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Irinotecan/Fluorouracil Combination in First-Line Therapy of Older and Younger Patients With Metastatic Colorectal Cancer: Combined Analysis of 2,691 Patients in Randomized Controlled Trials

Gunnar Folprecht, Matthew T. Seymour, Leonard Saltz, Jean-Yves Douillard, Hartmut Hecker, Richard J. Stephens, Timothy S. Maughan, Eric Van Cutsem, Philippe Rougier, Emmanuel Mitry, Ute Schubert, Claus-Henning Köhne

From the University Hospital Dresden; Medical School Hannover; and Klinikum Oldenburg, Germany; Cancer Research UK Clinical Centre, Cookridge Hospital, Leeds; Medical Research Council Clinical Trials Unit, London; and Velindre Hospital, Cardiff, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, NY; Centre R Gauducheau, St. Herblain; and Hôpital Ambroise Paré, Boulogne, France; and the University Hospital Gasthuisberg, Leuven, Belgium

Corresponding author: Gunnar Folprecht, MD, University Hospital Dresden, Fetscherstr 74, Dresden, Germany 01307; e-mail: gunnar.folprecht{at}uniklinikum-dresden.de

	ABSTRACT

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Purpose Uncertainty exists about whether elderly patients benefit to the same extent as younger patients from combination therapy with irinotecan in the first-line treatment of metastatic colorectal cancer (CRC).

Patients and Methods Combined analysis was carried out with source data from the fluorouracil (FU)/folinic acid (FA) and the irinotecan/FU/FA arms of four first-line, phase III trials of CRC to investigate the efficacy and safety of combination and monotherapy in elderly (age 70 years; n = 599) compared with younger (age < 70 years; n = 2,092) patients.

Results Response rates were improved with irinotecan-based combination therapy compared with FU/FA in patients both younger than 70 years and 70 years (46.6% v 29.0% P < .0001; and 50.5% v 30.3%, P < .0001, respectively). With irinotecan/FU/FA, progression-free survival was better for both younger (hazard ratio [HR], 0.77; 95% CI, 0.70 to 0.85; P < .0001) and elderly patients (HR, 0.75; 95% CI, 0.61 to 0.90; P = .0026). In younger patients, overall survival was improved with combination therapy (HR, 0.83; 95% CI, 0.75 to 0.92; P = .0003). The same trend was observed in elderly patients (HR, 0.87; 95% CI, 0.72 to 1.05; P = .15). There was no significant interaction between treatment arm and age in the regression analysis. The expected differences in toxicity between combination and monotherapy in elderly and younger patients were observed. A significant interaction between treatment and age (cutoff, 70 years) for vomiting and hepatotoxicity was not confirmed by analysis that used age as a continuous variable.

Conclusion Patients older than 70 years of age who were selected for inclusion in phase III trials derived similar benefits as younger patients from irinotecan-containing chemotherapy, and the risk of toxicity was similar.

	INTRODUCTION

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Combination of the newer cytotoxic drugs, oxaliplatin or irinotecan, with fluorouracil (FU)/folinic acid (FA) in the first-line therapy of metastatic colorectal cancer (CRC) has been associated in randomized clinical trials with an increase in the median overall survival of patients, from 8.5 months with the best supportive care¹ to more than 20 months.^2-5 Further improvements in efficacy were achieved when therapeutic antibodies were combined with chemotherapy.^6-8 These advances in treatment capability are especially important, because CRC is the second most common cause of cancer death in Europe and North America.⁹ However, the probability of generalizing the outcome of such trials to the community practice setting is not quantifiable, because the median age of patients enrolled on such studies is typically 10 years younger than the median age at first diagnosis in the wider patient population (eg, 71 years in the United States¹⁰). Indeed, CRC was reported to be the most common cancer in the United States in patients who were 75 years.¹¹

As a consequence of the lower representation of elderly patients in clinical trials, our knowledge of the performance of therapeutic regimens in this age group is often severely limited. Age limits in the inclusion criteria, comorbidity conditions, functional status, concerns regarding toxicity, and logistical reasons relating to the lack of social support for some elderly patients are all common and potential barriers to enrollment.¹² Presumably for similar reasons, this lower use of chemotherapy for elderly patients also extends to those treated outside clinical trials in community settings.^13,14

Combined analyses of data accrued from prospective clinical studies and inquiries to cancer registries have been used previously to investigate meaningful numbers of elderly patients. For instance, in a pooled analysis of patient data from seven randomized, phase III trials of patients with colon cancer, Sargent et al¹⁵ were able to show that selected elderly patients older than 70 years derived the same benefit from FU-based adjuvant therapy as younger patients without a relevant increase in toxic effects.

A prospective analysis by Popescu et al¹⁶ of 844 patients with advanced CRC who received first-line chemotherapy, comprised of an FU-containing regimen or raltitrexed, revealed that elderly patients with good performance status (PS) tolerated the chemotherapy as well as younger patients and derived similar benefits. However, there was a higher rate of grade 3 to 4 stomatitis reported in this study in elderly patients with CRC who received adjuvant therapy (P = .02). Subsequently, we showed in a pooled analysis of 3,825 patients who had received an FU-containing treatment in clinical trials that patients 70 years derived similar benefits from treatment in relation to efficacy and, further, that the benefit of infusional compared with bolus FU can be observed in elderly and younger patients.¹⁷

Although the combination of irinotecan with FU/FA has been shown to improve response rates and progression-free survival in four randomized studies and has shown a significant overall survival benefit in two, the gain in efficacy was associated with increased toxicity.^3,5,18 Against such a background, specific data regarding the efficacy and toxicity of irinotecan combinations in elderly patients are especially important. Our pooled analysis was undertaken to extend earlier observations and to consider the relative performance of FU/FA/irinotecan combinations compared with FU/FA alone in both elderly ( 70 years) and younger (< 70 years) patients.

	PATIENTS AND METHODS

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Source data from four randomized trials that compared FU/FA with or without irinotecan in first-line therapy were available.^3,5,18,19 The studies were open for recruitment from 1996 to 2003. Patients who had received first-line FU/FA or irinotecan/FU/FA treatment were included in our analysis.

For the purpose of this evaluation, patients were placed into two age groups: elderly ( 70 years) and younger (< 70 years) patients. Differences in proportional values were investigated by using the ² test. Kaplan-Meier plots and log-rank tests were used to examine differences in progression-free and overall survival. Corrections for multiple testing were not performed.

A logistic or Cox regression analysis was performed to explore the influence of age (as a categoric variable) and treatment arm (FU/FA v irinotecan/FU/FA) with regard to efficacy (response rate, progression-free survival, and overall survival), and a test of interaction between age and treatment was performed. PS (0, 1, > 1), number of tumor sites (1 v > 1), white blood cell count ( 10 v > 10 x 10⁹/L), level of alkaline phosphatase ( 300 v > 300 U/L), and lactate dehydrogenase level ( 250 v > 250 U/L) were used as covariates. Furthermore, the influence of age on the incidence of toxicity (grade 3) and the interaction between treatment and age with regard to toxicity (grade 3) were investigated in a logistic regression analysis.

Sixty-day mortality was calculated from Kaplan-Meier estimates and was compared with the ² test. A non–preplanned subgroup analysis was performed for the group of patients 75 years who were compared with the younger patient group (< 70 years). Data were analyzed using SPSS 12.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Study Population
The numbers of patients included from each individual study and their age distributions are listed in Table 1. One study compared bolus FU/FA with irinotecan/bolus FU/FA.¹⁸ In three studies, infusional FU/FA regimens (LV5FU2 [bimonthly leukovorin and FU],³ Arbeitsgemeinschaft Internistische Onkologie [AIO],^3,5 and simplified LV5FU2¹⁹) were investigated in comparison with their combinations with irinotecan. In total, 2,691 patients were eligible for consideration. A total of 599 patients (22.3%) were 70 years; 185 of these (6.9% of the total population) were 75 years. Patients who were 80 years were rare (< 1% of the entire group).

The ² tests to compare toxicities between elderly and younger patients were not significant. The 60-day mortality (4.1% v 4.2% for younger patients with or without irinotecan, respectively, and 6.4% v 3.7%, respectively, in the elderly population) was not significantly different (P = .43).

In the subgroup of older elderly patients ( 75 years), an exploratory analysis was performed, which revealed only one significant difference in comparison to younger patients: a greater rate of severe neutropenia in the FU/FA group (24.3% v 16.1%, P = .038). On comparison of the two treatment arms within this subgroup, significantly more nausea, vomiting, and diarrhea were observed in the FU/FA/irinotecan arm. No tests were performed for infection, thrombosis, and hepatic toxicity in patients aged 75 years because of the low patient number.

Efficacy
Efficacy comparisons were made for response rate, progression-free survival, and overall survival between elderly and younger patients within the treatment groups and between treatment arms (FU/FA alone v FU/FA/irinotecan) within the age groups (Table 4; Figs 1A, 1B, 1C, and 1D). In a comparison of the age groups, no differences between younger and elderly patients were found for response rate or overall survival. Progression-free survival was significantly longer for the elderly than for the younger patients in both treatment arms (9.2 months v 8.2 months with irinotecan/FU/FA, P = .041; and 7.0 months v 6.3 months with FU/FA, P = .022, respectively).

View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival (OS) and progression-free survival (PFS) according to treatment arm (irinotecan/fluorouracil [FU]/folinic acid [FA] or FU/FA) are shown for age groups (A) < 70 and (B) 70 years. Age group comparisons are shown for (C) irinotecan/FU/FA and (D) FU/FA.

When the treatment arms were compared, significantly greater response rates and a significantly longer progression-free survival were observed with irinotecan/FU/FA in both age groups (< 70 and 70 years; Table 4; Figs 1A and 1B). Overall survival was significantly longer with combination therapy in younger patients. In the age group 70 years, this trend did not reach the level of statistical significance (Table 4; Figs 1A and 1B).

In elderly patients, the overall survival curves for combination and monotherapy did not separate during the first months of treatment. Therefore, we calculated the Kaplan-Meier plots in relation to the FU administration route, which showed a trend toward an unfavorable survival in elderly patients with irinotecan plus bolus FU (Fig 2A). In contrast, this trend was not observed in the elderly patients who received infusional FU (hazard ratio [HR] for this subgroup, 0.82; 95% CI, 0.66 to 1.01; P = .058).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Overall survival (OS) in elderly patients ( 70 years) in relation to treatment arm (with or without irinotecan) and FU administration (bolus or infusion). (B) Subgroup analyses showing OS and progression-free survival (PFS) according to treatment arm (irinotecan/fluorouracil [FU]/folinic acid [FA] or FU/FA) for patients 75 years.

	DISCUSSION

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Both irinotecan- and oxaliplatin-based combinations with FU/FA are now accepted as standard first-line therapy for metastatic CRC. Further improvements may be expected from the inclusion of monoclonal antibodies and other targeted agents into these regimens. However, considering the increased levels of toxicity associated with combination therapy, it is uncertain whether elderly patients derive a substantial net benefit from this type of more intensive treatment, especially with respect to regimens that incorporate irinotecan. In accordance with the outcome of phase III trials,^20,21 the prescription information for irinotecan recommends a lower dose in elderly patients if this agent is used as monotherapy. However, Chau et al²² showed that the toxicity of irinotecan monotherapy was not significantly worse in 72 elderly patients compared with 267 younger patients.

Specific trials conducted to investigate the use of irinotecan in elderly patients are rare. A Spanish group performed a phase II study with irinotecan, infusional FU, and leucovorin in 85 patients who had a median age of 77 years.²³ A smaller study is reported by Souglakos et al²⁴ (30 patients with irinotecan, infusional FU, and leucovorin as first-line therapy). These trials have been reviewed recently and have supported the conclusion that there are no data to justify the dose modification of irinotecan in elderly patients.²⁵

To overcome the lack of adequately powered studies in elderly patients, we performed a combined analysis of source data from four clinical trials to examine the efficacy and tolerability of irinotecan/FU/FA compared with FU/FA alone. The resulting database included clinical information about 2,691 patients and allowed investigations of the influence of age on toxicity and efficacy and of the interaction between age and treatment. This large cohort, which included 599 patients 70 years, comprises, to our knowledge, the largest database of elderly patients with metastatic CRC to compare FU with combination therapy. The proportion of elderly patients in the current analysis (22%) is lower than in the general CRC patient population²⁶ but is comparable to similar studies that have investigated FU-containing chemotherapy in metastatic CRC.^16,17 This difference is explained by the greater comorbidity, impaired functional or mental status, or logistical reasons that result in the exclusion of elderly patients from participation in clinical trials.

The most important finding of the current analysis was that no interaction was identified, in relation to the efficacy of treatment and patient age, by using a statistical model that included the most important risk factors.²⁷ Considering the large number of patients analyzed in this study, it can be concluded that elderly patients ( 70 years) have the same benefit from irinotecan-containing combination therapy as younger patients. The current analysis therefore complements the earlier reports of adjuvant and first-line CRC studies, which have suggested that treatment benefits for elderly patients who received FU-based therapies were essentially comparable to those derived by younger patients.^15-17,28 It is also in accordance with a recent analysis of pooled data from four trials that investigated infusional FU/FA/oxaliplatin in different lines of therapy for CRC (614 patients 70 years, and 51% of those in the adjuvant setting), which found no interaction between treatment and age regarding efficacy but found slightly greater rates of grade 3 neutropenia and thrombocytopenia (P = .04).²⁹

When elderly and younger patients were compared in the current analysis, the only significant difference with respect to efficacy was a marginally longer progression-free survival in the elderly patient group. This observation is known from a former analysis of FU-containing schedules¹⁷ but has limited clinical relevance. PS, an important prognostic factor, showed an imbalance at baseline, in that there were more patients at PS1 in the FU/elderly group. This was included in the statistical model of the regression analysis. In contrast, the primary site is markedly less important for prognosis,²⁷ and the imbalance in this criterion was therefore deemed unlikely to have a major influence on the results.

The safety analysis addressed the question of whether elderly patients experienced greater levels of toxicity than younger patients. However, in the pooled analysis of all trials, early mortality in elderly patients was not significantly increased with combination therapy compared with monotherapy (6.4% v 3.7%). Hepatic toxicity was increased in elderly patients, especially in the FU/FA arm, and may be related to greater FU doses in the monotherapy arm. The dose-intensity was not available for analysis. However, hepatic toxicity is not the most relevant problem in clinical practice. The tendency towards less vomiting in elderly patients who received FU/FA might reflect a selection bias in study recruitment towards fit elderly patients. However, this observation might be an effect of multiple testing, especially because a significant interaction or influence was not confirmed by the analysis with age as a continuous variable. Age had influence on the occurrence of diarrhea but only in the analysis as a continuous parameter. One possible explanation is that there is an increased rate of diarrhea in older patients ( 75 years, Table 3). An additional influence of age on toxicity was not observed.

Interestingly, the subgroup of elderly patients who received irinotecan with bolus FU had a trend toward inferior overall survival during the first months of therapy compared with those who received irinotecan with infusional FU/FA. Indeed, the survival curve for the bolus FU group was lower than those curves for infusional or bolus FU/FA alone. In an independent review of studies that involved this combination, Rothenberg et al³⁰ noted an excess of treatment-associated early deaths in patients who received bolus FU/FA/irinotecan. The deaths were associated with the occurrence of multiple gastrointestinal toxicities and/or sudden unexpected thromboembolic events, and they occurred especially in elderly patients. Such an incidence of early deaths was not observed when the FU component of the combination was delivered to CRC patients infusionally.³¹ Our data do not support the further use of bolus FU with irinotecan in elderly patients. Other recent data have clarified that the bolus FU with irinotecan regimen should no longer be used in any patient.^32,33

In considering the outcome of this study, several possible confounding factors should be noted. First, the conclusions are formally valid only for the relatively fit subgroup of elderly patients who not only fulfilled the particular study inclusion criteria but were actually subsequently enrolled onto the clinical trials. Second, most of the patients were treated with infusional FU regimens (with or without irinotecan); therefore, safety concerns cannot be excluded for the irinotecan/bolus FU/FA regimens. Third, the majority of elderly patients were younger than 75 years, which is similar to some clinical trials designed for elderly patients.³⁴ Reports of larger cohorts of patients with CRC who are 75 years, in which comorbidities and restriction of PS play an even more important role, are rare. This relatively large cohort of 166—probably highly-selected—patients 75 years showed clearly that overall response was improved with combination therapy and that the HR for progression-free survival was similar to that for younger patients. However, uncertainty remains as to whether these older patients benefit from combination therapy with regard to overall survival (Fig 2B), as the patient number is still too small. A similar result was found in the British FOCUS2 trial, which enrolled 460 frail and elderly patients in a two-by-two factorial design onto an investigation of fluoropyrimidine ± oxaliplatin, and which included the substitution of infusional FU with capecitabine. Despite improved response rates and a trend to longer progression-free survival with oxaliplatin-based combination therapy, the quality of life was impaired with combination treatment compared with FU alone.³⁵ Overall survival was not the primary end point in the FOCUS2 trial, but the difference was limited (HR, 0.94).³⁵

The reason for these observations remains unclear, and it should be emphasized again that age alone had no interaction with treatment effect. Therefore, it can be speculated that increasing comorbidities even in these highly selected patients 75 years contributed to the overlapping survival curves.

Despite these limitations, our data show that fit elderly patients should not be excluded from combination chemotherapy with irinotecan simply on the grounds of advanced age. However, further investigation is especially important in frail patients, and the conclusions of this manuscript should not be extrapolated to patients with significant medical comorbidities or with a compromised PS. The recent FOCUS2 trial³⁵ showed that studies are feasible in this patient group. For both clinical practice and clinical trial design, the overall medical fitness of the patient, not the chronologic age, should be considered in the selection of appropriate therapy and therapeutic trial designs.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Matthew T. Seymour, Pfizer (C); Leonard Saltz, Bristol-Meyers Squibb (C), Imclone (C), Genentech (C), Bayer (C); Jean-Yves Douillard, Pfizer (C), Sanofi-aventis (C), Roche (C); Eric Van Cutsem, Pfizer (C); Emmanuel Mitry, Pfizer (C); Claus-Henning Köhne, Pfizer (C) Stock Ownership: None Honoraria: Gunnar Folprecht, Merck, Pfizer, Sanofi-aventis; Jean-Yves Douillard, Pfizer, Sanofi-aventis, Roche; Timothy S. Maughan, Pfizer; Emmanuel Mitry, Pfizer, Sanofi-aventis; Claus-Henning Köhne, Pfizer Research Funding: Gunnar Folprecht, Merck, Sanofi-aventis; Leonard Saltz, Pfizer, Bristol-Meyers Squibb, Genentech, Imclone, Roche, Taiho, Amgen, Bayer; Eric Van Cutsem, Pfizer; Claus-Henning Köhne, Pfizer Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Gunnar Folprecht, Matthew T. Seymour, Eric Van Cutsem, Claus-Henning Köhne

Administrative support: Gunnar Folprecht, Claus-Henning Köhne

Provision of study materials or patients: Matthew T. Seymour, Leonard Saltz, Jean-Yves Douillard, Richard J. Stephens, Timothy S. Maughan, Eric Van Cutsem, Philippe Rougier, Emmanuel Mitry, Claus-Henning Köhne

Collection and assembly of data: Gunnar Folprecht, Matthew T. Seymour, Richard J. Stephens, Timothy S. Maughan, Ute Schubert, Claus-Henning Köhne

Data analysis and interpretation: Gunnar Folprecht, Matthew T. Seymour, Leonard Saltz, Jean-Yves Douillard, Hartmut Hecker, Richard J. Stephens, Timothy S. Maughan, Eric Van Cutsem, Claus-Henning Köhne

Manuscript writing: Gunnar Folprecht, Claus-Henning Köhne

Final approval of manuscript: Gunnar Folprecht, Matthew T. Seymour, Leonard Saltz, Jean-Yves Douillard, Hartmut Hecker, Richard J. Stephens, Timothy S. Maughan, Eric Van Cutsem, Philippe Rougier, Emmanuel Mitry, Ute Schubert, Claus-Henning Köhne

	ACKNOWLEDGMENTS

 
We thank Jim Heighway for editorial support.

	NOTES

 
Supported by Pfizer.

Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2-5, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 16, 2007; accepted October 15, 2007.

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