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  1. 1. Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting TREVOR MCKIBBIN,a CHRISTOPHER R. FREI,b,c REBECCA E. GREENE,b,c PETER KWAN,b JODY SIMON,d JIM M. KOELLER b,c a University of Tennessee Health Science Center, Memphis, Tennessee, USA; b University of Texas at Austin College of Pharmacy, Austin, Texas, USA; c University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; d Geriatric Oncology Consortium, Baltimore, Maryland, USA Key Words. Colorectal cancer • Elderly • Bevacizumab • Oxaliplatin • Irinotecan • Disparity Disclosure: T.McK. is on the advisory board for Genentech. J.M.K. is a speaker for Pfizer, MGI Pharma, Lilly, and Abraxis. He is also an advisor for Bristol-Myers Squibb, Sanofi Aventis, AstraZeneca, Genentech, and Pharmion. Pfizer Oncology provided support for conducting data collection. The sponsor was not involved in the design and conduct of the study, analysis or interpretation of the data, or preparation of the manuscript. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers of the article. LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Identify reported differences between advanced colorectal cancer patients treated in community oncology clinics and those enrolled in clinical trials. 2. Describe gaps in the existing evidence for the treatment of elderly advanced colorectal cancer patients. 3. Describe the need for improving tools to appropriately select patients for treatment. This article is available for continuing medical education credit at ABSTRACT Background. The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have deter- mined the use and outcomes of the treatment of ad- vanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treat- ment and outcome. Methods. A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All med- ical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemo- therapy (irinotecan or oxaliplatin with a fluoropyrimi- Correspondence: Trevor McKibbin, Pharm.D., M.Sc., College of Pharmacy, University of Tennessee Health Science Center, 930 Mad- ison Suite 890, Memphis, Tennessee 38163, USA. Telephone: 901-448-7632; Fax: 901-448-5419; e-mail: tmckibbi@ Received March 12, 2008; accepted for publication June 28, 2008; first published online in THE ONCOLOGIST Express on August 11, 2008. ©AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/theoncologist.2008-0061 The Oncologist® Gastrointestinal Cancer The Oncologist 2008;13:876–885 byonOctober29,2010www.TheOncologist.comDownloadedfrom
  2. 2. dine) as initial therapy in young (age <65 years) and elderly (age >65 years) patients. Additional aims in- cluded age-based comparisons of the addition of bevaci- zumab to chemotherapy, overall chemotherapy use, all- cause mortality, and toxicity-related events. Results. Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, com- pared with 58% of elderly patients (p < .001). The use of each of the medications—irinotecan, oxaliplatin, and bevacizumab—was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02–1.39) and performance status score >2 (HR, 1.65; 95% CI, 1.41–1.91). Conclusion. Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival. The Oncologist 2008; 13:876–885 INTRODUCTION Colorectal cancer (CRC) is primarily a disease of the el- derly, with a median age at diagnosis of 71 years [1]. Nu- merous analyses report a startling underrepresentation of the elderly in cancer clinical trials, creating an evidence gap for the treatment of this large patient population [2–5]. Se- lective entry criteria and the patient referral process contrib- ute to this problem. Although the elderly are receiving increased attention in clinical trials, this subset of patients has not been adequately investigated, and reports of their outcomes in clinical trials are often limited to post-hoc anal- yses [6–9]. Despite these limitations, studies suggest that the benefit of chemotherapy treatment for advanced CRC is maintained in older patients [3, 6–9]. The limited evidence regarding the treatment of elderly advanced CRC patients leaves questions regarding the risks and benefits of in- tensive therapies in this population. Nevertheless, many elderly cancer patients in U.S. community oncology clin- ics receive treatment. It is therefore of interest to inves- tigate how age impacts the treatment of advanced CRC in community oncology clinics and what outcomes are at- tained from the therapies that are administered in this population. Several randomized clinical trials have demonstrated superior response rates and progression-free survival times with doublet therapy compared with single-agent fluoropy- rimidine therapy [10–12]. The monoclonal antibodies bev- acizumab and cetuximab have contributed further improvements in the response rate and overall survival when combined with chemotherapy [13, 14]. A meta-anal- ysis conducted by Grothey et al. [15] indicated that patients with advanced CRC received the greatest survival benefit when treated with all of the active therapeutic classes of medications during the course of treatment. Of note, pa- tients initiated on doublet therapy (irinotecan or oxaliplatin combined with a fluoropyrimidine) were more likely to re- ceive at least three active medications (5-fluorouracil, iri- notecan, and oxaliplatin). Thus, the objective of this study was to report the use of initial doublet therapy in elderly ad- vanced CRC patients compared with younger patients. The hypothesis was that fewer elderly patients received doublet therapy and monoclonal antibody therapy first-line for ad- vanced CRC, compared with younger patients. METHODS A national retrospective chart review was conducted to evaluate the management of advanced CRC in 10 commu- nity practices across the U.S. (in the states of CA, FL, MA, ME, MT, NV, NY, OH, TX). Clinics were required to have a minimum of five practicing oncologists; the clinics were independent from National Cancer Institute–Designated Cancer Centers and academic medical centers, and were inde- pendent from each other. Clinics were required to be able to identify charts via International Classification of Diseases – 9th revision code. All identified and available records were screened for inclusion. All medical records of patients diag- nosed with advanced CRC and initiating chemotherapy treat- ment after January 1, 2003 through 2006 were included. The primary objective was to compare the proportion of patients receiving doublet chemotherapy (irinotecan or oxali- platin combined with a fluoropyrimidine) as initial therapy in young (age Յ65 years) and elderly (age Ͼ65 years) patients. Secondary objectives included age-based comparisons of: (a) the addition of bevacizumab to the initial regimen; (b) overall chemotherapy and monoclonal antibody use; (c) all-cause mortality; (d) toxicity-related dose changes, delays, medica- tion changes, hospitalizations, and additional clinic visits; and (e) toxicity (diarrhea, neutropenia, etc.) leading to one of the events listed in the preceding endpoint. Patient demographics, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, prior history of chemotherapy (for patients with recurrent disease), all medications prescribed by the oncology clinic, treatment breaks, toxicity-related events, toxicities, and date of last follow-up or death were collected. The baseline ECOG PS score was determined using information documented in the patient records. All data were captured on-site using stan- 877McKibbin, Frei, Greene et al. byonOctober29,2010www.TheOncologist.comDownloadedfrom
  3. 3. dardized forms by a four-member research team consisting of oncology-trained pharmacists with research experience (TM, PK, JS, JMK). Data from the original data sheets were verified and entered into a relational database maintained in Microsoft Access௡ (Microsoft Corp., Redmond, WA). Be- cause of variability among the regimens used in the clinics, chemotherapeutic regimens were grouped into three cate- gories: (a) oxaliplatin and a fluoropyrimidine, (b) irinote- can and a fluoropyrimidine, and (c) a fluoropyrimidine alone. The monoclonal antibodies bevacizumab and cetux- imab did not receive U.S. Food and Drug Administration (FDA) approval until February 2004. Thus, only patients starting treatment for advanced CRC after May 1, 2004 were included in evaluations involving these medications. The retrospective design of this report relied on medical record documentation. Because of this, the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC AE) could not be employed reliably. Rather, when changes in care (e.g., dose changes, treatment delays, medication changes, hospitalizations, and addi- tional clinic visits) were required for management of ad- verse events, the change in care and the adverse events contributing to the change in care (e.g., fatigue, diarrhea, neutropenia) were recorded. Thus, when documented in the patient records as related to adverse events, we categorized dose changes, treatment delays, medication changes, hos- pitalizations, and additional clinic visits as “toxicity-related events.” The symptoms documented as leading to these events were recorded as “event-causing toxicities.” This provided a measure of the management of treatment com- plications and clinically significant adverse events, those resulting in changes in the treatment of the patients. For this analysis, treatment delays, hospitalizations, and dose changes related to adverse event management were analyzed as dichotomous (yes/no) variables. Toxicity-re- lated treatment delays were defined as any change from a planned treatment date that was related to toxicity. Statistical Analysis All statistical analyses were performed using JMP 6.0௡ software (SAS Corp., Cary, NC). Nominal data were com- pared using the ␹2 or Fisher’s exact test. Continuous, nor- mally distributed data were evaluated using the Student’s t-test; non-normally distributed data were evaluated using the Mann-Whitney U-test. It was determined that a sample size of 500 would provide at least 80% power to detect a 10% difference in the use of initial doublet therapy, assum- ing a two-sided ␣ of 0.05 and a ␹2 statistic. Logistic regression was performed to compute odds ra- tios (ORs) for the primary outcome of initial doublet che- motherapy. The following variables of interest were evaluated: age, disease status (recurrence versus new dis- ease), ECOG PS score, clinic site, and year of treatment ini- tiation. To control for confounding, variables significantly associated (p Ͻ .05) with initial doublet therapy in the ini- tial analysis were entered into a multivariate regression model to test whether age was a significant predictor after adjustment for all other variables in the model. Survival time was measured from the initiation of ther- apy for advanced CRC to the date of last follow-up or death. The Kaplan–Meier method was used to construct survival curves with the log-rank test for differences. The Cox pro- portional-hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for sur- vival, adjusted for potential confounders (initial doublet therapy and PS score). RESULTS Patient Population Five hundred twenty patients received 6,253 cycles of ther- apy. A range of 35–74 patients was included from each of 10 study sites. The median age was 66 years (range, 24–95 years) with 239 patients aged Յ65 years and 281 patients aged Ͼ65 years (Table 1). The baseline ECOG PS score was 0 or 1 for 76% of patients and 2 or 3 for 23% of patients. The PS score could not be determined for seven patients (1%). Fewer elderly patients had a baseline PS score of 0 (19% versus 37%; p Ͻ .001). In total, 298 patients (57%) were diagnosed with advanced CRC as new disease and 222 (43%) were diagnosed with recurrent CRC. Prior to chemo- therapy, 80% of patients underwent surgery—either as therapy for previous, lower-stage CRC or prior to chemo- therapy for newly diagnosed advanced CRC. Initial Therapy Among the elderly patients treated with chemotherapy for advanced CRC, 58% received doublet chemotherapy first line, compared with 84% of younger patients (p Ͻ .001) (Table 2). Furthermore, fewer elderly patients received ei- ther irinotecan with a fluoropyrimidine (15% versus 26%; p Ͻ .01) or oxaliplatin with a fluoropyrimidine (43% versus 58%; p Ͻ .001). In the first-line setting, significantly fewer cycles of chemotherapy were administered to the elderly patients than to the younger patients (median, 4 versus 7; p Ͻ .001). The top five regimens used first line in younger patients were (% of patients): 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (48%), irinotecan, 5-fluoroura- cil, and leucovorin (IFL) (13%), 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (10%), capecitabine plus oxali- platin (CapeOx) (9%), and the Roswell Park regimen (7%). This contrasted with the top five first-line regimens in the 878 Colorectal Cancer Therapy Among Elderly Patients byonOctober29,2010www.TheOncologist.comDownloadedfrom
  4. 4. elderly (% of patients): FOLFOX (31%), capecitabine (20%), Roswell Park (18%), CapeOx (12%), and IFL (10%). Among the 341 patients starting treatment after May 1, 2004, 44% of the elderly patients received bevacizumab combined with the first-line chemotherapy regimen, versus 63% of younger patients (p ϭ .001) (Table 2). Succeeding 5-year increments continued to demonstrate that smaller proportions of patients with advancing age were treated with initial doublet therapy or bevacizumab (Table 3). Logistic regression revealed an ECOG PS score of 2 or 3 to significantly reduce the odds of initial doublet therapy (OR, 0.42; 95% CI, 0.27–0.64). The variables of new disease, year of treatment initiation, and clinic site were not associated with initial doublet therapy. The fi- nal multivariate logistic regression model included age and PS score. In this model, the adjusted OR for the re- ceipt of initial doublet therapy for elderly patients was 0.29 (95% CI, 0.19–0.44) (Table 4). Models with in- creasing cutoffs for age consistently indicated a lower probability of receipt of doublet therapy with advanced age (Table 4). An initial PS score of 2 or 3 was also as- sociated with a lower likelihood of receiving initial dou- blet therapy in the final model, with an adjusted OR of 0.48 (95% CI, 0.31–0.75), compared with a PS score of 0 or 1. Table 1. Patient characteristics and prior therapy Characteristic Age < 65 Age > 65 p-value (n ‫؍‬ 239) (n ‫؍‬ 281) Age (range) 57 (24–65) 75 (66–95) – Performance status score 0 37% 19% Ͻ.001 1 47% 51% 2 16% 25% 3 1% 3% Unknown 1% 2% Male 56% 52% .4 Female 44% 48% Year of initial treatment 2003 22% 21% 2004 34% 34% .8 2005 28% 31% 2006 15% 14% 2007 1% 0% Median follow-up, days (range) 350 (13–1,358) 284 (1–1,238) .06 Disease status Recurrent 40% 45% .3 New diagnosis 60% 55% Prior therapy Surgery 79% 78% .8 None 21% 22% Prior therapy (recurrent disease only, n ϭ 222) 5-FU/leucovorin 74% 60% .04 5-FU/levamisole 6% 5% .8 Capecitabine 7% 5% .6 Irinotecan 17% 5% .01 Oxaliplatin 13% 3% .01 Radiation 27% 16% .07 Abbreviation: 5-FU, 5-fluorouracil. 879McKibbin, Frei, Greene et al. byonOctober29,2010www.TheOncologist.comDownloadedfrom
  5. 5. Overall Chemotherapy and Monoclonal Antibody Therapy Use Evaluating the entire course of therapy, significantly fewer elderly patients received oxaliplatin (62% versus 76%; p Ͻ .001), irinotecan (42% versus 56%; p ϭ .002), or bevaci- zumab (54% versus 72%; p Ͻ .001), compared with their younger counterparts. In the subgroup of patients receiving two or more lines of therapy (n ϭ 302), the elderly re- mained less likely to receive oxaliplatin (72% versus 87%; p ϭ .001), irinotecan (68% versus 78%; p ϭ .03), or bev- acizumab (57% versus 80%; p Ͻ .001) (Table 5). Coincid- ing with these data, fewer elderly patients in this subgroup received all three chemotherapy agents (irinotecan, oxali- platin, and a fluoropyrimidine) (48% versus 67%; p ϭ .001). The use of bevacizumab in younger patients re- mained higher in second- and third-line treatment (50% and 42%, respectively), compared with the elderly patients (35%, p Ͻ .01 and 26%, p ϭ .04, respectively). During the entire treatment course, significantly fewer cycles were ad- ministered to elderly patients than to younger patients— median (interquartile range), 8 (4–14) versus 12 (6–19); p Ͻ .001. Overall Survival Among the 520 patients, 192 deaths were recorded. The median survival time was estimated to be 19.1 months for elderly and 24.5 months for younger patients (p Ͻ .01) (Fig. 1). In the proportional hazards model, which included age, PS score, and initial doublet therapy, the adjusted HR for mortality for elderly patients was 1.19 (95% CI, 1.02–1.39; p ϭ .03) (Table 4). In this model, receipt of initial doublet therapy did not significantly reduce the hazard for mortality (HR, 0.96; 95% CI, 0.83–1.13; p ϭ .7). An initial PS score of 2 or 3 independently predicted a higher risk for mortality, compared with patients with a PS score of 0 or 1. Toxicity-Related Events Toxicity-related events were common in both groups. Overall, toxicity-related hospitalizations occurred in 21% of elderly patients, compared with 11% of younger patients (p Ͻ .01). Oxaliplatin plus a fluoropyrimidine resulted in significantly more elderly patients requiring hospitalization and additional clinic visits for the management of toxicity, compared with younger patients receiving the same cate- gory of treatment (Table 6). Of the elderly patients receiv- Table 2. Initial therapy received Age < 65 Age > 65 p-value (n ‫؍‬ 239) (n ‫؍‬ 281) Irinotecan or oxaliplatin plus a fluoropyrimidine 84% 58% Ͻ.001 Irinotecan plus a fluoropyrimidine 26% 15% Ͻ.01 Oxaliplatin plus a fluoropyrimidine 58% 43% Ͻ.001 Fluoropyrimidine alone 14% 39% Ͻ.001 n of cycles first-line, median (interquartile range) 7 (4–11) 4 (3–8) Ͻ.001 Patients treated after May 1, 2004 n of patients 156 185 Bevacizumab plus chemotherapy 63% 44% .001 Table 3. Additional age group therapy use—medications received during treatment course Age < 65 Age > 65 Age > 70 Age > 75 (n ‫؍‬ 239) (n ‫؍‬ 281) (n ‫؍‬ 205) (n ‫؍‬ 125) Initial doublet therapy 84% 58% 53% 42% Irinotecan 56% 42% 38% 32% Oxaliplatin 76% 62% 58% 50% Patients treated after May 1, 2004 n of patients 156 185 140 86 Bevacizumab 72% 54% 51% 48% Cetuximab 22% 18% 15% 17% 880 Colorectal Cancer Therapy Among Elderly Patients byonOctober29,2010www.TheOncologist.comDownloadedfrom
  6. 6. ing oxaliplatin and a fluoropyrimidine, 17% required additional clinic visits, compared with 8% of the younger patients (p ϭ .01), while 14% of the elderly patients re- quired hospitalization, compared with just 5% of the younger patients (p Ͻ .01). The use of irinotecan plus a fluoropyrimidine resulted in significantly more elderly patients requiring delays in treat- ment, compared with younger patients (59% versus 41%; p ϭ .02). Other toxicity-related endpoints did not differ sig- nificantly between younger and older patients in this regi- men category (Table 6). In the regimen category of a fluoropyrimidine alone, there were no significant differ- ences in toxicity-related events. Toxicity Leading to Clinical Events In the oxaliplatin and fluoropyrimidine category, diarrhea (32% versus 19%; p Ͻ .01) and dehydration (13% versus 6%; p ϭ .03) were significantly more prominent among the elderly patients (Table 7). Neurotoxicity events were more prevalent in the younger patients (26% versus 15%; p ϭ .02). Neutropenic events were also reported in more young patients than in the elderly (28% versus 18%; p ϭ .03). Of note, 35% of younger patients received a colony-stimulat- ing factor (G-CSF, PegG-CSF, or GM-CSF), compared with 18% of the elderly patients (p Ͻ .001). The use of erythropoiesis-stimulating agents was not different be- tween elderly and younger patients, with 47% of the el- derly and 42% of the younger patients receiving these agents (p ϭ .2). In the irinotecan and a fluoropyrimidine category, el- derly patients were more likely to have diarrhea (56% ver- sus 31%; p ϭ .001) and fatigue-related events (36% versus 17%; p Ͻ .01) reported (Table 7). There were trends toward more dehydration and more hydration days in the elderly patients, but these did not reach statistical significance. In the fluoropyrimidine alone category, diarrhea was the most frequently recorded toxicity for elderly and younger patients. There were no significant differences in the toxic- ities reported in this category. DISCUSSION This investigation reflects recent prescribing patterns and outcomes for elderly advanced CRC patients, a large seg- ment of the advanced CRC population that is often under- Table 4. Analysis of initial doublet therapy and overall survival Initial doublet therapya Unadjusted odds ratio 95% confidence interval p-value Adjusted odds ratio 95% confidence interval p-value Age Յ65 Reference Reference Ͼ65 0.27 0.18–0.41 Ͻ.001 0.29 0.19–0.44 Ͻ.001 Ͼ70 0.26 0.17–0.38 Ͻ.001 0.28 0.19–0.42 Ͻ.001 Ͼ75 0.19 0.13–0.3 Ͻ.001 0.19 0.13–0.31 Ͻ.001 Performance status score 0 or 1 Reference Reference 2 or 3 0.42 0.27–0.64 Ͻ.001 0.48 0.31–0.75 .001 Overall survivalb Unadjusted hazard ratio 95% confidence interval p-value Adjusted hazard ratio 95% confidence interval p-value Age Յ65 Reference Reference Ͼ65 1.23 1.07–1.43 .004 1.19 1.02–1.39 .03 Performance status score 0 or 1 Reference Reference 2 or 3 1.68 1.44–1.95 Ͻ.001 1.65 1.41–1.91 Ͻ.001 Initial doublet therapy 0.87 0.76–1.02 .09 0.96 0.83–1.13 .7 aUsing logistic regression. bUsing the Cox proportional hazards model. 881McKibbin, Frei, Greene et al. byonOctober29,2010www.TheOncologist.comDownloadedfrom
  7. 7. represented in clinical trials. As is evident by differences in the initial regimen, the approach to the treatment of elderly patients appears to differ significantly from that of younger patients. The elderly patients in this large, community- based study were less likely to receive initial doublet che- motherapy than younger patients. Further, they were less likely to receive irinotecan, oxaliplatin, and bevacizumab during the entire treatment course. Current literature recommends that age should not be the lone deciding factor in the treatment of advanced CRC [16]. Age may not accurately predict physiologic function, and varying levels of functional decline exist in elderly pa- tients of a given age [3, 17]. Nevertheless, the underrepre- sentation of the elderly in clinical trials generates questions regarding the benefits and risks associated with intensive treatment in this population [5, 18]. Multiple, well-de- signed, randomized, controlled clinical trials have investi- gated the therapy for advanced CRC [16, 19], but few investigations have reported the actual use and outcomes of these therapies in clinical practice. In an evaluation of 449 patients identified in the British Columbia Cancer Agency Registry between 2000 and 2002, Ho et al. [20] reported age to be a factor in the use of first-line therapy. In their obser- vation, the elderly were less likely to receive chemotherapy overall. When treated, the elderly were less likely to receive combination chemotherapy. However, data were limited to first-line treatment and did not account for sequential use of therapies over the treatment course. This report contained a higher proportion of poor PS pa- tients (23% PS score Ն2) than the larger, randomized, con- trolled trials reported in advanced CRC patients (Ͻ1%– 12% PS score 2) [6, 8, 10–13, 21–24]. In addition, the median age in our report is older than those reported in many of those same trials. This suggests that the population treated in the community may differ significantly from the Figure 1. Kaplan–Meier survival curve of advanced colorec- tal cancer patients by age group. Table 5. Overall chemotherapy and monoclonal antibody use Age < 65 Age > 65 p-value (n ‫؍‬ 239) (n ‫؍‬ 281) Lines of therapy received 1 100% 100% .6 2 59% 57% 3 32% 26% 4 17% 10% Ն5 7% 3% Fluoropyrimidinea 99% 99% .7 Irinotecana 78% 68% .03 Oxaliplatina 87% 72% .001 Received fluoropyrimidine, oxaliplatin, and irinotecana 67% 48% .001 Bevacizumab at anytimeb 72% 54% Ͻ.001 Cetuximab at anytimeb 22% 18% .5 a Includes only patients receiving two or more lines of therapy (n ϭ 302). b Includes only patients starting treatment after May 1, 2004 (n ϭ 341). 882 Colorectal Cancer Therapy Among Elderly Patients byonOctober29,2010www.TheOncologist.comDownloadedfrom
  8. 8. population represented in clinical trials, on which treatment recommendations are based. Despite these factors, the overall survival time esti- mated in this population approximated that reported in clin- ical trials, although survival was shorter in the elderly patients [13, 24]. The receipt of initial doublet therapy did not lead to a lower risk for mortality. This may be related to the sequential use of therapies in clinics, diluting the benefit of initial doublet therapy and leaving this analysis under- powered to find a small, but potentially meaningful, differ- ence. The nonrandomized population and retrospective design may have further confounded this result. Another possibility is that this population, on average older and with a poorer PS, did not benefit substantially from initial dou- blet therapy. However, this interpretation would need fur- ther confirmation in well-designed prospective trials. A poorer PS was an independent predictive factor for a lower likelihood of receiving initial doublet therapy and, coinciding with previous reports, a higher risk for mortality [25–27]. Few clinical trials explore treatment options for patients with a PS score of 2 or 3; further investigations re- garding eligibility for treatment and the optimal treatment of these patients are needed [28]. Measures such as the Comprehensive Geriatric Assessment (CGA) may be used to evaluate eligibility for treatment in the elderly [29]. However, few clinical trials report CGA measures, limiting its current value in the clinic [30]. Because few elderly patients are enrolled in randomized clinical trials, safety and efficacy data stem largely from pooled and post-hoc analyses [6, 7, 9]. In reports by Gold- berg et al. [6], Folprecht et al. [9], and Chau et al. [7], there were few differences in the incidence of grade Ն3 adverse events across age groups when measured by the NCI CTC AE, with the exception of slightly higher rates of neutrope- nia in the elderly. Interestingly, in this report, neutropenia and neurotoxicity had a significant impact on the treatment Table 6. Toxicity-related events by regimen category and age Toxicity-related events Fluoropyrimidine alonea Irinotecan plus a fluoropyrimidinea Oxaliplatin plus a fluoropyrimidinea Age < 65 Age > 65 p-value Age < 65 Age > 65 p-value Age < 65 Age > 65 p-value (n ‫؍‬ 87) (n ‫؍‬ 156) (n ‫؍‬ 99) (n ‫؍‬ 73) (n ‫؍‬ 178) (n ‫؍‬ 169) Hospitalization 6 10 .3 11 16 .3 5 14 Ͻ.01 Clinic visit 5 6 .8 12 15 .6 8 17 .01 Treatment delay 32 35 .7 41 59 .02 59 58 .9 Dose change 18 26 .2 31 30 .9 34 31 .6 Medication discontinuation 12 17 .3 21 23 .8 21 27 .2 a Percentage of patients affected. Table 7. Event-causing toxicity by regimen category and age Event-causing toxicity Fluoropyrimidine alonea Irinotecan plus a fluoropyrimidinea Oxaliplatin plus a fluoropyrimidinea Age <65 Age >65 p-value Age <65 Age >65 p-value Age <65 Age >65 p-value (n ‫؍‬ 87) (n ‫؍‬ 156) (n ‫؍‬ 99) (n ‫؍‬ 73) (n ‫؍‬ 178) (n ‫؍‬ 169) Neutropenia 5 5 .9 19 19 .9 28 18 .03 Thrombocytopenia 6 6 .9 6 2 .1 17 17 .9 Anemia 2 4 .7 7 3 .3 4 2 .3 Nausea and vomiting 10 14 .4 13 17 .4 14 17 .4 Diarrhea 23 30 .3 31 56 .001 19 32 Ͻ.01 Dehydration 7 10 .5 7 18 .09 6 13 .03 Hydration day 6 7 .7 10 21 .055 11 16 .2 Asthenia/fatigue 16 13 .5 17 36 Ͻ.01 24 22 .8 Neurotoxicity – – – – 26 15 .02 a Percentage of patients affected. 883McKibbin, Frei, Greene et al. byonOctober29,2010www.TheOncologist.comDownloadedfrom
  9. 9. of younger patients, particularly with regimens combining oxaliplatin with a fluoropyrimidine. The elderly patients had more events related to gastrointestinal symptoms, namely diarrhea, associated with doublet therapies. More elderly patients also required hospitalization for toxicity; this was a consistent trend across all treatment categories, with the oxaliplatin plus a fluoropyrimidine category reach- ing statistical significance. A potential explanation for this departure from the re- sults reported in clinical trials is the method used for cap- turing adverse event data. While clinical trials are able to prospectively and objectively assess toxicity, this report re- lied on documentation of toxicities related to specific, clin- ically relevant events (hospitalizations, dose changes, treatment delays, medication discontinuations, and addi- tional clinic visits). While these data may not reflect objec- tive measures, they reflect the impact of toxicities as drivers for clinical decisions. Objective data regarding adverse events impart valuable information, but alone do not con- vey information regarding the management of these events, which affect the majority of patients. In this report, nearly three of every four patients treated with combination che- motherapy and one half of the patients treated with fluoro- pyrimidines required a change in the treatment plan or additional hospitalizations or clinic visits for the manage- ment of toxicity. Data regarding comorbidities, which are known to oc- cur more frequently in the elderly, were not consistently available and not evaluated in this report [30]. The presence of comorbidities may have contributed to the poorer PS we observed in the elderly, may have contributed to poor pa- tient tolerance of therapy, may have precluded the ability to administer doublet chemotherapy in some, and is an impor- tant factor to consider when interpreting these results [31]. The conclusions that can be drawn from these data are limited. Patients were not randomized to treatment proto- cols, and the retrospective design lends itself to potential bi- ases. While objective measures of toxicity were not possible, the data reflect clinical practice and real-world management of treatment. These data suggest that elderly patients are more likely to require hospitalization for the management of toxicity related to therapy for advanced CRC. In conclusion, the elderly patients in this large, multi- center study were less likely to receive first-line doublet chemotherapy than younger patients. Overall, the elderly were more likely to experience a toxicity-related hospital- ization during the total course of care. A poorer PS was an additional predictor of both therapies received and a higher risk for mortality. Further investigations of suitable treat- ment selection in the elderly and those with a PS score of 2 or 3 are warranted and will aid in the appropriate manage- ment of these patients. AUTHOR CONTRIBUTIONS Conception/design: Trevor McKibbin, Christopher R. Frei, Rebecca E. Greene, Peter Kwan, Jody Simon, Jim M. Koeller Administrative support: Jim M. Koeller Collection/assembly of data: Trevor McKibbin, Peter Kwan, Jody Simon, Jim M. Koeller Data analysis and interpretation: Trevor McKibbin, Christopher R. Frei, Rebecca E. Greene, Peter Kwan, Jim M. Koeller Manuscript writing: Trevor McKibbin, Christopher R. Frei, Rebecca E. Greene, Peter Kwan, Jody Simon, Jim M. Koeller Final approval of manuscript: Trevor McKibbin, Christopher R. Frei, Rebecca E. Greene, Peter Kwan, Jody Simon, Jim M. Koeller ACKNOWLEDGMENTS The authors would like to thank Junling Wang, Ph.D., for her consultation regarding statistical analysis. REFERENCES 1 Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–130. 2 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 1999;341: 2061–2067. 3 Pasetto LM, Stefano T, Rossi E et al. Treatment of stage IV colorectal car- cinoma in elderly patients. Crit Rev Oncol Hematol 2005;54:145–155. 4 Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical tri- als for cancer drug registration: A 7-year experience by the US Food and Drug Administration. J Clin Oncol 2004;22:4626–4631. 5 Townsley CA, Selby R, Siu LL. Systematic review of barriers to the re- cruitment of older patients with cancer onto clinical trials. J Clin Oncol 2005;23:3112–3124. 6 Goldberg RM, Tabah-Fisch I, Bleiberg H et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bi- monthly in elderly patients with colorectal cancer. J Clin Oncol 2006;24: 4085–4091. 7 Chau I, Norman AR, Cunningham D et al. Elderly patients with fluoropy- rimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy. Br J Cancer 2004;91:1453–1458. 8 Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 2004;22:229–237. 9 Folprecht G, Cunningham D, Ross P et al. Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: A pooled analysis of clinical trials. Ann Oncol 2004;15:1330–1338. 10 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 2000;18:2938–2947. 11 Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with flu- orouracil compared with fluorouracil alone as first-line treatment for met- 884 Colorectal Cancer Therapy Among Elderly Patients byonOctober29,2010www.TheOncologist.comDownloadedfrom
  10. 10. astatic colorectal cancer: A multicentre randomised trial. Lancet 2000;355: 1041–1047. 12 Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucov- orin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–914. 13 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinote- can, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342. 14 Van Cutsem E, Nowacki M, Lang I. Randomized phase III study of irino- tecan and fluorouracil/FA with or without cetuximab in the first-line treat- ment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol 2007;25(suppl 18):164s. 15 Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxalipla- tin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005;23:9441–9442. 16 Sanoff HK, Bleiberg H, Goldberg RM. Managing older patients with colo- rectal cancer. J Clin Oncol 2007;25:1891–1897. 17 Wasil T, Lichtman SM. Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. The Oncologist 2005; 10:602–612. 18 Aapro MS, Köhne CH, Cohen HJ et al. Never too old? Age should not be a barrier to enrollment in cancer clinical trials. The Oncologist 2005;10:198– 204. 19 Goldberg RM. Therapy for metastatic colorectal cancer. The Oncologist 2006;11:981–987. 20 Ho C, O’Reilly S, Ng K et al. Population-based analysis of patients with advanced colorectal cancer: The impact of age on treatment and outcomes. J Clin Oncol 2005;23(suppl 16):274s. 21 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 On- col 2004;22:23–30. 22 Borner MM, Bernhard J, Dietrich D et al. A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: Efficacy, quality-of-life and toxicity. Ann Oncol 2005;16:282–288. 23 Colucci G, Gebbia V, Paoletti G et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 2005;23:4866–4875. 24 Hochster HS, Hart LL, Ramanathan RK et al. Safety and efficacy of oxali- platin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study. J Clin Oncol 2006;24(suppl 18):148s. 25 Burrows J, Lammersfeld C, Dahik S et al. Impact of self-reported perfor- mance status on survival in advanced colorectal cancer. J Clin Oncol 2004; 22(suppl 14):309s. 26 Köhne CH, Cunningham D, Di CF et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal can- cer: Results of a multivariate analysis of 3825 patients. Ann Oncol 2002; 13:308–317. 27 Mitry E, Douillard JY, Van Cutsem E et al. Predictive factors of survival in patients with advanced colorectal cancer: An individual data analysis of 602 patients included in irinotecan phase III trials. Ann Oncol 2004;15: 1013–1017. 28 Benavides M, García-Alfonso P, Cobo M et al. Weekly irinotecan (CPT- 11) in 5-FU heavily pretreated and poor-performance-status patients with advanced colorectal cancer. Med Oncol 2004;21:255–262. 29 Repetto L, Fratino L, Audisio RA et al. Comprehensive geriatric assess- ment adds information to Eastern Cooperative Oncology Group perfor- mance status in elderly cancer patients: An Italian Group for Geriatric Oncology Study. J Clin Oncol 2002;20:494–502. 30 Hurria A, Lichtman SM, Gardes J et al. Identifying vulnerable older adults with cancer: Integrating geriatric assessment into oncology practice. J Am Geriatr Soc 2007;55:1604–1608. 31 Extermann M, Hurria A. Comprehensive geriatric assessment for older pa- tients with cancer. J Clin Oncol 2007;25:1824–1831. 885McKibbin, Frei, Greene et al. byonOctober29,2010www.TheOncologist.comDownloadedfrom
  11. 11. DOI: 10.1634/theoncologist.2008-0061 2008;13;876-885; originally published online Aug 11, 2008;Oncologist and Jim M. Koeller Trevor McKibbin, Christopher R. Frei, Rebecca E. Greene, Peter Kwan, Jody Simon Setting Elderly Advanced Colorectal Cancer Patients in the Community Oncology Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for This information is current as of October 29, 2010 & Services Updated Information including high-resolution figures, can be found at: byonOctober29,2010www.TheOncologist.comDownloadedfrom