Abstract
Background
While safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) has been demonstrated in adults ≥75 years enrolled in clinical trials, safety and effectiveness outside the trial setting are less established.
Methods
We retrospectively collected cases of patients ≥ 75 years old diagnosed with stage III and metastatic CRC initiating treatment between January 2000 – January 2007 at two academic hospitals in Boston, MA. Cases were matched 1:2 ratio to control subjects who were <75 years old by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (1st vs. ≥2nd). The primary study endpoints were grade ≥3 treatment-associated toxicities and intolerance (number of dose delays/reductions and hospital/facility admissions during treatment). The secondary endpoint was overall survival.
Results
We identified 84 cases ≥75 years old (25% ≥ 80 years old) and 168 controls. In the cohort, 77% had colon cancer, 75% had metastatic disease, and 60% were receiving oxaliplatin as first-line therapy. There was no significant difference in grade ≥3 treatment-associated toxicities between the cases and controls (71.4% vs. 68.5%, p=0.63). Further there was no statistically significant difference between cases and controls for combined endpoints of any grade ≥3 toxicity or hospital/facility admission (p=0.92). With a median follow-up of 52 months, 2-year overall survival was similar between cases and controls (43% vs. 52%, p=0.87)
Conclusion
Older adults with stage III and metastatic colorectal cancer treated outside of a clinical trial experienced comparable safety and effectiveness of oxaliplatin-based chemotherapy regimens compared to younger adults.
Keywords: elderly, colorectal cancer, oxaliplatin, comparative effectiveness, chemotherapy toxicity, comorbid medical conditions
INTRODUCTION
Colorectal cancer accounts for approximately 10% of all new cancer cases and cancer-related deaths in the United States.1 The incidence and prevalence of colorectal cancer is expected to continue to rise with advancing age.1,2,10 Older adults are disproportionately affected by toxicity or suboptimal care than younger counterparts.2,4,5,6,9,10,12,13 Oxaliplatin-based chemotherapy is the standard of care in the adjuvant setting for stage III disease and a standard first-line treatment option in the metastatic setting, yet many older adults do not receive indicated chemotherapy1,2.
Most studies on treatment tolerance and efficacy in the elderly utilize pooled data to overcome limited enrollment of older adults to clinical trials. However, such analyses may still have limited generalizability since disproportionately few older patients are enrolled in clinical trials3–7. Given that the median age of diagnosis for colorectal cancer is 69 years,8 evaluation of the effectiveness and tolerance of oxaliplatin-based chemotherapy in older adults in a non-clinical trial population is warranted.
The objective of this case-control study is to compare the proportion of individuals at least 75 years old with pathologic stage III and metastatic colorectal cancer experiencing intolerance or toxicity to oxaliplatin-based chemotherapy regimens to that of individuals younger than 75 years old in a nonclinical trial cohort at two National Cancer Institute centers.
PATIENTS AND METHODS
Study Design and Patient Selection
This case-control study utilizes medical record review of 252 adults initiating oxaliplatin-based chemotherapy during January 1, 2000 to January 1, 2007 at Massachusetts General Hospital (MGH) and Dana-Farber Cancer Institute (DFCI), Boston, MA. We retrospectively collected cases of adults ≥75 years old diagnosed with pathologic stage III and metastatic colon or rectal adenocarcinoma, matched to two controls <75 years old by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (1st vs. ≥2nd). Following approval from the Institutional Review Board, data on patient characteristics as well as disease and treatment characteristics of cases and controls was obtained via medical record review of the longitudinal medical record. Patient characteristics include age at onset of therapy, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), body mass index (BMI), number of medications, and number and type of comorbid medical conditions (CMC). Disease and treatment characteristics include diagnosis, stage, type of oxaliplatin therapy, line of therapy, oncologist, number of dose reductions/delays, number of hospital/facility admissions, presence of grade ≥3 treatment-related toxicity, and reason for oxaliplatin discontinuation.
Study Endpoints
The primary study endpoints were proportion of patients experiencing grade ≥3 toxicities following initiation of oxaliplatin-based chemotherapy compared to matched controls and measures of intolerance to therapy. Intolerance is a measure of number of (1) dose delays (delay of scheduled treatment dose); (2) dose reductions; (3) hospital/facility admissions during the treatment period. Toxicity reflects all grade ≥3 treatment-related toxicities documented in the electronic medical record during the treatment period. Toxicity was defined as grade ≥3 if it met Common Terminology Criteria for Adverse Events version 3 criteria or if it resulted in termination of therapy. We also examined overall survival and impact of presence of CMC on rates of intolerance and toxicity. The CMC measured include cardiac comorbidity (congestive heart failure, coronary artery disease, hypertension), endocrine comorbidity (diabetes mellitus, hypothyroidism, hyperthyroidism), neurologic comorbidity (neuropathy, cerebrovascular accident), psychiatric comorbidity (depression, bipolar disorder), pulmonary comorbidity (asthma, chronic obstructive pulmonary disease), renal comorbidity (chronic kidney disease), vascular comorbidity (venothromboembolic disease) and other cancers. The number of medications evaluated does not include those prescribed as adjuncts to chemotherapy (e.g. antiemetics, stool softeners or antidiarrheal medications).
Statistical Considerations
Data analysis consisted of comparative analyses using the chi-squared test for binary comparisons of toxicity and specific comorbid conditions (except renal disease for which the Fisher’s exact p-value is reported due to low incidence). Krusal-Wallis and Wilcoxon p-values are reported for comparison of medians and means, respectively. In the exploratory analysis, conditional logistic regression (conditioned on the matched cohort) is performed to determine the association between CMC and medications and each individual measure of intolerance and rates of grade 3 or higher toxicity. Kaplan-Meier methodology and stratified log-rank tests are used to compare the overall survival of cases vs. controls. Since toxicity occurrence dates were not always available due to the retrospective nature of this study, conditional logistic regression was performed for overall survival at 1, 2 and 3 years from the later of date of initial visit or first oxaliplatin use. Patients whose follow-up was less than the analysis-specified time point (1, 2 or 3 years) and who are still alive at last contact were excluded from the respective survival analysis. Patients who died are included in all 3 analyses, regardless of their survival time. A total of 232 patients were included in the 1-year analysis, 221 in the 2-year analysis and 216 in the 3-year analysis.
RESULTS
Patient Enrollment and Characteristics
The analysis cohort consists of 252 adults (84 cases ≥75 years old: 168 matched controls <75 years old). Twenty-five percent of the cases were ≥80 at the time of diagnosis. The majority of patients were diagnosed with colon cancer (84% cases). Over 2/3 of patients (77% of stage III and 77% of metastatic patients) received intravenous, infusional 5-FU and leucovorin with oxaliplatin (FOLFOX) as opposed to alternative regimens [single agent oxaliplatin, bolus 5-FU and leucovorin with oxaliplatin (FLOX) or capecitabine with oxaliplatin (CAPEOX)]. The proportion of patients receiving FOLFOX without bevacizumab in the metastatic setting [57/124 (46%) controls and 13/65 (20%) cases] partially reflects the fact that this study included patients treated prior to FDA approval of bevacizumab in metastatic colorectal cancer in 2004.
The cohort is well-matched by hospital site, stage and line of therapy. The distributions of patient and tumor characteristics are similar between the cases and controls (Table 1). Compared to controls, patients ≥75 years have a greater mean number of comorbid conditions (cases 1.5, controls 1.0, p≤ 0.001) and medications (cases 4.8, controls 3.3, p≤ 0.001). Evaluation of each comorbid conditions reveals comparable distribution by age with the exception of adults ≥75 years having a statistically significant greater number of cardiac comorbidities than their younger counterparts (57% cases, 33% controls, p≤ 0.001).
Table 1.
Patient Distribution and Characteristics
| Characteristic | Cases (N=84) | Controls (N= 168) | P-value | |||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Gender | ||||||
| Female | 38 | 45.2 | 82 | 48.8 | 0.53 | |
| Male | 46 | 54.8 | 86 | 51.2 | ||
| ECOG Performance Status | ||||||
| 0 | 11 | 29.7 | 11 | 29.7 | 0.06 | |
| 1 | 22 | 59.5 | 22 | 59.5 | ||
| 2+ | 4 | 10.8 | 4 | 10.8 | ||
| Diagnosis | ||||||
| Colon | 71 | 84.5 | 124 | 73.8 | 0.06 | |
| Rectal | 13 | 15.5 | 44 | 26.2 | ||
| Stage | ||||||
| III | 18 | 21.4 | 44 | 26.2 | 0.27 | |
| IV/metastatic | 65 | 77.4 | 124 | 73.8 | ||
| Oxaliplatin regimen | ||||||
| Oxaliplatin monotherapya |
18 | 21.4 | 8 | 4.8 | <0.001 | |
| FOLFOXb | 60 | 71.4 | 146 | 86.9 | ||
| CapeOxc | 5 | 6.0 | 14 | 8.3 | ||
| FLOX | 1 | 1.2 | 0 | 0.0 | ||
| Line of therapy | ||||||
| 1st line | 50 | 59.5 | 100 | 59.5 | 1.00 | |
| 2+ line | 34 | 40.5 | 68 | 40.5 | ||
| BMI (mean, range) | 26.2 | (14.2–37.1) | 27.2 | (17.7–53.1) | 0.23* | |
| Number of medications (mean, range) | 4.8, 0–16 | 3.2, 0–13 | <0.001* | |||
| Number of Comorbid Medical Conditions (mean, range) | 1.5, 0–5 | 0.9, 0–4 | <0.001* | |||
| Comorbid Medical Condition (CMC) | ||||||
| Pulmonary | 8 | 9.5 | 11 | 6.5 | 0.40 | |
| Cardiac | 48 | 57.1 | 58 | 34.5 | <0.001 | |
| Vascular | 10 | 11.9 | 8 | 4.8 | 0.04 | |
| Renal | 4 | 4.8 | 1 | 0.6 | 0.03 | |
| Endocrine | 24 | 28.6 | 23 | 13.7 | 0.004 | |
| Neurologic | 6 | 7.1 | 6 | 3.6 | 0.21 | |
| Psychiatric | 7 | 8.3 | 25 | 14.9 | 0.14 | |
| Other cancer | 19 | 22.6 | 24 | 14.3 | 0.10 | |
P-values reported are Chi-square p-values unless otherwise noted
P-values reported are ANOVA p-values.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; CMC, comorbid medical conditions. Comorbid conditions are defined as follows: Pulmonary (asthma, chronic obstructive lung disease) Cardiac (congestive heart failure, coronary artery disease), Vascular (pulmonary embolism), Renal (chronic kidney disease), Endocrine (diabetes mellitus, hypothyroidism, hyperthyroidism), Neurologic (neuropathy, cerebrovascular accident), psychiatry (depression, bipolar disorder) and other cancer.
Oxaliplatin regimen:
Oxaliplatin monotherapy
all FOLFOX-based chemotherapy regimens including FOLFOX, FOLFOX + bevacizumab
all CapeOx-based chemotherapy regimens including includes CapeOx + bevacizumab
Intolerance and Toxicity
Rates of chemotherapy administration did not differ between cases and controls, by stage. There is no statistically significant difference in overall grade ≥3 treatment-related toxicity experienced by adults ≥75 years and their younger counterparts (56% cases, 65% controls, p=0.14). Further evaluation by individual toxicity reveals a statistically significant increase in grade ≥3 fatigue in patients ≥75 years (38% cases, 12% controls, p<0.001). Older patients did appear to have less grade ≥3 hematologic toxicity and neuropathy, which are not explained by rates of chemotherapy administration between cases and controls. There are no statistically significant differences in rates of intolerance for older compared to younger patients as measured by number of dose reductions (54% cases, 49% controls, p = 0.476) and number of dose delays (48% cases, 56% controls, p = 0.18). However older patients experienced statistically significant higher rates of hospital/facility admissions (43% cases, 29% controls p = 0.03). The majority of older patients were hospitalized for complications of their disease (progression, failure to thrive or pain) (71%); 6 patients for grade 3 or higher treatment-related toxicity and 4 patients were hospitalized for palliative or diagnostic procedures. In contrast, 65% of controls were hospitalized for complications of their disease (progression, failure to thrive or pain), 19% for grade 3 or higher treatment-related toxicity, and 7.4% for palliative or diagnostic procedures. Odds of intolerance and grade ≥ 3 toxicity to oxaliplatin-based chemotherapy are not increased by any CMC (Table 4) or by the number of medications (Table 5). There were no significant interactions of age (cases vs. controls) and number of CMC (0, 1–2, ≥3) for dose reduction or delay (p=0.40), hospital/facility admission (p=0.29) and grade ≥3 toxicity (p=0.85).
Table 4.
Odds of intolerance to oxaliplatin-based chemotherapy by comorbid medical conditions and number of medications€
| Characteristic | Dose delay | Dose reduction | Hosp/ Facility admission | |||
|---|---|---|---|---|---|---|
| OR | (95% CI) | OR | (95% CI) | OR | (95% CI) | |
| # Concurrent medications | 1.00 | (1.00, 1.00) | 0.10 | (1.00, 1.00) | 1.00 | (1.00, 1.00) |
| Comorbid Condition | ||||||
| Pulmonary | 1.65 | (0.49, 5.53) | 1.15 | (0.32, 4.11) | 0.59 | (0.17, 2.10) |
| Cardiac | 0.68 | (0.36, 1.26) | 1.20 | (0.63, 2.29) | 0.92 | (0.45, 1.85) |
| Vascular | 1.22 | (0.42, 3.58) | 2.64 | (0.67, 10.36) | 9.45 | (1.15, 77.96) |
| Renal * | 0.17 | (0.02, 1.60) | -- | 2.73 | (0.23, 33.00) | |
| Endocrine | 1.39 | (0.66, 2.94) | 0.85 | (0.38, 1.88) | 1.49 | (0.66, 3.35) |
| Neurologic | 0.53 | (0.13, 2.04) | 3.39 | (0.64, 17.93) | 2.96 | (0.72, 12.08) |
| Psychiatric | 0.92 | (0.35, 2.45) | 0.93 | (0.37, 2.36) | 1.26 | (0.40, 4.00) |
| Any comorbidity | 0.93 | (0.70, 1.23) | 1.15 | (0.83, 1.59) | 1.33 | (0.96, 1.83) |
Key:
Medications that are adjuncts to chemotherapy, e.g. antiemetics, antidiarrheals and stool-softeners, are excluded
OR, odds ratio (>1 implies positive association, <1 implies negative association) CI, 95% confidence interval
Conditional logistic regression (conditioned on matched set) was performed for occurrence of dose delay (yes/no), occurrence of dose reduction (yes/no) and hospital or facility admission (yes/no).
All patients with renal comorbidities had at least one dose reduction
Table 5.
Odds of grade ≥ 3 toxicity with oxaliplatin-based chemotherapy by comorbid medical condition (CMC)
| CMC | Hematologic Toxicity | Neurologic Toxicity | Gastrointestinal Toxicity | Fatigue Toxicity | Any Toxicity | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| OR | (95% CI) | OR | (95% CI) | OR | (95% CI) | OR | (95% CI) | OR | (95% CI) | |
| Pulmonary | 1.88 | (0.39, 8.92) | 0.19 | (0.02, 1.72) | 0.33 | (0.06, 1.80) | 1.18 | (0.30, 4.63) | 0.67 | (0.19, 2.32) |
| Cardiac | 0.35 | (0.15, 0.78) | 0.74 | (0.36, 1.50) | 0.75 | (0.33, 1.70) | 1.57 | (0.73, 3.35) | 0.76 | (0.38, 1.50) |
| Vascular | 1.50 | (0.43, 5.23) | 0.35 | (0.07, 1.73) | 2.12 | (0.47, 9.48) | 3.58 | (0.91, 14.11) | 2.10 | (0.52, 8.43) |
| Renal* | -- | -- | -- | 0.59 | (0.05, 7.43) | 0.17 | (0.02, 1.60) | |||
| Endocrine | 0.87 | (0.36, 2.12) | 0.75 | (0.30, 1.89) | 2.63 | (1.02, 6.82) | 1.96 | (0.81, 4.76) | 0.95 | (0.43, 2.08) |
| Neurologic | 1.00 | (0.18, 5.46) | 0.80 | (0.16, 4.12) | 1.23 | (0.26, 5.75) | 3.36 | (0.83, 13.55) | 2.43 | (0.60, 9.78) |
| Psychiatric | 1.82 | (0.62, 5.40) | 1.11 | (0.37, 3.34) | 0.50 | (0.13, 1.93) | 0.28 | (0.08, 1.00) | 0.79 | (0.30, 2.07) |
| Other cancer | 0.84 | (0.30, 2.32) | 1.06 | (0.46, 2.47) | 2.22 | (0.69, 7.10) | 1.81 | (0.76, 4.32) | 0.74 | (0.32, 1.71) |
All patients with renal comorbidities had neurologic toxicities and only one each had any hematologic or GI toxicities, so valid logistic regressions could not be performed for these toxicities.
For added clinical significance, we examined the impact of age on combined endpoints of any grade ≥ 3 toxicity or hospital/facility admission. While overall rates of toxicity or admission occurred for over 2/3 of the cohort, the rate of toxicity or admission did not differ significantly between cases and controls (77.4% vs. 76.8%, p=0.92). These results did not appreciably differ when comparing those age <80 (77.5%) to those age ≥ 80 (71.4%), p=0.53; or those age 75–79 (79.4%) to ≥ 80 (71.4%), p=0.45.
Exploratory Analysis of Chemotherapy Effectiveness
Analyses of overall survival are exploratory. Survival was calculated as the time period from date of oxaliplatin initiation (DOO) to date of death. For patients for whom initial oxaliplatin start date is unknown (due to initiating care elsewhere), survival from date of initial oncologic visit (DOV) was calculated. Patients who were still alive at the date of last contact were censored at this date. Overall survival at 1, 2, and 3 years is similar between adults ≥ 75 years and younger patients at a median follow-up time of 52 months (OS at 1 year = 68% cases, 79% controls; 2 year = 43% cases, 57% controls; 3 year = 36% cases, 43% controls, p = 0.25) (Figure 1). As expected, overall survival is greater for patients with stage III vs. metastatic disease (Figure 2). However, overall survival appeared similar for cases and controls regardless of stage of disease (Figure 2).
Figure 1. Kaplan Meir Overall Survival for Oxaliplatin-based chemotherapy – cases vs. controls.§.
Key
§ Overall survival from the later of either date of oxaliplatin initiation or initial oncologic visit to time of death.
DOO: Date of oxaliplatin initiation
DOV: Date of initial oncologic visit
Figure 2. Kaplan-Meier curve: Overall survival by stage from later of DOO or DOV: cases vs. controls.
P-values:
Overall, p<0.001
Stage III cases vs. controls, p=0.986
Stage IV cases vs. controls, p=0.097
DISCUSSION
We evaluated the toxicity and intolerance of oxaliplatin-based chemotherapy regimens in adults ≥75 years with stage III and metastatic colorectal cancer compared to matched younger cohort receiving treatment at two academic hospitals in Boston, Massachusetts. The study shows that older age does not have a statistically significant impact on rates of intolerance or toxicity with oxaliplatin-based chemotherapy. While analysis of individual toxicities reveals an increased rate of grade ≥ 3 treatment-related fatigue experienced by adults ≥ 75 years, the overall grade ≥ 3 treatment-related toxicity does not differ significantly between cases and controls. Older patients were observed to have higher rates of hospitalization compared to younger patients; however the majority of hospitalizations in both groups were due to complications of their disease. We also sought to determine if there is a difference in the number of comorbid medical conditions for older compared to younger adults and whether that impacts rates of intolerance or toxicity. The study shows that older adults have a greater mean total number of comorbid conditions and medications than their younger counterparts. However, the absolute number each comorbid condition is similar between cases and controls, with the exception of a significantly greater number of cases with cardiac comorbid conditions (p<0.001). This finding is likely explained by the high prevalence of cardiac disease in the general population and the increased risk with older age9. Further, the presence of an increased mean number of comorbid conditions does not have a statistically significant impact on rates of intolerance or toxicity in this cohort. In exploratory analysis, overall survival is similar between cases and controls at a median follow-up of 52 months.
Overall, this study shows similar rates of tolerance and toxicity patterns for older adults ≥ 75 years with stage III and metastatic colorectal cancer and their younger counterparts, with no significant difference in overall survival in exploratory analysis between the two age groups. The finding of significantly increased grade ≥ 3 fatigue in elderly patients receiving oxaliplatin-based chemotherapy has been previously demonstrated by Goldberg et al7 and warrants further exploration.
One pooled analysis and three subset analyses of oxaliplatin-based chemotherapy failed to demonstrate a survival benefit in the adjuvant setting for older adults10–13. While updated survival outcomes from the MOSAIC study show a superior 5-year disease-free survival and 6-year overall survival for stage III patients, subset analysis of the older cohort showed that observed disease-free survival benefit at 3 years in patients ≥ 65 was not maintained after 6 years of follow-up14, 17. Similarly older adults receiving bolus fluorouracil in combination with oxaliplatin (FLOX) did not derive a disease-free survival benefit at 7 years compared to younger patients14. Pooled analysis of the Adjuvant Colon Cancer End Points (ACCENT) database, incorporating the MOSAIC and NSABP C-07 trials, demonstrated no disease-free or overall survival benefit of oxaliplatin-based chemotherapy compared to 5-FU/LV in patients age ≥7015. Subsequent evaluation of oxaliplatin in this population is based on a phase III trial comparing capecitabine and oxaliplatin to bolus 5-FU/LV in 1,886 (N=409 ≥ 70 years) stage III colon cancer. These data did not support survival benefit among older adults, although the study was underpowered in this age group.16 Hazard ratios for 5-year overall survival was 0.94 (95% CI 0.66, 1.34) for ≥ 70 years and for 3-year disease-free survival was 0.87 (95% CI 0.63, 1.18) for ≥ 70 years in comparison to younger patients. Furthermore, older adults experience more grade 3 or higher toxicity with lower dose intensity.
Analysis regarding the mechanism of this observed lack of survival benefit in the adjuvant setting is forthcoming from MOSAIC13 and NSABP C-0712 investigators. Thus far, lack of overall survival benefit is not explained by differences in dose intensity, tumor characteristics or comorbid medical conditions of elderly patients based on MOSAIC data presented at ASCO 201013. Further analysis is needed regarding the impact of dose intensity, number and severity of comorbid medical conditions and toxicity on survival outcomes for older adults receiving oxaliplatin in the adjuvant setting in clinical trials17. In an analysis of 6,465 patients age ≥75 from four population-based cohorts in the adjuvant setting, Sanoff et al noted declining use of adjuvant chemotherapy and oxaliplatin with increasing age18. However, 3-year overall survival was higher among those who did receive adjuvant chemotherapy, specifically those receiving oxaliplatin in SEER-Medicare, but not other cohorts.
In the metastatic setting, survival benefit is confounded by deaths from competing medical conditions in the older population. Consequently, tolerance and toxicity are more significant metrics of treatment outcome. The present study confirms prior examination of an effectiveness cohort in the metastatic setting for oxaliplatin-based chemotherapy and demonstrates no statistically significant difference in treatment tolerance, toxicity or survival in exploratory analysis for older adults (≥ 75 years) compared to a matched younger cohort (< 75 years). In a medical record review of treatment patterns for metastatic colorectal cancer in community oncology practices, McKibbin et al noted that patients ≥65 years were less likely to receive combination therapy with oxaliplatin than their younger counterparts19. Yet, those patients who receive oxaliplatin-based therapy appear to derive a similar survival benefit to younger patients. In a pooled analysis of 614 patients enrolled in three advanced colorectal cancer trials and one in the adjuvant setting (MOSAIC), Goldberg et al noted similar efficacy and toxicity profile for patients regardless of age7. While older adults appeared to receive similar survival benefit to historic controls, 67% of patients experienced grade ≥3 toxicity7, reflecting a significant degree of intolerance to oxaliplatin within a highly selected clinical trial population.
Despite the fact that the prevalence of colorectal cancer is higher in older adults, prior studies rarely have sufficient representation of adults ≥ 75 years to provide adequate data to draw conclusions regarding tolerance and toxicity of oxaliplatin-based chemotherapy regimens. The cohort of patients enrolled in our study has the unique strength of providing information on the older population that tends to be under-represented in clinical trials. In this cohort 25% of the cases enrolled are ≥ 80 years in comparison to a pooled analysis of 3 metastatic and one adjuvant oxaliplatin-based chemotherapy trials in which only 4% of the analysis cohort was ≥ 75 years, with less than 1% of the cohort ≥ 80 years7.
Limitations of our study are those inherent to retrospective case-control studies relying on medical record review. We are unable to confirm the completeness of the comorbid medical condition extrapolation or comment on severity. However, both hospitals utilize an electronic medical record with actively maintained problem lists. While toxicities recorded occurred during the active treatment period, we did not include specific dates of occurrence relative to initiation of oxaliplatin, limiting validity of survival analysis. For that reason survival analysis is exploratory for the sake of generating hypotheses regarding observed survival differences in the literature for older and younger adults. We cannot detail the cause of death for patients enrolled, thus any survival mentioned may include non-cancer related death from competing medical conditions. Lastly, while the population studied did not participate in randomized clinical trials, there remains a potential selection bias given that patients able to receive treatment at an NCI center may differ from those managed in community settings.
The present analysis provides important information regarding safety and comparative effectiveness of oxaliplatin-based chemotherapy in older adults with stage III and metastatic colorectal cancer not enrolled in clinical trials. Further investigation is needed to adequately prospectively assess the degree to which survival outcomes are impacted by toxicity and intolerance in older adults with metastatic colorectal cancer. Additionally, data detailing competing cause of death among older adults with colorectal cancer may clarify the incremental benefit of combination chemotherapy regimens.
We have shown that age itself is not predictive of tolerance or toxicity to oxaliplatin-based chemotherapy regimens, even when considering older adults in this study had a greater mean number of comorbid medical conditions compared to younger patients. Hence there is a need for accurate assessment tools to guide clinical decision-making for older adults. The Cancer-Specific Geriatric Assessment developed by Hurria et al20, validated17,21. It has been shown to predict treatment outcomes better than ECOG PS or physician judgment alone17,20,22–24 as well as toxicity with chemotherapy regimens17, providing useful clinical adjunct information beyond age, comorbid medical conditions or medications alone. Further validation in advanced colorectal cancer is ongoing in a cooperative group study.
Based on the present literature, older adults appear to have similar safety and effectiveness of oxaliplatin-based chemotherapy in the non-clinical trial setting for both stage III and metastatic colorectal cancer. This result is similar to prior analyses in the metastatic setting7 and some10,25, but not all11, studies in the adjuvant setting. Further study in larger cohorts is warranted to determine if the observed effect is attenuated by the presence or severity of comorbid medical conditions within this growing subset of patients. Until the findings in this regional study are confirmed, we suggest oncologists consider extending standard chemotherapy treatment to all patients regardless of age for stage III and metastatic colorectal cancer. Further, incorporation of geriatric assessment strategies may increase patient receipt of standard and tolerable treatment regardless of age.
Table 2.
Frequency of oxaliplatin-based chemotherapy intolerance and grade ≥3 toxicity
| Characteristic | Cases (N=84) | Controls (N= 168) | P-value | |||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Intolerance | ||||||
| Dose reduction | 45 | 53.6 | 82 | 48.8 | 0.48 | |
| Dose delay | 40 | 47.6 | 95 | 56.5 | 0.18 | |
| Hospital/facility admission | 36 | 42.9 | 49 | 29.2 | 0.03 | |
| Toxicity | ||||||
| Hematologic | 16 | 19.0 | 59 | 35.1 | 0.01 | |
| Neurologic | 10 | 11.9 | 43 | 25.6 | 0.01 | |
| Gastrointestinal | 21 | 25.0 | 32 | 19.0 | 0.27 | |
| Dermatologic | 1 | 1.2 | 1 | 0.6 | 0.62 | |
| Fatigue | 32 | 38.1 | 20 | 11.9 | <0.001 | |
| Other | 10 | 11.9 | 18 | 10.7 | 0.78 | |
| Any grade ≥ 3 toxicity | 60 | 71.4 | 115 | 68.5 | 0.63 | |
Table 3.
Reason for discontinuation of oxaliplatin
| Reason | Cases(N= 84) | Controls (N= 168) | P-value | ||
|---|---|---|---|---|---|
| No. | % | No. | % | ||
| Progression | 46 | 54.8 | 60 | 35.7 | 0.004 |
| Completion | 14 | 16.7 | 38 | 22.6 | 0.27 |
| Toxicity | 14 | 16.7 | 40 | 23.8 | 0.19 |
| Loss to follow-up | 10 | 11.9 | 3 | 1.8 | <0.001 |
| Patient preference | 0 | 0.0 | 9 | 5.4 | 0.03 |
ACKNOWLEDGEMENTS
American Society of Clinical Oncologists Young Investigator Award, Program in Cancer Outcomes Research Training NIH R25CA092203, Dana-Farber Cancer Institute Gastrointestinal SPORE Career Development Award NIH 5P50CA127003-05
Footnotes
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Supported by American Society of Clinical Oncology/Hartford Foundation Young Investigator Award 2008
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