One of the more promising chemotherapeutic agents for patients with metastatic colorectal cancer is oxaliplatin (Eloxatin), a third-generation platinum derivative with a unique mechanism of action. Preclinical studies
ABSTRACT: One of the more promising chemotherapeutic agents for patients withmetastatic colorectal cancer is oxaliplatin (Eloxatin), a third-generationplatinum derivative with a unique mechanism of action. Preclinical studiescorroborated by results from early trials suggested that oxaliplatin could beparticularly advantageous when used in combination with fluorouracil(5-FU)/leucovorin. In addition, early studies of oxaliplatin as monotherapyshowed clear activity similar in magnitude to that observed with other activeagents. When administered as neoadjuvant therapy in patients with unresectableliver metastases, the responses were substantial enough for some patients toundergo potentially curative hepatic resection. These trials also demonstrated areasonable safety profile for oxaliplatin. In light of the accumulating data onthe use of oxaliplatin in advanced colorectal cancer, the North Central CancerTreatment Group (NCCTG) and other cooperative groups developed trials to furtherdefine the specific therapeutic roles and optimal regimens of oxaliplatincombined with 5-FU and leucovorin, as well as other agents. A number of studiesare underway in the United States, including the three-arm NCCTG N9741 trial inpatients with previously untreated metastatic colorectal cancer, the NCCTG N9841trial in patients who progressed on 5-FU/leucovorin, and the National SurgicalAdjuvant Breast and Bowel Project (NSABP) C-07 adjuvant trial for stage II andIII colorectal cancer. [ONCOLOGY14(Suppl 11):42-47, 2000]
The treatment of colorectal carcinomapresents many challenges to the clinician. Among those are the presence ofintrinsic or the development of acquired drug resistance, the aggressive natureof the disease, and (most notably) the limited number of treatment options.[1-3]Although fluorouracil (5-FU) has been the mainstay of treatment for colorectalcancer for 4 decades, as a single agent it is associated with only a 10% to 15%objective response rate. Patients treated with5-FU can expect to achieve a median survival of about 10 months.[4-6]
The addition of folinic acid, also known as leucovorin,increases the response rate, but does not improve the overall median survivalregardless of delivery as bolus 5-FU/leucovorin or as a continuous or short-term(24- to 48-hour) infusion.[7-11] While regimens consisting of short-terminfusions of5-FU with high-dose leucovorin have acceptable tolerability and are widely usedfor the treatment of colorectal cancer, especially in Europe, the fact that themedian survival reported in most trials using these regimens is in the range of9 to 14 months has prompted the search for alternative approaches totreatment.[7,9-11]
One of the more promising new treatment options for patientswith metastatic colorectal cancer is oxaliplatin (Eloxatin), a third-generationplatinum derivative with a unique mechanism of action.[3,12,13] Oxaliplatin isamong the few drugs that have activity against human colorectal cancers. Invitro, human tumor xenograft, and clinical studies indicate that it issynergistic with 5-FU and leucovorin.[3,12,13]
Phase II and III clinical trials conducted in Europe show thatthe combination of oxaliplatin with 5-FU/leucovorin is effective as first- or second-line treatment for patients withmetastatic colorectal cancer. Objective response rates as first-line treatmentwere > 50% and as second-line treatment, ranged between 20% and 45%. However,the trials comparing triple- drug therapy to 5-FU/leucovorin did not show asignificant advantage in terms of mean duration of survival compared to5-FU/leucovorin alone. These trials did, however, meet their original goals ofdemonstrating a significant improvement in response rate and progression-freesurvival. Thus, a number of studies are currently underway in North America thatare exploring various oxaliplatin combination regimens to help determine theoptimal dosage and administration schedule of combination therapy (Table1).
Rationale and Design
Because of the discovery and development of a number of activenew agents, the treatment of colon and rectal cancer is at a crossroads.5-FU/leucovorin regimens have been the standard treatment for decades, and amultitude of regimens using differing doses, sequences, and lengths of drugdelivery (ranging from bolus to continuous administration) have been studied. Inaddition, several combination regimens of 5-FU/leucovorin plus irinotecan(CPT-11, Camptosar) have shown promise, including the weekly schedule ofadministration widely known as the Saltz regimen (named after the physician whodeveloped and initially tested this regimen).
Based on a randomized study comparing 5-FU/leucovorin withirinotecan plus 5-FU/leucovorin and irinotecan alone, the Oncologic DrugsAdvisory Committee (ODAC) of the US Food and Drug Administration (FDA) approvedthe three-drug regimen as first-line therapy of advanced colorectal cancer inMarch 2000. The approval was based on an improvement in response rate (from 21%to 39%) in the two- vs three-drug regimen, and a commensurate improvement inmedian survival of 2.2 months (from 12.6 to 14.8 months). When asked if theSaltz regimen should henceforth be considered the new regimen to which otheragents or multidrug regimens should be compared, ODAC answered in theaffirmative. This had major consequences for ongoing and future trial designs.
The Redesign Process
The North Central Cancer Treatment Group (NCCTG) N9741 study hasundergone several metamorphoses since it first opened in November 1998. It wasoriginally designed as a four-arm trial comparing three regimens of5-FU/leucovorin plus irinotecan vs the Mayo/NCCTG regimen control arm:5-FU at 425 mg/m2 plus leucovorin at 20 mg/m2.
The rationale for using the 5-FU at 425 mg/m2 plus leucovorin at20 mg/m2 regimen as the control arm was based on a meta-analysis published in1992 that showed a 23% response rate and a 12-month median survival for theregimen. This was still the expectation for the overall success rate in thecontrol group when trial NCCTG N9741 began.
However, one 5-FU/leucovorin regimena 2-g/24-hour infusion of5-FUwas dropped because of toxicity issues. Shortly after the study opened,and oxaliplatin became available for US trials, the study was amended (June1999) to include three oxaliplatin arms. Thus, the NCCTG N9741 trial temporarilybecame a six-arm study in which patients were randomized to one of six treatmentregimens: (1) 5-FU/leucovorin (Mayo/NCCTG), (2) 5-FU/leucovorin plus irinotecan(Saltz simultaneous), (3) 5-FU/leucovorin plus irinotecan (Mayo sequential), (4)irinotecan plus oxaliplatin (combination), (5) 5-FU/leucovorin plus oxaliplatin (bolus), or (6)5-FU/leucovorin plus oxaliplatin (infusion).
In June 2000, the study was finally amended because of twoissues. First, the ODAC’s suggestion that the Saltz regimen should be the newcomparator arm in future trials made it necessary to delete the old comparatorarm of 5-FU/leucovorin (Mayo/NCCTG regimenarm 1) from the study. Second, thethird and fifth arms of the study were noted to be associated with excessivetoxicity, including several treatment-related patient deaths. In addition, theinvestigators participating in the trial and the leaders of the gastrointestinalcommittees from the cooperative groups participating in the trial now felt thata simpler three-arm trial was a better design. By comparing arms 2, 4, and 6,the most important variations of these three active agents could be examinedside by side, and results would be available much sooner than would have beenpossible with the six-arm trial (Figure 1).
Mayo Sequential Regimen: Mullany and coworkers firstdescribed sequence-dependent synergy in colon cancer xenografts when they notedthat the optimal interval between administration of irinotecan and 5-FU wasabout 24 hours. Consequently, a three-drug regimen was developed on the basis oflaboratory studies performed by Fonseca et al at the Mayo Clinic.
This phase I study in 56 patients began initially with theadministration of a very low dose of irinotecan plus5-FU due to concerns about synergistic diarrhea. Although most of thepatients were refractory to previous therapy, there were 10 partial or minorresponses. Toxicity consisted of the usual diarrhea, neutropenia, and vomiting.Doses recommended for further testing were irinotecan at 275 mg/m2 administeredon day 1, and 5-FU at 400 mg/m2 plus leucovorin at 20mg/m2 administered on days2 to 5.
Because this regimen is repeated every 3 weeks, the doseintensity of 5-FU and leucovorin is similar to that of the standard Mayo regimendescribed by Poon and coworkers, which is given every 4 or 5 weeks. However,5 of the first 60 patients accrued to this arm died, possibly oftreatment-related causes. Therefore, it appeared unlikely that this regimenwould prove to be superior to the one developed by Saltz and colleagues, and itwas certainly more toxic. Thus, rather than reduce the doses prescribed by thisregimen, the arm was dropped from the trial.
Oxaliplatin Bolus Regimen: In the United States, manymembers of the Gastrointestinal (GI) Intergroup and others regarded bolus 5-FUdosing as the most familiar method by which to administer 5-FU and leucovorin.Therefore, an oxaliplatin regimen given in concert with bolus 5-FU was includedin this trial. This regimen was based on a European trial in 115 patients whoprogressed after being treated with a regimen of 5-FU plus leucovorin(unpublished data on file, Sanofi-Synthelabo). Oxaliplatin at 130 mg/m2 wasadministered on day 1, followed by5-FU at 320 mg/m2 plus leucovorin at 20 mg/m2 on days 1 to 5. (This regimen wasrepeated every 3 weeks.)
Although the response rate in the original report was 13%, thiswas a second-line regimen and therefore, was felt to have demonstratedsufficient activity to merit further testing. Both the median time toprogression (4.3 months) and median survival (10.1 months) were similar to therates reported with other second-line regimens. The main toxicities includednausea, neutropenia, and neuropathy.
Early in the NCCTG N9741 trial, after about 25 patients hadreceived this regimen, three deaths occurred due to toxicity. All the patientsdeveloped fatigue, neutropenia, and dehydration, and died within 1 or 2 weeksfollowing treatment. Representatives of the National Cancer Institute (NCI), thecooperative groups participating in the trial, and patient representatives helda meeting to discuss these reports. As a result, the doses of both oxaliplatinand 5-FU were reduced.
Patients in the oxaliplatin bolus regimen arm of the N9741 trialthen began to receive oxaliplatin at 100 mg/m2 on day 1, followed by 5-FU at 280mg/m2 plus leucovorin at 20 mg/m2 on days 1 to 5. When two additionaltreatment-related deaths were observed at the reduced dose level, this arm ofthe trial was dropped.
Saltz Regimen: One of the most widely used 5-FU/leucovorinplus irinotecan regimens is the Saltz regimen, which is based on a weeklyinfusion of 5-FU at 500 mg/m2 plus leucovorin at 20mg/m2 plus irinotecan at 125 mg/m2 administered for 4 to 6 weeks. The dose of irinotecan is essentially thesame as if it were given weekly without 5-FU. However, Saltz and collaboratorsempirically reduced the dose of leucovorin from the typical Roswell Park weeklyregimen of 500 mg/m2 to 20 mg/m2 because of concerns about the potential forsynergistic diarrhea. This regimen was originally tested in a phase I study thatestablished the current drug doses and safety of the program. Data fromParnes and collaborators at the University of Maryland and other centerssupport this decision.
In the three-arm trial described above (reported in The NewEngland Journal of Medicine in September 2000), 683 previously untreatedpatients were randomized to one of three treatment arms: (1) 5-FU at 500 mg/m2plus leucovorin at 20 mg/m2 plus irinotecan at 125mg/m2 weekly for 4 of every 6weeks (Saltz regimen), (2) 5-FU at 425 mg/m2 plus leucovorin at 20mg/m2 dailyfor 5 days every 4 weeks (Mayo control), or (3) irinotecan at 125 mg/m2 weeklyfor 4 of every 6 weeks.
When these preliminary results were first reported as anabstract at the 1999 meeting of the American Society of Clinical Oncology(ASCO), there was no statistically significant survival advantage for thethree-drug regimen compared with the Mayo control and irinotecan regimens (15.2vs 14.3 vs 13.8 months, respectively). However, with additional follow-up, thedata as noted above indicated a statistically significant difference of 2.2months in median survival between the three-drug Saltz regimen and the Mayocontrol regimen. The main toxicities associated with the Saltz regimen have beenneutropenia and diarrhea. Mature data and the ODAC’s decision required achange in the study design described earlier.
Oxaliplatin Infusion Regimen: The folfox4/de Gramont regimenwas chosen as another oxaliplatin treatment arm for the trial based on data fromanother trial, in which 420 previously untreated patients received a 2-hourinfusion of leucovorin (200 mg/m2), followed by 5-FU as a400-mg/m2 bolus and a 600-mg/m2 infusion over 22 hours on days 1 and 2. Patients were randomizedto one of two groupsone group received an infusion of oxaliplatin at 85 mg/m2on day 1, while the other group did not receive oxaliplatin. The median time toprogression was 9.0 months in the oxaliplatin arm compared with 6.2 months inthe group that did not receive oxaliplatin (P = .0003). Median survival in thetwo arms was 16.2 vs 14.7 months, respectively (P = .12). Neuropathy,diarrhea, and neutropenia were again the main toxicities.
Oxaliplatin/Irinotecan Combination Regimen: This regimen wasincluded in the trial because it lacked either 5-FU or leucovorin, and was basedon a phase I trial by Wasserman and collaborators in which 41 previously treatedpatients received oxaliplatin at 85 mg/m2 plus irinotecan at 200mg/m2 on day 1repeated every 3 weeks. Although the activity of this regimen has not beenreported in a phase II study, there was a surprisingly strong response rate(41%) in the phase I trial. The main toxicities were neutropenia anddiarrhea (personal communication). The simplicity of this regimen isparticularly interesting because patients would only need to come in for oneoffice visit every 3 weeks.
Enrollment criteria are as follows histologically orcytologically documented cancer of the colon or rectum, stage IV disease notamenable to resection, measurable or evaluable disease, age > 18 years with alife expectancy of at least 4 months, performance status of 0 to 2, and adequateorgan function. Patients who have received adjuvant therapy may be enrolled ifthey completed therapy 12 months prior to study enrollment.
Exclusion criteria are a history of a second, primary cancer,prior chemotherapy for stage IV disease, previous pelvic radiation for rectalcancer, uncontrolled intercurrent illness, allergy to platinum compounds orserotonin receptor (5-HT3) drugs, brain metastasis, or pregnancy and/orlactation.
The main objectives of this trial are to: (1) compare the timeto progression on all arms to the control arm, (2) compare the time toprogression across study arms, (3) evaluate toxicity, response rate, andsurvival, and (4) compare the quality of life of the various regimens based onthe system distress scale (SDS) and questionnaire developed to address specificside effects, such as sensory neuropathy.
The revised accrual goal for the three-arm version of NCCTGN9741 is 1,180 patients, at a planned rate of 50 patients per month. As ofOctober 2000, the study has accrued over 650 patients, and approximately 50 newpatients per month are being enrolled. The anticipated date for trial closure isthe first quarter of 2002. Investigators from the Cancer and Leukemia Group B(CALGB), the Eastern Cooperative Oncology Group (ECOG), The National CancerInstitute of Canada (NCIC), and the Southwest Oncology Group (SWOG) have alljoined the NCCTG in this effort.
The NCCTG N9841 trial is an ongoing, randomized, phase III trialin patients who had progressed on any regimen of 5-FU plus leucovorin. Patientsare randomized to either irinotecan at 350 mg/m2 (Cunningham regimen) every 3weeks or oxaliplatin plus 5-FU/leucovorin (folfox 4/de Gramont regimen).In the case of disease progression, patients may cross over to the alternativeregimen. Thus, this trial may provide information on these regimens asthird-line therapy as well as information on their activity and toxicity assecond-line therapy.
The accrual goal is 560 patients, with approximately 140patients currently enrolled. As with trial N9741, investigators from ECOG andSWOG are participating in this trial.
The primary end point of N9841 is overall survival. In addition,investigators will evaluate and compare response rates and toxicity, and willemploy the same modified tools as used in trial N9741 to compare quality oflife. Inclusion and exclusion criteria were also the same as those used inN9741, except that patients were required to have progressed either on5-FU/leucovorin or within 6 months of completing5-FU, with or without leucovorin, as adjuvant therapy. Patients were noteligible for study enrollment if they received more than one prior chemotherapyregimen for advanced disease or if they previously received irinotecan asfirst-line therapy.
Other oxaliplatin-based NCCTG trials are currently ongoing or inthe late planning stages. Resection is the primary end point in one small study(NCCTG 97-46-51) in previously treated patients with multiple, poorly located,or large liver metastases. Other end points include response rate, time toprogression, and survival. The accrual goal is 39 patients, and 33 have beenenrolled to date.
While several patients have responded and have undergonecomplete resection of their liver metastases, these results are preliminary. Dr.Steven Alberts is the primary investigator of this trial, which is based on theexperience of Dr. Henri Bismuth. Although patients in the United States withunresectable liver-limited disease rarely undergo hepatic resection followingchemotherapy, Bismuth and collaborators demonstrated that aggressive surgery(including multiple resections in the same patient) can produce a cure in somepatients.
Drs. Steven Alberts and Henry Pitot are the principalinvestigators of a postmetastectomy study (N9945) in patients with resectedliver-limited colorectal cancer that will open in early 2001. All patients willundergo hepatic arterial infusion with floxuridine (FUDR) plus dexamethasoneadministered on days 1 to 14 and oxaliplatin plus 5-FU/leucovorin (folfox 4regimen) on days 21 and 22; this regimen will be repeated every 5 weeks. Theaccrual goal is 45 patients, and the primary end point is 2-year overallsurvival.
As Kemeny and coauthors noted in a 1999 article in The NewEngland Journal of Medicine, although acceptable control of liver disease can beachieved, patients who relapse tend to do so outside the liver. Thus, thereis a need for better systemic treatment to combine with hepatic arterialinfusion, and trial N9945 is an attempt to address this issue.
The availability of irinotecan, oxaliplatin, and 5-FU has raisedthe question of whether patients who have progressed on previous therapiesshould receive all three of these agents simultaneously in combination or insequential regimens. To address this issue, the NCCTG N9842 trial was designedto assess second-line treatment with oxaliplatin plus 5-FU/leucovorin (folfox4)in patients with colorectal cancer who progressed following irinotecan plus5-FU/leucovorin treatment. Dr. Henry Pitot is again the principal investigatorof this trial. The end points include response rate, time to progression, andsurvival. The study will open in late 2000, with an accrual goal of 40 patients.
A second trial will examine second-line therapy in twoadditional cohorts. Patients who received prior irinotecan plus oxaliplatin asfirst-line therapy will be given 5-FU/leucovorin, and patients who receivedprior oxaliplatin plus5-FU/leucovorin will be given irinotecan instead of oxaliplatin.
Two parallel phase I studies opened in January 2000 in patientswith solid tumors. Patients are being randomized to one of two regimens: (1)oxaliplatin plus irinotecan plus 5-FU/leucovorin administered weekly with theSaltz regimen, or (2) oxaliplatin plus irinotecan plus 5-FU/leucovorinadministered every 3 weeks using the day 1 to 5 Mayo regimen. This study hasaccrued 19 patients. Dose reductions have been necessary principally because ofhematologic toxicity, and it is too early at this time to report any results.
The National Surgical Adjuvant Breast and Bowel Project C-07trial is an open-label, multicenter study of adjuvant treatment in patients withcompletely resected stage II or III colon cancer. The study opened in March2000, and 2,400 patients will be enrolled over the next 3 years. Patients willbe risk-stratified according to institution and the number of positive nodes(eg, 0, 1-3, 4). The primary end point of the study is disease-free survival;secondary end points are overall survival and toxicity. Patients will berandomized to one of two treatment arms: (1) 5-FU at 500 mg/m2 bolus plusleucovorin at500 mg/m2 weekly for 8 weeks (Roswell Park regimen), or (2) the same5-FU/leucovorin regimen plus oxaliplatin at 85 mg/m2 during weeks 1, 3, and 5.
Inclusion criteria are stage II or III completely resected coloncancer, a 10-year life expectancy (excluding a diagnosis of cancer),randomization within 42 days of resection, adequate organ function, and ECOGperformance status of 0 to 2. Exclusion criteria are the presence of othermalignant tumors (including prior colon cancer), histology other thanadenocarcinoma, rectal cancer, incomplete or noncurative surgery, clinicalperipheral neuropathy, or pregnancy/lactation. The investigators will alsocollect data on pathologic correlates, including thymidylate synthase content,dihydropyrmidine dehydrogenase content, microsatellite instability, DNA repairdefects, and microarray-based comparative genomic hybridization.
For more than 4 decades, the treatment of colorectal cancer hasbeen based on the optimization of 5-FU chemotherapy, and only within the pastfew years has the introduction of new chemotherapeutic agents with novelmechanisms of action, such as oxaliplatin and irinotecan, created newtherapeutic options.
Oxaliplatin first attracted research interest because of itsparticularly high in vitro activity in cisplatin (Platinol)-resistant celllines, and later preclinical observations of synergy with 5-FU, even in 5-FU-resistantxenografts. As a result, oxaliplatin was studied in a variety of settings asfirst- or second-line treatment for metastatic colorectal cancer. Results fromthose early trials suggested that therapy with oxaliplatin could be particularlyadvantageousin terms of response rate and duration of progression-freesurvivalwhen used in combination with 5-FU/leucovorin.
In addition, there have been promising results from earlystudies of oxaliplatin as monotherapy and as neoadjuvant therapy in patients with unresectableliver metastases. These trials also demonstrated a reasonable safety profile.Although oxaliplatin can produce diarrhea, nausea, and hematologic suppression,its main cumulative dose-limiting toxicity is peripheral sensory neuropathy thatis at least partially reversible after the discontinuation of therapy.
In light of the accumulating data on the use of oxaliplatin inadvanced colorectal cancer, there has been a concerted effort by the NCCTG andother cooperative groups to further elucidate the specific therapeutic roles andregimens of oxaliplatin. In the United States, a number of studies are underwayor in the late planning stage, including the three-arm NCCTG N9741 trial, thetwo-arm NCCTG N9841 trial in patients who have progressed on 5-FU/leucovorin, anadjuvant trial for stage II and III colorectal cancer (NSABP C-07), and the manyother trials described in this article.
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