The article by Drs. Khayat and Gil-Delgado outlines the exciting new developments in the treatment of advanced colorectal cancer with irinotecan (CPT-11 [Camptosar]) and oxaliplatin. Although the development of these drugs provides an alternative to fluorouracil (5-FU) in the treatment of this common tumor, it is still unclear how to optimally integrate these promising compounds into therapy for colorectal cancer.
The article by Drs. Khayat and Gil-Delgadooutlines the exciting new developments in the treatment of advanced colorectalcancer with irinotecan (CPT-11 [Camptosar]) and oxaliplatin. Although thedevelopment of these drugs provides an alternative to fluorouracil (5-FU) in thetreatment of this common tumor, it is still unclear how to optimally integratethese promising compounds into therapy for colorectal cancer.
Improving the Efficacy of 5-FU
Fluorouracil has remained the mainstay of the treatment ofadvanced colorectal cancer for over 40 years. Unfortunately, only about 20% ofpatients who receive 5-FU demonstrate objective responses by standard criteria.Over the past 25 years, a tremendous effort has been made to improve theefficacy of 5-FU. One such line of research has shown that, compared with bolusadministration, protracted intravenous infusion produces a marginally higherrate of response but is also associated with reduced toxicity.[1,2]
Biochemical modulatorseg, methotrexate, interferon-alpha,and, most extensively, leucovorinhave also been explored to increase theantitumor activity of 5-FU. In a meta-analysis of nine randomized trials of 5-FUalone vs 5-FU plus leucovorin for advanced cancer, a significant improvement inresponse rate was seen in patients who received 5-FU and leucovorin. However,this level of improvement in response rate failed to translate into asignificant survival advantage.
In 1996, based on trials reviewed by the US Food and DrugAdministration (FDA), irinotecan was approved as a second-line treatment forpatients with colorectal cancer whose disease had progressed after 5-FU-basedtherapy. Initial approval was based on tumor response alone. The survivalbenefit of irinotecan as a second-line treatment in colorectal cancer refractoryto bolus 5-FU was clearly shown in two phase III randomized studies conducted inEurope. The results of those studies led to full approval of this drug in theUnited States.[5,6]
The survival benefit of irinotecan administered in combinationwith 5-FU and leucovorin as first-line treatment for advanced colorectal cancerwas demonstrated recently in two phase III randomized studies. The first trialcompared weekly irinotecan plus 5-FU/leucovorin to 5-FU/leucovorin (Mayoregimen) or weekly irinotecan. Objective response rates documented byinvestigators were noted in 50% of patients receiving the three-drug combinationvs 28% of patients receiving 5-FU/leucovorin (confirmed response rate: 39% vs21%, P < .001). Median survival for the irinotecan/5-FU/leucovorin armwas 14.8 months vs 12.6 months for the 5-FU/leucovorin arm (P = .04).Grade 3 (severe) diarrhea was more common during treatment withirinotecan/5-FU/leucovorin, but the incidence of grade 4 (life-threatening)diarrhea was similar in both groups.
The other trial, conducted in Europe, also found a significantadvantage in favor of the irinotecan/5-FU/leucovorin combination vs infusional5-FU/leucovorin in terms of median overall survival (17.4 vs 14.1 months, P = .035),progression-free survival (6.7 vs 4.4 months, P < .001), and confirmedobjective response (35% vs 22%, P < .005). All these end pointsdemonstrated the modest but definite superiority of the combination ofirinotecan, 5-FU, and leucovorin.
After many years of clinical trials in colorectal cancer,however, several issues remain unresolved. Data from the European trials suggestthat infusional 5-FU in combination therapy might be a better approach, both interms of activity and toxicity. Whether sequential rather than concomitantadministration of these drugs could achieve a similar effect with less toxicityis still somewhat uncertain. Retrospective data from the combination trialssuggest that a survival benefit is maintained, even when the majority ofpatients assigned to single-agent therapy initially received subsequentsecond-line chemotherapy or other salvage treatments. Only a well-designed trialwith a fixed crossover design, such as the MRC CR-08 ("FOCUS") trialin the United Kingdom, may find a definitive answer.
Furthermore, should the combination of irinotecan, 5-FU, andleucovorin be considered as the first-line treatment in a subgroup of patientswith poor performance status (³ ECOG 2), or withabnormal organ system function for survival, toxicity, and clinical benefit?Ultimately, biological markers that may predict response or toxicity fromstandard chemotherapy drugs may help determine which patients should receiveirinotecan, 5-FU, and leucovorin as the first-line treatment.
Historical controls, from the era prior to standard adjuvantchemotherapy, demonstrated cure rates for stage III (lymph node positive) coloncancer of about 40% to 50%. Adjuvant chemotherapy with 5-FU/leucovorinincreased the 5-year overall survival rate to 60% or 65%.[10,11] Since thedegree of antitumor activity may improve the success of adjuvant treatment,regimens with higher antitumor response rates could logically be expected toprovide superior results in the adjuvant setting. An ongoing phase III USintergroup study (Cancer and Leukemia Group B [CALGB]-89803) that is randomizingpatients with stage III colon cancer to either standard weekly 5-FU/leucovorinor irinotecan, 5-FU, and leucovorin may provide the answer.
There are also several similar trials (eg, ACCORD2, AERO R98) inEurope evaluating the same issue, with the use of infusional 5-FU methods.Because all patients with metastatic disease may not benefit equally fromcombination chemotherapy, all patients at different risks in the adjuvantsetting may not necessarily require or achieve the same degree of benefit frommore intensive treatment approaches. Trials specifically addressing high-risknode-positive patients may provide early and more profound evidence of thebenefit achieved with combination chemotherapy.
Role of Oxaliplatin
Oxaliplatin, a diaminocyclohexane (DACH) platin, inhibits DNAreplication and transcription through the formation of intra- and interstrandDNA adducts. The drug has demonstrated synergistic antitumor activity incombination with 5-FU and leucovorin both in vitro and in vivo.[12,13] In phaseII trials, the clinical activity of oxaliplatin as first-line monotherapy hasbeen shown to be similar to that of single-agent irinotecan. Phase II trialsevaluating the combination of oxaliplatin and 5-FU/leucovorin as initial therapyfor patients with metastatic colorectal cancer (using chronomodulated drugadministration schedules) suggested increased cytotoxicity, manifested byencouraging response rates, as well as improved progression-free and overallsurvival.[15,16]
Based on these encouraging data, European investigatorsconducted two randomized trials comparing oxaliplatin in combination with 5-FUand leucovorin vs 5-FU/leucovorin alone as first-line therapy in patients withmetastatic colorectal cancer (EFC 2961 and EFC 2962).[17,18] The results ofthese trials showed a statistically significant benefit in objective responserate favoring oxaliplatin (53% vs 16% in EFC 2961; 50.7% vs 22.3% in EFC 2962),and progression-free survival (8.7 vs 6.1 months, P = .048, in EFC 2961;9.0 vs 6.2 months, P = .0003, in EFC 2962). Although a trend toward alonger median survival was seen in the oxaliplatin-treated groups, thedifference did not achieve statistical significance in either study (16.2 vs14.7 months, P = .12, in EFC 2962; 19.4 vs 19.9 months in EFC 2961).Because oxaliplatin did not demonstrate a detectable impact on prolongingoverall survival, it was not approved by the FDA for use in the first-linetreatment of advanced colorectal cancer.
The explanation for this discrepancy is not clear. Subtle, butclinically important differences in baseline patient characteristics could haveobscured assessment of the impact of oxaliplatin on survival. When thesebaseline differences were taken into account by Cox regression analysis, overallsurvival was significantly enhanced by the addition of oxaliplatin to first-linetherapy in the EFC 2962 study (P = .0001).
Other possible explanations are that the effects of oxaliplatinare too transient to have an impact on overall survival, or that the use ofother salvage therapies (eg, surgery or irinotecan) influenced survival results.It is also possible that the infusional 5-FU/leucovorin control arm in bothtrials was more active than the bolus control arms in other studies, manifestedby an unusually good survival among patients in the control arms in bothoxaliplatin trials.
Of patients in the control arm, 57% received oxaliplatin aftertreatment with 5-FU/leucovorin failed in EFC 2961, and 37% of patients in EFC2962 received poststudy chemotherapy with oxaliplatin and/or irinotecan as wellas salvage surgery. The sample size of both studies was relatively small, whichmay explain why significant differences in response rate and progression-freesurvival did not translate into a statistically significant survival benefit.This underscores the need for trials with adequate sample sizes that are able toproperly assess modest yet clinically worthwhile benefits.
Studies of the combination of oxaliplatin and 5-FU/leucovorin inthe second-line setting have shown encouraging results. However, severalimportant questions still need to be answered, including the impact ofre-treatment with alternative methodologies of 5-FU/leucovorin in thecombination. As a second-line therapy, how much activity is due to oxaliplatin,and how much is secondary to a change in the dose or schedule of5-FU/leucovorin?
A pivotal trial currently underway in the United States isattempting to answer these questions. Patients with advanced colorectal cancerin whom disease progressed after treatment with irinotecan/5-FU/leucovorin arebeing randomized to one of three arms: (1) a control arm of bolus plusinfusional 5-FU and leucovorin (de Gramont regimen), (2) oxaliplatin as a singleagent every 2 weeks, or (3) the combination of 5-FU, leucovorin, andoxaliplatin.
In summary, the combination of irinotecan, 5-FU, and leucovorinhas been confirmed as a new first-line treatment for advanced colorectal cancer.Several important clinical trials are in the process of clarifying the role ofoxaliplatin in the treatment of patients with metastatic colorectal cancer.
In addition to developing new agents for this disease, clinicalresearch should be directed at optimizing and individualizing therapy forpatients to achieve maximal clinical benefit. In this regard, the use ofcombination chemotherapy before planned hepatic resection for liver metastasesis among the most exciting possibilities for improvement, and may convert thetherapy of some patients from palliative to curative treatment.
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