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Irinotecan Plus Fluorouracil/Leucovorin for Metastatic Colorectal Cancer: A New Survival Standard

^a Memorial Sloan-Kettering Hospital, New York, New York, USA; ^b Centre Rene Gauducheau, Nantes, France; ^c Pharmacia Corporation, Peapack, New Jersey, USA; ^d Aventis, SA, Antony, France

Correspondence: Leonard B. Saltz, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-2501; Fax: 212-794-7186; e-mail: saltzl{at}mskcc.org

	ABSTRACT

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Background. Irinotecan is a topoisomerase I inhibitor that prolongs survival in patients with colorectal cancer refractory to fluorouracil (5-FU) and leucovorin (LV). This demonstrated activity of irinotecan as effective second-line therapy for colorectal cancer led to evaluation of combination irinotecan/5-FU/LV as first-line therapy for patients with metastatic disease. The results of two prospective phase III randomized, controlled, multicenter, multinational clinical trials in patients with previously untreated metastatic colorectal cancer served as the basis for U.S. and European approval of irinotecan/5-FU/LV for this indication. An overview of the findings of these two pivotal studies provides insights regarding the application of this new combination in clinical practice.

Methods. Patients were randomly assigned to receive 5-FU/LV, either alone, or with concurrent irinotecan. The study conducted primarily in North America (study 1), employed bolus 5-FU/LV schedules, while the study performed primarily in Europe (study 2), employed infusional 5-FU/LV regimens. Major endpoints included tumor response rate, time to tumor progression (TTP), overall survival, quality of life, and safety.

Results. In study 1, the respective confirmed response rates for irinotecan/5-FU/LV versus 5-FU/LV were 39% and 21% (p < .001); median TTPs were 7.0 months and 4.3 months, respectively (p = .004). In study 2, response rates for irinotecan/5-FU/LV versus 5-FU/LV alone were 35% and 22% (p = .005); median TTPs were 6.7 months and 4.4 months, respectively (p < .001). Survival time increased significantly with irinotecan/5-FU/LV versus 5-FU/LV alone in both studies (study 1: median 14.8 months versus 12.6 months, p = .042; study 2: median 17.4 months versus 14.1 months, p = .032). The combined analysis of the data from the two studies showed median survivals of 15.9 months versus 13.3 months, favoring the irinotecan-containing combinations (stratified-by-study p = .003). Patients in study 1 had a 36% lower risk of tumor progression and a 20% lower risk of death with the irinotecan combination than with 5-FU/LV alone; comparable risk reduction values in study 2 were 42% and 23%. While grade 3 diarrhea and vomiting were more common with irinotecan/5-FU/LV, grade 4 neutropenia, neutropenic fever, and mucositis were less common with irinotecan/5-FU/LV than with the Mayo Clinic 5-FU/LV regimen.

Conclusion. The combination of irinotecan/5-FU/LV is superior to 5-FU/LV alone as first-line therapy for patients with metastatic colorectal cancer, offering consistently improved tumor control and prolonged survival. Irinotecan-based combination therapy sets a new survival standard for the treatment of this life-threatening disease.

Key Words. Irinotecan • Fluorouracil • Leucovorin • Camptothecin • Antineoplastic agents • Colorectal neoplasms • Quality of life • Randomized controlled trials • Human • Prognosis

	INTRODUCTION

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Until recently, patients with colorectal cancer had few available chemotherapeutic options. In the absence of any more effective agent, 5-fluorouracil (5-FU) served as the mainstay of treatment for patients with advanced colorectal cancer for nearly 45 years [1]. A fluorinated pyrimidine, 5-FU acts by inhibiting thymidylate synthase, an enzyme necessary for the production of thymidine nucleotides required for DNA synthesis. 5-FU is usually given in combination with leucovorin (LV), a biomodulating agent that increases the binding of 5-FU to thymidylate synthase, thereby increasing the inhibition of DNA synthesis and enhancing the antitumor effect of 5-FU. This approach has increased response rates from 11% with 5-FU alone to 23% with 5-FU/LV but has provided no meaningful survival benefit (median survival 11.0 months with 5-FU alone versus 11.5 months with 5-FU/LV) [2]. Attempts to improve the efficacy of 5-FU by administration of protracted continuous infusions also showed a significant increase in response rate to 22%, but again, without improvement in survival beyond one year [3].

Irinotecan (CPT-11, CAMPTOSAR^®, Pharmacia Corporation; Peapack, NJ; CAMPTO^®, Aventis SA, Antony, France), a topoisomerase I inhibitor, offers a mechanism of action completely different from that of 5-FU in the treatment of colorectal cancer. Irinotecan and its metabolites bind to a complex of DNA and topoisomerase I (an enzyme required for unwinding of DNA during replication), inducing DNA strand breaks and consequent tumor cell death [4]. Irinotecan has shown antitumor activity in patients with colorectal cancer when administered alone as first-line therapy [5-8] or as second-line therapy after 5-FU failure [5, 7-9]. In two randomized phase III studies in patients who experienced failure of first-line 5-FU, irinotecan was compared with either best supportive care or with intensive 5-FU-based infusional therapy. Both studies showed a statistically significant survival benefit for patients treated with irinotecan [10, 11]. The activity of irinotecan against untreated and 5-FU-resistant colorectal cancer led to studies of this agent in combination with 5-FU/LV as first-line therapy for this disease.

Recently Douillard et al. and Saltz et al. reported the results of two studies conducted in parallel at a combined total of 154 institutions located primarily in North America and Europe [12, 13]. These studies evaluated irinotecan combined with either bolus (study 1: Saltz) or infusional 5-FU/LV (study 2: Douillard) in previously untreated patients with metastatic colorectal cancer. Both studies demonstrated statistically significant clinical benefits with the irinotecan/5-FU/LV combinations, including improved tumor control and prolonged survival. The major efficacy and safety results of these studies are summarized in this review.

	PATIENTS AND METHODS

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Patient Demographics and Study Design
Both studies were large multinational, multicenter, randomized, open-label, controlled trials with similar inclusion and exclusion criteria. Male or female patients were eligible for enrollment if they were aged 18 years or older (but not more than 75 years for study 2), had a histologic diagnosis of colorectal cancer with unresectable measurable metastases and a performance status of 0-2, and had adequate hematologic, renal, and hepatic function. They could not have received prior chemotherapy for metastatic disease, or 5-FU-based adjuvant chemotherapy during the 12 months (study 1) or six months (study 2) preceding study entry. Patients who had previously undergone pelvic radiotherapy were excluded from study 1, but could enter study 2. All patients provided written informed consent before being enrolled.

In study 1, patients were prospectively stratified according to age (<65 or 65 years), time from initial diagnosis (<6 or 6 months), performance status (0 or 1-2), and prior adjuvant 5-FU-based therapy (yes or no). The patients were then randomized to one of three treatment regimens: irinotecan/bolus 5-FU/LV, bolus 5-FU/LV, or irinotecan alone. The treatment scheme for study 1 is depicted in Figure 1. In study 2, each study site chose one of two infusional regimens for administration of 5-FU/LV according to local clinical practice or preference, i.e., either the once-weekly regimen of the Arbeitsgemeinschaft Internische Onkologie (AIO) cooperative German group for oncology [14] (designated A1 and B1 in Fig. 1), or the every-two-week regimen of de Gramont [15] (designated as A2 and B2 in Fig. 1). Once a site selected its preferred regimen (either AIO or de Gramont), patients at the site were randomized to receive that method of 5-FU/LV administration, with or without irinotecan. After initial treatment, doses in all treatment arms of both studies could be adjusted according to specified guidelines to accommodate individual patient tolerance to the study drugs [12, 13]. Treatment was continued until tumor progression, the occurrence of unacceptable toxicity, or the patient withdrew consent.

View larger version (28K): [in this window] [in a new window]   Figure 1. Treatment regimens for studies 1 and 2.

	EVALUATIONS

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The major clinical efficacy endpoints were similar in the two studies; both evaluated objective tumor response rates, time to tumor progression (TTP), and survival. In study 1, tumor measurements were obtained every six weeks until week 24, and then every 12 weeks until the end of study treatment. In study 2, tumor measurements were obtained after each chemotherapy cycle (every six to seven weeks) and at the end of study treatment. Objective tumor responses were confirmed at least four weeks after the first documentation of response. In both studies, quality of life (QOL) was measured at the start of each treatment cycle using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Following completion of study drug treatment, data were collected on post-study treatment for colorectal cancer and on survival.

Safety was evaluated in terms of adverse events, laboratory abnormalities, and deaths. Adverse-event assessments and complete blood counts were performed weekly, and chemistry studies were performed at the beginning of each chemotherapy cycle.

	STATISTICAL METHODS

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In study 1, a sample size of 220 patients per treatment arm was considered necessary to detect a 40% improvement in TTP (i.e., median TTP from five to seven months) in the irinotecan/5-FU/LV arm versus the 5-FU/LV arm with a power of 85% (two-tailed unstratified log-rank test, alpha of .05). In study 2, assuming a response rate of 35% for the 5-FU/LV arm and 50% for the irinotecan/5-FU/LV arm, a total of 338 evaluable patients (169 per arm) was considered necessary to provide 80% power to detect a significant difference in response rate (two-tailed chi-square test, alpha of .05). In the statistical comparison of irinotecan/5-FU/LV versus 5-FU/LV, results for patients who received regimens A1 and A2 were combined, as were results from patients treated with B1 and B2.

For both studies, time-to-event endpoints (e.g., duration of response, TTP, survival) were analyzed by Kaplan-Meier curves and unstratified log-rank tests. Response rates were compared using chi-square tests. The influence of stratification factors and other baseline characteristics on confirmed objective tumor response rates were assessed using multiple logistic regression modeling. Similarly, TTP and survival were assessed using Cox proportional hazard regression modeling. Changes in QOL subscale scores were assessed using analysis of variance for repeated measures. In study 1, worst changes from baseline were compared with Student's t-tests.

Irinotecan alone was included as a third treatment arm in study 1 only to document the efficacy and safety associated with its first-line single-agent use; consequently no hypotheses regarding its comparative efficacy were tested.

	RESULTS

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Patients
The studies enrolled a combined total of 1,070 patients treated at 154 multinational sites. A small number of patients were untreated or received a treatment regimen to which they were not originally randomized. Table 1 summarizes the populations for the two studies.

With respect to baseline laboratory values, carcinoembryonic antigen (CEA) and total bilirubin levels were generally similar across the two studies. However, there were notably greater proportions of patients with a depressed hemoglobin level, elevated WBC, or abnormal serum lactate dehydrogenase (LDH) in study 1 than in study 2. These laboratory abnormalities are consistent with the performance status findings, possibly indicating greater tumor burden or tumor-related organ dysfunction among the patients in study 1.

	EFFICACY

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Efficacy data for studies 1 and 2 are summarized in Table 3. Remarkable consistency between the studies was observed when examining the efficacy outcome measures.

	RESPONSE RATES

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CEA
Serum CEA was assessed systematically during study 1. CEA response (50% decrease from baseline in serum CEA during treatment) was evaluated in patients with elevated baseline CEA values and at least one CEA assessment while on treatment. The CEA response rate with irinotecan/ 5-FU/LV was substantially higher than with 5-FU/LV; this difference was significant (p < .001) (Table 3).

TTP
TTP was significantly longer in both studies for patients who received irinotecan/5-FU/LV than for those who received 5-FU/LV (study 1: median 7.0 months versus 4.3 months, p = .004; study 2: median 6.7 months versus 4.4 months, p < .001). As in the case of response rate, TTP was universally improved in all patient subgroups [16]. Kaplan-Meier TTP curves for both studies are shown in Figure 2.

View larger version (17K): [in this window] [in a new window]   Figure 2. TTP—Kaplan-Meier estimates from two phase III studies.

View larger version (18K): [in this window] [in a new window]   Figure 3. Survival—Kaplan-Meier estimates from two phase III studies.

Single-Agent Irinotecan Results
A single-agent irinotecan arm was included in study 1 only to document the activity of this agent as monotherapy. Efficacy results in this arm of the study appeared generally similar to those observed with 5-FU/LV alone (Table 3).

Post-Study Treatment
Over 90% of the patients had follow-up information regarding post-study anticancer therapy. In study 1, 52% of these patients in the irinotecan/5-FU/LV-treated arm received some form of second-line therapy, compared with 70% in the 5-FU/LV-treated arm. For 56% of the patients in the 5-FU/LV arm, this second-line regimen consisted of irinotecan as a single agent or in combination. In study 2, 49% of patients in the irinotecan/5-FU/LV arm received post-study therapy compared with 65% of those in the 5-FU/LV arm. In this study, 34% of the 5-FU/LV-treated patients given post-study chemotherapy received second-line irinotecan (Table 4).

	SAFETY

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The most frequently occurring adverse effects noted in studies 1 and 2 are shown in Table 6. For study 2, this review focuses on the safety data from the FDA-approved de Gramont irinotecan/5-FU/LV regimen and the corresponding 5-FU/LV control. In both studies, approximately 23% of patients treated with the combination irinotecan/5-FU/LV regimens experienced grade 3-4 diarrhea compared with approximately 10% to 14% of patients receiving 5-FU/LV alone. This difference was primarily in the incidence of grade 3 diarrhea; grade 4 diarrhea was comparably infrequent in the treatment and control arms of the two trials; for example, in study 1, the incidence was 8% in the irinotecan/5-FU/LV arm and 7% in the 5-FU/LV arm. As expected, grade 3-4 vomiting was somewhat more common with irinotecan-based therapy but occurred in <10% of patients in any of the combination arms.

For neutropenia, only grade 4 events are usually associated with clinical consequences. Of interest, the frequency of grade 4 neutropenia with combination irinotecan/5-FU/LV therapy (24%) in study 1 was essentially half that observed in patients receiving 5-FU/LV in the control group (43%) and proportionately fewer patients experienced neutropenic fever when contrasting irinotecan/5-FU/LV (7%) with 5-FU/LV (15%). In study 2, where schedules of chemotherapy administration were similar, grade 4 neutropenia was more frequently seen when irinotecan was added to 5-FU/LV (10%) than with 5-FU/LV alone (1%). The incidence of neutropenic fever was also higher in the irinotecan/5-FU/LV arm (5.0%) than in the 5-FU/LV arm (1%); however, these rates of neutropenic complications are quite low when contrasted with many other chemotherapy regimens [21].

Discontinuations due to adverse events were acceptably low across all arms of both studies. The incidence of treatment-related death ranged from 0% to 1% in all treatment groups.

	QOL

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The primary repeated measures analyses of variance of changes from baseline in QOL in both studies showed no significant differences between the treatment arms. In study 1, results were significantly better with irinotecan/5-FU/LV than with 5-FU/LV when comparing worst changes from baseline for the subscales of role functioning, fatigue, appetite loss, and pain [22]. In study 2, deterioration of performance status occurred later in patients treated with the irinotecan combination than in those treated with 5-FU/LV alone (median 11.2 months versus 9.9 months, p = .046).

	DISCUSSION

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Attempts to improve outcome in patients with metastatic colorectal cancer with modified 5-FU-based regimens, while generally resulting in higher response rates, have failed to significantly improve survival [3, 4]. However, the results of recent studies of the topoisomerase I inhibitor irinotecan have improved the outlook for patients with this disease. In these studies, irinotecan was shown to improve survival, first as single-agent second-line therapy [10, 11], and now as a component of first-line treatment with 5-FU/LV [12, 13, 17].

The two phase III randomized multicenter, multinational, controlled studies reviewed here compared the efficacy and safety of new combinations of irinotecan/5-FU/LV to that of traditional regimens of 5-FU/LV given as first-line therapy of metastatic colorectal cancer. The studies were similar in that they enrolled analogous patient populations, evaluated similar efficacy and safety endpoints, and applied standardized methods of analysis. The trials were complementary in that they assessed the use of irinotecan in combination with two different methods of 5-FU/LV administration (bolus and infusional therapy). Study 1 compared a new combination of irinotecan/bolus 5-FU/LV with that of the Mayo Clinic regimen of bolus 5-FU/LV that had been most widely employed in North America. Study 2 symmetrically determined the therapeutic ratio associated with adding irinotecan to two different infusional 5-FU/LV regimens that were widely used in Europe. Because the comparator regimens have been commonly used in oncology practices worldwide, the two studies provide clinicians with insights into the efficacy and safety of the new combinations relative to familiar standards.

The efficacy results of the two studies were remarkably consistent and show that the combination of irinotecan with 5-FU provides patients with significant reductions in tumor size in conjunction with prolonged suppression of tumor growth. The confirmed objective response rates with the irinotecan/5-FU/LV arms (39% and 35%) were 1.5 to 2 times those in the 5-FU/LV arms (21% and 22%), and these differences were statistically significant. In studies 1 and 2, respectively, TTP was significantly improved with combination treatment (medians, 7.0 and 6.7 months) relative to treatment with 5-FU/LV alone (medians, 4.3 and 4.4 months). Assessment of response rates and TTP across demographic and disease-related subgroups showed improvements with irinotecan-based combination therapy in all prospectively defined subgroups [16]. These results indicate that irinotecan/5-FU/LV has the potential to offer better tumor control to all patients who are eligible for first-line combination chemotherapy.

The most important finding of the studies was that first-line irinotecan/5-FU/LV combination treatment provided a statistically significant survival advantage. It is particularly noteworthy that this advantage occurred even though most control patients received second-line irinotecan therapy after on-study failure of 5-FU/LV. These results suggest that early combination irinotecan/5-FU/LV may be superior to sequential administration of first-line 5-FU followed by second-line irinotecan. The combination therapy survival outcomes noted among patients with good performance status accentuate this observation [16]. Such findings were presaged by the results of a prior study in metastatic colorectal cancer in which early administration of chemotherapy before symptom development was compared with delayed treatment after symptom development; as in the current experience, early therapy in that study resulted in significantly better survival [23].

Cox regression modeling, which assessed treatment effect adjusted for significant prognostic factors, provided further evidence that combination therapy with irinotecan/5-FU improves TTP and survival. This analysis indicated that irinotecan/5-FU/LV treatment resulted in an approximate 40% reduction in the relative risk of tumor progression and a 20% decrease in the relative risk of death.

In both studies, gastrointestinal toxicities were more common with combination treatment, but grade 4 diarrhea— largely defined by the need for hospitalization for supportive care—was infrequent (<8%). In study 1, grade 4 neutropenia, neutropenic fever, and mucositis were observed less often with weekly irinotecan/5-FU/LV than with Mayo Clinic bolus 5-FU/LV alone; data from other studies that compared weekly versus monthly 5-FU/LV therapy [24, 25] suggest that this reduced toxicity with combination therapy is most likely due to the differences in 5-FU/LV scheduling between the arms. In study 2, clinically relevant grade 3 and 4 events, e.g., vomiting, mucositis, and neutropenic fever, were infrequent with the de Gramont irinotecan/5-FU/LV regimen. The safety findings were supported by the results of the QOL analyses, which showed that administration of irinotecan in combination with 5-FU/LV did not result in significant worsening of QOL.

Attempts to improve outcomes in patients with metastatic colorectal cancer with the limited tools of 5-FU and LV have been the source of decades of frustration and disappointment. Irinotecan has now broken the barrier to improved survival, first as single-agent second-line therapy, and now as a component of first-line combination treatment. The studies discussed here are the first trials to document that the combination of a new agent with 5-FU/LV can safely benefit patients with metastatic colorectal cancer by inducing tumor shrinkage, extending tumor control, and significantly prolonging life without an impairment of QOL. The strength and consistency of the data from these large complementary studies led the FDA's Oncology Drug Advisory Committee (ODAC) to conclude that irinotecan/5-FU/LV should be the reference standard against which future first-line therapies for metastatic colorectal cancer are compared.

Given the positive findings in patients with metastatic disease, several trials in the U.S. and Europe are comparing irinotecan/5-FU/LV with 5-FU/LV as adjuvant therapy for patients with stage III colon cancer; it is hoped that the addition of irinotecan to 5-FU/LV will offer an increased opportunity for cure in patients with early-stage disease.

Related articles in The Oncologist: Irinotecan: A New Agent Comes of Age. Saltz LB. The Oncologist 2001;6:65. Irinotecan (CPT-11): Recent Developments and Future Directions–Colorectal Cancer and Beyond. Rothenberg ML. The Oncologist 2001;6:66-80.

 

	ACKNOWLEDGMENTS

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The work described in this publication was supported by grants from Pharmacia Corporation, Peapack, NJ, and Aventis SA, Antony, France.

L.S. and J-Y.D. have received major research support and honoraria as consultants for both Pharmacia Corporation and Aventis Corporation.

	REFERENCES

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1. Mayer RJ. Moving beyond fluorouracil for colorectal cancer. N Engl J Med 2000;343:963-964.[Free Full Text]
2. Advanced Colorectal Cancer Meta-analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992;10:896-903.[Abstract]
3. Meta-analysis Group in Cancer. Efficacy of IV continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-308.[Abstract/Free Full Text]
4. Pommier Y, Tanizawa A, Kohn KW. Mechanisms of topoisomerase I inhibition by anticancer drugs. In: Liu LF, ed. Advances in Pharmacology. New York: Academic Press, 1994;29B:73-92.
5. Shimada Y, Yoshino M, Wakui A et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 1993;11:909-913.[Abstract/Free Full Text]
6. Conti JA, Kemeny NE, Saltz LB et al. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996;14:709-715.[Abstract/Free Full Text]
7. Pitot HC, Wender DB, O'Connell MJ et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 1997;15:2910-2919.[Abstract]
8. 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 1997;15:251-260.[Abstract/Free Full Text]
9. Rothenberg ML, Cox JV, DeVore RF et al. A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 1999;85:786-795.[CrossRef][Medline]
10. Cunningham D, Pyrhonen 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 1998;352:1413-1418.[CrossRef][Medline]
11. Rougier P, Van Cutsem E, Bajetta E et al. Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998;352:1407-1412.[CrossRef][Medline]
12. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905-914.[Abstract/Free Full Text]
13. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-1047 [Erratum, Lancet 2000;355:1372].
14. Köhne CH, Schöffski P, Wilke H et al. Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 1998;16:418-426.[Abstract]
15. 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 1997;15:808-815.[Abstract/Free Full Text]
16. Knight RD, Miller LL, Pirotta N et al. First-line irinotecan (C), fluorouracil (F), leucovorin (L) especially improves survival (OS) in metastatic colorectal cancer (MCRC) patients (PT) with favorable prognostic indicators. Proc Am Soc Clin Oncol 2000;19:991a.
17. Saltz LB, Douillard J, Pirotta N et al. Combined analysis of two phase III randomized trials comparing irinotecan (C), fluorouracil (F), leucovorin (L) versus F alone as first-line therapy of previously untreated metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 2000;19:242a.
18. Kemeny N, Niedzwiecki D, Shurgot B et al. Prognostic variables in patients with hepatic metastases from colorectal cancer. Importance of medical assessment of liver involvement. Cancer 1989;63:742-747.[CrossRef][Medline]
19. Rougier P, Milan C, Lazorthes F et al. Prospective study of prognostic factors in patients with unresected hepatic metastases from colorectal cancer. Br J Surg 1995;82:1397-1400.[Medline]
20. Miller LL, Petit RG, Elfring GL. Evaluation of carcinoembryonic antigen (CEA) levels during CPT-11 treatment of patients with previously treated colorectal cancer. Proc Am Soc Clin Oncol 1998;17:297a.
21. American Society of Clinical Oncology. American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1994;12:2471-2508.[Abstract/Free Full Text]
22. Locker PK, Miller LL, Pirotta N et al. Weekly irinotecan (C) combined with 5-fluorouracil (F) and leucovorin (L) in patients with untreated metastatic colorectal cancer (MCRC): impact on quality of life. Proc Am Soc Clin Oncol 2000;19:620a.
23. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. J Clin Oncol 1992;10:904-911.[Abstract]
24. 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 1994;12:14-20.[Abstract]
25. 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 1995;13:1303-1311.[Abstract]

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