Trial of Rothenberg et al--Rothenberg and colleagues developed a regimen in which irinotecan(Drug information on irinotecan) and 5-FU plus leucovorin were administered in alternating cycles. The rationale for this schedule was to ensure that full doses of all three agents could be administered by avoiding the potential for overlapping side effects that may occur with concomitant drug administration. [reference 24 and Mace Rothenberg, MD, personal communication, December, 1997]
In this trial, irinotecan was administered at 100 mg/m2/d each week for 4 weeks, followed by a 2-week rest period. It is noteworthy that the irinotecan dose used by Rothenberg et al is lower than that recommended for single-agent therapy in the package insert (125 mg/m2/d). It is also lower than the dose employed in the previously discussed Saltz regimen (125 mg/m2/d), which combines irinotecan with 5-FU plus leucovorin. The regimen of 5-FU plus leucovorin used by Rothenberg et al is that popularized by Poon et al, which calls for leucovorin 20 mg/m2/d and 5-FU 425 mg/m2/d on days 1 to 5 every 4 weeks.
Of the 71 patients enrolled in the trial, 23 had partial or complete remissions (32%; 95% CI, 21.5% to 43.3%). The median time to tumor progression was 6.9 months. The median survival is 17.6 months.
The principal toxicities were diarrhea, nausea and vomiting, neutropenia, and stomatitis. During the irinotecan segment of therapy, 20% of patients developed grade 3 or 4 diarrhea, as compared with 5% who experienced grade 3 to 4 diarrhea after 5-FU plus leucovorin. The grade 3 and 4 toxicity statistics for irinotecan and 5-FU/leucovorin were 3% and 0%, respectively, for vomiting; 16% and 12%, respectively, for neutropenia; and 0% and 3%, respectively, for stomatitis.
The authors concluded that both the activity and toxicity patterns of the alternating schedule were similar to those seen when each regimen is given alone. The median survival data are intriguing. Confirmation of these findings in a randomized trial seems to be warranted to discern whether the high median survival was due to treatment effect or to inadvertent selection of patients with better prognoses or more indolent disease.
Diarrhea is one of the dose-limiting toxicities for patients treated with either irinotecan or 5-FU/leucovorin programs. Therefore, when combining the two regimens, the potential exists for severe gastrointestinal toxicity. If the agents produce synergistic diarrhea, combining the drugs safely in clinically meaningful doses may be impossible.
The trial by Parnes et al described above is an example of a study in which this toxicity proved to be enough of a problem that the investigators chose to abandon their administration schedule. The actual outcomes of therapy in the three other trials described above indicated that irinotecan and 5-FU plus leucovorin could be combined at doses that are the same or nearly the same as those used when the drugs are administered alone without producing undue gastrointestinal toxicity.
Mechanisms of Drug-Induced Diarrhea
The finding that gastrointestinal toxicity does not preclude administration of reasonable doses of both irinotecan and 5-FU is both encouraging and surprising. An explanation for this may be found in some data in the literature, which suggest that the diarrhea produced by the two agents results from different mechanisms of damage to the gastrointestinal tract.
Fluorouracil Plus Leucovorin--In a study of 16 patients with advanced colorectal cancer who were assessed by the cellobiose/mannitol test before and after 5-FU treatment, 5-FU plus leucovorin was shown to increase small intestine permeability. After chemotherapy, small intestine permeability increased from 0.016 ± 0.011 to 0.029 ± 0.025 (P < .05). A correlation was noted between the number of days of diarrhea and the increased intestinal permeability score (P = .05).
The authors concluded that diarrhea due to 5-FU plus leucovorin appears to be related to small intestinal damage. In this circumstance, the use of concomitant medications to both diminish small intestinal permeability and slow intestinal transit time in order to maximize fluid and electrolyte reabsorption could reduce diarrhea.
A number of investigators have reported that octreotide(Drug information on octreotide) (Sandostatin) has beneficial effects on 5-FU-related diarrhea.[27,28] The principal mode of action by which octreotide is thought to reduce the diarrhea noted in patients with VIPomas is suppression of the associated small bowel hypersecretory state that correlates with elevated levels of vasoactive intestinal peptide (VIP). The finding that octreotide suppresses 5-FU-induced diarrhea appears to substantiate the role of increased small bowel permeability as the mechanism of 5-FU-induced diarrhea. In the trial by Cascinu et al, octreotide was more effective than loperamide(Drug information on loperamide) in suppression of diarrhea.
Irinotecan--Ikuno et al have administered irinotecan to mice and examined intestinal cell proliferation, differentiation of colonocytes, and apoptosis, as well as levels of intestinally active secretogogues, such as serotonin and VIP. Histologic evaluation revealed vacuolation of absorptive epithelial cells associated with apoptosis in the mucosal cells of the ileum and goblet-cell hyperplasia in the cecum. The former two processes cause water and electrolyte malabsorption in the ileum, while the latter process causes mucin hypersecretion from the cecum. There was neither an increase in the number of intestinal enterochromaffin cells nor an increase in VIP levels, indicating that irinotecan-induced diarrhea likely results from a different mechanism from that thought to account for 5-FU-induced diarrhea.
Araki et al found evidence of hemorrhagic enterocolitis in small and large bowel samples obtained after intraperitoneal injection of irinotecan in athymic mice. The maximal change was noted in the cecum at day 10.
Loperamide is effective in the treatment of irinotecan-induced diarrhea and allows dose escalation to occur that is not possible without this antidiarrheal therapy. The trials reported by Saltz et al, Parnes et al, Fonseca et al, and Rothenberg et al have prescribed the intensive loperamide treatment program described by Abigerges et al.
The ability to administer relatively high doses of both irinotecan and 5-FU plus leucovorin has been somewhat surprising. It does suggest, however, that it may be possible to take advantage of the augmented activity observed in human tumor xenografts and in vitro in the clinical setting.
A number of recent and ongoing clinical trials in North America and elsewhere have investigated combinations of irinotecan plus 5-FU and leucovorin in patients with advanced colorectal cancer. The drugs have been administered in a simultaneous, sequential, or alternating fashion. All of these regimens have been associated with tumor responses. Since none of the regimens has been compared in a phase III setting, the optimal dose and schedule from among those tested to date is not yet known.
An intergroup phase III trial in which several irinotecan and 5-FU plus leucovorin regimens are to be compared to 5-FU plus leucovorin alone in patients with metastatic, previously untreated colorectal cancer is in the planning stages. The three-drug combination program is also slated to be tested in the adjuvant setting in patients with stage III colon cancer in a North American intergroup trial.