Older patients with colon cancer: is adjuvant chemotherapy safe and effective?

PURPOSE: To investigate the efficacy and toxicity of fluorouracil-based adjuvant chemotherapy in patients aged 70 years and older with resected Stage II or III colon cancer who are at high risk for recurrence. BACKGROUND: Colorectal cancer accounts for 15% of all cancers in men and women and, after lung cancer, is the second-leading cause of cancer overall and the first in women aged 75 and older.1 Older patients with cancer do not receive what is considered to be standard chemotherapy and are treated less often than younger patients regardless of the disease site or stage at diagnosis.2,3 Adjuvant chemotherapy for colon cancer reduces the risk of death significantly, compared with surgery alone.4,5 Currently, fluorouracil plus leucovorin for 6 to 8 months is standard adjuvant treatment for node-positive Stage III colon cancer.6,7 The benefits of fluorouracil-based therapy for Stage II colon cancer are unclear. For all patients with colon carcinoma in the National Cancer Data Base, the use of surgery plus chemotherapy declined with age; 40% of patients younger than 50 received both treatments, compared with 20% of patients aged 70 to 79. There is now accumulating evidence suggesting that selected older patients can receive the same benefit as their younger counterparts, without a significant increase in toxic effects. A careful appraisal of the treatment of older patients with adjuvant chemotherapy for colon cancer is presented. DATA SOURCES: All reported studies (except three trials that have not yet completed follow-up and one trial unavailable because of computer malfunction) comparing postoperative fluorouracil plus leucovorin or fluorouracil plus levamisole with surgery alone were identified using a Medline search, a search of bibliographies, and discussion with the leaders of each identified trial. STUDY SELECTION CRITERIA: Seven studies that met the following criteria were included in this pooled analysis: inclusion of patients aged 70 and older; type of chemotherapy used was fluorouracil plus leucovorin or fluorouracil plus levamisole, treatment started between 21 and 56 days after surgery, and patients with Stage II or III adenocarcinoma of the colon who underwent curative resection were enrolled. In all seven trials, patients with Stage II or III colon cancer were randomly assigned to chemotherapy or no treatment after surgery. Five studies tested fluorouracil in doses ranging from 370 to 425 mg/m2 of body surface area and leucovorin in doses ranging from 20 to 200 mg/m2 daily for 5 days, repeated every 4 to 5 weeks. The duration of treatment in the trials of fluorouracil plus leucovorin was six cycles in four of the trials and 12 cycles in the fifth. In the other two trials, fluorouracil was administered by rapid intravenous injection at a dose of 450 mg/m2 on 5 consecutive days. On day 28, weekly injections of the same dose were given to the patient. Throughout treatment, levamisole was administered orally at a dose of 50 mg three times daily from Day 1 through 3 and repeated every 2 weeks. The duration of treatment in both trials of fluorouracil plus levamisole was 1 year. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria or the World Health Organization Toxicity Scale. In all trials, patients were examined and toxicity data were documented at least monthly. DATA EXTRACTION: The outcome and toxic effects recorded for each patient were obtained from all seven trials. The primary endpoints were overall survival (defined as time from study entry to death) and time to recurrence (defined as the time from study entry to first confirmed relapse). Data on overall survival and time to recurrence were analyzed up to 8 years from the date of randomization. The primary statistical goal of the analysis was to test for an age-by-treatment interaction. The results were presented using 10-year age groups. Multivariate models were used to adjust for baseline performance status and stage. Relationships between rates of adverse events and age were analyzed using Pearson statistics. Hazard ratios (HRs), with accompanying 95% confidence intervals (CIs), were reported for comparisons of patients who received chemotherapy and those who did not. RESULTS: Of 3,347 patients from seven randomized trials, 86 (2.5%) were deemed ineligible and were excluded from the pooled analysis. Of the rest, 43% had Stage II and 57% Stage III disease. A Death without the recurrence of cancer: The probability of death without recurrence of cancer was strongly associated with age. The oldest patients had a higher probability of dying without evidence of recurrence (13%) than the youngest patients (2%). In addition, 32% of deaths of the oldest patients but only 5% of deaths of the youngest patients were due to causes other than the cancer. Approximately 30% of the patients in each group died with recurrence of cancer over the 8-year follow-up period. B Effect of chemotherapy: Adjuvant chemotherapy had a significant positive effect on overall survival and time to tumor recurrence (P < .001 for each). The 5-year overall survival was 71% for those who received adjuvant therapy, compared with 64% for those untreated (HR for death from any cause = 0.76; 95% CI = 0.68–0.85). The 5-year recurrence-free rate was 69% in treated patients, compared with 58% in untreated patients (HR for recurrence = 0.68; 95% CI = 0.60–0.76). No significant interaction was observed between age and efficacy of treatment. The P-values for the test of interaction in which age was divided into four categories were 0.61 for overall survival and 0.33 for the time to tumor recurrence. The overall survival and freedom from recurrence was similar in the adjuvant treatment and no adjuvant treatment groups according to age group for the first 5 years of follow-up. After 5 years, patients aged 70 and older had decreased overall survival because of death from other causes. C Adverse events according to age group: Although it was not a randomized comparison, patients treated with fluorouracil plus levamisole had significantly more leukopenia and nausea or vomiting (P = .001 and P = .05, respectively), whereas those treated with fluorouracil plus leucovorin had significantly more stomatitis and diarrhea (P = .001 for both comparisons). Therefore, separate analysis of toxicity according to age for the two treatment regimens was performed. Age was not significantly related to the rate of Grade 3 or higher nausea or vomiting, stomatitis, or diarrhea in patients treated with fluorouracil plus leucovorin or fluorouracil plus levamisole. Leukopenia was significant in patients with levamisole and fluorouracil treatment (31% of subject ≥70 vs 17% of subject <70, P < .001) and borderline significantly higher in patients with fluorouracil and leucovorin treatment (8% of subjects ≥70 vs 4% of subjects <70, P = .05). CONCLUSION: This analysis supports the benefit of adjuvant chemotherapy in patients with resected Stage II and III colon cancer. There is no evidence that the susceptibility of colon cancer to chemotherapy differs in younger and older patients. In this analysis, older patients did not have higher rates of nausea, vomiting, stomatitis, or diarrhea than younger patients. Leukopenia was significantly higher in older patients who received fluorouracil and levamisole and was borderline significantly higher in those who received fluorouracil and leucovorin. No reductions in the dose of fluorouracil are recommended for patients with altered renal or hepatic function, because this may decrease the efficacy.7 The patients enrolled in these trials may not be representative of all older patients with colon cancer.