive factor for pathologic response in this study PURPOSE To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy ( RT ) followed by surgery and postoperative flurouracil (FU)/leucovorin ( LV ) in patients with rectal cancer . PATIENTS AND METHODS Patients ( n = 94 ) with potentially resectable tumors , ultrasound at stages T2N+ ( n = 4 ) , T3 ( n = 77 ) , T4 ( n = 13 ) were treated with UFT ( 400 mg/m2/d , 5 days a week for 5 weeks ) and concomitant RT to the pelvis ( 45 Gy ; 1.8 Gy/d over 5 weeks ) . Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV . Primary end points included downstaging , pathologic responses , and sphincter-preserving surgery . Secondary end points were recurrence-free survival and overall survival . RESULTS All patients received the full RT dose . Fifteen patients ( 16 % ) needed UFT dose reduction . Preoperative G3 + toxicities included diarrhea ( 14 % ) , leukopenia ( 1 % ) , thrombocytopenia ( 1 % ) , and nausea ( 4 % ) . The downstaging rate was 54 % , pathologic complete response ( pCR ) was 9 % and , in an additional 23 % , there were only residual microscopic foci . When cellular viability criteria were taken into account , the pCR was 15 % . From 43 patients with abdominoperineal resection indication , 11 ( 25 % ) had sphincter-preserving surgery performed . Postoperative scheduled chemotherapy dose was not administered to 24 % of patients because of G3 + toxicity ( diarrhea , 8 % ; mucositis , 9 % ; and leukopenia , 7 % ) . Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without . At 3 years , actuarial patterns of failure were pelvic , 5 % and distant , 11 % . OS was 75 % . CONCLUSION UFT combined with RT is safe and effective . In resectable rectal cancer , if preoperative treatment is considered , this approach can be an option Networks of investigators have begun sharing best practice s , tools and methods for analysis of associations between genetic variation and common diseases . A Network of Investigator Networks has been set up to drive the process , sponsored by the Human Genome Epidemiology Network . A workshop is planned to develop consensus guidelines for reporting results of genetic association studies . Published literature data bases will be integrated , and unpublished data , including ' negative ' studies , will be captured by online journals and through investigator networks . Systematic review s will be exp and ed to include more meta-analyses of individual-level data and prospect i ve meta-analyses . Field synopses will offer regularly up date d overviews BACKGROUND The object of this phase II study was to assess the impact of preoperative external radiation therapy combined with UFT and leucovorin on tumor response , sphincter preservation and tumor control in patients with rectal carcinoma . PATIENTS AND METHODS Forty-one patients with resectable extraperitoneal rectal adenocarcinoma received radiation therapy and two courses of chemotherapy . Chemotherapy consisted of a 2-h infusion of 6S-steroisomer of leucovorin ( 6SLV ) 250 mg/m2 on day 1 , oral 6SLV 7.5 mg every 12 h on days 2 - 14 , and UFT either 350 or 300 mg/m2 on days 1 to 14 every 28 days . Six additional courses of chemotherapy were given after surgery . RESULTS Seven of 16 patients ( 43 % ) who received 350 mg/m2/day of UFT had grade 3 - 4 diarrhea and two other patients ( 12 % ) had grade 3 - 4 dermatitis . The next 25 patients received 300 mg/m2/day of UFT and only 14 % of them had grade 3 - 4 diarrhea . Surgery consisted of low-anterior resection in 26 patients ( 63 % ) and abdominal-perineal amputation in 15 ( 37 % ) . There were six histological complete responses ( 15 % ) . Downstaging occurred in 25 patients ( 63 % ) . The overall survival at 3 years was 90 % and the pelvic disease-free survival 92 % . CONCLUSIONS Preoperative therapy with radiotherapy and UFT-6SLV downstaged 63 % of tumors and allowed a sphincter-preserving procedure in some patients . Toxicity was moderate . This scheme is convenient because of the oral administration of chemotherapy Objective : To identify a biomarker profile associated with tumor response to chemoradiation ( CRT ) in locally advanced rectal cancer . Background : Rectal cancer response to neoadjuvant CRT is variable . Whereas some patients have a minimal response , others achieve a pathologic complete response ( pCR ) and have no viable cancer cells in their surgical specimens . Identifying biomarkers of response will help select patients more likely to benefit from CRT . Methods : This study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery . Tumor DNA from pretreatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes . Genetic biomarkers were correlated with tumor response to CRT ( pCR vs non-pCR ) , and the association of single or combined biomarkers with tumor response was determined . Results : Thirty-three of 132 ( 25 % ) patients achieved a pCR and 99 ( 75 % ) patients had non-pCR . Three individual markers were associated with non-pCR ; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation ( P = 0.0145 ) , cyclin D1 G870A ( AA ) polymorphism ( P = 0.0138 ) , and methylenetetrahydrofolate reductase ( NAD(P)H ) C677 T ( TT ) polymorphism ( P = 0.0120 ) . Analysis of biomarker combinations revealed that none of the 27 patients with both tumor protein p53 ( p53 ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations had a pCR . Further , in patients with both p53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations or the cyclin D1 G870A ( AA ) polymorphism or the methylenetetrahydrofolate reductase ( NAD(P)H ) C677 T ( TT ) polymorphism ( n = 52 ) the association with non-pCR was further strengthened ; 51 of 52 ( 98 % ) of patients were non-pCR . These biomarker combinations had a validity of more than 70 % and a positive predictive value of 97 % to 100 % , predicting that patients harboring these mutation/polymorphism profiles will not achieve a pCR . Conclusions : A specific biomarker profile is strongly associated with non-pCR to CRT and could be used to select optimal oncologic therapy in rectal cancer patients . Clinical Trials.org Identifier : NCT00335816 BACKGROUND : A prospect i ve study was undertaken to evaluate the response and toxicity of neoadjuvant chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer . PATIENTS AND METHODS : Since 1995 , 30 patients ( 18 males ; median age , 56 ( range , 25–83 ) years ) have received preoperative chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer . All patients underwent an endorectal ultrasound , CT scan , and review in our multidisciplinary Gastrointestinal Tumor Board before treatment . All patients had pathology-demonstrated invasive adenocarcinoma of the rectum . Eleven patients were Stage T3N0 , 14 were T3N1 , and five were T4N1 . Patients received radiotherapy to the primary tumor and draining lymph nodes ( 45 Gy ) followed by a tumor boost ( 50.4–54 Gy ) . Protracted-venous-infusion 5-fluorouracil ( 225 mg/m2 per day , seven days per week ) was administered throughout treatment . Surgical resection was performed six to ten weeks after completing chemoradiotherapy . Using endorectal ultrasound measurements , the primary tumor was a median of 4 ( range , 0–12 ) cm from the anal verge , encompassed 50 ( range , 20–90 ) percent of the rectal circumference , and was 6 ( range , 3–12 ) cm in diameter . RESULTS : No Grade 4 toxicity was observed during chemoradiotherapy . Three patients experienced Grade 3 toxicity ( diarrhea ) , and four patients required a treatment interruption of greater than three days . All patients completed at least 90 percent of the prescribed radiotherapy dose . All patients underwent surgical resection . Ninety-four percent had clear surgical margins . All pathologic specimens had significant evidence of necrosis , hyalinization , and fibrosis . Thirty-three percent of the specimens had a complete pathologic response ( defined as no evidence of viable tumor cells ) . Of the 19 patients with ultrasound-staged N1 disease , only five had pathologic evidence of nodal involvement after chemoradiotherapy . Of the 25 patients with ultrasound-staged T3 disease , pathologic staging revealed eight with T0 , two with T1 , five with T2 , and ten with T3 disease . Of the five patients with ultrasound-staged T4 disease , pathologic staging revealed two with T0 , one with T2 , and two with T3 disease . No patient developed progressive disease while on treatment . Two patients have experienced local failure at 6 and 20 months , and one patient failed in the liver at seven months . Twenty-seven patients remain free of disease with a median follow-up of 20 ( range , 3–53 ) months . CONCLUSION : Our experience suggests that preoperative chemoradiotherapy is well tolerated , down-stages tumors , and sterilizes regional lymph nodes Background Preoperative combined-modality therapy ( CMT ) is the preferred treatment for locally advanced rectal cancer ( endorectal ultrasonography [ ERUS ] T3–4 , N1 , or clinical ly bulky ) and achieves a pathologic complete response ( pCR ) in 4 % to 33 % of patients . However , the prognostic significance of pCR remains unclear . Methods A prospect ively collected data base was queried to identify 200 patients with locally advanced disease treated from 1992 to 2002 . The pCR group was defined as having no evidence of viable tumor on pathologic analysis . The no-downstaging group was defined as no difference between the pre-CMT ERUS stage and the pathologic stage . Those achieving some downstaging but not pCR were excluded . Patients were treated with CMT ( 5040 cGy of radiation and 5-fluorouracil – based chemotherapy ) followed by surgery , and 51 ( 85 % ) in the pCR group and 129 ( 92 % ) in the no-downstaging group ( P = .1 ) received postoperative chemotherapy .  Recurrence-free survival ( RFS ) and overall survival ( OS ) were determined by using the Kaplan-Meier method . Results The median follow-up was 38.6 months ( range , 18.2–124.9 months ) . The pCR ( n = 60 ) and control ( n = 140 ) groups were similar in age ( P = .6 ) , sex ( P = .4 ) , distance of the tumor from the anal verge ( P = .3 ) , pre-CMT ERUS stage ( P = .2 ) , and comorbidities ( P = .2 ) . The 5-year RFS was 96 % and 54 % in the pCR and control groups , respectively ( P < .00001 ) ; the 5-year OS was 90 % and 68 % ( P = .009 ) . Sphincter-preservation rates were higher in the pCR group ( P = .01 ) . Conclusions Rectal cancer patients with pCR after preoperative CMT have improved RFS , OS , and sphincter preservation compared with patients without downstaging . Because pCR seems to be associated with better outcome , an underst and ing of the factors governing the response to CMT should be pursued A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis Objective : Our aims were to ( 1 ) determine the long-term oncologic outcome for patients with rectal cancer treated with preoperative combined modality therapy ( CMT ) followed by total mesorectal excision ( TME )  , ( 2 ) identify factors predictive of oncologic outcome , and ( 3 ) determine the oncologic significance of the extent of pathologic tumor response . Summary Background Data : Locally advanced ( T3–4 and /or N1 ) rectal adenocarcinoma is commonly treated with preoperative CMT and TME . However , the long-term oncologic results of this approach and factors predictive of a durable outcome remain largely unknown . Methods : Two hundred ninety-seven consecutive patients with locally advanced rectal adenocarcinoma at a median distance of 6 cm from the anal verge ( range 0–15 cm ) were treated with preoperative CMT ( radiation : 5040 centi-Gray ( cGy ) and 5-fluorouracil (5-FU)-based chemotherapy ) followed by TME from 1988 to 2002 . A prospect ively collected data base was queried for long-term oncologic outcome and predictive clinicopathologic factors . Results : With a median follow-up of 44 months , the estimated 10-year overall survival ( OS ) was 58 % and 10 year recurrence-free survival ( RFS ) was 62 % . On multivariate analysis , pathologic response > 95 % , lymphovascular invasion and /or perineural invasion ( PNI ) , and positive lymph nodes were significantly associated with OS and RFS . Patients with a > 95 % pathologic response had a significantly improved OS ( P = 0.003 ) and RFS ( P = 0.002 ) . Conclusions : Treatment of locally advanced rectal cancer with preoperative CMT followed by TME can provide for a durable 10-year OS of 58 % and RFS of 62 % . Patients who achieve a > 95 % response to preoperative CMT have an improved long-term oncologic outcome , a novel finding that deserves further study PURPOSE To assess toxicity and long-term results of preoperative chemoradiotherapy in rectal cancer . METHODS AND MATERIAL S Between 1989 and 1997 , as a phase II study , 66 patients with T3 M0 , rectal cancer received preoperatively a 45 Gy dose pelvic radiotherapy ( XRT ) combined with two 5-day chemotherapy courses ( CT ) of 5-Fluorouracil ( 5-FU ) and Leucovorin ( LV ) delivered the first and fifth week of XRT . For each CT course , LV:20 mg/m2/d1-d5 , . While the 5-FU dose was variable from 450 to 350 mg/m2/d first course and 370 to 350 mg/m2/d second course . Surgery was planned 3 weeks later . RESULTS XRT-CT was stopped in 1 patient due to progressive disease . CT was stopped in 1 patient due to toxicity . Grade s 2 and 3 diarrhea were observed in 8 and 3 patients , respectively . One patient died from acute diarrhea due to deviation from recommendations ; 60 patients went to surgery . Among the 58 patients operated on for cure , 5 had an R1-resection . After a 4.5-year median follow-up , the 5-year pelvic disease-free survival was 92 % for the whole group and 96 % in the R0-resection group . CONCLUSION Preoperative combined XRT-5-FU-LV is feasible if optimal XRT and patients are carefully managed . The recommended 5-FU daily dose is 350 mg/m2 for both CT courses . This approach is currently tested in a large EORTC phase III trial
INTRODUCTION The current management of locally advanced rectal cancer involves total mesorectal excision , which may be preceded by neo-adjuvant chemoradiotherapy ( CRT ) .
Individual patient response to CRT is variable and reproducible biomarkers of response are needed .
The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene ( KRAS ) in rectal cancer remains equivocal .
The aim of the current study was to systematic ally appraise the effect of KRAS mutation on outcomes following CRT for rectal cancer .