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Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4085-4091 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9039 Pooled Analysis of Safety and Efficacy of Oxaliplatin Plus Fluorouracil/Leucovorin Administered Bimonthly in Elderly Patients With Colorectal Cancer
From the University of North Carolina, Chapel Hill, NC; Sanofi-Aventis; Hôpital Saint Antoine; Hôpital Tenon, Paris, France; Institut J Bordet, Bruxelles, Belgium; Vanderbilt Hospital, Nashville, TN; and the Mayo Clinic, Rochester, MN. Address reprint requests to Daniel J. Sargent, PhD, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; e-mail: sargent.daniel{at}mayo.edu
Purpose: Oxaliplatin, fluorouracil, and leucovorin are commonly used to treat advanced and resected colorectal cancer. This analysis compares the safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly (FOLFOX4) in patients age younger than and at least 70 years.
Patients and Methods: This retrospective analysis included 3,742 colorectal cancer patients (614 age
Results: Grade Conclusion: FOLFOX4 maintains its efficacy and safety ratio in selected elderly patients with colorectal cancer. Its judicious use should be considered without regard to patient age, although scant data are available among patients older than 80 years.
Colorectal cancer is the world's third most common cancer. Each year, more than 300,000 new cases are diagnosed in the United States and Europe, with more than 800,000 cases worldwide. The incidence of colorectal cancer increases continuously with increasing age. Changing demographics in developed countries, with the elderly representing an increasing proportion of the population, will result in a growing number of cases of colorectal cancer unless screening and prevention measures curtail these trends.1,2 Currently, the median patient age at diagnosis of colorectal cancer in the United States is 72 years. On a daily basis, patients and their physicians make choices about whether to embark on a course of adjuvant chemotherapy designed to eliminate micrometastatic disease after potentially curative surgery, or whether to administer treatment and which treatment to choose for advanced disease. In older patients, the importance that the chosen regimen has an acceptable toxicity profile is accentuated because such individuals may not be as robust as their younger counterparts, and because they may place a different value on the time and logistical challenges relevant to a course of treatment. For years, standard treatment in both adjuvant and palliative settings has been based on fluorouracil (FU). In both settings, this treatment has been shown to be as effective and equally tolerated in elderly patients as in younger patients.3,4 The favorable efficacy and toxicity profile of the commonly used FU/leucovorin (LV5FU2) program, in which fluorouracil is delivered as a 46- to 48-hour infusion, has led many physicians to choose this program over bolus FU-based regimens. The activity of this regimen has been enhanced significantly by combining it with new agents, including the diaminocyclohexane platinum compound oxaliplatin.5 The advantages of this combination have been seen in the adjuvant setting and also in both chemotherapy-naïve and pretreated patients with advanced disease.6-9 Oxaliplatin combined with FU is generally well tolerated, with neutropenia and sensory neuropathy as the most clinically significant and often the dose-limiting toxicities. Despite the increase in incidence of colorectal cancer with age, elderly patients tend to be under-represented in clinical trials.10,11 Physicians choose to whom they offer opportunities to enroll in clinical trials, and age is likely relevant in that decision.12,13 If offered the opportunity, patients then decide whether they wish to enroll in clinical trials; older patients may make those decisions differently than younger individuals. Consequently, individual studies seldom have sufficient numbers of patients older than age 70 to provide adequate data to allow robust conclusions regarding the tolerability and efficacy of specific regimens. To address this practical issue specifically for the oxaliplatin plus fluorouracil/leucovorin administered bimonthly (FOLFOX4) regimen in colorectal cancer, we conducted a retrospective, age-based, pooled analysis using individual patient data from four randomized clinical trials. These studies all administered the same FOLFOX4 regimen. In all four studies, FOLFOX4 was compared with the standard of care at the time for the stage of disease (either FU and leucovorin, or irinotecan plus FU and leucovorin). The four trials formed the basis for the US Food and Drug Administration approval of FOLFOX4 in the treatment of metastatic colorectal cancer (first- and second-line settings) and in the stage III setting (after complete surgical resection).
Study Design A retrospective analysis was conducted using data in the Sanofi-Aventis (Paris, France) database from patients with colorectal cancer enrolled onto four clinical trials using the FOLFOX4 regimen. This chemotherapy regimen calls for oxaliplatin 85 mg/m2 (day 1) plus hybrid bolus and infusional fluorouracil and leucovorin (days 1 and 2) administered bimonthly. The results of these trials have been reported individually previously.6-9 Study A, the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, enrolled 2,246 patients with completely resected stage II/III colon cancer between October 1998 and January 2001.7 Patients age 18 to 75 years were randomly assigned to receive LV5FU2 or FOLFOX4. Final efficacy results on the primary end point, 3-year disease-free survival, have been reported, but overall 5-year survival data have not yet matured. Between August 1995 and July 1997, study B (de Gramont et al6) enrolled a total of 420 patients receiving first-line treatment for advanced colorectal cancer and evaluated the benefit of the addition of oxaliplatin to the LV5FU2 treatment. The main inclusion criteria were advanced adenocarcinoma of the colon or rectum, at least one measurable lesion, no previous treatment with chemotherapy for metastatic disease, adequate organ function, age 18 to 75, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.
Study C (Goldberg et al9) enrolled a total of 795 patients between May 1999 and April 2001. Patients received the standard irinotecan with FU/LV (IFL) regimen or one of two experimental programs, FOLFOX4 alone or irinotecan plus oxaliplatin. The main inclusion criteria were advanced adenocarcinoma of the colon or rectum, at least one measurable or assessable lesion, no previous treatment with chemotherapy for metastatic disease, adequate hepatic and renal function, age
Between November 2000 and February 2002, study D (Rothenberg et al8) enrolled a total of 821 patients,
Statistical Methods Efficacy end points analyzed were response rate, progression or disease-free survival (P/DFS), and overall survival. Response rate was analyzed for the three trials in advanced colorectal cancer (studies B, C, and D). In each of these three trials, the relative benefit of FOLFOX compared with control for response rate was explored using logistic regression. For the end point of P/DFS, all four studies were included in a Cox regression model, stratified for the patient's original study.15 For the three studies in advanced disease, P/DFS was defined as the time to the first event of progression or death, for the adjuvant study, P/DFS was defined as the time to the first of recurrence or death. For all end points, the presence of a treatment-study interaction was tested for by comparing a model with a single treatment term versus a model with a study-specific treatment effect term using a likelihood ratio test. All analyses were conducted using the SAS System version 8.0 (SAS Institute, Cary NC), with P < .05 used to denote statistical significance.
A total of 3,743 patients were enrolled onto the four studies. The trials included 1,567 patients age younger than 70 and 314 patients (16% of the total population) age 70 or older treated with FOLFOX4. Baseline and demographic data are summarized by age group in Table 1. Patient age was well balanced within each study and overall between FOLFOX4 and control groups. Patients age 70 or older were more likely to have PS of 1 or 2 than those younger than 70 (ECOG PS 2, 4% v 2%, respectively; P = .029), although, as expected, few PS 2 patients were enrolled onto these trials. The age distribution of patients was similar across the three clinical settings: adjuvant, first line, and second line (Table 2).
Rates of grade  3 adverse events by age group for patients treated with FOLFOX 4 are listed in Table 3. Significant between-study heterogeneity was observed only for infection. Specifically, the relationship between age and risk of severe FOLFOX4 adverse events did not differ between the adjuvant, first-line advanced-disease, and second-line advanced disease trials for all other toxicities. Hematologic toxicity of grade 3 was more common in elderly patients compared with those age younger than 70, specifically neutropenia (43% age < 70, 49% age 70; P = .04), and thrombocytopenia (2% age < 70, 5% age 70; P = .04). The rates of diarrhea, nausea/vomiting, and fatigue did not differ by age group, nor did the rate of grade 3 neurologic adverse events (14% age < 70, 12% age 70; P = .37). Over all studies, grade 3 infection did not differ by age; however, for study C (Goldberg), infection was more common in younger patients (14% age < 70, 6% age 70; P = .10), whereas in study D infection was more common in older patients (1% age < 70, 7% in age 70; P = .02). Modeling age as a continuous variable increased the statistical significance of the relationship between age and increased neutropenia (P < .0001), and age and increased thrombocytopenia (P < .0001), and the relationship between age and increased fatigue became significant (P = .003). The relationship between increased age and decreased nausea/vomiting also became significant when age was modeled as a continuous variable (P < .001). The fact that these relationships became significant when age was modeled as a continuous variable suggests a modest but real relationship between an increasing event rate and age that increases steadily with age but is not specific to age younger than 70 v 70. In the sensitivity analysis of all adverse events grade 2, no significant association between adverse events and age was observed for any adverse event type (data not shown).
The rates of any grade 3 adverse event and any grade 3 nonhematologic adverse event did not differ by age group when age was modeled as either a dichotomous or continuous variable. In addition, the rate of death as a result of any cause in the first 60 days from random assignment did not differ by age group (1.1% age < 70, 2.3% age 70; P = .15). Response rate was analyzed in the three studies of advanced disease. In a pooled analysis of these three studies, in a multivariate model adjusting for study and PS, age was not associated with likelihood of response (P = .20). Significant between-study heterogeneity was observed in the relative benefit of FOLFOX4 versus control (P < .001), necessitating a study-by-study comparison of the response rate benefit for FOLFOX4. FOLFOX4 improved the response rate significantly in all three trials compared with control, with odds ratios for response of 3.42 (95% CI, 2.25 to 5.25), 1.65 (95% CI, 1.15 to 2.38), and 7.22 (95% CI, 3.18 to 16.35) in favor of FOLFOX4 in studies B, C, and D, respectively. The differences observed between these odds ratios from the three trials were likely due to the fact that in study C FOLFOX4 was compared with IFL, whereas in studies B and D, it was compared with LV5FU2. In none of the three studies was there a significant age-treatment interaction. The relationships between age, treatment, and response rate did not change when age was modeled as a continuous variable.
Age was not associated with differences in P/DFS (P = .70), and no treatment by study heterogeneity was observed (P = .33). In all patients, FOLFOX4 was associated with improved P/DFS overall (hazard ratio [HR] = 0.69; 95% CI, 0.63 to 0.76; P < .0001), and this did not differ by patient age (HR = 0.70; 95% CI, 0.63 to 0.77 for age < 70; HR = 0.65; 95% CI, 0.52 to 0.81 for age
Survival data were mature for the three advanced-disease trials. No between-trial heterogeneity was observed in the treatment effect (P = .13). FOLFOX4 was associated with an improved overall survival compared with control, with an HR in favor of FOLFOX4 of 0.78, (95% CI, 0.69 to 0.87; P < .0001). After adjusting for treatment, age was not significantly associated with survival (P = .22). The benefit of FOLFOX4 compared with control did not depend on patient age (HR = 0.77; 95% CI, 0.67 to 0.88 for age < 70; HR = 0.82; 95% CI, 0.63 to 1.06 for age 70; P = .79 for age-treatment interaction; Table 4). Forest plots of the FOLFOX4 versus control comparison by age group for overall survival are shown in Figure 3. The relationships among age, treatment, and overall survival did not change when age was modeled as a continuous variable.
Among those receiving therapy at cycles 1, 3, 6, and 12, significant between-study heterogeneity was observed at all cycles (P = .02 for cycles 1 and 3, and P < .001 for cycles 6 and 12), necessitating a study-by-study comparison. Considering the disparate times to progression/recurrence in the adjuvant, first-line, and second-line settings, this is an expected finding. Although the dose-intensity did differ between studies, the dose-intensity did not differ between patients age younger than 70 and 70 at any cycle for any study for either oxaliplatin or infusional FU. The number of patients remaining on therapy did not differ by age for cycle 3, but by cycle 6 and 12, a smaller percentage of age 70 patients remained on study, which was significant for three of the four trials by cycle 12 (Table 5).
Changing the standard of care in clinical oncology generally requires large, randomized, phase III trials. The financial and time-related costs involved in such trials require carefully chosen sample sizes to be as small as possible to address the primary study hypothesis. Thus, pooled analyses of relevant subpopulations that share common characteristics (such as a single tumor type treated with the same or similar regimens) can help address practical questions that face oncologists and patients; these results cannot be discerned from individual studies. In this analysis we pooled the individual patient data from four trials in patients with colon cancer treated with a common regimen, FOLFOX4, comparing them with the control arms in the studies with a focus on answering three questions. First, do patients older than age 70 derive the same benefit from this therapy? The answer to this question is clear: there is no difference in efficacy derived between younger and older patients enrolled onto these trials with respect to response rate, relapse/progression-free survival, or overall survival. The second question that we sought to address was whether older patients experience a different pattern or severity of adverse events compared with younger patients. Overall, the analysis showed similar toxicity patterns in the two age groups. Increased rates of neutropenia and thrombocytopenia were observed in the older patients, however, efficacy outcomes were no different between the two age groups. Thus, it appears that the relative incidences of these two toxicity differences did not compromise outcomes. In addition, drug delivery doses did not differ significantly by patient age. Fatigue emerged as a statistically significant difference between the age groups when analyzed using age as a continuous rather than dichotomous variable; this is not an adverse event that is usually life threatening, and this event generally reverses at therapy cessation. It is important to note that there was no difference in the incidence of treatment-associated deaths or neuropathy as a consequence of age. Finally, we investigated whether older patients received similar drug doses and therapy duration as younger patients. Similar doses were delivered regardless of age across the three lines of therapy, suggesting that increasing age did not adversely affect drug delivery. In the setting of advanced disease, older patients did not remain on therapy as long as younger patients. This may be explained by the increasing likelihood that patients were symptomatic at this later stage in their disease due to their cancers; alternatively, older patients and their physicians might have a lower threshold for discontinuing therapy in this setting. Despite the fact that approximately 50% of patients who have advanced colorectal cancer are older than age 70 in the United States, only 16% of patients enrolled onto these trials were age 70 or older. These older patients who enrolled onto these trials clearly are a select group, suggesting that generalizations derived from this study must be applied cautiously to individual older patients. In particular, three of the four trials restricted eligibility to those patients age 75 or younger. Additional study is required to identify more precisely treatment benefit in those age 80 or older. In conclusion, on the basis of a pooled analysis of 3,742 patients, age alone should not be a limiting factor for decision making for patients with colorectal cancer who are considering treatment with FOLFOX4. Factors that are more relevant are PS,4 the presence and absence of comorbid medical conditions, and social factors. As with patients of any age, for individual patients older than age 70, a careful assessment of the relative risks and benefits of aggressive treatment must be performed by the caregivers and communicated to the patients before embarking on a treatment program. Caution must be advised in treating patients older than age 80 because scant data exist regarding tolerance for or benefits from FOLFOX4 in this population. Careful monitoring for toxicity and rapid intervention with supportive care measures when toxicity occurs is also a mandatory component of optimal care; the importance of such measures cannot be overemphasized, particularly in older patients.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
Supported by a grant from Sanofi-Aventis. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ries LAG, Eisner MP, Kosary CL, et al: (eds): SEER Cancer Statistics Review 1973-1998. Bethesda, MD, National Cancer Institute, 2001 2. Ferlay J: Globocan 2000. Lyon, France, IARC Press, 2001 3. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097, 2001 4. D'Andre SD, Sargent DJ, Cha SS, et al: 5-Fluorouracil-based chemotherapy for advanced colorectal cancer in elderly patients: A North Central Cancer Treatment Group Study. Clin Colorectal Cancer 4:325-331, 2005[Medline] 5. Schmoll HJ: The role of oxaliplatin in the treatment of advanced metastatic colorectal cancer: Prospects and future directions. Semin Oncol 29:34-39, 2002[Medline] 6. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 7. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 8. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003 9. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 10. Trimble EL, Carter CL, Cain D, et al: Representation of older patients in cancer treatment trials. Cancer 74:2208-2214, 1994[CrossRef][Medline] 11. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999 12. Monfardini S, Sorio R, Boes GH, et al: Entry and evaluation of elderly patients in European Organization for Research and Treatment of Cancer (EORTC) new-drug-development studies. Cancer 76:333-338, 1995[CrossRef][Medline] 13. Goodwin JS, Hunt WC, Samet JM: Determinants of cancer therapy in elderly patients. Cancer 72:594-601, 1993[CrossRef][Medline] 14. Scheffe H: The Analysis of Variance. New York, NY, Wiley, 1959 15. Cox DR: Regression models and life-tables. J R Stat Soc Series B 34:187-202, 1972 Submitted April 4, 2006; accepted June 26, 2006. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test was used to compare the percentage of patients receiving any study therapy by age group at the selected cycles. Quality-of-life data were not collected in a uniform manner among these studies, and quality-of-life measures are not considered in this analysis. 
