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Prospective Phase II Trial of Irinotecan, 5-Fluorouracil, and Leucovorin in Combination as Salvage Therapy for Advanced Colorectal Cancer

Gil-Delgado, Maria Angeles, M.D., Ph.D.; Guinet, François, M.D.; Castaing, Denis, M.D., Ph.D.; Adam, René, M.D.., Ph.D.; Coeffic, David, M.D.; Durrani, Amjad K. S.; Bismuth, Henri; Khayat, David, M.D., Ph.D.

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American Journal of Clinical Oncology: February 2001 - Volume 24 - Issue 1 - p 101-105
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Colorectal cancer is one of the most common malignancies in the Western world, with more than 300,000 new cases diagnosed in Europe and the United States each year. 1 Although surgery is the principal treatment for patients with colorectal cancer, the long-term survival of patients in this setting is poor, because almost half of the patients with surgically resectable disease at diagnosis will develop metastatic disease and subsequently die. Patients who have relapsed after surgery or who present with metastatic disease at diagnosis have a poor prognosis, and although active treatments are possible, their effect remains mainly palliative.

Current therapy strategies in patients with colorectal malignancy are based on 5-fluorouracil (5-FU), which can produce response rates of approximately 11% as a single agent. Strategies aimed at enhancing the therapeutic efficacy of 5-FU have involved changes in its administration schedule and also its combination with other anticancer or biochemical modulating agents. Promising results have been achieved with 5-FU plus folinic acid, and this combination is currently used as the standard first-line chemotherapy for colorectal cancer 2,3 with the capacity to produce a response rate between 19% and 38%, a median progression-free survival between 6 and 8 months and a median survival ranging from 10 to 15 months with acceptable toxicity. A review of 7 studies carried out over the last 12 years with different modes of administration of this combination have showed that the administration of bimonthly high doses of leucovorin and 5-FU regimen compared with the NCCTG-Mayo Clinic standard schedule (leucovorin: 20 mg/m2 day followed by 5-FU bolus: 425 mg/m2/day; for 5 days every 4 weeks) produces results that are superior in terms of response rate and progression-free survival. 4

Despite recent advances, there is still a fundamental need to develop new combinations that will improve tumor response rate and survival, and the incorporation of new anticancer agents may offer some new hope. In recent years, the results of innovative research and a measure of good fortune have produced several promising new agents, among which is the novel inhibitor of the DNA enzyme topoisomerase I, irinotecan. Irinotecan (CPT-11) is a water-soluble, semisynthetic derivative of the antineoplastic agent, camptothecin. In vivo, CPT-11 is converted by the liver to a metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), which appears to contribute to the antitumor activity of CPT-11. 5 CPT-11 possesses a novel mechanism of action that is dependent on the inhibition of the eukaryotic enzyme, DNA topoisomerase I. This leads to accumulation of a drug-stabilized cleavable complex and then to arrest of DNA replication and cell death. Irinotecan has demonstrated significant antitumor activity against a variety of tumor cell lines in vitro and in vivo, including tumors expressing the P-glycoprotein-mediated, multidrug-resistant phenoptype. 6 Encouraging results have been obtained in phase I trials with a diversity of malignancies including colorectal cancer. 7 The efficacy of CPT-11 given as a single agent in colorectal cancer has been evaluated in Europe, the United States, and Japan as first- and second-line treatment in more than 300 patients, achieving a similar response rate in both chemonaive and previously treated patients ranging from 13% to 32%. 8 The largest phase II study of CPT-11 has been carried out in Europe, where it achieved a response rate of 16.1% in a subset of patients refractory to 5-FU-based chemotherapy. The results suggest a lack of cross-resistance between the two drugs. In this trial, the response rate in chemonaive patients was 18.8% (n = 48%) and 17.7% in previously treated patients. 9

Neutropenia and diarrhea are the major dose-limiting toxicities of CPT-11. Neutropenia is reversible and short, with rapid recovery (nadir on days 9–10). Delayed diarrhea may be circumvented by the use of high doses of loperamide.

Fluorouracil/leucovorin combinations represent the standard first-line therapy for patients with metastatic disease, 4 and are also finding a role in adjuvant therapy. 10 Since irinotecan has become established as able to provide a worthwhile level of activity in colorectal cancer, it was a logical development to proceed to studies that combine it with the standard combination. Combination studies must be evaluated both in terms of enhancement of the activity which would have been expected from each component and also to assess carefully any evidence of increased toxicity over and above that which is anticipated.



The protocol was designed following the recommendations of the Helsinki Declaration. All patients had histologic evidence of colorectal cancer with evidence of recurrent tumor after surgery or of metastatic disease. Eligibility criteria for patients included age ≥ 18 years, performance status ≤ 2 (World Health Organization scale), and the presence of progressive disease with measurable or assessable lesions. Blood counts and chemistry were to be within normal limits: absolute leukocyte count ≥ 4,000/μl; neutrophil count ≥ 1,500/μl; platelets ≥ 100,000/μl; adequate liver function (serum bilirubin < 1.5 mg/dl; serum transaminase levels ≤ three times the upper limit of normal, alkaline phosphatase less than 2.5 times the upper limit of normal); adequate renal function (creatinine < 2 mg/dl or creatinine clearance > 50 ml/min, blood urea nitrogen level < 25 mg/dl). No other severe medical conditions that would preclude active treatment were to be present. Pregnant and breast-feeding women, patients with a history of other malignancy (except for skin cancer or carcinoma in situ of cervix), active infection, or signs of leptomeningeal and brain involvement, previous extensive abdominal radiotherapy, and with a history of angina or myocardial infarction were excluded.

Prior chemotherapy or radiotherapy was required to have ended at least 4 weeks before study entry. Pretreatment evaluation included a complete medical history and physical examination, imaging of measurable and nonmeasurable but assessable disease, chest radiographs, and electrocardiogram. A complete and differential blood cell count and biochemical profiles were obtained at baseline and were determined every 2 weeks. Tumor markers (carcinoembryonic antigen and CA 19.9) were obtained at baseline and at the start of each two cycles. Tumor imaging was performed after every 4 cycles (8 weeks).

Treatment Plan

After inclusion, patients received the following scheme: irinotecan (CPT-11) 180 mg/m2 (30-minute IV infusion) on day 1; leucovorin 200 mg/m2 (2-hour infusion) on days 1 and 2; fluorouracil 400 mg/m2 bolus injection (loading dose) followed by 5-FU 600 mg/m2 during 22-hour infusion on day 1 and day 2. The treatment schedule was repeated every 15 days.

Patients were treated until there was evidence of disease progression or unacceptable toxicity.

No dose reductions were permitted. Low blood counts at day 15 led to treatment delays of 1 or 2 weeks until recovery (leukocyte ≥ 3,000/mm3; neutrophil count ≥ 1,000/mm3; platelets ≥ 100,000/mm3). A maximum delay of 3 weeks was permitted, beyond which the treatment was discontinued. For other toxic manifestations, the same rule was applied. Monitoring of the full blood count before day 15 was not routinely undertaken, and therefore nadir counts were not documented.

Assessments of response were performed according to World Health Organization criteria 14 after every four cycles of therapy with repeat of those clinical and routine imaging procedures that had been used to define the extent of the disease at presentation (computed tomography scan, magnetic resonance imaging/scan, isotope bone scan). All patients were assessed for response following “intention to treat” rules.

Complete responses were defined as the disappearance of all known lesions on two separate measurements at least 4 weeks apart; partial response as a reduction of each lesion by at least 50%; stable disease as a decrease of less than 50% or an increase of less than 25% with no new lesions; progressive disease as an increase of greater than 25% or appearance of new lesions.

Progression-free survival and overall survival were calculated from the date to study registration until the date on which progression disease was documented or patient death, respectively. 15 The time event curves were drawn up using the Kaplan-Meier method.

Toxicity was also assessed by the WHO criteria 14 every 15 days, with clinical evaluation and biochemical analysis repeated also every 15 days and at the end of treatment. Tumor markers were performed every month and at the end of treatment. Electrocardiography was performed at study entry and was repeated monthly.


Patient Characteristics

Thirty-nine patients from two institutions entered this trial from January 1997 and October 1998, with the following demographic characteristics: median age 59 years (range, 35–78 years), 63% were men, and 90% with good Performance Status (0–1). The majority had colon cancer at diagnosis (67%), 75% had liver involvement, and 90% were previously treated for advanced disease; 35 of them had received at least one treatment with a 5-FU/leucovorin–containing regimen for metastatic disease and 80% had relapsed while receiving a 5-FU/leucovorin schedule. The following patients were inevaluable: two patients were considered lost to follow-up immediately after inclusion, and four other patients were inevaluable for efficacy (two patients had previous other cancer, one patient underwent surgery on completion of the second cycle, and one patient did not have an assessable lesion) (Table 1).

Table 1
Table 1:
Patient characteristics


A total of 287 cycles of the CPT-11/leucovorin-5-FU combination were administered during the study with a median per patient of 7 cycles (range: 1–20 cycles). Dose intensity of the study regimens reflected the need for delays (20%) in treatments, mainly because of neutropenia. Granulocyte colony-stimulating factor was administered in only 4% of cycles. The median dose intensity of 5-FU was 910 mg/m2/week (range, 580–1,000 mg/m2/week), which corresponds to 91% of the intended dose; the median dose intensity of irinotecan was 82 mg/m2/week (range: 52–90 mg/m2/week), corresponding to 91% of scheduled dose.


Thirty-seven patients were evaluated for toxicity, and two patients had missing toxicity data. The most common grade III to IV toxicity observed was neutropenia, which occurred in 29% of patients, corresponding to 7% of cycles administered. Neutropenia was generally brief, lasting more than 7 days in only 22 cycles. However, a neutrophil count of less 1.0 × 109/l at day 15 accounted for most of the treatment delays in 9 patients. Fever developed in four patients during periods of neutropenia. Neither severe thrombocytopenia nor anemia was observed. Grade III diarrhea was experienced by 10% of patients in at least 1 cycle. Other severe toxicities occurred rarely, except severe asthenia, which was experienced by 16% of patients. Grade I to II hand–foot syndrome developed in only three patients. Grade III alopecia was experienced by 18% of patients. There were no drug-related treatment discontinuations or toxic deaths in this cohort of patients (Table 2).

Table 2
Table 2:
Hematologic and nonhematologic toxicity

Response to Therapy

Eight of 33 patients attained an objective response (24%; 95% confidence interval: 9–39%), and an additional 12 had their disease stabilized or achieved minor response for an overall level of tumor control (partial response plus no change) of 60% (Table 3). Responses were observed in lung (one patient) and in liver metastasis (seven partial responses plus one minor response). These eight patients underwent partial hepatectomy, resulting in complete response in all them. The median duration of response, taking surgery into account, was 14 months (range, 6+–25+ months).

Table 3
Table 3:
Response rate (intent to treat)

The median overall survival was 11 months (range: 2–23 months), at 2.5 years of follow-up. The probability of survival at 1 year is 38%.


This phase II study was designed to characterize the antitumor activity and toxicity of CPT-11 in combination with bolus fluorouracil, followed by continuous infusion 5-FU and high-dose leucovorin given every 2 weeks according to the salvage regimen reported by Ducreux et al. and De Gramont et al. 11–13 These investigators’ phase I study has shown that this combination is feasible without any overlap in the toxicity of each drug. The current study establishes the recommended dose for phase II trials at 180 mg/m2 of irinotecan when combined with 5-FU according to the De Gramont regimen, 12 and has shown this to be safe and effective as well as achieving a high response rate in heavily pretreated patients. The present phase II study has confirmed the feasibility and the antitumor activity of this regimen in patients with previously treated metastatic colorectal cancer. The schedule has produced 8 partial responses and reached a response rate of 21% (95% confidence interval 10–32), whereas an additional 30% had stable disease; thus, tumor control was obtained for 51% of patients. Furthermore, 20% of patients underwent surgery, permitting long-term complete remission to be obtained in patients who had liver metastases. The clinical benefit of this result is supported by a documentation of a median survival of 11 months. The data are consistent with those observed in the phase I trial with the same regimen and schedule, in which 12 of 55 patients responded to the therapy, resulting in an objective response rate of 22%, for a median overall survival of 15 months (range: 2–23 months). When a close comparison with the phase I study is made, it is apparent that half of the patients were treated at dose levels greater than those used in this trial without obtaining an improvement in the response rate at the higher dose levels. At the 180 mg/m2 cohort in the dose-finding study, only 1 of 11 patients achieved an objective response. It would appear that the dose and schedule defined by this trial serve the combined aims of generating sufficient efficacy to establish disease control and permit resection of persistent disease while limiting overall toxicity to levels that can be tolerated even in patients with extensive exposure to prior therapy. With the combination of surgical management for residual metastatic lesions, the results of this combination produced a median survival of 11 months, which compares favorably with that obtained with CPT11 therapy in second-line treatment or with schedules alternating CPT11 and 5-FU. 16–19 This combination is routinely proposed as first-line therapy for advanced colorectal cancer. 20

Acknowledgment: The authors thank Carolina Jimenez Navarro for her help in consulting patient’s files, Steve Johnson and François Delgado for advice, and Corinne Pierre and Brigitte Cedreau for technical assistance.


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Advanced colorectal cancer; Combination chemotherapy; Phase II trials; Irinotecan—; 5-Fluorouracil; Folinic acid

© 2001 Lippincott Williams & Wilkins, Inc.