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Gastrointestinal Cancer

Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting

^aUniversity of Tennessee Health Science Center, Memphis, Tennessee, USA; ^bUniversity of Texas at Austin College of Pharmacy, Austin, Texas, USA; ^cUniversity of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; ^dGeriatric Oncology Consortium, Baltimore, Maryland, USA

Key Words. Colorectal cancer • Elderly • Bevacizumab • Oxaliplatin • Irinotecan • Disparity

Correspondence: Trevor McKibbin, Pharm.D., M.Sc., College of Pharmacy, University of Tennessee Health Science Center, 930 Madison Suite 890, Memphis, Tennessee 38163, USA. Telephone: 901-448-7632; Fax: 901-448-5419; e-mail: tmckibbi{at}utmem.edu

Received March 12, 2008; accepted for publication June 28, 2008; first published online in THE ONCOLOGIST Express on August 11, 2008.

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

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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.
   

	ABSTRACT

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Background. The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment 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 medical 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 chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age 65 years) and elderly (age >65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab 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, compared 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.

	INTRODUCTION

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Colorectal cancer (CRC) is primarily a disease of the elderly, with a median age at diagnosis of 71 years [1]. Numerous 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]. Selective entry criteria and the patient referral process contribute 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 analyses [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 intensive therapies in this population. Nevertheless, many elderly cancer patients in U.S. community oncology clinics receive treatment. It is therefore of interest to investigate how age impacts the treatment of advanced CRC in community oncology clinics and what outcomes are attained 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 fluoropyrimidine therapy [10–12]. The monoclonal antibodies bevacizumab and cetuximab have contributed further improvements in the response rate and overall survival when combined with chemotherapy [13, 14]. A meta-analysis 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, patients initiated on doublet therapy (irinotecan or oxaliplatin combined with a fluoropyrimidine) were more likely to receive at least three active medications (5-fluorouracil, irinotecan, and oxaliplatin). Thus, the objective of this study was to report the use of initial doublet therapy in elderly advanced CRC patients compared with younger patients. The hypothesis was that fewer elderly patients received doublet therapy and monoclonal antibody therapy first-line for advanced CRC, compared with younger patients.

	METHODS

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A national retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community 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 independent 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 diagnosed with advanced CRC and initiating chemotherapy treatment after January 1, 2003 through 2006 were included.

The primary objective was to compare the proportion of patients receiving doublet chemotherapy (irinotecan or oxaliplatin combined with a fluoropyrimidine) as initial therapy in young (age 65 years) and elderly (age >65 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, medication 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 standardized 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). Because of variability among the regimens used in the clinics, chemotherapeutic regimens were grouped into three categories: (a) oxaliplatin and a fluoropyrimidine, (b) irinotecan and a fluoropyrimidine, and (c) a fluoropyrimidine alone. The monoclonal antibodies bevacizumab and cetuximab 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 additional clinic visits) were required for management of adverse 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, hospitalizations, 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 complications 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-related 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 compared using the ² or Fisher's exact test. Continuous, normally 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, assuming a two-sided of 0.05 and a ² statistic.

Logistic regression was performed to compute odds ratios (ORs) for the primary outcome of initial doublet chemotherapy. The following variables of interest were evaluated: age, disease status (recurrence versus new disease), ECOG PS score, clinic site, and year of treatment initiation. To control for confounding, variables significantly associated (p < .05) with initial doublet therapy in the initial 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 therapy 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 proportional-hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for survival, adjusted for potential confounders (initial doublet therapy and PS score).

	RESULTS

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Patient Population
Five hundred twenty patients received 6,253 cycles of therapy. 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 65 years and 281 patients aged >65 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 < .001). In total, 298 patients (57%) were diagnosed with advanced CRC as new disease and 222 (43%) were diagnosed with recurrent CRC. Prior to chemotherapy, 80% of patients underwent surgery—either as therapy for previous, lower-stage CRC or prior to chemotherapy for newly diagnosed advanced CRC.

View larger version (24K): [in this window] [in a new window]   Figure 1. Kaplan–Meier survival curve of advanced colorectal cancer patients by age group.

Toxicity Leading to Clinical Events
In the oxaliplatin and fluoropyrimidine category, diarrhea (32% versus 19%; p < .01) and dehydration (13% versus 6%; p = .03) were significantly more prominent among the elderly patients (Table 7). Neurotoxicity events were more prevalent in the younger patients (26% versus 15%; p = .02). Neutropenic events were also reported in more young patients than in the elderly (28% versus 18%; p = .03). Of note, 35% of younger patients received a colony-stimulating factor (G-CSF, PegG-CSF, or GM-CSF), compared with 18% of the elderly patients (p < .001). The use of erythropoiesis-stimulating agents was not different between elderly and younger patients, with 47% of the elderly and 42% of the younger patients receiving these agents (p = .2).

In the fluoropyrimidine alone category, diarrhea was the most frequently recorded toxicity for elderly and younger patients. There were no significant differences in the toxicities reported in this category.

	DISCUSSION

Top Learning Objectives Abstract Introduction Methods Results Discussion Author Contributions Acknowledgments References

 
This investigation reflects recent prescribing patterns and outcomes for elderly advanced CRC patients, a large segment of the advanced CRC population that is often underrepresented 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 chemotherapy 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 patients of a given age [3, 17]. Nevertheless, the underrepresentation of the elderly in clinical trials generates questions regarding the benefits and risks associated with intensive treatment in this population [5, 18]. Multiple, well-designed, randomized, controlled clinical trials have investigated 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 observation, 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 patients (23% PS score 2) than the larger, randomized, controlled trials reported in advanced CRC patients (<1%–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 population represented in clinical trials, on which treatment recommendations are based.

Despite these factors, the overall survival time estimated in this population approximated that reported in clinical 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 underpowered to find a small, but potentially meaningful, difference. 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 doublet therapy. However, this interpretation would need further 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 regarding 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 Goldberg et al. [6], Folprecht et al. [9], and Chau et al. [7], there were few differences in the incidence of grade 3 adverse events across age groups when measured by the NCI CTC AE, with the exception of slightly higher rates of neutropenia in the elderly. Interestingly, in this report, neutropenia and neurotoxicity had a significant impact on the treatment 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 reaching statistical significance.

A potential explanation for this departure from the results reported in clinical trials is the method used for capturing adverse event data. While clinical trials are able to prospectively and objectively assess toxicity, this report relied on documentation of toxicities related to specific, clinically relevant events (hospitalizations, dose changes, treatment delays, medication discontinuations, and additional clinic visits). While these data may not reflect objective measures, they reflect the impact of toxicities as drivers for clinical decisions. Objective data regarding adverse events impart valuable information, but alone do not convey 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 chemotherapy and one half of the patients treated with fluoropyrimidines required a change in the treatment plan or additional hospitalizations or clinic visits for the management of toxicity.

Data regarding comorbidities, which are known to occur 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 patient tolerance of therapy, may have precluded the ability to administer doublet chemotherapy in some, and is an important 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 protocols, and the retrospective design lends itself to potential biases. 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, multicenter study were less likely to receive first-line doublet chemotherapy than younger patients. Overall, the elderly were more likely to experience a toxicity-related hospitalization 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 treatment selection in the elderly and those with a PS score of 2 or 3 are warranted and will aid in the appropriate management of these patients.

	AUTHOR CONTRIBUTIONS

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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

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The authors would like to thank Junling Wang, Ph.D., for her consultation regarding statistical analysis.

	REFERENCES

Top Learning Objectives Abstract Introduction Methods Results Discussion Author Contributions Acknowledgments References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: theoncologist.2008-0061v1 theoncologist.2008-0061v2 13/8/876    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McKibbin, T. Articles by Koeller, J. M. Search for Related Content PubMed PubMed Citation Articles by McKibbin, T. Articles by Koeller, J. M.