Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer
Thierry André, M.D., Corrado Boni, M.D., Lamia Mounedji-Boudiaf, M.D., Matilde Navarro, M.D., Josep Tabernero, M.D., Tamas Hickish, M.D., Clare Topham, M.D., Marta Zaninelli, M.D., Philip Clingan, M.D., John Bridgewater, M.D., Isabelle Tabah-Fisch, M.D., Aimery de Gramont, M.D., for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators
Background The standard adjuvant treatment of colon canceris fluorouracil plus leucovorin (FL). Oxaliplatin improves theefficacy of this combination in patients with metastatic colorectalcancer. We evaluated the efficacy of treatment with FL plusoxaliplatin in the postoperative adjuvant setting.
Methods We randomly assigned 2246 patients who had undergonecurative resection for stage II or III colon cancer to receiveFL alone or with oxaliplatin for six months. The primary endpoint was disease-free survival.
Results A total of 1123 patients were randomly assigned toeach group. After a median follow-up of 37.9 months, 237 patientsin the group given FL plus oxaliplatin had had a cancer-relatedevent, as compared with 293 patients in the FL group (21.1 percentvs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002).The rate of disease-free survival at three years was 78.2 percent(95 percent confidence interval, 75.6 to 80.7) in the groupgiven FL plus oxaliplatin and 72.9 percent (95 percent confidenceinterval, 70.2 to 75.7) in the FL group (P=0.002 by the stratifiedlog-rank test). In the group given FL plus oxaliplatin, theincidence of febrile neutropenia was 1.8 percent, the incidenceof gastrointestinal adverse effects was low, and the incidenceof grade 3 sensory neuropathy was 12.4 percent during treatment,decreasing to 1.1 percent at one year of follow-up. Six patientsin each group died during treatment (death rate, 0.5 percent).
Conclusions Adding oxaliplatin to a regimen of fluorouraciland leucovorin improves the adjuvant treatment of colon cancer.
Colorectal cancer is the second leading cause of death fromcancer in Western countries1; 40 to 50 percent of patients whoundergo potentially curative surgery alone ultimately relapseand die of metastatic disease.2 The most important prognosticindicator of survival in early colon cancer is the stage ofthe tumor (T, according to the tumor–node–metastasis[TNM] classification), determined by the depth of penetrationthrough the bowel wall, and the number of involved lymph nodes.3
The demonstration that postoperative adjuvant treatment withfluorouracil and levamisole reduced the mortality rate by 33percent among patients with stage III colon cancer4 promptedseveral trials, which established six months of treatment withfluorouracil plus leucovorin (FL) as the standard adjuvant chemotherapyfor stage III colon cancer.5,6,7,8,9,10,11 Oxaliplatin is athird-generation platinum derivative, which, when combined withfluorouracil and leucovorin, is among the most effective chemotherapiesfor metastatic colorectal cancer.12,13,14,15 To determine whetheroxaliplatin can also benefit patients with disease in an earlierstage, we conducted an international phase 3 clinical trialin patients with stage II or III colon cancer — the MulticenterInternational Study of Oxaliplatin/5-Fluorouracil/Leucovorinin the Adjuvant Treatment of Colon Cancer (MOSAIC).
Methods
Patients
Patients were eligible if they had undergone complete resectionof histologically proven stage II (T3 or T4,N0,M0) or stageIII (any T,N1 or N2,M0) colon cancer, as defined by the presenceof the inferior pole of the tumor above the peritoneal reflection— that is, at least 15 cm from the anal margin. Treatmenthad to be started within seven weeks after surgery. Other eligibilitycriteria included an age of 18 to 75 years; a Karnofsky performance-statusscore of at least 60; a carcinoembryonic antigen level of lessthan 10 ng per milliliter; the absence of prior chemotherapy,immunotherapy, or radiotherapy; and adequate blood counts andliver and kidney function. Written informed consent was requiredfrom all patients, and the study was approved by the ethicscommittees of the participating centers.
Treatment
Eligible patients were randomly assigned to receive FL aloneor with oxaliplatin. In the FL group, each cycle comprised a2-hour infusion of 200 mg of leucovorin per square meter ofbody-surface area followed by a bolus of 400 mg of fluorouracilper square meter and then a 22-hour infusion of 600 mg of fluorouracilper square meter given on 2 consecutive days every 14 days,for 12 cycles. In the group given FL plus oxaliplatin, the sameFL regimen was used, plus a two-hour infusion of 85 mg of oxaliplatin(Eloxatin, Sanofi-Synthelabo) per square meter on day 1, givensimultaneously with leucovorin, with the use of a Y infusiondevice. The use of disposable pumps (LV5 infusors, Baxter Healthcare)allowed outpatients to receive a continuous infusion of fluorouracil.
Adverse effects were graded according to the Common ToxicityCriteria of the National Cancer Institute, version 1. Accordingto these criteria, a score of 1 indicates mild adverse effects,a score of 2 moderate adverse effects, a score of 3 severe adverseeffects, and a score of 4 life-threatening adverse effects.Dose reductions were based on the worst adverse effects observedduring the previous cycle. The dose of oxaliplatin was to bereduced to 75 mg per square meter in the event of persistent(at least 14 days) paresthesias, temporary painful paresthesias,or functional impairment. Oxaliplatin was discontinued in casesof persistent painful paresthesias or functional impairment.Together with reductions in the dose of oxaliplatin, the bolusdose of fluorouracil was reduced to 300 mg per square meterand the infusion to 500 mg per square meter in the event ofgrade 3 or 4 neutropenia or thrombocytopenia (or both), diarrhea,stomatitis, or other drug-related adverse effects of grade 3.Only the dose of fluorouracil was scheduled to be reduced inthe event of skin-related adverse effects of grade 3 or 4. Treatmentwas delayed by up to three weeks until the patient recoveredfrom various adverse effects, the neutrophil count exceeded1500 per cubic millimeter, and the platelet count exceeded 100,000per cubic millimeter. Chemotherapy was stopped in the eventof cardiac or neurocerebellar adverse effects or grade 3 or4 allergic reactions.
Follow-up
Patients were assessed before randomization, every two weeksduring treatment, and then every six months for five years.The baseline assessment involved a medical history taking, physicalexamination, biologic tests, measurement of the carcinoembryonicantigen level, chest radiography, and abdominal ultrasonographyor computed tomography. Patients were monitored for adverseeffects throughout the treatment period and until 28 days afterthe last cycle of chemotherapy, unless treatment-related adverseeffects required additional follow-up.
The diagnosis of recurrence was made on the basis of imagingand, if necessary, cytologic analysis or biopsy. An elevatedcarcinoembryonic antigen level as a solitary finding was notaccepted as evidence of relapse. Neurologic adverse effectswere to be reported at each visit during follow-up and wereassessed with the use of the neurosensory section of the CommonToxicity Criteria of the National Cancer Institute, version1.
Statistical Analysis
Randomization was performed centrally, and the minimizationmethod was used to balance treatment allocation according tothe TNM stage (T2 or T3 vs. T4 and N0, N1, or N2), the presenceor absence of bowel obstruction or tumor perforation, and themedical center. The sample size of 2200 patients was calculatedunder the assumptions of a three-year disease-free survivalrate of 73 percent in the control group and 79 percent in thegroup given FL plus oxaliplatin, with a ratio of stage II diseaseto stage III disease of 0.4:0.6, an enrollment period and afollow-up period of three years, a decrease in the risk of relapseafter three years, a statistical power of 90 percent, and analpha value of 0.05 and two-sided P values derived with theuse of the log-rank test. The primary efficacy variable wasdisease-free survival, defined as the time from randomizationto relapse or death, whichever occurred first. Second colorectalcancers were considered relapses, whereas noncolorectal tumorswere disregarded in the analyses.
The primary statistical analysis of efficacy was the comparison,after three years of follow-up, of disease-free survival betweengroups according to the intention-to-treat principle, with theuse of a two-sided log-rank test stratified according to baselinedisease stage. Hazard ratios and 95 percent confidence intervalswere calculated with the use of the Cox proportional-hazardsmodel. Survival curves were drawn according to Kaplan–Meiermethods.
To assess the consistency of the effect of treatment on disease-freesurvival across prognostic subgroups, we calculated hazard ratiosand 95 percent confidence limits for subgroups defined accordingto the following variables: sex, age, disease stage (II vs.III), baseline serum carcinoembryonic antigen level, numberof involved lymph nodes (4 vs. >4), T classification (T4vs. T1, T2, or T3), degree of cellular differentiation (wellvs. poorly differentiated), and the presence or absence of perforation,obstruction, and venous invasion.
The cutoff date of the analysis was April 22, 2003. The durationof follow-up was defined as the number of months from randomizationto the cutoff date.
Secondary end points were safety, including long-term adverseeffects, and overall survival, measured from the time of randomizationto death from any cause. With a median follow-up of three years,it is too early to compare the two treatment groups statisticallyin terms of survival, and only descriptive analyses of overallsurvival are presented. Safety analyses included patients whohad received at least one cycle of treatment.
Organization of the Trial
The concept underlying this study was developed by Dr. de Gramont,and the investigation was designed by the investigators andSanofi-Synthelabo. Data were collected, managed, and analyzedby the sponsor. The article was written by the investigators,on the basis of data and statistical analyses provided by Sanofi-Synthelabo.
A data and safety monitoring board of independent experts reviewedsafety data every six months during the treatment period toprovide the sponsor with independent advice on the progressof the study and on safety. No interim analysis was plannedor performed.
Results
Study Population
Between October 1998 and January 2001, 2246 patients were enrolledat 146 centers in 20 countries: 1123 patients were randomlyassigned to receive FL plus oxaliplatin and 1123 to receiveFL without oxaliplatin. Of these patients, 1108 received atleast one cycle of FL plus oxaliplatin and 1111 received atleast one cycle of FL. The patients' characteristics were wellmatched in the two groups (Table 1). In both groups, 60 percentof the patients had stage III disease and 40 percent had stageII disease. The overall median time between surgery and thestart of chemotherapy was 5.7 weeks (range, 1.1 to 17.0).
Table 1. Baseline Characteristics of the Patients in the Group Given Fluorouracil and Leucovorin (FL) plus Oxaliplatin and the FL Group.
A total of 41 patients (1.8 percent) did not strictly meet eligibilitycriteria related to baseline disease. In one patient in eachgroup, the resection of primary tumor was incomplete. Four patientsin the group given FL plus oxaliplatin and six in the FL grouphad a history of cancer, including colorectal cancer. Thirteenpatients (four in the group given FL plus oxaliplatin and ninein the FL group) had stage IV cancer, and three patients (twoin the group given FL plus oxaliplatin and one in the FL group)had cancer of the middle or lower rectum. Four patients in thegroup given FL plus oxaliplatin and nine in the FL group hadvarious other eligibility-criteria violations.
Chemotherapy
The median number of cycles of chemotherapy received was 12in both groups; 74.7 percent of patients in the group givenFL plus oxaliplatin and 86.5 percent in the FL group receivedthe planned 12 cycles. In the group that received FL plus oxaliplatin,the median dosage of oxaliplatin was 34.2 mg per square meterper week across all cycles received and 36.5 mg per square meterper week across cycles including oxaliplatin. In both cases,more than 80 percent of the planned dose was actually given(80.5 percent and 85.9 percent, respectively). The dose of fluorouracilreceived was 84.4 percent of the planned dose in the group givenFL plus oxaliplatin and 97.7 percent of the planned dose inthe FL group.
Safety
Neutropenia, diarrhea, and vomiting were the most frequent grade3 or 4 adverse effects in the group given FL plus oxaliplatin(Table 2). Grade 3 or 4 neutropenia was much commoner with FLplus oxaliplatin than with FL (41.1 percent vs. 4.7 percent,P<0.001) but was complicated by fever or infection in only1.8 percent of cases (20 patients) in the group given FL plusoxaliplatin and in 0.2 percent of cases (2 patients) in theFL group (P<0.001). The incidence of thromboembolic eventsamong patients who received at least one cycle of the assignedregimen was similar in the two groups (63 of 1108 patients [5.7percent] and 72 of 1111 patients [6.5 percent], respectively).
Table 2. Adverse Events in the Group Given Fluorouracil and Leucovorin (FL) plus Oxaliplatin and the FL Group.
Although 92.1 percent of patients treated with FL plus oxaliplatinhad peripheral neuropathy during treatment, half of these episodeswere of grade 1 (Table 3). Of the 137 patients (12.4 percent)who had grade 3 peripheral neuropathy during treatment, grade3 symptoms were still present in 8 patients at the six-monthfollow-up visit and in 5 patients at the one-year visit. In12 patients, grade 3 peripheral neurosensory symptoms appearedafter the end of treatment, and 6 of these patients had persistentgrade 3 symptoms after one year. In total, 11 of 1018 patients(1.1 percent) who were assessed one year after the end of treatmentcontinued to have grade 3 peripheral neurosensory symptoms.This number dropped to five (0.5 percent) after 18 months (Table 3).
Table 3. Incidence of Neurosensory Symptoms during Treatment and Follow-up in the Group Given Fluorouracil, Leucovorin, and Oxaliplatin.
Twelve patients — six in each group (0.5 percent) —died within 1 month after the end of treatment; these includedthree deaths in each group during the first 60 days of treatment.In the group given FL plus oxaliplatin, four patients died ofinfection or sepsis (two with neutropenia) and two of intracranialhemorrhage. In the FL group, one patient each died of sepsis,Stevens–Johnson syndrome in the context of severe diarrheaand fluconazole treatment, and anoxic cerebral infarction; onepatient committed suicide; and two died suddenly from cardiaccauses.
Follow-up
There was good compliance with follow-up visits. The mean timebetween visits was 5.97 months in the group given FL plus oxaliplatinand 5.98 months in the FL group. The median interval was 6.01months in both groups.
Disease-free Survival
At the time of analysis (median follow-up, 37.9 months), 237patients in the group given FL plus oxaliplatin (21.1 percent)had relapsed or died, as compared with 293 (26.1 percent) inthe FL group. The hazard ratio for recurrence in the group givenFL plus oxaliplatin, as compared with the FL group, was 0.77(P=0.002), corresponding to a 23 percent reduction in the riskof relapse. The probability of disease-free survival at threeyears was 78.2 percent (95 percent confidence interval, 75.6to 80.7 percent) in the group given FL plus oxaliplatin and72.9 percent (95 percent confidence interval, 70.2 to 75.7 percent)in the FL group (P=0.002 by the stratified log-rank test) (Table 4and Figure 1).
Figure 1. Kaplan–Meier Estimates of Disease-free Survival in the Group Given Fluorouracil and Leucovorin (FL) and the Group Given FL plus Oxaliplatin, According to the Intention to Treat.
The hazard ratio for recurrence in the group given FL plus oxaliplatin, as compared with the FL group, was 0.77 (95 percent confidence interval, 0.65 to 0.91; P=0.002).
Among patients with stage III disease, the hazard ratio forrelapse was 0.76 (95 percent confidence interval, 0.62 to 0.92)in the group given FL plus oxaliplatin, as compared with theFL group, and the three-year disease-free survival rate was72.2 percent and 65.3 percent, respectively (Figure 2). Amongpatients with stage II disease, the hazard ratio for relapsewas 0.80 (95 percent confidence interval, 0.56 to 1.15) in thegroup given FL plus oxaliplatin, as compared with the FL group,and the three-year disease-free survival rates were 87.0 percentand 84.3 percent, respectively (Figure 2).
Figure 2. Kaplan–Meier Estimates of Disease-free Survival in the Group Given Fluorouracil and Leucovorin (FL) and the Group Given FL plus Oxaliplatin, According to the Stage of Disease and the Intention to Treat.
A Cox-model analysis showed that the reduced risk of recurrencewith FL plus oxaliplatin was similar in patients with stageII and those with stage III disease (P=0.77). Calculation ofhazard ratios and 95 percent confidence intervals (Figure 3)showed that the reduced risk of relapse was consistent in allsubgroups defined on the basis of prognostic factors at baseline.
Figure 3. Hazard Ratios and 95 Percent Confidence Intervals for Recurrence in the Group Given Fluorouracil and Leucovorin (FL) plus Oxaliplatin, as Compared with the FL Group, According to Baseline Prognostic Factors and the Intention to Treat.
CEA denotes carcinoembryonic antigen.
Overall Survival
At the time of the cutoff date of the primary analysis, 133patients had died in the group given FL plus oxaliplatin, ascompared with 146 patients in the FL group (hazard ratio fordeath, 0.90; 95 percent confidence interval, 0.71 to 1.13),and the probability of survival at three years was 87.7 percentand 86.6 percent, respectively. Most of the patients who diedhad stage III disease (104 in the group given FL plus oxaliplatinand 119 in the FL group); the hazard ratio for death in thissubgroup was 0.86 (95 percent confidence interval, 0.66 to 1.11).
Discussion
In previous trials, the addition of oxaliplatin to fluorouraciland leucovorin doubled the response rate and prolonged progression-freesurvival among patients with metastatic colorectal cancer.14The efficacy and safety of this regimen were recently confirmedin a large, randomized, phase 3 trial, which found that thisapproach was superior (with respect to all efficacy variables,including overall survival) to the combination of irinotecan,fluorouracil (given as a bolus), and leucovorin.15 Our trialwas designed to test the efficacy of adjuvant treatment withthe regimen of FL plus oxaliplatin. We chose disease-free survivalas the primary end point of the study because, like others,16we believe that the absence of relapse is the best indicatorof efficacy, since it relates directly to the effect of thetreatment under investigation. By allowing early appraisal ofthe results, the use of three-year disease-free survival asthe primary end point for adjuvant trials of patients with coloncancer should permit rapid evaluation of new treatments. Whetherdisease-free survival should be a primary end point is stillunder discussion, but a recent analysis of several studies supportsthe appropriateness of the use of three-year disease-free survivalas a good predictor of five-year overall survival in trialsof adjuvant treatment of colon cancer.17
Disease-free survival in the FL group in our study falls withinthe highest range reported in most studies of adjuvant treatmentof colon cancer with FL.6,7,8,18,19 The improvement in disease-freesurvival among patients who were treated with FL plus oxaliplatincorresponds to a relative reduction in the risk of recurrenceof 23 percent. Since most relapses after curative surgery occurwithin the first three years, we consider our results in thisrespect to be complete.
Although it is agreed that patients with stage III disease benefitfrom adjuvant treatment, whether all patients with stage IIdisease should receive such treatment remains debatable. Thiscontroversy was sustained for years by the contradictory conclusionsof two large groups of investigators. The National SurgicalAdjuvant Breast and Bowel Project concluded that the relativebenefits of treatment were largely the same for stage II andstage III tumors,20 whereas the International Multicentre PooledAnalysis of B2 Colon Cancer Trials (IMPACT B2) failed to demonstratea statistically significant benefit for stage II tumors.21
A recent meta-analysis from the Mayo Clinic,22 which evaluatedindividual data on 3300 patients who were enrolled in five randomizedtrials, including those analyzed in IMPACT B2, concluded thatpatients with stage II disease could benefit from adjuvant chemotherapy,but to a lesser extent than patients with stage III tumors.Indeed, the absolute benefit among patients with stage II diseaseis only half as great as that among patients with stage IIIdisease, and twice as many patients with stage II tumors arerequired in such studies in order to detect a difference.
A test for interaction is an appropriate statistical approachto the question of whether the benefit of adjuvant treatmentdiffers between stage II and stage III colorectal cancer.23In our study, this test showed no significant interaction betweenthe stage of disease and the treatment, indicating that FL plusoxaliplatin benefited both stage II and stage III colorectalcancer. From a clinical standpoint, stage II colon cancer occursin a heterogeneous, node-negative population in which clinicaland biologic prognostic factors other than the status of lymph-nodeinvolvement need to be taken into account. Tools are being developedto help physicians assess the risk–benefit ratio of adjuvantchemotherapies for individual patients.22
With no clear consensus on the most effective FL regimen tobe used for adjuvant treatment, we chose a twice-monthly regimenbecause of its efficacy and low rates of adverse effects inpatients with advanced colorectal cancer, alone and in combinationwith oxaliplatin.12,14,24 Supporting our decision are recentresults demonstrating that this approach to adjuvant therapyis less toxic than monthly bolus injections of FL and is justas effective.18 This approach led to a straightforward studydesign, since the treatment in both groups was similar exceptfor the addition of oxaliplatin in the group given FL plus oxaliplatin.The improved disease-free survival in the FL-plus-oxaliplatingroup is thus directly linked to oxaliplatin.
The main safety concern regarding the use of oxaliplatin isperipheral neuropathy. Oxaliplatin induces frequent, transient,distal paresthesias during or shortly after the first minutesof infusion. In some cases these neurosensory symptoms increasein intensity with cumulative doses, persist between cycles,and interfere with function (in the case of grade 3 effects).12,14,25We observed grade 3 peripheral neuropathy in 12.4 percent ofpatients who were receiving oxaliplatin. At one year, 11 patients(1.1 percent) had grade 3 neuropathy. Among them, two were foundto have underlying disease that could have caused these symptoms(diabetes and hemiplegia, respectively). Although more frequentamong patients receiving FL plus oxaliplatin than among thosetreated with FL alone, grade 3 or 4 neutropenia led to feveror infection in only 1.8 percent of patients in the former group.Similar findings have been reported among patients with metastaticcolorectal cancer.14 From a safety standpoint, the rate of deathfrom any cause was similarly low during treatment in both groupsand, at 0.5 percent, is among the lowest figures reported intrials of adjuvant chemotherapy.5,18,26,27
Figures for overall survival at this stage of the study arepreliminary, and no conclusion can be drawn about differencesin survival between the treatment groups. Since the median overallsurvival from the time of diagnosis of metastatic colorectalcancer is approximately 20 months,13,14,15,28 we expect thatthe effect of oxaliplatin on survival will become apparent withinthe next 2 years.
Supported by Sanofi-Synthelabo.
Dr. Boni reports having received consulting fees from Sanofi-Synthelaboand Lilly; Dr. Tabernero consulting and lecture fees from Sanofi-Synthelabo;and Dr. Hickish consulting and lecture fees from Sanofi-Synthelabo,Aventis, and Roche. Dr. Topham reports having equity ownershipin Sanofi-Synthelabo and having received lecture fees from Sanofi-Synthelaboand consulting fees from Roche and Baxter. Dr. Bridgewater reportshaving received consulting fees from Novartis Consumer Health;Dr. Clingan consulting fees from Sanofi-Synthelabo and RocheAustralia; and Dr. de Gramont consulting and lecture fees fromSanofi-Synthelabo and Baxter. Dr. Mounedji-Boudiaf and Dr. Tabah-Fischare employed by Sanofi-Synthelabo.
We are indebted to all those who have contributed to the conductand analysis of the MOSAIC trial, including the 146 investigatorsfrom France, the United Kingdom, Spain, Italy, Belgium, Greece,Hungary, the Netherlands, Portugal, Germany, Sweden, Austria,Poland, Denmark, Norway, Australia, Israel, Cyprus, Singapore,and Switzerland who enrolled patients in the study; to the membersof the data and safety monitoring board, especially Marc Buyse(statistician); to the dedicated teams from Sanofi-Synthelabo,including Christelle Lorenzato and Robert Bigelow (statisticaldepartment) and Jeanne Marceau-Suissa, Nathalie Lebail, andNoelle Muller (clinical development); and to Daniel Sargent(Mayo Clinic) for the discussion of the results.
Source Information
From Hôpital Tenon, Paris (T.A.); GERCOR Oncology Multidisciplinary Group, Paris (T.A., A.G.); Arcispedale Santa Maria Nuova, Reggio Emilia, Italy (C.B.); Sanofi-Synthelabo, Paris (L.M.-B., I.T.-F.); Hospital Duran i Reynals, l'Hospitalet de Llobregat, Llobregat, Spain (M.N.); Vall d'Hebron University Hospital, Barcelona, Spain (J.T.); Dorset Cancer Centre, Royal Bournemouth and Poole Hospitals, Bournemouth, United Kingdom (T.H.); Royal Surrey County Hospital, Guildford, Surrey, United Kingdom (C.T.); Ospedale Borgotrento, Verona, Italy (M.Z.); Southern Medical Day Care Centre, Wollongong, Australia (P.C.); North Middlesex Hospital, London (J.B.); and Hôpital Saint-Antoine, Paris (A.G.).
Address reprint requests to Dr. de Gramont at Hôpital Saint Antoine, 184 rue du Faubourg Saint Antoine, Paris 75012, France, or at aimery.de-gramont{at}sat.ap-hop-paris.fr.
References
GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide, version 1.0. IARC CancerBase no. 5. Lyon, France: IARC Press, 2001.
Obrand DI, Gordon PH. Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Dis Colon Rectum 1997;40:15-24. [CrossRef][Medline]
Colon and rectum. In: American Joint Committee on Cancer. AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott–Raven, 1997:83-90.
Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil as adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-358. [Abstract]
Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879-1887. [Free Full Text]
International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995;345:939-944. [CrossRef][Web of Science][Medline]
O'Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-250. [Free Full Text]
Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999;17:3553-3559. [Free Full Text]
O'Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998;16:295-300. [Free Full Text]
Haller DG, Catalano PJ, Macdonald JS, Mayer RJ. Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: five-year final report of INT-0089. Prog Proc Am Soc Clin Oncol 1998;17:256a.
Zaniboni A. Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: impact on disease-free survival and overall survival. J Clin Oncol 1997;15:2432-2441. [Free Full Text]
Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999;17:3560-3568. [Free Full Text]
Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136-147. [Free Full Text]
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-2947. [Free Full Text]
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30. [Free Full Text]
Elfenbein GJ. Stem-cell transplantation for high-risk breast cancer. N Engl J Med 2003;349:80-82. [Free Full Text]
Sargent D, Wieand S, Goldberg R, et al. 3 Year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. Rockville, Md.: Food and Drug Administration, November 2003. (Accessed May 10, 2004, at http://www.fda.gov/cder/drug/cancer_endpoints/Sargent/index.htm.)
Andre T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003;21:2896-2903. [Free Full Text]
Francini G, Petrioli R, Lorenzini L, et al. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology 1994;106:899-906. [Web of Science][Medline]
Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999;17:1349-1355. [Free Full Text]
International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999;17:1356-1363. [Free Full Text]
Gill S, Loprinzi CL, Sargent DJ, et al. Using a pooled analysis to improve the understanding of adjuvant therapy (AT) benefit for colon cancer (CC). Prog Proc Am Soc Clin Oncol 2003;22:253a.
Buyse M, Piedbois P. Should Dukes' B patients receive adjuvant therapy? A statistical perspective. Semin Oncol 2001;28:Suppl 1:20-24. [Web of Science][Medline]
de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997;15:808-815. [Free Full Text]
Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M. Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 1990;25:299-303. [CrossRef][Web of Science][Medline]
Rothenberg ML, Meropol NJ, Poplin EA, Van Cutsem E, Wadler S. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001;19:3801-3807. [Free Full Text]
Wolmark N, Bryant J, Smith R, et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 1998;90:1810-1816. [Free Full Text]
Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX 6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229-237. [Free Full Text]
de Gramont, A., Hubbard, J., Shi, Q., O'Connell, M. J., Buyse, M., Benedetti, J., Bot, B., O'Callaghan, C., Yothers, G., Goldberg, R. M., Blanke, C. D., Benson, A., Deng, Q., Alberts, S. R., Andre, T., Wolmark, N., Grothey, A., Sargent, D.
(2010). Association Between Disease-Free Survival and Overall Survival When Survival Is Prolonged After Recurrence in Patients Receiving Cytotoxic Adjuvant Therapy for Colon Cancer: Simulations Based on the 20,800 Patient ACCENT Data Set. JCO
28: 460-465
[Abstract][Full Text]
Storey, D. J., Sakala, M., McLean, C. M., Phillips, H. A., Dawson, L. K., Wall, L. R., Fallon, M. T., Clive, S.
(2010). Capecitabine combined with oxaliplatin (CapOx) in clinical practice: how significant is peripheral neuropathy?. Ann Oncol
0: mdp594v1-mdp594
[Abstract][Full Text]
Eveno, C., Nemeth, J., Soliman, H., Praz, F., de The, H., Valleur, P., Talbot, I. C., Pocard, M.
(2010). Association Between a High Number of Isolated Lymph Nodes in T1 to T4 N0M0 Colorectal Cancer and the Microsatellite Instability Phenotype. Arch Surg
145: 12-17
[Abstract][Full Text]
Markowitz, S. D., Bertagnolli, M. M.
(2009). Molecular Basis of Colorectal Cancer. NEJM
361: 2449-2460
[Full Text]
Jorissen, R. N., Gibbs, P., Christie, M., Prakash, S., Lipton, L., Desai, J., Kerr, D., Aaltonen, L. A., Arango, D., Kruhoffer, M., Orntoft, T. F., Andersen, C. L., Gruidl, M., Kamath, V. P., Eschrich, S., Yeatman, T. J., Sieber, O. M.
(2009). Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer. Clin. Cancer Res.
15: 7642-7651
[Abstract][Full Text]
Ramanathan, R. K., Rothenberg, M. L., de Gramont, A., Tournigand, C., Goldberg, R. M., Gupta, S., Andre, T.
(2009). Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies. Ann Oncol
0: mdp509v1-mdp509
[Abstract][Full Text]
Eiden, C., Philibert, L., Bekhtari, K., Poujol, S., Malosse, F., Pinguet, F.
(2009). Physicochemical stability of oxaliplatin in 5% dextrose injection stored in polyvinyl chloride, polyethylene, and polypropylene infusion bags. Am J Health Syst Pharm
66: 1929-1933
[Abstract][Full Text]
van Steenbergen, L. N., Rutten, H. J. T., Creemers, G. J., Pruijt, J. F. M., Coebergh, J. W. W., Lemmens, V. E. P. P.
(2009). Large age and hospital-dependent variation in administration of adjuvant chemotherapy for stage III colon cancer in southern Netherlands. Ann Oncol
0: mdp482v1-mdp482
[Abstract][Full Text]
Lansdorp-Vogelaar, I., van Ballegooijen, M., Zauber, A. G., Habbema, J. D. F., Kuipers, E. J.
(2009). Effect of Rising Chemotherapy Costs on the Cost Savings of Colorectal Cancer Screening. JNCI J Natl Cancer Inst
101: 1412-1422
[Abstract][Full Text]
Zaanan, A., Cuilliere-Dartigues, P., Guilloux, A., Parc, Y., Louvet, C., de Gramont, A., Tiret, E., Dumont, S., Gayet, B., Validire, P., Flejou, J.-F., Duval, A., Praz, F.
(2009). Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. Ann Oncol
0: mdp383v1-mdp383
[Abstract][Full Text]
Park, S. B., Lin, C. S.-Y., Krishnan, A. V., Goldstein, D., Friedlander, M. L., Kiernan, M. C.
(2009). Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain
132: 2712-2723
[Abstract][Full Text]
Zafar, S. Y., Marcello, J. E., Wheeler, J. L., Rowe, K. L., Morse, M. A., Herndon, J. E. II, Abernethy, A. P.
(2009). Longitudinal Patterns of Chemotherapy Use in Metastatic Colorectal Cancer. J Oncol Pract
5: 228-233
[Abstract][Full Text]
Kumar, S., Chang, E. Y., Frankhouse, J., Dorsey, P. B., Lee, R. G., Johnson, N.
(2009). Combination of Microsatellite Instability and Lymphocytic Infiltrate as a Prognostic Indicator for Adjuvant Therapy in Colon Cancer. Arch Surg
144: 835-840
[Abstract][Full Text]
Okoshi, K., Nagayama, S., Furu, M., Mori, Y., Yoshizawa, A., Toguchida, J., Sakai, Y.
(2009). A Case Report of Pathologically Complete Response of a Huge Rectal Cancer after Systemic Chemotherapy with mFOLFOX6. Jpn J Clin Oncol
39: 528-533
[Abstract][Full Text]
Allegra, C. J., Yothers, G., O'Connell, M. J., Sharif, S., Colangelo, L. H., Lopa, S. H., Petrelli, N. J., Goldberg, R. M., Atkins, J. N., Seay, T. E., Fehrenbacher, L., O'Reilly, S., Chu, L., Azar, C. A., Wolmark, N.
(2009). Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer. JCO
27: 3385-3390
[Abstract][Full Text]
Andre, T., Boni, C., Navarro, M., Tabernero, J., Hickish, T., Topham, C., Bonetti, A., Clingan, P., Bridgewater, J., Rivera, F., de Gramont, A.
(2009). Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial. JCO
27: 3109-3116
[Abstract][Full Text]
Van Cutsem, E., Labianca, R., Bodoky, G., Barone, C., Aranda, E., Nordlinger, B., Topham, C., Tabernero, J., Andre, T., Sobrero, A. F., Mini, E., Greil, R., Di Costanzo, F., Collette, L., Cisar, L., Zhang, X., Khayat, D., Bokemeyer, C., Roth, A. D., Cunningham, D.
(2009). Randomized Phase III Trial Comparing Biweekly Infusional Fluorouracil/Leucovorin Alone or With Irinotecan in the Adjuvant Treatment of Stage III Colon Cancer: PETACC-3. JCO
27: 3117-3125
[Abstract][Full Text]
O'Connell, M. J.
(2009). Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In. JCO
27: 3082-3084
[Full Text]
Kemeny, N., Capanu, M., D'Angelica, M., Jarnagin, W., Haviland, D., Dematteo, R., Fong, Y.
(2009). Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. Ann Oncol
20: 1236-1241
[Abstract][Full Text]
Nordlinger, B., Van Cutsem, E., Gruenberger, T., Glimelius, B., Poston, G., Rougier, P., Sobrero, A., Ychou, M., on behalf of the European Colorectal Metastases Tr,
(2009). Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol
20: 985-992
[Abstract][Full Text]
Van Cutsem, E., Oliveira, J., On behalf of the ESMO Guidelines Working Group,
(2009). Primary colon cancer: ESMO Clinical Recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol
20: iv49-iv50
[Full Text]
Ychou, M., Raoul, J.-L., Douillard, J.-Y., Gourgou-Bourgade, S., Bugat, R., Mineur, L., Viret, F., Becouarn, Y., Bouche, O., Gamelin, E., Ducreux, M., Conroy, T., Seitz, J.-F., Bedenne, L., Kramar, A.
(2009). A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol
20: 674-680
[Abstract][Full Text]
Park, S. B., Goldstein, D., Lin, C. S.-Y., Krishnan, A. V., Friedlander, M. L., Kiernan, M. C.
(2009). Acute Abnormalities of Sensory Nerve Function Associated With Oxaliplatin-Induced Neurotoxicity. JCO
27: 1243-1249
[Abstract][Full Text]
Sargent, D., Sobrero, A., Grothey, A., O'Connell, M. J., Buyse, M., Andre, T., Zheng, Y., Green, E., Labianca, R., O'Callaghan, C., Seitz, J. F., Francini, G., Haller, D., Yothers, G., Goldberg, R., de Gramont, A.
(2009). Evidence for Cure by Adjuvant Therapy in Colon Cancer: Observations Based on Individual Patient Data From 20,898 Patients on 18 Randomized Trials. JCO
27: 872-877
[Abstract][Full Text]
Waldman, S. A., Hyslop, T., Schulz, S., Barkun, A., Nielsen, K., Haaf, J., Bonaccorso, C., Li, Y., Weinberg, D. S.
(2009). Association of GUCY2C Expression in Lymph Nodes With Time to Recurrence and Disease-Free Survival in pN0 Colorectal Cancer. JAMA
301: 745-752
[Abstract][Full Text]
BIR, A. S., FORA, A. A., LEVEA, C., FAKIH, M. G.
(2009). Spontaneous Regression of Colorectal Cancer Metastatic to Retroperitoneal Lymph Nodes. Anticancer Res
29: 465-468
[Abstract][Full Text]
Papamichael, D., Audisio, R., Horiot, J.-C., Glimelius, B., Sastre, J., Mitry, E., Van Cutsem, E., Gosney, M., Kohne, C.-H., Aapro, M.
(2009). Treatment of the elderly colorectal cancer patient: SIOG expert recommendations. Ann Oncol
20: 5-16
[Abstract][Full Text]
Martinez-Cardus, A., Martinez-Balibrea, E., Bandres, E., Malumbres, R., Gines, A., Manzano, J. L., Taron, M., Garcia-Foncillas, J., Abad, A.
(2009). Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer. Molecular Cancer Therapeutics
8: 194-202
[Abstract][Full Text]
Bilchik, A. J.
(2008). Perioperative Carcinoembryonic Antigen Measurements to Predict Curability After Liver Resection for Colorectal Metastases--Invited Critique. Arch Surg
143: 1158-1159
[Full Text]
Yokoo, S., Masuda, S., Yonezawa, A., Terada, T., Katsura, T., Inui, K.-i.
(2008). Significance of Organic Cation Transporter 3 (SLC22A3) Expression for the Cytotoxic Effect of Oxaliplatin in Colorectal Cancer. Drug Metab. Dispos.
36: 2299-2306
[Abstract][Full Text]
Mitry, E., Fields, A. L.A., Bleiberg, H., Labianca, R., Portier, G., Tu, D., Nitti, D., Torri, V., Elias, D., O'Callaghan, C., Langer, B., Martignoni, G., Bouche, O., Lazorthes, F., Van Cutsem, E., Bedenne, L., Moore, M. J., Rougier, P.
(2008). Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials. JCO
26: 4906-4911
[Abstract][Full Text]
Grothey, A.
(2008). Surrogate endpoints for overall survival in early colorectal cancer from the clinician's perspective. Stat Methods Med Res
17: 529-535
[Abstract]
Lurje, G., Zhang, W., Schultheis, A. M., Yang, D., Groshen, S., Hendifar, A. E., Husain, H., Gordon, M. A., Nagashima, F., Chang, H. M., Lenz, H.-J.
(2008). Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol
19: 1734-1741
[Abstract][Full Text]
Geoerger, B., Doz, F., Gentet, J.-C., Mayer, M., Landman-Parker, J., Pichon, F., Chastagner, P., Rubie, H., Frappaz, D., Le Bouil, A., Gupta, S., Vassal, G.
(2008). Phase I Study of Weekly Oxaliplatin in Relapsed or Refractory Pediatric Solid Malignancies. JCO
26: 4394-4400
[Abstract][Full Text]
Tuffaha, H. W, Treish, I. M, Zaru, L.
(2008). The use and effectiveness of granulocyte colony-stimulating factor in primary prophylaxis for febrile neutropenia in the outpatient setting. J Oncol Pharm Pract
14: 131-138
[Abstract]
Vasilevskaya, I. A., Selvakumaran, M., O'Dwyer, P. J.
(2008). Disruption of Signaling through SEK1 and MKK7 Yields Differential Responses in Hypoxic Colon Cancer Cells Treated with Oxaliplatin. Mol. Pharmacol.
74: 246-254
[Abstract][Full Text]
Qvortrup, C., Yilmaz, M., Ogreid, D., Berglund, A., Balteskard, L., Ploen, J., Fokstuen, T., Starkhammar, H., Sorbye, H., Tveit, K., Pfeiffer, P.
(2008). Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil. Ann Oncol
19: 1154-1159
[Abstract][Full Text]
Schwartz, R. N.
(2008). Management of early and advanced colorectal cancer: Therapeutic issues. Am J Health Syst Pharm
65: S8-S14
[Abstract][Full Text]
Keating, N. L., Landrum, M. B., Klabunde, C. N., Fletcher, R. H., Rogers, S. O., Doucette, W. R., Tisnado, D., Clauser, S., Kahn, K. L.
(2008). Adjuvant Chemotherapy for Stage III Colon Cancer: Do Physicians Agree About the Importance of Patient Age and Comorbidity?. JCO
26: 2532-2537
[Abstract][Full Text]
Glimelius, B., Sorbye, H., Balteskard, L., Bystrom, P., Pfeiffer, P., Tveit, K., Heikkila, R., Keldsen, N., Albertsson, M., Starkhammar, H., Garmo, H., Berglund, A.
(2008). A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol
19: 909-914
[Abstract][Full Text]
Di Paolo, A., Lencioni, M., Amatori, F., Di Donato, S., Bocci, G., Orlandini, C., Lastella, M., Federici, F., Iannopollo, M., Falcone, A., Ricci, S., Del Tacca, M., Danesi, R.
(2008). 5-Fluorouracil Pharmacokinetics Predicts Disease-free Survival in Patients Administered Adjuvant Chemotherapy for Colorectal Cancer. Clin. Cancer Res.
14: 2749-2755
[Abstract][Full Text]
Greene, F. L., Sobin, L. H.
(2008). The Staging of Cancer: A Retrospective and Prospective Appraisal. CA Cancer J Clin
58: 180-190
[Abstract][Full Text]
Goel, S.
(2008). Reporting of Subset Analysis: Where Do We Draw the Line?. JCO
26: 2062-2063
[Full Text]
Ng, R., Pond, G. R., Tang, P. A., MacIntosh, P. W., Siu, L. L., Chen, E. X.
(2008). Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006. Ann Oncol
19: 481-486
[Abstract][Full Text]
Van Cutsem, E., Verslype, C., Beale, P., Clarke, S., Bugat, R., Rakhit, A., Fettner, S. H., Brennscheidt, U., Feyereislova, A., Delord, J.-P
(2008). A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients. Ann Oncol
19: 332-339
[Abstract][Full Text]
Berglund, A., Cedermark, B., Glimelius, B.
(2008). Is it deleterious to delay the start of adjuvant chemotherapy in colon cancer stage III?. Ann Oncol
19: 400-402
[Full Text]
Ezumi, K., Yamamoto, H., Murata, K., Higashiyama, M., Damdinsuren, B., Nakamura, Y., Kyo, N., Okami, J., Ngan, C. Y., Takemasa, I., Ikeda, M., Sekimoto, M., Matsuura, N., Nojima, H., Monden, M.
(2008). Aberrant Expression of Connexin 26 Is Associated with Lung Metastasis of Colorectal Cancer. Clin. Cancer Res.
14: 677-684
[Abstract][Full Text]
Weiser, M. R., Landmann, R. G., Kattan, M. W., Gonen, M., Shia, J., Chou, J., Paty, P. B., Guillem, J. G., Temple, L. K., Schrag, D., Saltz, L. B., Wong, W. D.
(2008). Individualized Prediction of Colon Cancer Recurrence Using a Nomogram. JCO
26: 380-385
[Abstract][Full Text]
Tsimberidou, A. M., Wierda, W. G., Plunkett, W., Kurzrock, R., O'Brien, S., Wen, S., Ferrajoli, A., Ravandi-Kashani, F., Garcia-Manero, G., Estrov, Z., Kipps, T. J., Brown, J. R., Fiorentino, A., Lerner, S., Kantarjian, H. M., Keating, M. J.
(2008). Phase I-II Study of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy in Patients With Richter's Syndrome or Fludarabine-Refractory Chronic Lymphocytic Leukemia. JCO
26: 196-203
[Abstract][Full Text]
Zlobec, I., Baker, K., Minoo, P., Jass, J. R., Terracciano, L., Lugli, A.
(2008). Node-Negative Colorectal Cancer at High Risk of Distant Metastasis Identified by Combined Analysis of Lymph Node Status, Vascular Invasion, and Raf-1 Kinase Inhibitor Protein Expression. Clin. Cancer Res.
14: 143-148
[Abstract][Full Text]
Grothey, A.
(2007). Biological Therapy and Other Novel Therapies in Early-Stage Disease: Are They Appropriate?. Clin. Cancer Res.
13: 6909s-6912s
[Abstract][Full Text]
Benson, A. B. III
(2007). New Approaches to Assessing and Treating Early-Stage Colon and Rectal Cancers: Cooperative Group Strategies for Assessing Optimal Approaches in Early-Stage Disease. Clin. Cancer Res.
13: 6913s-6920s
[Abstract][Full Text]
Aschele, C., Lonardi, S.
(2007). Multidisciplinary treatment of rectal cancer: medical oncology.. Ann Oncol
18: 1908-1915
[Full Text]
Sargent, D. J., Patiyil, S., Yothers, G., Haller, D. G., Gray, R., Benedetti, J., Buyse, M., Labianca, R., Seitz, J. F., O'Callaghan, C. J., Francini, G., Grothey, A., O'Connell, M., Catalano, P. J., Kerr, D., Green, E., Wieand, H. S., Goldberg, R. M., de Gramont, A.
(2007). End Points for Colon Cancer Adjuvant Trials: Observations and Recommendations Based on Individual Patient Data From 20,898 Patients Enrolled Onto 18 Randomized Trials From the ACCENT Group. JCO
25: 4569-4574
[Abstract][Full Text]
Grossman, S. R., Lyle, S., Resnick, M. B., Sabo, E., Lis, R. T., Rosinha, E., Liu, Q., Hsieh, C.-C., Bhat, G., Frackelton, A. R. Jr., Hafer, L. J.
(2007). p66 Shc Tumor Levels Show a Strong Prognostic Correlation with Disease Outcome in Stage IIA Colon Cancer. Clin. Cancer Res.
13: 5798-5804
[Abstract][Full Text]
Diaz-Rubio, E., Tabernero, J., Gomez-Espana, A., Massuti, B., Sastre, J., Chaves, M., Abad, A., Carrato, A., Queralt, B., Reina, J. J., Maurel, J., Gonzalez-Flores, E., Aparicio, J., Rivera, F., Losa, F., Aranda, E.
(2007). Phase III Study of Capecitabine Plus Oxaliplatin Compared With Continuous-Infusion Fluorouracil Plus Oxaliplatin As First-Line Therapy in Metastatic Colorectal Cancer: Final Report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. JCO
25: 4224-4230
[Abstract][Full Text]
Mayer, R. J.
(2007). Should Capecitabine Replace Infusional Fluorouracil and Leucovorin When Combined With Oxaliplatin in Metastatic Colorectal Cancer?. JCO
25: 4165-4167
[Full Text]
Sezeur, A., Chatelet, F.P., Cywiner, Ch., de Labriolle-Vaylet, Cl., Chastang, C., Billotey, Cl., Malafosse, M., Gallot, D., Betton, P., Montravers, F., Carvajal-Gonzalez, S., Askienazy, S., Talbot, J.N., Rain, J.D., Milhaud, G., Saumon, G., Barbet, J., Gruaz-Guyon, A.
(2007). Pathology Underrates Colon Cancer Extranodal and Nodal Metastases; Ex vivo Radioimmunodetection Helps Staging. Clin. Cancer Res.
13: 5592s-5597s
[Abstract][Full Text]
Meropol, N. J.
(2007). A Renewed Call for Equipoise. JCO
25: 3392-3394
[Full Text]
Saltz, L. B., Niedzwiecki, D., Hollis, D., Goldberg, R. M., Hantel, A., Thomas, J. P., Fields, A. L.A., Mayer, R. J.
(2007). Irinotecan Fluorouracil Plus Leucovorin Is Not Superior to Fluorouracil Plus Leucovorin Alone As Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803. JCO
25: 3456-3461
[Abstract][Full Text]
Iddings, D. M., Koda, E. A., Grewal, S. S., Parker, R., Saha, S., Bilchik, A.
(2007). Association of Angiogenesis Markers With Lymph Node Metastasis in Early Colorectal Cancer. Arch Surg
142: 738-745
[Abstract][Full Text]
Punt, C. J. A., Buyse, M., Kohne, C.-H., Hohenberger, P., Labianca, R., Schmoll, H. J., Pahlman, L., Sobrero, A., Douillard, J.-Y.
(2007). Endpoints in Adjuvant Treatment Trials: A Systematic Review of the Literature in Colon Cancer and Proposed Definitions for Future Trials. JNCI J Natl Cancer Inst
99: 998-1003
[Abstract][Full Text]
Kemeny, N.
(2007). Presurgical Chemotherapy in Patients Being Considered for Liver Resection. The Oncologist
12: 825-839
[Abstract][Full Text]
Morris, E. J. A., Maughan, N. J., Forman, D., Quirke, P.
(2007). Identifying Stage III Colorectal Cancer Patients: The Influence of the Patient, Surgeon, and Pathologist. JCO
25: 2573-2579
[Abstract][Full Text]
Wilson, T. R., McLaughlin, K. M., McEwan, M., Sakai, H., Rogers, K. M.A., Redmond, K. M., Johnston, P. G., Longley, D. B.
(2007). c-FLIP: A Key Regulator of Colorectal Cancer Cell Death. Cancer Res.
67: 5754-5762
[Abstract][Full Text]
Fuse, N., Doi, T., Ohtsu, A., Takeuchi, S., Kojima, T., Taku, K., Tahara, M., Muto, M., Asaka, M., Yoshida, S.
(2007). Feasibility of Oxaliplatin and Infusional Fluorouracil/Leucovorin (FOLFOX4) for Japanese Patients with Unresectable Metastatic Colorectal Cancer. Jpn J Clin Oncol
37: 434-439
[Abstract][Full Text]
Spunt, S. L., Freeman, B. B. III, Billups, C. A., McPherson, V., Khan, R. B., Pratt, C. B., Stewart, C. F.
(2007). Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors. JCO
25: 2274-2280
[Abstract][Full Text]
O'Dwyer, P. J., Eckhardt, S. G., Haller, D. G., Tepper, J., Ahnen, D., Hamilton, S., Benson, A. B. III, Rothenberg, M., Petrelli, N., Lenz, H.-J., Diasio, R., DuBois, R., Sargent, D., Sloan, J., Johnson, C. D., Comis, R. L., O'Connell, M. J.
(2007). Priorities in Colorectal Cancer Research: Recommendations From the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups. JCO
25: 2313-2321
[Abstract][Full Text]
Kuebler, J. P., Wieand, H. S., O'Connell, M. J., Smith, R. E., Colangelo, L. H., Yothers, G., Petrelli, N. J., Findlay, M. P., Seay, T. E., Atkins, J. N., Zapas, J. L., Goodwin, J. W., Fehrenbacher, L., Ramanathan, R. K., Conley, B. A., Flynn, P. J., Soori, G., Colman, L. K., Levine, E. A., Lanier, K. S., Wolmark, N.
(2007). Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: Results From NSABP C-07. JCO
25: 2198-2204
[Abstract][Full Text]
Land, S. R., Kopec, J. A., Cecchini, R. S., Ganz, P. A., Wieand, H. S., Colangelo, L. H., Murphy, K., Kuebler, J. P., Seay, T. E., Needles, B. M., Bearden, J. D. III, Colman, L. K., Lanier, K. S., Pajon, E. R. Jr, Cella, D., Smith, R. E., O'Connell, M. J., Costantino, J. P., Wolmark, N.
(2007). Neurotoxicity From Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: NSABP C-07. JCO
25: 2205-2211
[Abstract][Full Text]
Benson, A. B. III
(2007). The Hope for Today--The Promise for Tomorrow: Will Oncologists Meet the Challenge?. JCO
25: 2156-2158
[Full Text]
Ahmad, A., Chen, S. L., Bilchik, A. J.
(2007). Role of Repeated Hepatectomy in the Multimodal Treatment of Hepatic Colorectal Metastases. Arch Surg
142: 526-532
[Abstract][Full Text]
Muss, H. B., Biganzoli, L., Sargent, D. J., Aapro, M.
(2007). Adjuvant Therapy in the Elderly: Making the Right Decision. JCO
25: 1870-1875
[Abstract][Full Text]
Sanoff, H. K., Bleiberg, H., Goldberg, R. M.
(2007). Managing Older Patients With Colorectal Cancer. JCO
25: 1891-1897
[Abstract][Full Text]
Wolpin, B. M., Meyerhardt, J. A., Mamon, H. J., Mayer, R. J.
(2007). Adjuvant Treatment of Colorectal Cancer. CA Cancer J Clin
57: 168-185
[Abstract][Full Text]
Linch, M, Cunningham, D, Mingo, O, Stiles, A, Farquhar-Smith, W.
(2007). Renal tubular acidosis due to oxaliplatin. Ann Oncol
18: 805-806
[Full Text]
Tsujino, T., Seshimo, I., Yamamoto, H., Ngan, C. Y., Ezumi, K., Takemasa, I., Ikeda, M., Sekimoto, M., Matsuura, N., Monden, M.
(2007). Stromal Myofibroblasts Predict Disease Recurrence for Colorectal Cancer. Clin. Cancer Res.
13: 2082-2090
[Abstract][Full Text]
Wang, W.-S., Lin, J.-K., Lin, T.-C., Chen, W.-S., Jiang, J.-K., Wang, H.-S., Chiou, T.-J., Liu, J.-H., Yen, C.-C., Chen, P.-M.
(2007). Oral Glutamine Is Effective for Preventing Oxaliplatin-Induced Neuropathy in Colorectal Cancer Patients. The Oncologist
12: 312-319
[Abstract][Full Text]
Gelibter, A. J., Di Segni, S., Zeuli, M., Milella, M., Ferretti, G., Nuzzo, C., Cognetti, F.
(2007). Old Age: Biologic Versus Chronologic. JCO
25: e8-e8
[Full Text]
Schmoll, H.-J., Cartwright, T., Tabernero, J., Nowacki, M. P., Figer, A., Maroun, J., Price, T., Lim, R., Van Cutsem, E., Park, Y.-S., McKendrick, J., Topham, C., Soler-Gonzalez, G., de Braud, F., Hill, M., Sirzen, F., Haller, D. G.
(2007). Phase III Trial of Capecitabine Plus Oxaliplatin As Adjuvant Therapy for Stage III Colon Cancer: A Planned Safety Analysis in 1,864 Patients. JCO
25: 102-109
[Abstract][Full Text]
Rodel, C., Liersch, T., Hermann, R. M., Arnold, D., Reese, T., Hipp, M., Furst, A., Schwella, N., Bieker, M., Hellmich, G., Ewald, H., Haier, J., Lordick, F., Flentje, M., Sulberg, H., Hohenberger, W., Sauer, R.
(2007). Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer. JCO
25: 110-117
[Abstract][Full Text]
Gill, S., Blackstock, A. W., Goldberg, R. M.
(2007). Colorectal Cancer. Mayo Clin Proc.
82: 114-129
[Abstract][Full Text]
Popat, S, Chen, Z, Zhao, D, Pan, H, Hearle, N, Chandler, I, Shao, Y, Aherne, W, Houlston, R.
(2006). A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer. Ann Oncol
17: 1810-1817
[Abstract][Full Text]
Portier, G., Elias, D., Bouche, O., Rougier, P., Bosset, J.-F., Saric, J., Belghiti, J., Piedbois, P., Guimbaud, R., Nordlinger, B., Bugat, R., Lazorthes, F., Bedenne, L.
(2006). Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial. JCO
24: 4976-4982
[Abstract][Full Text]
4 vs. >4), T classification (T4 vs. T1, T2, or T3), degree of cellular differentiation (well vs. poorly differentiated), and the presence or absence of perforation, obstruction, and venous invasion. 
Previous
