Adjuvant chemotherapy use and adverse events among older patients with stage III colon cancer

Abstract

Context: Randomized trials suggest adjuvant chemotherapy is effective for older patients with stage III colon cancer. However, older patients are less likely to receive this therapy than younger patients, perhaps because of concern about adverse effects.

Objective: To evaluate adjuvant chemotherapy use and outcomes for older patients with stage III colon cancer from well-defined population-based settings and health care systems.

Design: Observational study of adjuvant chemotherapy use and outcomes by age using Poisson regression to estimate the number of adverse events adjusted for demographic and clinical factors, including comorbid illness and specific elements of chemotherapy regimens documented with clinically detailed medical record reviews and patient and surrogate surveys.

Setting: Five geographically defined regions (Alabama, Iowa, Los Angeles County, northern California, and North Carolina), 5 integrated health care delivery systems, and 15 Veterans Affairs hospitals.

Patients: Six hundred seventy-five patients diagnosed with stage III colon cancer from 2003 through 2005 who underwent surgical resection and were followed up for as long as 15 months postdiagnosis.

Main outcome measures: Chemotherapy regimen, dose, duration, and annualized mean number of adverse events stratified by age.

Results: Of 202 patients aged 75 years and older, 101 (50%) received adjuvant chemotherapy compared with 87% of 473 younger patients (difference, 37%; 95% confidence interval [CI], 30%-45%). Among patients who received adjuvant chemotherapy, 14 patients (14%) aged 75 years and older and 178 younger patients (44%) received a regimen containing oxaliplatin (difference, 30%; 95% CI, 21%-38%). Older patients were less likely to continue treatment, such that by 150 days, 99 patients (40%) aged 65 years and older and 68 younger patients (25%) had discontinued chemotherapy (difference, 15%; 95% CI, 7%-23%). Overall, 162 patients (24%) had at least 1 adverse clinical event, with more events among patients treated with vs without adjuvant chemotherapy (mean, 0.39 vs 0.16; difference, 0.23; 95% CI, 0.11-0.36; P < .001). Among patients receiving adjuvant chemotherapy, adjusted rates of late clinical adverse events were lower for patients 75 years and older (mean, 0.28) vs for younger patients (0.35 for ages 18-54 years, 0.52 for ages 55-64 years, and 0.45 for ages 65-74 years; P = .008 for any age effect).

Conclusion: Among patients with stage III colon cancer who underwent surgical resection and received adjuvant chemotherapy, older patients in the community received less-toxic and shorter chemotherapy regimens, and those treated had fewer adverse events than younger patients.

Figure 1

Cohort Characteristics

Figure 2. Cumulative Proportions of Patients Discontinuing Chemotherapy by Specified Day by Age

¹Y-axis shows % patients discontinuing chemotherapy at specified time period. ²X-axis shows the time window during which adjuvant chemotherapy is discontinued. For each age-specific curve, the data points show the % patients who have discontinued adjuvant chemotherapy by the end of the specified time window. Across all of the time windows listed in the x-axis, the n associated with the denominator is constant and includes all patients who initiate adjuvant chemotherapy (n=513). ³For example, within the time window from 1-30 days following adjuvant chemotherapy initiation, across respectively increasing age categories, 2, 3, 7, and 10% of patients have discontinued treatment (p=0.014). *p-values indicate differences in probability of chemotherapy discontinuation by age for surviving patients as of 30, 60, 90, 120, and 150 days after chemotherapy initiation using Cox proportional hazard model. As noted, older patients are significantly more likely to discontinue chemotherapy at all time points (i.e., 30, 60, 90, 120, and 150 days). Note that the % patients having last chemotherapy date as of 180 days does not differ by age.(not shown).

Figure 3. Adjusted Yearly Late Adverse Event Rates¹

¹Poisson Models are adjusted for: gender (male); married or living together; race/ethnicity (Hispanic, Black, Asian with White as reference group); survey type (brief, surrogate- with full survey as reference group); age (<55, 55-64, 65-74 years- with >=75 years as reference group); income ($20,000 and $20-40,000- with >$40,000 as reference group); pre-diagnosis health status; comorbidity (none, mild, moderate- with severe as reference group); early (from 90 days before to <=30 days post-surgical resection); history of prior cancer; early do-not-resuscitate order; study sites; calendar date for colon cancer diagnosis; adjuvant chemotherapy (vs. none); number of days from diagnosis to chemotherapy initiation; reduced dose adjuvant chemotherapy; chemotherapy duration >=6 months; and count of # of days from 1^st to last chemotherapy dose). For Figure 3.A, adjuvant chemotherapy is defined as any adjuvant chemotherapy with no adjuvant chemotherapy as reference group. For Figure 3.B, adjuvant chemotherapy is defined as oxaliplatin-containing, non-oxaliplatin-containing, or missing regimen vs. none. Regardless of whether the model included adjuvant chemotherapy as a single dummy variable (Figure 3.A) or as regimen-specific dummies (not shown), adjuvant chemotherapy significantly predicts late adverse events. ² Among adjuvant chemotherapy users (light colored bar in Figure 3.A), adjusted rates of late clinical adverse events show a reverse U-distribution across increasing age categories with the oldest patients having a lower adverse event rate than patients in the other age categories (0.345, 0.519, 0.446, 0.277; p=0.0080 for any age effect, and p=0.0125 for analysis of the effect of age categories beyond that explained by the youngest age category*no chemotherapy interaction). This p-value corresponds to a multiple degree of freedom likelihood ratio test for which there is no difference statistic and corresponding confidence interval,, similar to an F-test in an ANOVA model. ³Among non-chemotherapy users (lower square-marked curve in Figure 3.A), late adverse events are highest among youngest patients (p=0.0125). ⁴Figure 3.B shows adjusted yearly late adverse event rates are significantly higher for patients using oxaliplatin (upper diamond-marked solid curve in Figure 3.B) as compared with patients using non-oxaliplatin based regimens (lower triangle-marked solid curve in Figure 3.B) across all four age categories (p<.001). ⁵Adjusted yearly late adverse event rates differ significantly among oxaliplatin users (upper diamond-marked solid curve vs. square-marked hyphenated line, p = 0.015) according to whether neuropathy is included or excluded in the definition of the adverse events. Adjusted yearly late adverse event rates for oxaliplatin users vs. non-users are higher when neuropathy is included in the model (upper diamond-marked solid curve in Figure 3.B vs. lower triangle-marked solid curve in Figure 3.B). Once neuropathy is excluded from the list of late adverse events, there is no difference between oxaliplatin and non-oxaliplatin users (No difference between middle square-marked dotted curve and lower triangle-marked solid curve in Figure 3.B).