Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer
Leonard B. Saltz, M.D., John V. Cox, D.O., Charles Blanke, M.D., Lee S. Rosen, M.D., Louis Fehrenbacher, M.D., Malcolm J. Moore, M.D., Jean A. Maroun, M.D., Stephen P. Ackland, M.B., B.S., Paula K. Locker, M.S., Nicoletta Pirotta, M.S., Gary L. Elfring, M.S., Langdon L. Miller, M.D., for The Irinotecan Study Group
Background The combination of fluorouracil and leucovorin hasuntil recently been standard therapy for metastatic colorectalcancer. Irinotecan prolongs survival in patients with colorectalcancer that is refractory to treatment with fluorouracil andleucovorin. In a multicenter trial, we compared a combinationof irinotecan, fluorouracil, and leucovorin with bolus dosesof fluorouracil and leucovorin as first-line therapy for metastaticcolorectal cancer. A third group of patients received irinotecanalone.
Methods Patients were randomly assigned to receive irinotecan(125 mg per square meter of body-surface area intravenously),fluorouracil (500 mg per square meter as an intravenous bolus),and leucovorin (20 mg per square meter as an intravenous bolus)weekly for four weeks every six weeks; fluorouracil (425 mgper square meter as an intravenous bolus) and leucovorin (20mg per square meter as an intravenous bolus) daily for fiveconsecutive days every four weeks; or irinotecan alone (125mg per square meter intravenously) weekly for four weeks everysix weeks. End points included progression-free survival andoverall survival.
Results Of 683 patients, 231 were assigned to receive irinotecan,fluorouracil, and leucovorin; 226 to receive fluorouracil andleucovorin; and 226 to receive irinotecan alone. In an intention-to-treatanalysis, as compared with treatment with fluorouracil and leucovorin,treatment with irinotecan, fluorouracil, and leucovorin resultedin significantly longer progression-free survival (median, 7.0vs. 4.3 months; P=0.004), a higher rate of confirmed response(39 percent vs. 21 percent, P<0.001), and longer overallsurvival (median, 14.8 vs. 12.6 months; P=0.04). Results foririnotecan alone were similar to those for fluorouracil andleucovorin. Grade 3 (severe) diarrhea was more common duringtreatment with irinotecan, fluorouracil, and leucovorin thanduring treatment with fluorouracil and leucovorin, but the incidenceof grade 4 (life-threatening) diarrhea was similar in the twogroups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia,and neutropenic fever were less frequent during treatment withirinotecan, fluorouracil, and leucovorin. Adding irinotecanto the regimen of fluorouracil and leucovorin did not compromisethe quality of life.
Conclusions Weekly treatment with irinotecan plus fluorouraciland leucovorin is superior to a widely used regimen of fluorouraciland leucovorin for metastatic colorectal cancer in terms ofprogression-free survival and overall survival.
The antimetabolite fluorouracil is widely used to treat metastaticcolorectal cancer, the second-leading cause of death from cancerin North America.1 The drug inhibits thymidylate synthase, anenzyme required for the synthesis of DNA.2 It is commonly administeredwith leucovorin, a reduced folate (tetrahydrofolate) that increasesthe affinity of fluorouracil for thymidylate synthase. Amongvarious schedules of administration, the efficacy of the MayoClinic bolus regimen, in which the two drugs are injected dailyfor five days every four weeks, has been validated in randomizedtrials3,4,5 and is frequently used as first-line therapy formetastatic colorectal cancer.
Irinotecan (Camptosar, Pharmacia) is a potent inhibitor of topoisomeraseI, a nuclear enzyme involved in the unwinding of DNA duringreplication.6,7,8 Irinotecan has demonstrated antitumor activityagainst metastatic colorectal cancer when used alone as first-linetreatment9,10,11,12 or as second-line treatment after the failureof fluorouracil.10,11,12,13,14,15,16,17,18 In randomized phase3 trials, second-line irinotecan extended survival significantlyas compared with supportive care19 or infusions of fluorouraciland leucovorin as a second-line therapy.20
The mechanism of action of irinotecan and its activity againstuntreated and fluorouracil-resistant colorectal cancer werethe rationale for combining irinotecan with fluorouracil andleucovorin as first-line therapy for this disease. A phase 1study21 developed a combination regimen based on the weeklyirinotecan schedule that had been the most widely studied inthe United States.9,11,13,14,16,18,22 We conducted a phase 3trial in which the combination of irinotecan, fluorouracil,and leucovorin was compared with the Mayo Clinic bolus regimenof fluorouracil and leucovorin as a first-line treatment formetastatic colorectal cancer. A third group of patients wastreated with irinotecan alone to determine the activity of thisdrug as a single agent in a multicenter trial.
Methods
Study Design and Entry Criteria
We conducted a phase 3, randomized, open-label, multicentertrial. To be eligible, patients had to have histologically documentedcolorectal cancer and measurable metastatic disease; an EasternCooperative Oncology Group (ECOG) performance status of 0, 1,or 2; and adequate organ function. Prior therapy for metastaticdisease was not permitted; patients who had received adjuvantfluorouracil-based therapy were eligible if they had remainedfree of disease for at least one year after the completion ofadjuvant therapy. Patients who had received pelvic irradiationwere excluded. The protocol was approved by the institutionalreview boards of all participating institutions, and all patientsgave written informed consent before enrollment.
Stratification, Randomization, and Therapy
Patients were stratified according to age (<65 years vs.65 years), ECOG performance status (0 vs. 1 or 2), intervalfrom diagnosis to enrollment (<6 months vs. 6 months), andhistory of adjuvant therapy with fluorouracil (yes vs. no) andwere then randomly assigned to one of three regimens (Table 1).Treatment was continued until one of the following occurred:disease progression, unacceptable adverse effects, or the withdrawalof consent by the patient. After the first treatment, the doseswere adjusted to accommodate individual levels of tolerance.The severity of adverse effects was evaluated with use of theNational Cancer Institute Common Toxicity Criteria (version1.0), in which a grade of 0 indicates no adverse effects, agrade of 1 minor effects, a grade of 2 moderate effects, a gradeof 3 severe effects, and a grade of 4 life-threatening effects.The doses of irinotecan and fluorouracil (in the triple-druggroup) were reduced by 20 percent during a cycle if a grade2 adverse effect occurred and were omitted in the event of agrade 3 or 4 effect. Once the adverse effect resolved, treatmentwas resumed; the dose was reduced by 20 percent in the caseof a grade 3 adverse effect and by 40 percent in the case ofa grade 4 adverse effect or neutropenic fever. After grade 3or 4 mucositis, only the doses of fluorouracil were reduced.For the Mayo Clinic bolus regimen, the doses of fluorouracilwere reduced by 20 percent after a grade 3 adverse effect andby 40 percent after a grade 4 effect or neutropenic fever.
Supportive care included intensive treatment with loperamide23for late diarrhea. Atropine was given as needed for irinotecan-relatedcholinergic symptoms.24,25 Antiemetic agents were provided atthe discretion of the treating physician. The prophylactic useof colony-stimulating factors was not permitted.
Evaluation of Patients
Tumors were measured every 6 weeks through week 24 and thenevery 12 weeks until the tumor progressed. An objective responsewas defined as a reduction of at least 50 percent in the areaof all measurable lesions on computed tomographic (CT) or otherscanning. Confirmed objective responses were those for whicha follow-up scan obtained at least four weeks later demonstratedthe persistence of the response. Tumor progression was definedas an increase of at least 25 percent in the overall area ofthe tumor or the appearance of new lesions. The determinationof responses and progression was based on investigator-reportedmeasurements. Safety assessments and complete blood counts wereperformed weekly. Serum chemical values and the quality of lifewere assessed at the beginning of each treatment cycle. TheQuality of Life Questionnaire of the European Organization forResearch and Treatment of Cancer (version 2) was used to assessthe quality of life. On this test, scores can range from 0 to100, with higher scores on functional scales and lower scoreson symptom scales indicating a better quality of life. Dataon subsequent treatments for colorectal cancer and survivalwere collected approximately every three months after the endof the study treatment.
Statistical Analysis
The primary end point was progression-free survival. Progression-freesurvival was defined as the length of time from randomizationto disease progression or to death from disease progressionor unknown causes. For patients who were removed from the studyor died of causes unrelated to colorectal cancer, progression-freesurvival was conservatively defined as the time from randomizationto the last date on which the patient was known to be free ofprogressive disease.
Past experience suggested that the median progression-free survivalwith fluorouracil and leucovorin would be five months.4,5 Weestimated that 220 patients would be needed in each group inorder to detect a 40 percent improvement in median progression-freesurvival, to seven months, with triple-drug therapy with a powerof 0.85.
In the evaluation of efficacy end points, all patients enrolledin the study were included and analyzed according to the intention-to-treatprinciple. In the analysis of treatment administration and adverseeffects, only the patients who actually received treatment wereassessed. (Of the 683 patients who enrolled in the study, the16 who were not treated were excluded from this part of theanalysis and the adverse effects in the 4 patients who receivedthe wrong treatment were attributed to the drugs they actuallyreceived.) We used two-tailed, unstratified, log-rank tests,with a P value of 0.05 or less considered to indicate statisticalsignificance, in the analyses comparing time-to-event end pointsbetween the triple-drug group and the two-drug group, whichwere selected a priori as the only groups to be used in statisticalhypothesis testing. For response rates, we used chi-square teststo compare these two groups. We assessed changes in subscalescores of the quality of life between groups using analysisof variance for repeated measures, whereas we used Student'st-tests to compare the greatest worsening in the quality oflife from base line.
We used proportional-hazards modeling with forward selectionto determine the influence of the patients' base-line characteristicson response, progression-free survival, and overall survival.A P value of less than 0.05 was considered to indicate statisticalsignificance. Interactions between treatment and the variousfactors with a P value of less than 0.10 were assessed. Predefinedbase-line characteristics for this analysis included the fourstratification factors and other potentially prognostic factors:sex, race or ethnic group, the site of the primary tumor, thetime from diagnosis of disease to the occurrence of metastasis,the number of involved organs, the presence or absence of liverinvolvement, hemoglobin level, white-cell count, and serum levelsof carcinoembryonic antigen, lactate dehydrogenase, and totalbilirubin.
Results
Characteristics of the Patients
A total of 683 patients were enrolled in the study and randomlyassigned to one of the three treatments between May 1996 andMay 1998 at 71 sites in the United States, Canada, Australia,and New Zealand. Data were collected for an additional 19 monthsafter accrual ended, with data on survival collected throughDecember 1999. The intention-to-treat population comprised 231patients in the group assigned to receive irinotecan, fluorouracil,and leucovorin; 226 patients in the group assigned to receivefluorouracil and leucovorin; and 226 patients in the group assignedto receive irinotecan alone. After the exclusion of the 16 patientswho never received therapy and the 4 who received the wrongtreatment, the treated population included 225 patients whoreceived irinotecan, fluorouracil, and leucovorin; 219 patientswho received fluorouracil and leucovorin; and 223 patients whoreceived irinotecan alone.
Table 2 shows the base-line characteristics of the patients,all of which were balanced among the treatment groups exceptfor the proportion of men, which was greater in the triple-druggroup than in the two-drug group (65 percent vs. 54 percent,P=0.02). The median age was just over 60 years. More than 50percent of the patients had an ECOG performance status of 1or 2 at base line. Approximately 35 percent of the patientsin each group had at least two organs involved, with the liverbeing the most common site of metastatic disease. Because mostpatients had metastatic disease at diagnosis, only about 10percent of them had received adjuvant therapy. In violationof the entry criteria, nine patients had received pelvic radiotherapy.There were no significant differences in base-line laboratoryvalues among the groups.
Table 2. Base-Line Characteristics of the Patients.
Treatment
The median duration of treatment with irinotecan, fluorouracil,and leucovorin was 5.5 months. For patients who received fluorouraciland leucovorin and those who received irinotecan alone, themedian durations of treatment were 4.1 months and 3.9 months,respectively. The median relative intensity of the dose of irinotecan(calculated as the actual dose delivered divided by the intendeddose) was similar in the group given irinotecan alone and thegroup given irinotecan, fluorouracil, and leucovorin (75 percentvs. 72 percent). The median relative intensity of the dose offluorouracil in the triple-drug group was lower than that inthe two-drug group (71 percent vs. 86 percent). This lower doseintensity may have resulted, in part, from the weekly reductionsin dose permitted with the triple-drug regimen.
Among patients with follow-up data, 52 percent of those whoreceived irinotecan, fluorouracil, and leucovorin during thestudy, 70 percent of those who received fluorouracil and leucovorin,and 79 percent of those who were given irinotecan alone receivedadditional chemotherapy after the study treatment ended. Themajority of patients (56 percent) in the group given fluorouraciland leucovorin received an irinotecan-based regimen after thestudy. Oxaliplatin or other investigational agents were administeredto fewer than 5 percent of patients in any group.
Efficacy
Progression-free survival, the primary end point of the study,was significantly longer among patients who were assigned toreceive irinotecan, fluorouracil, and leucovorin than amongthose assigned to receive fluorouracil and leucovorin (median,7.0 months vs. 4.3 months; P=0.004) (Table 3). Progression-freesurvival among patients who were assigned to receive irinotecanalone (median, 4.2 months) was similar to that among patientswho were assigned to receive fluorouracil and leucovorin. TheKaplan–Meier estimates of progression-free survival inthe three groups are shown in Figure 1.
Figure 1. Kaplan–Meier Estimates of Progression-free Survival.
The P value was derived from a log-rank test comparing the triple-drug group with the two-drug group.
The objective rate of response was 50 percent among patientswho were assigned to receive irinotecan, fluorouracil, and leucovorinand 28 percent among those assigned to receive fluorouraciland leucovorin (P<0.001). The rates of objective responsesthat were confirmed by imaging tests four to six weeks laterwere also significantly higher among patients in the triple-druggroup than among those in the two-drug group (39 percent vs.21 percent, P<0.001). The rates of objective and confirmedresponses with irinotecan alone (29 percent and 18 percent,respectively) were similar to those with fluorouracil and leucovorin(28 percent and 21 percent, respectively). A complete responsewas seen in six patients in the triple-drug group, two patientsin the two-drug group, and four patients assigned to receiveirinotecan alone. The median duration of confirmed responsewas approximately nine months in all groups.
The median survival of patients who were assigned to receiveirinotecan, fluorouracil, and leucovorin was 14.8 months, ascompared with 12.6 months among patients who were assigned toreceive fluorouracil and leucovorin (P=0.04). The median survivalof patients assigned to receive irinotecan alone was similarto that of patients assigned to receive fluorouracil and leucovorin(12.0 vs. 12.6 months). The Kaplan–Meier survival curvesare shown in Figure 2.
Figure 2. Kaplan–Meier Estimates of Overall Survival.
The P value was derived from a log-rank test comparing the triple-drug group with the two-drug group.
Proportional-Hazards Modeling
Multiple regression modeling of the rates of objective responserevealed no interactions between treatment and the stratificationfactors or other potentially prognostic factors. The additionof irinotecan to therapy with fluorouracil and leucovorin virtuallydoubled the response rates in all predefined subgroups of patients.
For progression-free and overall survival, we used Cox regressiontechniques to compare the effects of irinotecan, fluorouracil,and leucovorin with those of fluorouracil and leucovorin inthe context of the stratification factors and other predefinedbase-line clinical characteristics (Table 4). Factors predictiveof improved progression-free survival and overall survival werea normal lactate dehydrogenase level and an excellent performancestatus (a score of 0). A hemoglobin level of at least 11 g perdeciliter and a normal white-cell count were predictive of betterprogression-free survival and overall survival, respectively.Unexpectedly, an age of 65 years or older was also associatedwith a longer progression-free survival. Treatment with irinotecan,fluorouracil, and leucovorin remained a significant independentpredictor of longer progression-free survival (P<0.001) andoverall survival (P= 0.03) when other significant base-linecharacteristics were taken into account. Treatment with irinotecan,fluorouracil, and leucovorin was associated with a 36 percentreduction in the risk of progression and a 22 percent reductionin the risk of death relative to treatment with fluorouraciland leucovorin alone (Table 4). No relevant interactions betweentreatment and other factors were identified for progression-freesurvival, indicating that progression-free survival was improvedin all the predefined subgroups of patients. In the comparisonof irinotecan, fluorouracil, and leucovorin with fluorouraciland leucovorin, the reduction in the risk of death among patientswith a normal lactate dehydrogenase level was 43 percent, ascompared with a reduction of 12 percent among those with anelevated lactate dehydrogenase level, suggesting a possibleinteraction of the lactate dehydrogenase level with treatmentwith respect to survival (P=0.07).
As shown in Table 5, 22.7 percent of patients who were givenirinotecan, fluorouracil, and leucovorin had diarrhea of grade3 or 4, as compared with 13.2 percent of patients who were givenfluorouracil and leucovorin and 31.0 percent of patients whowere given irinotecan alone. The difference between the triple-druggroup and the two-drug group was primarily in the incidenceof grade 3 diarrhea; the incidence of grade 4 diarrhea was similarin the two groups (7.6 percent and 7.3 percent). The group givenirinotecan alone had an incidence of grade 4 diarrhea of 12.6percent. Vomiting of grade 3 or 4 was more common with combinationregimens that included irinotecan. Mucositis of grade 3 or 4occurred in only 2.2 percent of patients who received irinotecanalone or in combination. As expected, the Mayo Clinic bolusregimen of fluorouracil and leucovorin was associated with amuch higher frequency of grade 3 or 4 mucositis (16.9 percent).Moreover, the frequency of grade 4 neutropenia during treatmentwith irinotecan, fluorouracil, and leucovorin was almost halfthat observed during treatment with fluorouracil and leucovorin(24.0 percent vs. 42.5 percent); neutropenic fever was alsoless common with irinotecan, fluorouracil, and leucovorin thanwith fluorouracil and leucovorin (7.1 percent vs. 14.6 percent).Irinotecan alone was associated with the lowest incidence ofgrade 3 or 4 neutropenia. The incidence of treatment-relateddeath was approximately 1 percent in all three groups.
Table 5. Adverse Events among Patients Who Received the Assigned Treatment.
Quality of Life
Analyses of the quality of life showed that there were no significantdifferences between the group given irinotecan, fluorouracil,and leucovorin and the group given fluorouracil and leucovorin(Figure 3). In univariate analyses in which we compared thegreatest worsening in the quality of life from base line, themean increases in the severity of symptoms were smaller in thetriple-drug group than in the two-drug group with respect tofatigue (increase in severity, 8 percent vs. 20 percent), anorexia(1 percent decrease vs. 9 percent increase), and pain (increase,1 percent vs. 8 percent) (P<0.05 for all comparisons, byStudent's t-test). As indicated by the measurement of the greatestdeclines from base line in role functioning (the ability toperform the activities of daily living), the triple-drug grouphad a smaller decrease in function than the two-drug group (decrease,6 percent vs. 13 percent; P<0.05 by Student's t-test). Theextent of the changes in other subscales in this analysis wasnot significantly different between the groups.
Figure 3. Mean (±SE) Changes from Base Line in Scores on the Global Health Status Subscale of the Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer.
On this scale, scores can range from 0 to 100, with higher scores indicating a better quality of life.
Discussion
In this phase 3, randomized study, we compared the clinicalbenefits of a combination of irinotecan plus fluorouracil andleucovorin with those of fluorouracil and leucovorin alone asfirst-line therapy for metastatic colorectal cancer. The controlregimen of fluorouracil and leucovorin that we used has beenone of the most commonly used treatments for metastatic colorectalcancer in North America; thus, our findings can give practitionersinsight into the relative efficacy and safety of the new regimenas contrasted with a familiar standard.
The base-line clinical characteristics of the treatment groupswere similar except for a greater proportion of men in the groupassigned to receive irinotecan, fluorouracil, and leucovorinthan in the group assigned to receive fluorouracil and leucovorin.However, this difference did not appear to influence the results;when sex was tested in multivariate analyses, it was not significantlypredictive of the outcome.
Our results show that, as compared with fluorouracil-based therapy,the combination of irinotecan, fluorouracil, and leucovorinsignificantly delays disease progression while reducing thesize of tumors. Progression-free survival was significantlylonger among patients who were assigned to receive irinotecan,fluorouracil, and leucovorin than among those assigned to receivefluorouracil and leucovorin (median progression-free survival,7.0 and 4.3 months, respectively; P=0.004), with an averagereduction of 36 percent in the risk of disease progression atany given time. The rates of response with irinotecan, fluorouracil,and leucovorin were close to double those with fluorouraciland leucovorin (50 percent vs. 28 percent, P<0.001). Improvementsin response rates and progression-free survival were observedin every subgroup of patients in the triple-drug group, includingthose with a poor ECOG performance status, an age of 65 yearsor older, extensive disease, a history of adjuvant therapy,or abnormal laboratory values at base line.
Treatment with irinotecan, fluorouracil, and leucovorin wasalso associated with a statistically significant improvementin overall survival (median, 14.8 months, as compared with 12.6months in the group assigned to fluorouracil and leucovorin;P=0.04). Evaluation of the hazard ratio for the three-drug grouprelative to the two-drug group indicated that, at any giventime, the relative risk of death in the triple-drug group wasan average of 22 percent lower. The improvement in survivalin the patients who received the triple-drug combination isparticularly notable because over half the patients in the controlgroup eventually received irinotecan as second-line therapy.Thus, concurrent first-line administration of irinotecan andfluorouracil appears to be superior to sequential administration.
We performed a Cox regression analysis of prognostic factorsidentified in other trials19,20,26,27,28 and confirmed thata good performance status, fewer metastatic sites, relativelynormal laboratory results (normal lactate dehydrogenase andbilirubin levels, normal white-cell count, and a hemoglobinlevel of at least 11 g per deciliter) are associated with betteroutcomes. After adjustment for these factors, the differencebetween the group given irinotecan, fluorouracil, and leucovorinand the group given fluorouracil and leucovorin remained significantwith respect to improvements in both progression-free survival(P<0.001) and overall survival (P=0.03).
As stipulated by the protocol, the irinotecan-alone group wasnot the focus of statistical testing. However, as expected,the efficacy results in this group were generally consistentwith those observed with fluorouracil and leucovorin alone.
The results of our study complement the findings of anotherphase 3 trial comparing irinotecan, fluorouracil, and leucovorinwith fluorouracil and leucovorin as first-line therapy for metastaticcolorectal cancer.29 That study, conducted primarily in Europe,randomly assigned 385 patients to receive either irinotecanplus infusions of fluorouracil and leucovorin or infusions offluorouracil and leucovorin alone. The results of both studiesare remarkably consistent; in the European trial, progression-freesurvival was significantly improved with the triple-drug therapyas compared with the two-drug therapy (median, 6.7 months vs.4.4 months; P<0.001). Likewise, the confirmed objective responserate in the group given irinotecan, fluorouracil, and leucovorinwas significantly higher than the rate in the group given fluorouraciland leucovorin (35 percent vs. 22 percent, P<0.005). Theaddition of irinotecan resulted in an improvement in survivalof approximately 20 percent (median, 17.4 months vs. 14.1 months;P=0.03), results that were similar to those in our study.
In our study, the incidence of grade 3 diarrhea was greaterwith triple-drug therapy than with two-drug therapy. However,grade 4 diarrhea — largely defined by the need for hospitalizationfor supportive care — was infrequent (<8 percent) inboth groups. The incidence of grade 4 diarrhea was lower withirinotecan, fluorouracil, and leucovorin than with irinotecanalone, perhaps because the neutropenia induced by fluorouraciland leucovorin in the three-drug group prompted early midcyclereductions in the dose of irinotecan and fluorouracil that loweredthe risk of grade 4 diarrhea.
Vomiting of grade 3 or 4 was more common with irinotecan, fluorouracil,and leucovorin than with fluorouracil and leucovorin, but itoccurred in less than 10 percent of patients in the three-druggroup, and its incidence might have been further reduced withthe more frequent use of prophylactic serotonin-antagonist antiemetics.Mucositis of grade 3 or 4, grade 4 neutropenia, and neutropenicfever occurred less often with triple-drug therapy than withtwo-drug therapy. This finding most likely results from differencesin the scheduling of fluorouracil and leucovorin treatmentsin the two regimens; the combination of fluorouracil and leucovorinis associated with lower rates of these adverse effects whenit is given weekly.4,5 Treatment-related death was rare (a rateof 1 percent in all groups). Furthermore, analysis of the qualityof life indicated that the combination of irinotecan with fluorouraciland leucovorin did not worsen the quality of life as comparedwith that reported with fluorouracil and leucovorin.
In conclusion, we found that combining irinotecan with fluorouraciland leucovorin benefits patients with metastatic colorectalcancer. As compared with a widely used regimen of fluorouraciland leucovorin, the triple-drug therapy was associated withhigher rates of tumor regression, progression-free survival,and overall survival without compromising the quality of life.The combination of irinotecan, fluorouracil, and leucovorinis now being compared with a weekly regimen of fluorouraciland leucovorin as adjuvant therapy for patients with stage IIIcolon cancer to determine whether it will increase rates ofcure in patients with an earlier stage of the disease.
Presented in preliminary form at the 19th Annual Meeting ofthe American Society of Clinical Oncology, Atlanta, May 15–18,1999.
Supported by Pharmacia.
We are indebted to Bonnie Keller, Mary Anne Needham, Dawn Wikel,Jodi Tiffany, Margie Bruns, Dawn Price, and Sally Boos for meticulousdata review; to Angelina Pastorelli and Luca Cuomo for conscientiousdata management; to Patricia Newman, Nicola Amos, Jo Gordon,and Monica McDonald for attentive site management; and to BonnieAyotte, Mary Fitzjohn, and Cheryl Krause for diligent administrativesupport.
* Additional principal investigators are listed in the Appendix.
Source Information
From Memorial Sloan-Kettering Cancer Center, New York (L.B.S.); U.S. Oncology, Dallas (J.V.C.); the Vanderbilt Cancer Center, Nashville (C.B.); UCLA Medical Center, Los Angeles (L.S.R.); Kaiser Permanente Medical Center, Vallejo, Calif. (L.F.); Princess Margaret Hospital, Toronto (M.J.M.); Ottawa Regional Cancer Center, Ottawa, Ont., Canada (J.A.M.); Newcastle Mater Misericordiae Hospital, Waratah, N.S.W., Australia (S.P.A.); and Pharmacia Corporation, Peapack, N.J. (P.K.L., N.P., G.L.E., L.L.M.).
Address reprint requests to Dr. Saltz at the Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
References
Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33. [Abstract]
Grem JL. 5-Fluoropyrimidines. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy: principles and practice. 2nd ed. Philadelphia: Lippincott-Raven, 1996:149-211.
Poon MA, O'Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989;7:1407-1418. [Abstract]
Buroker TR, O'Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994;12:14-20. [Abstract]
Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 1995;13:1303-1311. [Abstract]
Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991;51:4187-4191. [Free Full Text]
Jaxel C, Kohn KW, Wani MC, Wall ME, Pommier Y. Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 1989;49:1465-1469. [Free Full Text]
Hsiang YH, Lihou MG, Liu LF. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989;49:5077-5082. [Free Full Text]
Conti JA, Kemeny NE, Saltz LB, et al. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996;14:709-715. [Free Full Text]
Shimada Y, Yoshino M, Wakui A, et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 1993;11:909-913. [Free Full Text]
Pitot HC, Wender DB, O'Connell MJ, et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 1997;15:2910-2919. [Abstract]
Rougier P, Bugat R, Douillard JY, et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997;15:251-260. [Free Full Text]
Rothenberg ML, Eckardt JR, Kuhn JG, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996;14:1128-1135. [Free Full Text]
Pazdur R, Zinner R, Rothenberg ML, et al. Age as a risk factor in irinotecan (CPT-11) treatment of 5-FU-refractory colorectal cancer. Prog Proc Am Soc Clin Oncol 1997;16:260a. abstract.
Van Cutsem E, Rougier P, Droz JP, Marty M, Bleiberg H. Clinical benefit of irinotecan (CPT-11) in metastatic colorectal cancer (CRC) resistant to 5-FU. Prog Proc Am Soc Clin Oncol 1997;16:268a. abstract.
Von Hoff DD, Rothenberg ML, Pitot HC, et al. Irinotecan (CPT-11) therapy for patients with previously treated metastatic colorectal cancer (CRC): overall results of FDA-reviewed pivotal US clinical trials. Prog Proc Am Soc Clin Oncol 1997;16:228a. abstract.
Rothenberg ML, Hainsworth JD, Rosen L, et al. Phase II study of irinotecan (CPT-11) 250 mg/m2 given every-other-week in previously treated colorectal cancer patients. Prog Proc Am Soc Clin Oncol 1998;17:284a. abstract.
Rothenberg ML, Cox JV, DeVore RF, et al. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 1999;85:786-795. [CrossRef][Medline]
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413-1418. [CrossRef][Medline]
Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998;352:1407-1412. [Erratum, Lancet 1998;352:1634.] [CrossRef][Medline]
Saltz LB, Kanowitz J, Kemeny NE, et al. Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 1996;14:2959-2967. [Abstract]
Rothenberg ML, Kuhn JG, Burris HA III, et al. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 1993;11:2194-2204. [Free Full Text]
Abigerges D, Armand JP, Chabot GG, et al. Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 1994;86:446-449. [Free Full Text]
Gandia D, Abigerges D, Armand JP, et al. CPT-11-induced cholinergic effects in cancer patients. J Clin Oncol 1993;11:196-197. [Medline]
Petit RG, Rothenberg ML, Mitchell EP, Compton LD, Miller LL. Cholinergic symptoms following CPT-11 infusion in a phase II multicenter trial of 250 mg/m2 irinotecan (CPT-11) given every two weeks. Prog Proc Am Soc Clin Oncol 1997;16:268a. abstract.
Kemeny N, Niedzwiecki D, Shurgot B, Oderman P. Prognostic variables in patients with hepatic metastases from colorectal cancer: importance of medical assessment of liver involvement. Cancer 1989;63:742-747. [CrossRef][Medline]
Rougier P, Milan C, Lazorthes F, et al. Prospective study of prognostic factors in patients with unresected hepatic metastases from colorectal cancer. Br J Surg 1995;82:1397-1400. [Medline]
Miller LL, Petit RG, Elfring GL. Evaluation of carcinoembryonic antigen (CEA) levels during CPT-11 treatment of patients with previously treated colorectal cancer. Prog Proc Am Soc Clin Oncol 1998;17:297a. abstract.
Doulliard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047. [Erratum, Lancet 2000;355:1372.] [CrossRef][Medline]
Appendix
Additional principal investigators of the Irinotecan Study Groupwere as follows: Evansville Cancer Center, Evansville, Ind.— R. Ballou; Western Hospital, Footscray, Victoria, Australia— R. Basser; Toronto Sunnybrook Regional Cancer Center,Toronto — G. Bjarnason; Ochsner Cancer Institute, NewOrleans — A. Brown; Yale Comprehensive Cancer Center,New Haven, Conn. — B. Burtness; Comprehensive Cancer Center,Clarksville, Tenn. — T. Butler; Sutter Cancer Center,Sacramento, Calif. — V. Caggiano; Salem Research Group,Winston-Salem, N.C. — N. Chrysson; Royal Prince AlfredHospital, Camperdown, N.S.W., Australia — S. Clarke; Universityof Virginia Health Science Center, Charlottesville — R.Cohen; University of Colorado Health Sciences Center, Denver— A. Cohn; Nova Scotia Cancer Center, Halifax, Canada— B. Colwell; Mid-Atlantic Consultants in Hematology–Oncology,Norfolk, Va. — P. Conkling; Hôtel-Dieu de Québec,Quebec, Que., Canada — F. Couture; Knoxville, Tenn. —T. Dobbs; Community Cancer Care, Indianapolis — W. Dugan;St. John's Mercy Hospital, St. Louis — J. Eckhardt; MarinOncology Associates, Greenbrae, Calif. — P. Eisenberg;Cross Cancer Institute, Edmonton, Alta., Canada — A. Fields;Hamilton Regional Cancer Center, Hamilton, Ont., Canada —A. Figueredo; Wellington Hospital, Wellington South, New Zealand— M. Findlay; Ball Memorial Hospital, Muncie, Ind. —W. Fisher; Joe Arrington Cancer Research and Treatment Center,Lubbock, Tex. — C. Geyer, Jr.; Prince of Wales Hospital,Randwick, N.S.W., Australia — D. Goldstein; Sidney KimmelCancer Center, San Diego, Calif. — J. Gutheil; Sarah CanonCancer Center, Nashville — J. Hainsworth; University ofPennsylvania Cancer Center, Philadelphia — D. Haller;St. Luke's Medical Center, Milwaukee — J. Hanson; DunedinHospital, Dunedin, New Zealand — M. Jeffery; Sacré-CoeurHospital, Montreal — B. L'Esperance; Jean Brown Associates,Salt Lake City — G. Litton; Indiana University, Indianapolis— P. Loehrer; Lombardi Cancer Center, Washington, D.C.— J. Marshall; Oncology Center at Providence Park, Mobile,Ala. — M. Meshad; Roswell Park Cancer Institute, Buffalo,N.Y. — N. Meropol; Jefferson Medical College, Philadelphia— E. Mitchell; Austin and Repatriation Medical Centre,Heidelberg, Victoria, Australia — P. Mitchell; ColumbusCooperative Community Oncology Program (CCOP), Columbus, Ohio— T. Moore; University of Illinois at Chicago, Chicago— M. Mullane; Queen Elizabeth Hospital, Woodville, S.A.,Australia — K. Patterson; Parrish Center Medical Plaza,Owensboro, Ky. — D. Prajapati; Bowman Gray Hospital, Winston-Salem,N.C. — F. Richards; Peter MacCallum Cancer Institute,East Melbourne, Victoria, Australia — D. Rischin; SwedishHospital Medical Center, Seattle — S. Rivkin; ChristchurchHospital, Christchurch, New Zealand — B. Robinson; MarshfieldClinic, Marshfield, Wis. — D. Rushing; Veterans AffairsMedical Center, Miami, Fla. — N. Savaraj; University OncologyAssociates, Chattanooga, Tenn. — L. Schlabach; WinthropUniversity Hospital, Mineola, N.Y. — J. Schneider; ComprehensiveCancer Center, Huntsville, Ala. — M. Schreeder; BritishColumbia Cancer Agency, Vancouver, Canada — A. Shah; Universityof Michigan Medical Center, Ann Arbor — D. Smith; St.Joseph Mercy Hospital, Ann Arbor, Mich. — P. Stella; LoyolaUniversity of Chicago, Maywood, Ill. — L. Swinnen; OregonHematology–Oncology Associates, Portland — G. Takahasi;Royal Victoria Hospital, Montreal — M. Trudeau; Sir CharlesGairdner Hospital, Nedlands, W.A., Australia — G. VanHazel; Montefiore Medical Center, Bronx, N.Y. — S. Wadler;Kingsport Hematology–Oncology Associates, Kingsport, Tenn.— S. Woodley; Health Science Cancer Centre, St. John's,Newf., Canada — R. Wong; Boston Cancer Center, Memphis,Tenn. — F. Yunus.
Hendifar, A., Yang, D., Lenz, F., Lurje, G., Pohl, A., Lenz, C., Ning, Y., Zhang, W., Lenz, H.-J.
(2009). Gender Disparities in Metastatic Colorectal Cancer Survival. Clin. Cancer Res.
15: 6391-6397
[Abstract][Full Text]
Koizumi, W., Boku, N., Yamaguchi, K., Miyata, Y., Sawaki, A., Kato, T., Toh, Y., Hyodo, I., Nishina, T., Furuhata, T., Miyashita, K., Okada, Y.
(2009). Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer. Ann Oncol
0: mdp371v1-mdp371
[Abstract][Full Text]
Grothey, A., Sargent, D. J.
(2009). Reply to F. Montagnani et al. JCO
27: e134-e135
[Full Text]
Goldberg, R. M., Sargent, D. J., Morton, R. F., Green, E., Sanoff, H. K., McLeod, H., Buckner, J.
(2009). NCCTG Study N9741: Leveraging Learning from an NCI Cooperative Group Phase III Trial. The Oncologist
14: 970-978
[Abstract][Full Text]
Grothey, A.
(2009). Review: Medical treatment of advanced colorectal cancer in 2009. Therapeutic Advances in Medical Oncology
1: 55-68
[Abstract]
van Hazel, G. A., Pavlakis, N., Goldstein, D., Olver, I. N., Tapner, M. J., Price, D., Bower, G. D., Briggs, G. M., Rossleigh, M. A., Taylor, D. J., George, J.
(2009). Treatment of Fluorouracil-Refractory Patients With Liver Metastases From Colorectal Cancer by Using Yttrium-90 Resin Microspheres Plus Concomitant Systemic Irinotecan Chemotherapy. JCO
27: 4089-4095
[Abstract][Full Text]
Bessard, A., Sole, V., Bouchaud, G., Quemener, A., Jacques, Y.
(2009). High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor {alpha} fusion protein, in metastatic melanoma and colorectal cancer. Molecular Cancer Therapeutics
8: 2736-2745
[Abstract][Full Text]
Kozloff, M., Yood, M. U., Berlin, J., Flynn, P. J., Kabbinavar, F. F., Purdie, D. M., Ashby, M. A., Dong, W., Sugrue, M. M., Grothey, A., for the investigators of the BRiTE study,
(2009). Clinical Outcomes Associated with Bevacizumab-Containing Treatment of Metastatic Colorectal Cancer: The BRiTE Observational Cohort Study. The Oncologist
14: 862-870
[Abstract][Full Text]
Kopetz, S., Chang, G. J., Overman, M. J., Eng, C., Sargent, D. J., Larson, D. W., Grothey, A., Vauthey, J.-N., Nagorney, D. M., McWilliams, R. R.
(2009). Improved Survival in Metastatic Colorectal Cancer Is Associated With Adoption of Hepatic Resection and Improved Chemotherapy. JCO
27: 3677-3683
[Abstract][Full Text]
KIM, J. C., ROH, S. A., CHO, D. H., KIM, T. W., YOON, S. N., KIM, C. W., YU, C. S., KIM, S. Y., KIM, Y. S.
(2009). Chemoresponsiveness Associated with Canonical Molecular Changes in Colorectal Adenocarcinomas. Anticancer Res
29: 3115-3123
[Abstract][Full Text]
Poultsides, G. A., Servais, E. L., Saltz, L. B., Patil, S., Kemeny, N. E., Guillem, J. G., Weiser, M., Temple, L. K.F., Wong, W. D., Paty, P. B.
(2009). Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment. JCO
27: 3379-3384
[Abstract][Full Text]
Lim, H. J., Gill, S., Speers, C., Melosky, B., Barnett, J., Fitzgerald, C., O'Reilly, S., Kennecke, H.
(2009). Impact of Irinotecan and Oxaliplatin on Overall Survival in Patients With Metastatic Colorectal Cancer: A Population-Based Study. J Oncol Pract
5: 153-158
[Abstract][Full Text]
Cohen, S. J., Punt, C. J. A., Iannotti, N., Saidman, B. H., Sabbath, K. D., Gabrail, N. Y., Picus, J., Morse, M. A., Mitchell, E., Miller, M. C., Doyle, G. V., Tissing, H., Terstappen, L. W. M. M., Meropol, N. J.
(2009). Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol
20: 1223-1229
[Abstract][Full Text]
Kim, G. P., Sargent, D. J., Mahoney, M. R., Rowland, K. M. Jr, Philip, P. A., Mitchell, E., Mathews, A. P., Fitch, T. R., Goldberg, R. M., Alberts, S. R., Pitot, H. C.
(2009). Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841. JCO
27: 2848-2854
[Abstract][Full Text]
Onaitis, M. W., Petersen, R. P., Haney, J. C., Saltz, L., Park, B., Flores, R., Rizk, N., Bains, M. S., Dycoco, J., D'Amico, T. A., Harpole, D. H., Kemeny, N., Rusch, V. W., Downey, R.
(2009). Prognostic Factors for Recurrence After Pulmonary Resection of Colorectal Cancer Metastases.. Ann. Thorac. Surg.
87: 1684-1688
[Abstract][Full Text]
Inoue, Y., Toiyama, Y., Tanaka, K., Miki, C., Kusunoki, M.
(2009). A Comprehensive Comparative Study on the Characteristics of Colorectal Cancer Chemotherapy. Jpn J Clin Oncol
39: 367-375
[Abstract][Full Text]
Overman, M. J., Varadhachary, G. R., Kopetz, S., Adinin, R., Lin, E., Morris, J. S., Eng, C., Abbruzzese, J. L., Wolff, R. A.
(2009). Phase II Study of Capecitabine and Oxaliplatin for Advanced Adenocarcinoma of the Small Bowel and Ampulla of Vater. JCO
27: 2598-2603
[Abstract][Full Text]
Bidard, F.-C., Tournigand, C., Andre, T., Mabro, M., Figer, A., Cervantes, A., Lledo, G., Bengrine-Lefevre, L., Maindrault-Goebel, F., Louvet, C., de Gramont, A.
(2009). Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study. Ann Oncol
20: 1042-1047
[Abstract][Full Text]
TORIGOE, S., OGATA, Y., MATONO, K., SHIROUZU, K.
(2009). Molecular Mechanisms of Sequence-dependent Antitumor Effects of SN-38 and 5-Fluorouracil Combination Therapy against Colon Cancer Cells. Anticancer Res
29: 2083-2089
[Abstract][Full Text]
OGAWA, M., WATANABE, M., ETO, K., OMACHI, T., KOSUGE, M., HANYU, K., NOAKI, L., FUJITA, T., YANAGA, K.
(2009). Clinicopathological Features of Perforated Colorectal Cancer. Anticancer Res
29: 1681-1684
[Abstract][Full Text]
Fakih, M. G., Pendyala, L., Fetterly, G., Toth, K., Zwiebel, J. A., Espinoza-Delgado, I., Litwin, A., Rustum, Y. M., Ross, M. E., Holleran, J. L., Egorin, M. J.
(2009). A Phase I, Pharmacokinetic and Pharmacodynamic Study on Vorinostat in Combination with 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Refractory Colorectal Cancer. Clin. Cancer Res.
15: 3189-3195
[Abstract][Full Text]
Sargent, D. J., Kohne, C. H., Sanoff, H. K., Bot, B. M., Seymour, M. T., de Gramont, A., Porschen, R., Saltz, L. B., Rougier, P., Tournigand, C., Douillard, J.-Y., Stephens, R. J., Grothey, A., Goldberg, R. M.
(2009). Pooled Safety and Efficacy Analysis Examining the Effect of Performance Status on Outcomes in Nine First-Line Treatment Trials Using Individual Data From Patients With Metastatic Colorectal Cancer. JCO
27: 1948-1955
[Abstract][Full Text]
Adam, R., Wicherts, D. A., de Haas, R. J., Ciacio, O., Levi, F., Paule, B., Ducreux, M., Azoulay, D., Bismuth, H., Castaing, D.
(2009). Patients With Initially Unresectable Colorectal Liver Metastases: Is There a Possibility of Cure?. JCO
27: 1829-1835
[Abstract][Full Text]
Van Cutsem, E., Kohne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A., D'Haens, G., Pinter, T., Lim, R., Bodoky, G., Roh, J. K., Folprecht, G., Ruff, P., Stroh, C., Tejpar, S., Schlichting, M., Nippgen, J., Rougier, P.
(2009). Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer. NEJM
360: 1408-1417
[Abstract][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]
Chen, E., Jonker, D., Gauthier, I., MacLean, M., Wells, J., Powers, J., Seymour, L.
(2009). Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer. Clin. Cancer Res.
15: 1481-1486
[Abstract][Full Text]
Aranda, E., Valladares, M., Martinez-Villacampa, M., Benavides, M., Gomez, A., Massutti, B., Marcuello, E., Constenla, M., Camara, J. C., Carrato, A., Duenas, R., Reboredo, M., Navarro, M., Diaz-Rubio, E.
(2009). Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol
20: 251-257
[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]
Czock, D., Rasche, F. M., Boesler, B., Shipkova, M., Keller, F.
(2009). Irinotecan in Cancer Patients with End-Stage Renal Failure. The Annals of Pharmacotherapy
43: 363-369
[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]
KOLINSKY, K., ZHANG, Y.-E, DUGAN, U., HEIMBROOK, D., PACKMAN, K., HIGGINS, B.
(2009). Novel Regimens of Capecitabine Alone and Combined with Irinotecan and Bevacizumab in Colorectal Cancer Xenografts. Anticancer Res
29: 91-98
[Abstract][Full Text]
Zhu, A. X., Ready, N., Clark, J. W., Safran, H., Amato, A., Salem, N., Pace, S., He, X., Zvereva, N., Lynch, T. J., Ryan, D. P., Supko, J. G.
(2009). Phase I and Pharmacokinetic Study of Gimatecan Given Orally Once a Week for 3 of 4 Weeks in Patients with Advanced Solid Tumors. Clin. Cancer Res.
15: 374-381
[Abstract][Full Text]
Matsumura, Y.
(2008). Polymeric Micellar Delivery Systems in Oncology. Jpn J Clin Oncol
38: 793-802
[Abstract][Full Text]
Fisher, G. A., Kuo, T., Ramsey, M., Schwartz, E., Rouse, R. V., Cho, C. D., Halsey, J., Sikic, B. I.
(2008). A Phase II Study of Gefitinib, 5-Fluorouracil, Leucovorin, and Oxaliplatin in Previously Untreated Patients with Metastatic Colorectal Cancer. Clin. Cancer Res.
14: 7074-7079
[Abstract][Full Text]
Alberts, S. R., Wagman, L. D.
(2008). Chemotherapy for Colorectal Cancer Liver Metastases. The Oncologist
13: 1063-1073
[Abstract][Full Text]
O'Neil, B. H., Goldberg, R. M.
(2008). Innovations in Chemotherapy for Metastatic Colorectal Cancer: An Update of Recent Clinical Trials. The Oncologist
13: 1074-1083
[Abstract][Full Text]
Ward, J., Guthrie, J. A., Sheridan, M. B., Boyes, S., Smith, J. T., Wilson, D., Wyatt, J. I., Treanor, D., Robinson, P. J.
(2008). Sinusoidal Obstructive Syndrome Diagnosed With Superparamagnetic Iron Oxide-Enhanced Magnetic Resonance Imaging in Patients With Chemotherapy-Treated Colorectal Liver Metastases. JCO
26: 4304-4310
[Abstract][Full Text]
Meulenbeld, H. J., van Steenbergen, L. N., Janssen-Heijnen, M. L. G., Lemmens, V. E. P. P., Creemers, G. J.
(2008). Significant improvement in survival of patients presenting with metastatic colon cancer in the south of The Netherlands from 1990 to 2004. Ann Oncol
19: 1600-1604
[Abstract][Full Text]
Kabbinavar, F. F., Wallace, J. F., Holmgren, E., Yi, J., Cella, D., Yost, K. J., Hurwitz, H. I.
(2008). Health-Related Quality of Life Impact of Bevacizumab When Combined with Irinotecan, 5-Fluorouracil, and Leucovorin or 5-Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. The Oncologist
13: 1021-1029
[Abstract][Full Text]
Kaufman, H. L., Lenz, H.-J., Marshall, J., Singh, D., Garett, C., Cripps, C., Moore, M., von Mehren, M., Dalfen, R., Heim, W. J., Conry, R. M., Urba, W. J., Benson, A. B. III, Yu, M., Caterini, J., Kim-Schulze, S., DeBenedette, M., Salha, D., Vogel, T., Elias, I., Berinstein, N. L.
(2008). Combination Chemotherapy and ALVAC-CEA/B7.1 Vaccine in Patients with Metastatic Colorectal Cancer. Clin. Cancer Res.
14: 4843-4849
[Abstract][Full Text]
McKibbin, T., Frei, C. R., Greene, R. E., Kwan, P., Simon, J., Koeller, J. M.
(2008). Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting. The Oncologist
13: 876-885
[Abstract][Full Text]
Carethers, J. M.
(2008). Review: Systemic treatment of advanced colorectal cancer: Tailoring therapy to the tumor. Therapeutic Advances in Gastroenterology
1: 33-42
[Abstract]
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]
van Iersel, L. B. J., Gelderblom, H., Vahrmeijer, A. L., van Persijn van Meerten, E. L., Tijl, F. G. J., Putter, H., Hartgrink, H. H., Kuppen, P. J. K., Nortier, J. W. R., Tollenaar, R. A. E. M., van de Velde, C. J. H.
(2008). Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients. Ann Oncol
19: 1127-1134
[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]
Hecht, J. R.
(2008). Current and emerging therapies for metastatic colorectal cancer: Applying research findings to clinical practice. Am J Health Syst Pharm
65: S15-S21
[Abstract][Full Text]
O'Connell, M. J., Campbell, M. E., Goldberg, R. M., Grothey, A., Seitz, J.-F., Benedetti, J. K., Andre, T., Haller, D. G., Sargent, D. J.
(2008). Survival Following Recurrence in Stage II and III Colon Cancer: Findings From the ACCENT Data Set. JCO
26: 2336-2341
[Abstract][Full Text]
Sobrero, A. F., Maurel, J., Fehrenbacher, L., Scheithauer, W., Abubakr, Y. A., Lutz, M. P., Vega-Villegas, M. E., Eng, C., Steinhauer, E. U., Prausova, J., Lenz, H.-J., Borg, C., Middleton, G., Kroning, H., Luppi, G., Kisker, O., Zubel, A., Langer, C., Kopit, J., Burris, H. A. III
(2008). EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer. JCO
26: 2311-2319
[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]
Adam, R., Wicherts, D. A., de Haas, R. J., Aloia, T., Levi, F., Paule, B., Guettier, C., Kunstlinger, F., Delvart, V., Azoulay, D., Castaing, D.
(2008). Complete Pathologic Response After Preoperative Chemotherapy for Colorectal Liver Metastases: Myth or Reality?. JCO
26: 1635-1641
[Abstract][Full Text]
Xue, H., Sawyer, M. B., Field, C. J., Dieleman, L. A., Murray, D., Baracos, V. E.
(2008). Bolus Oral Glutamine Protects Rats against CPT-11-Induced Diarrhea and Differentially Activates Cytoprotective Mechanisms in Host Intestine but Not Tumor. J. Nutr.
138: 740-746
[Abstract][Full Text]
Kohne, C.-H., Folprecht, G., Goldberg, R. M., Mitry, E., Rougier, P.
(2008). Chemotherapy in Elderly Patients with Colorectal Cancer. The Oncologist
13: 390-402
[Abstract][Full Text]
Folprecht, G., Seymour, M. T., Saltz, L., Douillard, J.-Y., Hecker, H., Stephens, R. J., Maughan, T. S., Van Cutsem, E., Rougier, P., Mitry, E., Schubert, U., Kohne, C.-H.
(2008). Irinotecan/Fluorouracil Combination in First-Line Therapy of Older and Younger Patients With Metastatic Colorectal Cancer: Combined Analysis of 2,691 Patients in Randomized Controlled Trials. JCO
26: 1443-1451
[Abstract][Full Text]
Sapra, P., Zhao, H., Mehlig, M., Malaby, J., Kraft, P., Longley, C., Greenberger, L. M., Horak, I. D.
(2008). Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11-Refractory Model. Clin. Cancer Res.
14: 1888-1896
[Abstract][Full Text]
Zalcberg, J. R., Rosen, L. S., Abdi, E., Davis, I. D., Gutheil, J., Schnell, F. M., Cesano, A., Gayko, U., Chen, M.-G., Clarke, S.
(2008). Role of Palifermin in Fluorouracil-Based Therapy for Metastatic Colorectal Cancer. JCO
26: 1386-1387
[Full Text]
Ramsay, E. C., Anantha, M., Zastre, J., Meijs, M., Zonderhuis, J., Strutt, D., Webb, M. S., Waterhouse, D., Bally, M. B.
(2008). Irinophore C: A Liposome Formulation of Irinotecan with Substantially Improved Therapeutic Efficacy against a Panel of Human Xenograft Tumors. Clin. Cancer Res.
14: 1208-1217
[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]
Lievre, A., Bachet, J.-B., Boige, V., Cayre, A., Le Corre, D., Buc, E., Ychou, M., Bouche, O., Landi, B., Louvet, C., Andre, T., Bibeau, F., Diebold, M.-D., Rougier, P., Ducreux, M., Tomasic, G., Emile, J.-F., Penault-Llorca, F., Laurent-Puig, P.
(2008). KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab. JCO
26: 374-379
[Abstract][Full Text]
Grothey, A., Hedrick, E. E., Mass, R. D., Sarkar, S., Suzuki, S., Ramanathan, R. K., Hurwitz, H. I., Goldberg, R. M., Sargent, D. J.
(2008). Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107. JCO
26: 183-189
[Abstract][Full Text]
Pawlik, T. M., Schulick, R. D., Choti, M. A.
(2008). Expanding Criteria for Resectability of Colorectal Liver Metastases. The Oncologist
13: 51-64
[Abstract][Full Text]
Becouarn, Y., Senesse, P., Thezenas, S., Boucher, E., Adenis, A., Cany, L., Jacob, J. H., Cvitkovic, F., Montoto-Grillot, C., Ychou, M.
(2007). A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (irinotecan + oxaliplatin, IRINOX) and two standard arms (LV5 FU2 + irinotecan or LV5 FU2 + oxaliplatin) in first-line metastatic colorectal cancer: a study of the Digestive Group of the Federation Nationale des Centres de Lutte Contre le Cancer. Ann Oncol
18: 2000-2005
[Abstract][Full Text]
Tang, M. J., Tai, I. T.
(2007). A Novel Interaction between Procaspase 8 and SPARC Enhances Apoptosis and Potentiates Chemotherapy Sensitivity in Colorectal Cancers. J. Biol. Chem.
282: 34457-34467
[Abstract][Full Text]
Buyse, M., Burzykowski, T., Carroll, K., Michiels, S., Sargent, D. J., Miller, L. L., Elfring, G. L., Pignon, J.-P., Piedbois, P.
(2007). Progression-Free Survival Is a Surrogate for Survival in Advanced Colorectal Cancer. JCO
25: 5218-5224
[Abstract][Full Text]
Tabernero, J., Van Cutsem, E., Diaz-Rubio, E., Cervantes, A., Humblet, Y., Andre, T., Van Laethem, J.-L., Soulie, P., Casado, E., Verslype, C., Valera, J. S., Tortora, G., Ciardiello, F., Kisker, O., de Gramont, A.
(2007). Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer. JCO
25: 5225-5232
[Abstract][Full Text]
Jonker, D. J., O'Callaghan, C. J., Karapetis, C. S., Zalcberg, J. R., Tu, D., Au, H.-J., Berry, S. R., Krahn, M., Price, T., Simes, R. J., Tebbutt, N. C., van Hazel, G., Wierzbicki, R., Langer, C., Moore, M. J.
(2007). Cetuximab for the Treatment of Colorectal Cancer. NEJM
357: 2040-2048
[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]
Kornprat, P., Jarnagin, W. R., DeMatteo, R. P., Fong, Y., Blumgart, L. H., D'Angelica, M.
(2007). Role of Intraoperative Thermoablation Combined With Resection in the Treatment of Hepatic Metastasis From Colorectal Cancer. Arch Surg
142: 1087-1092
[Abstract][Full Text]
Fuchs, C. S., Marshall, J., Mitchell, E., Wierzbicki, R., Ganju, V., Jeffery, M., Schulz, J., Richards, D., Soufi-Mahjoubi, R., Wang, B., Barrueco, J.
(2007). Randomized, Controlled Trial of Irinotecan Plus Infusional, Bolus, or Oral Fluoropyrimidines in First-Line Treatment of Metastatic Colorectal Cancer: Results From the BICC-C Study. JCO
25: 4779-4786
[Abstract][Full Text]
Tomlinson, J. S., Jarnagin, W. R., DeMatteo, R. P., Fong, Y., Kornprat, P., Gonen, M., Kemeny, N., Brennan, M. F., Blumgart, L. H., D'Angelica, M.
(2007). Actual 10-Year Survival After Resection of Colorectal Liver Metastases Defines Cure. JCO
25: 4575-4580
[Abstract][Full Text]
Tang, P. A., Bentzen, S. M., Chen, E. X., Siu, L. L.
(2007). Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy. JCO
25: 4562-4568
[Abstract][Full Text]
Sorbye, H., Kohne, C.-H., Sargent, D. J., Glimelius, B.
(2007). Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: A proposal for standardization of patient characteristic reporting and stratification. Ann Oncol
18: 1666-1672
[Abstract][Full Text]
Yoshino, T., Boku, N., Onozawa, Y., Hironaka, S., Fukutomi, A., Yamaguchi, Y., Hasuike, N., Yamazaki, K., Machida, N., Ono, H.
(2007). Efficacy and Safety of an Irinotecan plus Bolus 5-Fluorouracil and L-Leucovorin Regimen for Metastatic Colorectal Cancer in Japanese Patients: Experience in a Single Institution in Japan. Jpn J Clin Oncol
37: 686-691
[Abstract][Full Text]
Zhang, W., Press, O. A., Haiman, C. A., Yang, D. Y., Gordon, M. A., Fazzone, W., El-khoueiry, A., Iqbal, S., Sherrod, A. E., Lurje, G., Lenz, H.-J.
(2007). Association of Methylenetetrahydrofolate Reductase Gene Polymorphisms and Sex-Specific Survival in Patients With Metastatic Colon Cancer. JCO
25: 3726-3731
[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]
Dy, G. K., Krook, J. E., Green, E. M., Sargent, D. J., Delaunoit, T., Morton, R. F., Fuchs, C. S., Ramanathan, R. K., Williamson, S. K., Findlay, B. P., Pockaj, B. A., Sticca, R. P., Alberts, S. R., Pitot, H. C. IV, Goldberg, R. M.
(2007). Impact of Complete Response to Chemotherapy on Overall Survival in Advanced Colorectal Cancer: Results From Intergroup N9741. JCO
25: 3469-3474
[Abstract][Full Text]
de Gramont, A., Buyse, M., Abrahantes, J. C., Burzykowski, T., Quinaux, E., Cervantes, A., Figer, A., Lledo, G., Flesch, M., Mineur, L., Carola, E., Etienne, P.-L., Rivera, F., Chirivella, I., Perez-Staub, N., Louvet, C., Andre, T., Tabah-Fisch, I., Tournigand, C.
(2007). Reintroduction of Oxaliplatin Is Associated With Improved Survival in Advanced Colorectal Cancer. JCO
25: 3224-3229
[Abstract][Full Text]
Haines, I. E.
(2007). Questions About the Role of Palifermin in Fluorouracil-Based Therapy for Metastatic Colorectal Cancer. JCO
25: e24-e25
[Full Text]
Tomita, N., Fukunaga, M., Okamura, S., Narahara, H., Uedo, N., Ishihara, R., Ishida, H., Furukawa, H., Gotoh, M., Takiuchi, H.
(2007). Phase I/II Study of CPT-11 plus UFT in Patients with Advanced/Recurrent Colorectal Cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG): Protocol 0102. Jpn J Clin Oncol
37: 521-527
[Abstract][Full Text]
Welter, S., Jacobs, J., Krbek, T., Krebs, B., Stamatis, G.
(2007). Long-Term Survival After Repeated Resection of Pulmonary Metastases From Colorectal Cancer. Ann. Thorac. Surg.
84: 203-210
[Abstract][Full Text]
Pfannschmidt, J., Dienemann, H., Hoffmann, H.
(2007). Surgical Resection of Pulmonary Metastases From Colorectal Cancer: A Systematic Review of Published Series. Ann. Thorac. Surg.
84: 324-338
[Abstract][Full Text]
65 years), ECOG performance status (0 vs. 1 or 2), interval from diagnosis to enrollment (<6 months vs. 
Previous
