OR WAIT null SECS
Fluorouracil (5-FU) has remained the standard therapy for the treatment of advanced colorectal cancer for over 40 years. Unfortunately, only a minority of patients experience objective clinical response.
ABSTRACT: Fluorouracil (5-FU) has remained the standard therapy for thetreatment of advanced colorectal cancer for over 40 years. Unfortunately, only aminority of patients experience objective clinical response. Discussed hereinare attempts to improve on the activity of 5-FU by biochemically modulating itsaction. In addition, novel agents for the treatment of advanced colorectalcancer (oral fluoropyrimidines, oxaliplatin, and irinotecan) are discussed. Oralfluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU)provide the convenience of oral delivery with a marked reduction in febrileneutropenia and mucositis. Recent randomized trials with these agents havedemonstrated therapeutic activity that is comparable with intravenous schedulesof 5-FU plus leucovorin. Compared to 5-FU, both oxaliplatin and irinotecan haveuniquely different mechanisms of action and have demonstrated clinical activityin patients whose disease has progressed with 5-FU treatment. Combinations ofeither irinotecan or oxaliplatin plus 5-FU/leucovorin have demonstrated that theaddition of these agents to 5-FU/leucovorin improves response rates and time toprogression compared to 5-FU/leucovorin alone. Combination chemotherapy regimenswith these novel agents are rapidly being introduced into the adjuvant setting. [ONCOLOGY14(Suppl 14):40-46, 2000]
Since its discovery in the late 1950s, fluorouracil (5-FU) has been investigated in several different dosing regimens, including a daily bolus schedule for 5 consecutive days, weekly bolus schedules, and continuous infusions extending over weeks. Clinical trials have suggested the importance of constant exposure to 5-FU to obtain optimal therapeutic results. Protracted intravenous infusions appear to improve response rates and survival compared with bolus administration[3,4] and the administration of 5-FU over prolonged periods of time may also be associated with reduced toxicity.[3,5] The toxicity profile of 5-FU is schedule dependent. While stomatitis and hand-foot syndrome (palmar-plantar erythrodysesthesia) are associated with continuous or protracted infusions, neutropenia and diarrhea are the dose-limiting toxicities of bolus schedules.[3,6]
One approach to improving the activity of 5-FU has been the addition of biochemical modulators. Several modulators have been studied, including leucovorin, N-(phosphonacetyl)-L-aspartate (PALA), methotrexate, trimetrexate, and interferon alfa.
Leucovorin is the most extensively used 5-FU biochemical modulator. In a meta-analysis of nine randomized clinical trials of advanced colorectal cancer comparing 5-FU alone with 5-FU plus IV leucovorin, patients receiving 5-FU/leucovorin showed a significant improvement in response rate in comparison with patients receiving 5-FU alone. However, improvement in response rates failed to convey a significant survival advantage.
The dose and schedule of leucovorin required for the optimal modulation of 5-FU has not been clearly defined. Leucovorin doses ranging from 20 to 500 mg/m2/d have been administered on daily x 5 days, bimonthly, or weekly schedules. A low-dose leucovorin regimen (leucovorin at 20 mg/m2/d plus 5-FU at 425 mg/m2/d for 5 consecutive days administered every 4 to 5 weeks) is commonly used in the United States, both for the treatment of metastatic colorectal cancer and as adjuvant therapy. This schedule often serves as a standard regimen in phase III advanced colorectal cancer trials evaluating new agents. Another commonly used regimen is a weekly regimen (leucovorin at 500 mg/m2 plus 5-FU at 500 mg/m2 administered weekly for 6 consecutive weeks followed by a 2-week rest).
These two regimens have similar response rates and survival. The median survival of advanced colorectal cancer patients treated with these regimens is approximately 1 year. Dose-limiting (grade 3/4) toxicities of the low-dose regimen are primarily oral mucositis (24% of patients) and neutropenia (29% of patients), whereas diarrhea is the predominant toxicity of the weekly regimen (32% of patients). These regimens of 5-FU plus leucovorin have been associated with toxicity-related hospitalizations in 20% to 30% of treated patients.
Although the modulation of 5-FU by leucovorin has been suggested as a standard of care for patients with metastatic colorectal cancer, a Southwest Oncology Group (SWOG) trial suggested that a protracted infusion of 5-FU has a favorable toxicity profile and trend toward improved survival compared with six other 5-FU regimens. This trial randomly allocated 500 patients to receive one of the following treatments: 5-FU IV bolus, 5-FU plus low-dose oral leucovorin, 5-FU plus high-dose leucovorin, 5-FU continuous infusion, 5-FU 24-hour infusion, and 5-FU 24-hour infusion plus PALA. Response rates ranged between 15% and 29% with a median survival for the entire group of 14 months.
An alternative schedule of 5-FU plus leucovorin uses a bimonthly high-dose leucovorin and 5-FU regimen. The schedule, investigated by de Gramont et al, has been extensively examined in France. This bimonthly schedule was compared to the low-dose leucovorin schedule (daily x 5). The investigators observed a more favorable toxicity profile and higher response rate for the bimonthly schedule. However, no statistically significant improvement in overall survival was noted with the bimonthly schedule.
The combination of interferon alfa plus 5-FU appeared promising in phase II studies of patients with metastatic colorectal cancer.[12-14] Unfortunately, randomized phase III trials that compared the combination of 5-FU plus interferon either with 5-FU alone or 5-FU plus leucovorin concluded that interferon afforded no benefit with regard to response rates and overall survival. Toxicity in the interferon arm increased significantly.
Trimetrexate, another dihydrofolate reductase inhibitor, potentiates the cytotoxicity of 5-FU. Phase II studies demonstrated objective responses with trimetrexate in combination with high-dose leucovorin and 5-FU in patients previously treated with 5-FU chemotherapy. However, grade 3 or 4 diarrhea and hypersensitivity occurred.
Several new agents are under development for the treatment of colorectal cancer. Some of these, including oral fluoropyrimidines, oxaliplatin, and irinotecan (Camptosar, CPT-11), are reviewed herein.
A protracted IV infusion of 5-FU may be an optimal schedule, resulting in continuous exposure of tumor cells to active 5-FU concentrations. This delivery system requires indwelling catheters, which can lead to line infection, line slippage, or thrombosis. Oral dosing of fluoropyrimidines would circumvent this problem. The bioavailability of oral 5-FU has been demonstrated to be erratic, precluding reliable dosing by this administration route. The erratic absorption of 5-FU may be attributed to varying levels of dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. DPD is the primary catabolic enzyme of 5-FU with an estimated 85% of an administered 5-FU dose being catabolized by this enzyme. This problem of erratic 5-FU absorption from the gastrointestinal tract was overcome by the development of 5-FU prodrugs that are well absorbed enterally and then enzymatically converted to 5-FU. A second method to circumvent inconsistent oral absorption of 5-FU is to inactivate DPD.
Tegafur is a prodrug of 5-FU, while uracil is a competitive inhibitor of DPD allowing for sustained 5-FU levels. UFT is a combination of tegafur and uracil in a 1:4 molar ratio. The combination of UFT plus oral leucovorin is referred to as Orzel. Leucovorin was added to modulate biochemically the 5-FU generated from tegafur. The clinical development of UFT was reviewed by Hoff. Its previously demonstrated activity and favorable toxicity profile led to further development of UFT/leucovorin as an alternative to standard IV 5-FU/leucovorin for metastatic colorectal cancer. The results of two multinational phase III trials comparing the oral regimen of UFT/leucovorin to IV 5-FU/leucovorin as the initial treatment for patients with metastatic colorectal cancer have been reported.[20,21]
In one trial, 816 patients were randomly allocated to an intravenous dosing schedule of 5-FU/leucovorin or to oral UFT/leucovorin. The primary end point of the study was to compare survival data for patients, with a careful analysis of drug toxicity, quality of life, control of disease-related symptoms, and response rate. UFT at 300 mg/m2/d was administered in three daily doses for 28 consecutive days, followed by 1 week of rest. Oral leucovorin was administered with the UFT three times per day. The leucovorin dose initially was 75 mg/d in the United States but was later changed to 90 mg/d due to the worldwide availability of 15-mg leucovorin tablets. The control regimen was IV 5-FU/leucovorin administered for 5 consecutive days, with cycles repeated every 28 days.
For the primary end point of survival, the treatment arms were equivalent. The median survival was 12.4 months for UFT/leucovorin-treated patients and 13.4 months for 5-FU/leucovorin-treated patients. There was no statistical difference in the response rates of the two treatment arms. The response rate (complete plus partial response) in the UFT/leucovorin arm was 12% and 15% in the 5-FU/leucovorin arm. While producing equivalent survival to 5-FU/leucovorin treatment, UFT/leucovorin was associated with safety advantages.
Severe (Common Toxicity Criteria grade 3 or 4) myelosuppression was uncommon with UFT/leucovorin. Severe neutropenia occurred in only 1% of UFT/leucovorin courses compared with 56% with 5-FU/leucovorin. There were no incidences of febrile neutropenia with UFT/leucovorin (vs 13% with 5-FU/leucovorin). There was no significant difference between the two treatment groups in the incidence of severe diarrhea (21% with UFT/leucovorin vs 16% with 5-FU/leucovorin), and the occurrence of stomatitis of any grade was much lower with UFT/leucovorin. Severe nausea and vomiting was seen in 13% of UFT/leucovorin vs 10% of 5-FU/leucovorin courses.
A second trial was designed to compare time to progression between patients receiving an IV 5-FU/leucovorin regimen or UFT/leucovorin. A total of 380 patients were randomly allocated to one of the two treatment arms, receiving either UFT at 300 mg/m2/d plus oral leucovorin at 90 mg/d, both administered for 28 days with a 1-week rest, or IV 5-FU at 425 mg/m2/d and leucovorin at 20 mg/m2/d given for 5 days every 35 days. For the primary end point of time to progression, the treatment arms were equivalent, with a median of 3.4 months in the UFT/leucovorin arm vs 3.3 months in the 5-FU/leucovorin arm. The median survival time was 12.2 and 11.9 months, respectively. Response rates were similar in both arms (11% for UFT/leucovorin vs 9% for 5-FU/leucovorin).
This study also demonstrated significant improvements in safety with UFT/leucovorin compared with 5-FU/leucovorin. Severe neutropenia was seen in 3% of patients in the UFT/leucovorin arm vs 31% of patients treated with 5-FU/leucovorin. UFT/leucovorin treatment also resulted in fewer episodes of febrile neutropenia and documented infection. The incidence of severe nausea and vomiting was the same in both arms (9%), while severe stomatitis/mucositis was seen in 2% of patients treated with UFT/leucovorin vs 16% of patients treated with 5-FU/leucovorin. Severe diarrhea was observed in 18% of UFT/leucovorin-treated patients vs 11% of 5-FU/leucovorin-treated patients.
Capecitabine (Xeloda) is a fluoropyrimidine carbamate that was developed as an oral alternative to 5-FU with greater tumor selectivity. It is absorbed intact in the gastrointestinal tract and converted to 5-FU by three enzymatic steps. High concentrations of 5-FU are achieved in tumor tissue because of the increased activity at this site of the final activating enzyme, thymidine phosphorylase. The differential exposure of normal and tumor tissues is expected to result in better efficacy and less toxicity. In chemotherapy-naive patients with advanced colorectal cancer, a phase II study compared three schedules of capecitabine: 1,331 mg/m2/d continuous x 12 weeks; 2,510 mg/m2/d x 2 weeks followed by a 1-week rest; or 1,657 mg/m2/d with the same intermittent schedule plus 60 mg/d of oral leucovorin. Based on the respective response rates of 19%, 28%, and 24%, and median time to progression of 17, 30, and 24 weeks, the intermittent schedule of capecitabine monotherapy was chosen for further development.
Results of two phase III trials with similar study rationale, objectives, and design were recently reported.[24,25] Both trials compared capecitabine (2,500 mg/m2/d x 2 weeks every 3 weeks) to 5-FU/leucovorin (Mayo regimen) as first-line treatment in metastatic colorectal cancer. The primary end point of the trials was to demonstrate at least equivalence in response rates. Secondary end points included comparing efficacy profile, safety profile, quality of life (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30), and medical care utilization.
The first trial, conducted in Europe, Australia, Taiwan, Israel, and New Zealand, enrolled 602 patients equally divided between the two treatment arms. The second trial, conducted in the United States, Canada, Mexico, and Brazil, enrolled 605 patients, with 302 patients randomized to the capecitabine arm and 303 patients randomized to the 5-FU/leucovorin arm. For the primary end point of tumor response, both trials demonstrated that capecitabine results in improved response rates compared with IV bolus 5-FU/leucovorin.
Taking all randomized patients using intent-to-treat analysis, investigator-assessed response rates (partial and complete response) for capecitabine-treated vs 5-FU/leucovorin-treated patients were 26.6% vs 17.9%, respectively (95% confidence interval [CI]: 1.9%-15.1%) in the first trial, and 24.8% vs 15.5%, respectively (95% CI: 2.8%-15.5%) in the second trial. In the first trial, median time to progression was 160 vs 144 days (log-rank test, P = .6501) and median overall survival was 404 vs 379 days (log-rank test, P = .8477), respectively, for the capecitabine vs 5-FU/leucovorin arm.
In the second trial, median time to progression was 131 vs 144 days (log-rank test, P = .7193) and median overall survival was 378 vs 400 days (log-rank test, P = .2363), respectively. Capecitabine had a favorable toxicity profile with significantly less treatment-related serious adverse events and hospitalizations compared with 5-FU/leucovorin. The most common adverse events with capecitabine were hand-foot syndrome and diarrhea; however, mucositis, neutropenia, febrile neutropenia, and alopecia were less frequent compared with 5-FU/leucovorin. These toxicities were similar to those seen in earlier studies of capecitabine and are similar to those obtained with protracted infusions of IV 5-FU.
Another strategy to improve the oral bioavailability of 5-FU is to inhibit DPD, thus allowing reliably consistent absorption of 5-FU from the gastrointestinal tract. Eniluracil (776C85) is an irreversible inactivator of DPD, and the bioavailability of oral 5-FU, when administered concurrently with eniluracil, exceeds 100%. The toxicity profile of this combination was acceptable, and schedule-dependent neutropenia was the dose-limiting toxicity. A multicenter phase II study evaluated the combination of oral 5-FU at 1.0 mg/m2 plus eniluracil at 10 mg/m2 twice daily for 4 weeks repeated every 5 weeks in patients with advanced colorectal cancer. Because of the lack of side effects, the protocol was amended to increase the doses of 5-FU plus eniluracil to 1.15 and 11.5 mg/m2, respectively. Phase III comparative trials evaluating this dose and schedule compared with IV 5-FU/leucovorin in previously untreated patients with metastatic colorectal cancer have completed patient accrual. (*Editor’s Note: Since this article was writtenthe industrial sponsor of eniluracil has discontinued development of the drug.)
Oxaliplatin (Eloxatin) is a novel diaminocyclohexane platinum agent that acts mainly by forming DNA adducts.[30,31] Synergy between oxaliplatin and 5-FU was initially demonstrated in preclinical models and subsequently observed in clinical trials. In a phase II trial of 90 patients with advanced colorectal cancer, the combination of chronomodulated 5-FU at 700 to 1,000 mg/m2/d, leucovorin at 300 mg/m2/d, and oxaliplatin at 25 mg/m2/d given for 4 days every 2 weeks produced a 67% response rate and a 19-month median survival duration. Subsequent phase III randomized trials evaluated the potential benefits of oxaliplatin when added to 5-FU/leucovorin as first-line therapy for patients with advanced colorectal cancer.
de Gramont et al randomized 420 patients to receive bimonthly 5-FU/leucovorin with or without 85 mg/m2 of oxaliplatin on day 1. The response rate, evaluated by independent radiological reviewers, showed 49.5% and 28.6% responses in patients treated with and without oxaliplatin, respectively. The corresponding median progression-free survival for each arm was 49.5 vs 26.9 weeks. A statistically significant effect on overall survival has not been demonstrated (log-rank test, P = .12). Second-line chemotherapy has been suggested as a factor that may have influenced the overall survival. A multivariate analysis of prognostic factors for overall survival revealed that oxaliplatin given in combination with 5-FU/leucovorin as first-line therapy is a significant prognostic factor (P = .0001) for longer survival, and poststudy chemotherapy with oxaliplatin and/or irinotecan was also found to be a significant independent prognostic factor (P = .0001).[34,35]
Giacchetti et al compared chronomodulated 5-FU/leucovorin administered every 3 weeks, with or without oxaliplatin at 125 mg/m2 given over 6 hours on day 1. Among 100 patients treated in each arm, overall response rates were 53% for the oxaliplatin-containing combination vs 16% (P < .001). The median progression-free survival was 8.7 vs 6.1 months, respectively. However, overall survival was equivalent in both arms (19.9 vs 19.4 months, respectively). This survival equivalence was attributed to crossover and surgery after chemotherapy. Of the 100 patients in the 5-FU/leucovorin arm, 57 crossed over to 5-FU/leucovorin plus oxaliplatin, with 17.5% of them obtaining an objective response. Furthermore, 35 patients in the 5-FU/leucovorin arm underwent surgery for metastatic disease, with 14 performed after crossover, of whom 6 were classified as having no evidence of disease.
Oxaliplatin plus 5-FU/leucovorin as second-line therapy has also shown promising results. In one trial, 46 patients with 5-FU-refractory colorectal cancer were treated with oxaliplatin at 100 mg/m2 administered as a 2-hour infusion on day 1, followed by leucovorin at 500 mg/m2/d on days 1 and 2, and 5-FU at 1.5-2 g/m2/d as a 24-hour infusion for 2 consecutive days every 2 weeks. The overall response rate was 46%, median progression-free survival duration was 7 months, and median survival duration was 17 months. Limiting toxicities were neutropenia and peripheral neuropathy. A second trial involved adding oxaliplatin at 85 mg/m2 every 2 weeks to the same 5-FU/leucovorin regimen under which patients had progressed. The overall response rate was 20%, with a median response duration of 37 weeks and median survival of 57 weeks. Although the response rate obtained in this trial was lower than that of the previous trial, it nonetheless attested that further responses can be obtained by the addition of oxaliplatin to 5-FU in patients with 5-FU-resistant disease.
Oxaliplatin with bimonthly 5-FU/leucovorin, recently evaluated by de Gramont et al, showed that a high oxaliplatin dose intensity was related to a higher response rate and an improved preogression-free survival. Patients who received oxaliplatin > 85 mg/m2 had a response rate of 39% (vs 19%, P = .03) and median PFS of 28 weeks (vs 26 weeks, P = .02), compared with patients who received oxaliplatin < 85 mg/m2. Survival at 1 year was 69% and 44%, respectively. A new study with increased oxaliplatin dose intensity at 130 mg/m2 plus lower 5-FU/leucovorin dose confirmed the high activity of dose-intense oxaliplatin plus 5-FU/leucovorin in pretreated patients resistant to 5-FU. The response rate was 52% among refractory patients, and this regimen appeared to be well tolerated. Other trials of oxaliplatin plus 5-FU/leucovorin using other widely used 5-FU-based regimens have confirmed the activity of this combination in advanced refractory colorectal cancer.[41,42]
Although oxaliplatin has been investigated primarily in combination chemotherapy regimens, its activity as a single agent in colorectal cancer has been described. In previously untreated patients with advanced colorectal cancer, two phase II trials assessed the activity of oxaliplatin administered at 130 mg/m2 over 2 hours every 3 weeks.[43,44] Response rates of 20% to 24% were noted, with median response duration of 6 to 7 months and median progression-free survival of approximately 4 months. Main toxic effects were peripheral neuropathy and laryngopharyngeal dysthesia. In previously treated patients, two studies involving the same oxaliplatin regimen produced an overall response rate of 10%, with 24% to 41% of patients achieving stable disease and a median survival duration of 8.5 months.
The results of phase I/II studies of oxaliplatin and irinotecan in 5-FU-refractory colorectal cancer patients were reported in 1996. Among the 34 treated patients, the overall response rate was 44%, with stable disease in another 35%, and a median time to progression of 7.5 months. Several other ongoing studies are underway exploring the efficacy of oxaliplatin against colorectal cancer, mostly as part of a combination regimen rather than as a single agent.
In 1996, the US Food and Drug Administration (FDA) granted conditional approval for the use of irinotecan, a semisynthetic camptothecin analog that acts by inhibiting topoisomerase I, as treatment for patients with colorectal cancer whose disease had progressed on 5-FU-based therapy. At that time, no standard second-line treatment was available for this refractory disease. In the FDA-reviewed pivotal trials,[48-52] patients treated with irinotecan at 125 mg/m2/wk for 4 weeks followed by 2 weeks of rest had a response rate of 15%, with a median response duration of 6 months. Additionally, for many of these patients, previously progressive disease stabilized for meaningful periods, and palliative benefits, such as pain relief, were noted among responders. The toxic effects of irinotecan, however, were considerable-30% of irinotecan-treated patients experienced grade 3 or 4 diarrhea, and 20% were hospitalized for management of toxic reactions. Other toxic effects included nausea, vomiting, and neutropenia.
Two randomized phase III trials conducted primarily in Europe eventually established the clinical benefit of irinotecan in the treatment of 5-FU-refractory colorectal cancer. These trials clarified the drug’s effect on survival, quality of life, and control of disease-related symptoms relative to either best supportive care or infusional 5-FU regimens.
The first study compared irinotecan plus best supportive care vs best supportive care alone in a 2:1 ratio, with 189 patients in the irinotecan arm and 90 patients in the best supportive care arm. Best supportive care included the use of antibiotics, analgesics, transfusions, corticosteroids, counseling, or any other symptomatic therapy (except irinotecan or other topoisomerase I inhibitor). The median survival was 9.2 months for the irinotecan arm vs 6.5 months for the best supportive care arm (P = .0001). With a median follow-up of 13 months, the 1-year overall survival rate for the irinotecan arm was 36.2% compared to 13.8% in the best supportice care arm. Multivariate analysis accounting for the imbalance in performance status between the two groups showed a statistically significant survival benefit for the irinotecan arm (P = .001). This translated to an increased death risk ratio of 1.71 for the best supportive care arm.
Survival without performance status deterioration (P = .0001), without weight loss of > 5% (P = .018), and pain-free survival (P = .003) were significantly better in the patients who received irinotecan. Quality of life was assessed with the EORTC QLQ-C30 questionnaire, which included a global health-status scale, five function scales, and nine symptom scales. Quality-of-life scores were significantly different between the two groups except for those pertaining to emotional function, nausea, sleep disturbance, and finances. All significant scores were in favor of the irinotecan group except for diarrhea.
The second randomized phase III trial compared irinotecan to infusional 5-FU-based chemotherapy as second-line treatment for metastatic colorectal cancer. Of 267 patients, 133 received irinotecan and 134 received one of three infusional 5-FU regimens. The median survival duration of the irinotecan group was 10.8 months, compared with 8.5 months for the 5-FU group (P = .035). With a median follow-up of 15 months, survival rate at 1 year was 45% and 32%, respectively. Progression-free survival duration was also improved in the patients treated with irinotecan (4.2 months vs 2.9 months, P = .03). Quality-of-life variables and control of disease-related symptoms in the two groups were comparable, median symptom-free survival duration was 8.1 vs 7.0 months (P = .23), and median pain-free survival duration was 10.3 vs 8.5 months (P = .06) for the irinotecan vs 5-FU groups, respectively. The irinotecan dose schedule employed in these trials was 350 mg/m2 IV every 3 weeks (or 300 mg/m2 if aged > 70 years or WHO performance status of 2). Although this dose schedule differs from the US dose schedule of 125 mg/m2 weekly x 4 every 6 weeks, the weekly and every-3-week dose schedules produced similar efficacy and adverse-effect profiles.
Irinotecan has also been investigated in combination with 5-FU/leucovorin. In one study of mostly heavily pretreated patients, the treatment schedule was irinotecan at 180 mg/m2 on day 1, leucovorin at 200 mg/m2 as a 2-hour infusion on days 1 and 2, and 5-FU at 400 mg/m2 loading dose followed by 600 mg/m2 continuous infusion over 22 hours on days 1 and 2, repeated every 2 weeks. With 41 of 44 evaluable patients, the overall response rate was 22%. Although no complete responses were observed, seven patients with a partial response were rendered as having no evidence of disease after resection of liver metastasis. The major toxic effects noted with irinotecan combined with 5-FU/leucovorin were neutropenia, diarrhea, and asthenia.
A trial in first-line treatment of patients with advanced colorectal cancer randomly allocated patients to three treatment groups. Conducted in the United States, Canada, and Australia, this trial had progression-free survival as the primary end point, and enrolled approximately 220 patients in each of the three treatment groups. Objective response rates (complete plus partial responses) were noted in 50% of patients receiving the three-drug combination vs 28% of patients receiving 5-FU/leucovorin (P < .001). The rate of objective response among patients who received single-agent irinotecan was 30%, similar to the 5-FU/leucovorin arm. Confirmed response rates at 4 to 6 weeks after initial response were noted in 39% with the irinotecan combination vs 21% in the 5-FU/leucovorin arm (P < .001). Confirmed response was 18% with irinotecan alone. Median duration of these confirmed responses was approximately 9 months in each group. Median survival for the irinotecan/5-FU/leucovorin arm was 14.8 months vs 12.6 for 5-FU/leucovorin. Median survival in the irinotecan only group was 12.0 months, again similar to 5-FU/leucovorin.
The combination of irinotecan/5-FU/leucovorin had manageable toxicities with similar frequency and severity as with 5-FU/leucovorin, without a detrimental effect on quality-of-life analysis. Based on the survival advantage associated with irinotecan/5-FU/leucovorin compared to standard treatment, the Oncology Drug Advisory Committee (ODAC) of the FDA unanimously recommended approval of the irinotecan combination in March 2000 as first-line therapy for patients with advanced colorectal carcinoma.
A second phase III trial examined the role of irinotecan combined with 5-FU/leucovorin in the first-line setting. This trial, conducted primarily in Europe, randomized 387 patients to receive either of two commonly used 5-FU/leucovorin regimens with or without irinotecan. Response rates were significantly improved with the use of irinotecan combinations. Confirmed response rates were 49% for irinotecan/5-FU/leucovorin vs 23% for 5-FU/leucovorin. Time to progression was 6.7 vs 4.4 months, median survival was 16.8 vs 14 months, and 1-year survival was 69% vs 59%, respectively, for patients treated with irinotecan/5-FU/leucovorin vs 5-FU/leucovorin. The investigators believed that the addition of irinotecan to 5-FU/leucovorin in the first-line setting of metastatic colorectal cancer increases response rate, significantly prolongs time to progression and survival, and prevents rapid deterioration of performance status, which allows the introduction of second-line therapy.
Less than a third of patients achieve an objective response to current 5-FU/leucovorin regimens, and the median survival of advanced colorectal cancer patients treated with our optimal treatments approximates 12 months.
The oral fluoropyrimidines provide interesting mechanisms of action that offer patient convenience and reduction in toxicities compared with bolus 5-FU/leucovorin schedules. Despite interesting theoretical advantages, such as tumor activation of 5-FU, dual biochemical modulation of 5-FU by uracil and leucovorin, or inactivation of tumoral DPD (a potential resistance mechanism), overall survival associated with these oral agents has not been demonstrated to be superior to conventional 5-FU/leucovorin schedules. Irinotecan and oxaliplatin are clearly active agents in advanced colorectal cancer both in chemotherapy-naive patients as well as in patients whose disease has progressed on initial fluorouracil-based chemotherapy. Regimens of 5-FU/leucovorin combined with either oxaliplatin or irinotecan have demonstrated improvement in surrogate clinical end points of response rate and time to progression.
The study by Saltz et al combining irinotecan and 5-FU/leucovorin has demonstrated a statistically significant improvement in progression-free and overall survival. This confirms this combination as a new standard treatment for metastatic colorectal cancer. Other indications for regimens containing irinotecan or oxaliplatin could include the adjuvant setting, and patients in whom tumor reduction is needed for palliation or for potential hepatic or pulmonary metastasectomy.
1. Heidelberger C, Chandler NK, Douglas H Jr: Fluorouracil pyrimidine: A new class of tumor inhibiting compounds. Nature 179:633-666, 1957.
2. Ansfield F, Klotz J, Nealon T, et al: A phase III study comparing the clinical utility of four regimens of 5-fluorouracil: A preliminary report. Cancer 39:34-40, 1977.
3. Lokich JJ, Ahlgren JD, Gullo JJ, et al: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology Program Study. J Clin Oncol 7:425-432, 1989.
4. The Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308, 1998.
5. Hansen RM, Quebbeman E, Anderson T: 5-Fluorouracil by protracted venous infusion. A review of current progress. Oncology 46:245-250, 1989.
6. Fraile RJ, Baker LH, Buroker TR, et al: Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Cancer Res 40:2223-2228, 1980.
7. Allegra CJ, Grem JL: Antimetabolites, in DeVita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology, 5th ed, pp 432-452. Philadelphia, Lippincott-Raven, 1997.
8. Advanced Colorectal Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.
9. 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 12:14-20, 1994.
10. 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 13:1303-1311, 1995.
11. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997.
12. Wadler S, Schwartz EL, Goldman M, et al: Fluorouracil and recombinant alfa-2a-interferon: An active regimen against advanced colorectal carcinoma. J Clin Oncol 7:1769-1775, 1989.
13. Pazdur R, Ajani JA, Patt YZ, et al: Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol 8:2027-2031, 1990.
14. Kemeny N, Younes A, Seiter K, et al: Interferon alpha-2a and 5-Fluorouracil for advanced colorectal carcinoma: Assessment of activity and toxicity. Cancer 66:2470-2475, 1990.
15. Hill M, Norman A, Cunningham D, et al: Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol 13:1297-1302, 1995.
16. Romanini A, Li WW, Colofiore JR, et al: Leucovorin enhances cytotoxicity of trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in Ccrf-Cem cells. J Natl Cancer Inst 84:1033-1038, 1992.
17. Conti JA, Kemeny N, Seiter K, et al: Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma. J Clin Oncol 12:695-700, 1994.
18. Diasio RB: Oral DPD-inhibitory fluoropyrimidine drugs. Oncology 14(suppl 9):19-23, 2000.
19. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anti-Cancer Drugs 9:479-490, 1998.
20. Pazdur R, Douillard J-Y, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999.
21. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of ORZEL® (oral uracil/tegafur (UFT) plus leucovorin (LV) versus parenteral 5-fluorouracil (5-FU) plus LV in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:264a, 1999.
22. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274-1281, 1998.
23. Findlay M, Van Cutsem E, Kocha W, et al: A randomised phase II study of Xeloda (capecitabine) in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 16:227a, 1997.
24. Twelves C, Harper P, Van Cutsem E, et al: A phase III trial (SO14796) of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999.
25. Cox JV, Pazdur R, Thibault A, et al: A phase III trial of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:265a, 1999.
26. Porter DJT, Chestnut WG, Merrill BM, Spector T: Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Bio Chem 267:5236-5242, 1992.
27. Baker SD, Khor SP, Adjei AA, et al: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 14:3085-3096, 1996.
28. Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 16:1450-1457, 1998.
29. Mani S, Beck T, Chevlen E, et al: A phase II open-label study to evaluate a 28-day regimen of oral 5-fluorouracil (5-FU) plus 776C85 for the treatment of patients with previously untreated metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 17:281a, 1998.
30. Butour JL, Mazard AM, Macquet JP: Kinetics of the reaction of cis-platinum compounds with DNA in vitro. Biochem & Biophys Res Commun 3:347-353, 1985.
31. Raymond E, Chaney SG, Taamma A, et al: Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol 9:1053-1071, 1998.
32. LÃ©vi F, Dogliotti L, Perpoint B, et al: A multicenter phase II trial of intensified chronotherapy with oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) in patients (pts) with previously untreated metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol 16:266a, 1997.
33. de Gramont A, Figer A, Seymour M, et al: A randomized trial of leucovorin (LV) and 5-fluorouracil (5FU) with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000.
34. de Gramont A, Figer A, Seymour M, et al: A randomized trial of leucovorin (LV) and 5-fluorouracil (5FU) with or without oxaliplatin in advanced colorectal cancer. Proc Am Soc Clin Oncol 17:257a, 1998.
35. Figer A, Louvet C, Homerin M, et al: Analysis of prognostic factors of overall survival (OS) in the randomized trial of bimonthly leucovorin and 5-fluorouracil regimen (LV5FU2) with or without oxaliplatin in advanced colorectal cancer. Proc Am Soc Clin Oncol 18:239a, 1999.
36. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment in metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000.
37. Giacchetti S, Brienza S, Focan C, et al: Contribution of second line oxaliplatin (OXA)-chronomodulated 5-fluorouracil-folinic acid (CM-5-FU-FA) and surgery to survival in metastatic colorectal cancer patients. Proc Am Soc Clin Oncol 17:273a, 1998.
38. de Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33:214-219, 1997.
39. Andre T, Louvet C, Raymond E, et al: Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen. Ann Oncol 9:1251-1253, 1998.
40. de Gramont A, Maindrault-Goebel F, Louvet C, et al: Evaluation of oxaliplatin dose-intensity with the bimonthly 48h leucovorin and 5-fluorouracil regimens (FOLFOX) in pretreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:265a, 1999.
41. Maindrault-Goebel F, de Gramont A, Louvet C, et al: High-dose oxaliplatin with the simplified 48h bimonthly leucovorin and 5-fluorouracil (5FU) regimen in pretreated metastatic colorectal cancer (FOLFOX). Proc Am Soc Clin Oncol 18:265a, 1999.
42. van Cutsem E, Szanto J, Roth A, et al: Evaluation of the addition of oxaliplatin to the same Mayo or German 5FU regimen in advanced refractory colorectal cancer. Proc Am Soc Clin Oncol 18:234a, 1999.
43. Bleiberg H, Brienza S, Gerard B, et al: Oxaliplatin combined with a high dose, 24-hour continuous 5-FU infusion and folinic acid based regimen in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 18:241a, 1999.
44. BÃ©couarn Y, Ychou M, Ducreux M, et al: Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 16:2739-2744, 1998.
45. DÃaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 9:105-108, 1998.
46. Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95-98, 1996.
47. Wasserman E, Kalla S, Misset JL, et al: Oxaliplatin (L-OHP) and irinotecan (CPT-11) phase I/II studies: Results in 5 FU refractory (FR) colorectal cancer (CRC) patients (pts). Proc Am Soc Clin Oncol 18:238a, 1999.
48. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944-5947, 1987.
49. 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 15:251-260, 1997.
50. Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996.
51. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910-2919, 1997.
52. 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 14:1128-1135, 1996.
53. Pitot HC: US pivotal studies of irinotecan in colorectal carcinoma. Oncology 12(suppl 6):48-53, 1998.
54. Cunningham D, PyrhÃ¶nen 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 352:1413-1418, 1998.
55. 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 352:1407-1412, 1998.
56. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993.
57. Pazdur R: Irinotecan: Toward clinical end points in drug development. Oncology 12(suppl 6):13-21, 1998.
58. Durrani ASK, Benhammouda A, Gil-Delgado MA, et al: Combination of irinotecan with leucovorin and 5-FU in advanced colorectal carcinoma-A phase II study. Proc Am Soc Clin Oncol 18:282a, 1999.
59. 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 14:2959-2967, 1996.
60. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000.
61. Douillard JY, Cunningham D, Roth AD, et al: A randomized phase III trial comparing irinotecan (IRI) + 5FU/folinic acid (FA) to the same schedule of 5FU/FA in patients with metastatic colorectal cancer as front line chemotherapy (CT). Proc Am Soc Clin Oncol 18:233a, 1999.