Originally published as JCO Early Release 10.1200/JCO.2005.04.5005 on April 17 2006

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Duration of Adjuvant Chemotherapy for Colon Cancer and Survival Among the Elderly

Alfred I. Neugut, Matthew Matasar, Xiaoyan Wang, Russell McBride, Judith S. Jacobson, Wei-Yann Tsai, Victor R. Grann, Dawn L. Hershman

From the Department of Medicine and the Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, and the Departments of Epidemiology and Biostatistics, Mailman School of Public Health, Columbia University; and the New York Presbyterian Hospital, New York, NY

Address reprint requests to Alfred I. Neugut, MD, PhD, Division of Medical Oncology, Columbia University Medical Center, 722 W 168th St, Rm 725, New York, NY 10032; e-mail: ain1{at}columbia.edu

	ABSTRACT

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Purpose In randomized trials, patients with stage III colon cancer who received 6 months of fluorouracil (FU)-based adjuvant chemotherapy had better survival than patients who did not. However, little is known about the predictors of, or the survival associated with, duration of chemotherapy in the community.

Patients and Methods The linked Surveillance, Epidemiology, and End Results-Medicare database was used to identify individuals 65 years of age diagnosed with stage III colon cancer between 1995 and 1999. We used logistic and Cox proportional hazards regression models to analyze factors associated with early discontinuation of FU-based chemotherapy among these elderly colon cancer patients.

Results Among 1,722 patients who received 1 to 7 months of FU-based chemotherapy, older age, being unmarried, and having comorbid conditions were associated with receiving less than 5 months of treatment. Among the 1,579 patients who survived 8 months, the 1,091 (69.1%) who received 5 to 7 months of treatment had lower overall (hazard ratio [HR], 0.59; 95%, CI 0.49 to 0.71) and colon cancer-specific (HR, 0.53; 95% CI, 0.43 to 0.66) mortality than the 488 (30.9%) who received 1 to 4 months of treatment.

Conclusion More than 30% of elderly patients who initiated FU-based chemotherapy for stage III colon cancer and survived for at least 8 months discontinued treatment early. Mortality rates among such patients were nearly twice as high as among patients who completed 5 to 7 months of treatment. If the association we observed between duration of treatment and survival is confirmed, additional investigation is warranted to determine whether dose-intensity, cumulative dose, or other factors related to receipt of full adjuvant treatment are responsible.

	INTRODUCTION

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The use of adjuvant chemotherapy for localized breast cancer and colon cancer has been among the most important advances in medical oncology in terms of lives saved.^1-3 For breast cancer adjuvant chemotherapy, studies have shown that patients who receive dose-intense treatment fare better than those who do not. Bonadonna et al⁴ demonstrated that the benefit of adjuvant chemotherapy was limited to patients who received 85% of the optimal dose, and that patients who received less treatment fared no better than those who received none. Large-scale clinical trials have established that dose reductions, delays, or interruptions of chemotherapy for breast cancer can reduce its benefits.^5-7 However, as many as 50% of patients either fail to initiate or do not receive all their recommended cycles of chemotherapy in a timely fashion.^8,9 Our group recently found that among women with breast cancer who initiated adjuvant chemotherapy, 28% terminated treatment early and that the earlier they terminated treatment, the higher was their mortality hazard ratio compared to those who completed treatment.¹⁰

Colon cancer is a significant public health problem in the United States. Among individuals age older than 75 years, it is the most frequently diagnosed malignancy^11,12 and the second leading cause of cancer death.^13-15 In the 1980s, the combination of fluorouracil (FU) with biochemically modulating agents, such as levamisole or folinic acid, was shown to extend survival for locally advanced stage III colon cancer.¹⁶ A meta-analysis confirmed the benefits of such chemotherapy for the elderly.¹⁷ Even before the North Central Cancer Treatment Group–National Cancer Institute of Canada trial reported that patients treated for 12 months do not fare better than those who received 6 months of adjuvant chemotherapy, 6 months of treatment was becoming accepted as the standard of care.³ No consensus has emerged at this time regarding the optimal dose-intensity of bolus FU.

We, and others, have found that elderly patients benefit as much from FU-based adjuvant chemotherapy as do younger node-positive colon cancer patients treated during clinical trials, but that 50% or more of elderly patients with stage III colon cancer do not receive treatment.^18-20

Since 1995, the standard of care for the adjuvant treatment of node-positive colon cancer has been FU-based chemotherapy administered for about 6 months,^16,21 but no studies have explored the prevalence and effects of early termination. Therefore, we have analyzed the frequency, determinants, and outcomes of early discontinuation of FU-based chemotherapy in a nationwide sample of elderly colon cancer patients.

	PATIENTS AND METHODS

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Data Source
Our analysis used a database developed by Potosky et al²² in 1993, in which the files of patients with cancer from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry were linked with their Medicare claims files. The SEER database provides information on tumor histology, location, stage of disease, and individual demographics, as well as primary surgical and radiation treatment and survival data for cancers occurring in a representative sample (approximately 14% during the period of our study) of the US population. The Medicare database, maintained by the Health Care Finance Administration (HCFA) complements the SEER data with extensive diagnostic, treatment, and cost information.

Sample Selection
We identified all individuals in the linked SEER-Medicare database diagnosed with primary colon cancer in the years 1995 to 1999 (n = 42,249), at age 65 years (n = 37,028), and in American Joint Cancer Committee stage III (n = 7975). We excluded 2,894 patients who were enrolled in a health maintenance organization (HMO) at any point from 12 months before to 8 months after initiation of FU chemotherapy or, for patients who did not receive FU, after surgery (HCFA does not collect claims data from risk-based HMOs) and/or were not covered by Medicare Parts A and B at any point during that time period. Of the remaining 5,081 patients, we also excluded 483 patients who did not have positive regional nodes confirmed on pathology and surgical resection of the tumor. We also excluded 57 who received chemotherapy that did not include FU and 808 who received more than 7 months of treatment because they could not be distinguished from patients intended to receive longer (eg, 12 month) regimens.

The remaining patients were categorized by duration of treatment, age group at diagnosis, year of diagnosis, race/ethnicity, sex, marital status, number of positive lymph nodes, tumor grade (well/moderately differentiated or poorly differentiated), comorbidity score, residence (metropolitan or nonmetropolitan area), the type of hospital in which they were diagnosed (teaching or nonteaching), and the socioeconomic status (SES) of their census tract/zip code.

We obtained data on age, race, sex, marital status, surgery, stage, tumor grade, lymph nodes, type of hospital, and area of residence from the SEER database, and data on comorbid conditions and treatment from Medicare.

Treatment With FU
Using HCFA codes and the Common Procedure Coding System (HCPCS code), we identified patients who had received FU (level II HCPCS J9190) either in a physician’s office or at an outpatient department within a hospital. Those who began FU within 120 days of their cancer diagnosis were classified as receiving adjuvant FU treatment. For patients who did not receive FU, we assessed whether level II HCPCS codes or International Classification of Diseases (9th revision, clinical modification [ICD9-CM] diagnostic codes from their physician claims files showed evidence of other chemotherapy delivery. Treatment duration was measured as the number of months between the first and last FU chemotherapy claims in patients who received no more than 7 months of treatment. The number of doses and the route of chemotherapy administration were not recorded. The validity of SEER-Medicare claims data for chemotherapy use in general, and FU use in particular, has been described previously.^23,24

SES
We generated an aggregate SES score from a hierarchy of income data from the 2000 census, following the method described by Bach et al.²⁵ Patients were ranked on a 1 to 5 scale, where 1 was the lowest value, based on a formula incorporating as many of the following as were available: median income in the census tract of residence, median income in the zip code of residence, census tract per capita income, and zip code per capita income; patients for whom all of these values were missing were assigned to the lowest SES category.

Comorbid Disease
To assess the prevalence of comorbid disease in our cohort, we used the Klabunde adaptation of the Charlson comorbidity index.^26-28 Medicare inpatient and outpatient claims were searched for ICD9-CM diagnostic codes indicating a history of myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, peptic ulcer disease, mild to severe liver disease, diabetes with/without end organ damage, hemiplegia, moderate or severe renal disease, or AIDS in the Medicare files from 12 months before to 1 month after their diagnosis of cancer. Each condition was weighted, and patients were assigned a score based on the Klabunde-Charlson index.²⁸

Survival
Survival time was calculated as the number of months from the cancer diagnosis date to the Medicare date of death. Those surviving past December 30, 2000, were classified as censored (alive at the end of follow-up) and contributed the time interval from their diagnosis date to the end of follow-up to the survival analysis. We used the SEER determination of cause of death from colon cancer using ICD8, ICD9, and ICD10. SEER updates these files annually.

Statistical Analysis
We used ² tests to compare patients who received 1 to 4 months and 5 to 7 months of treatment, with respect to the variables listed above. We then developed proportional hazards regression models to analyze the mortality associated with each incremental month of treatment, compared with no treatment. Among patients who received 1 to 7 months of treatment, we used logistic regression to estimate odds ratios (ORs) and 95% CIs for factors associated with receiving 5 to 7 versus 1 to 4 months of FU chemotherapy and with dying in the first 8 months given the baseline risk factors. We then excluded patients who died within the first 8 months from our analysis and developed Cox proportional hazards models to compare colon cancer–specific and overall mortality rates among patients who received 5 to 7 months of treatment with those for patients treated for 1 to 4 months, controlling for the baseline risk factors.

Propensity scoring is a technique used to measure the likelihood that a patient will be treated solely based on that patient’s independent predictors of treatment.²⁹ We used the coefficients for the predictors of 5 to 7 months (v 1 to 4 months) of treatment to assign to each patient a composite propensity score that could be used in lieu of the covariates included in the multivariable proportional hazards analysis. We added any covariates that remained statistically significant to the propensity score-adjusted model. The hazard ratio for the association of treatment duration with mortality derived from the propensity score–adjusted model did not differ appreciably from that derived from the multivariate analysis. We decided to present the multivariable analysis results because they include information about the association of mortality with the covariates.

Unadjusted Kaplan-Meier analyses were used to compare the two treatment groups with respect to colon cancer–specific and overall survival.

	RESULTS

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Baseline Characteristics of the Analysis Group
Of the 3,733 patients in the SEER-Medicare database who received a pathologically confirmed diagnosis of stage III colon cancer and were not members of an HMO during 1995 to 1999, most were non-Hispanic whites (86.5%), resided in a metropolitan area (87.6%), and were treated in nonteaching hospitals (79.1%; Table 1).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Proportional hazards ratios for mortality given each incremental month of treatment, compared with no treatment, among 1,579 patients who survived more than 8 months after diagnosis and received 1 to 7 months of adjuvant fluorouracil (FU) chemotherapy.

View this table: [in this window] [in a new window]   Table 2. Association of Demographic and Clinical Characteristics With 5-7 Months of Treatment Among All Patients Initiating FU*

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Kaplan-Meier colon cancer–specific survival among patients who survived more than 8 months after diagnosis, by duration of treatment. (B) Kaplan-Meier overall survival among patients who survived more than 8 months after diagnosis, by duration of treatment.

	DISCUSSION

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In a prior study by our group,¹⁹ mortality among patients who received any adjuvant FU was 37% lower than among those who received surgery alone. Our current analysis suggests that the benefit we observed previously was driven by patients who completed 6 months of treatment, consistent with the results of randomized trials.³

Some prior studies have found that black patients are less likely than white patients to initiate adjuvant therapy in the treatment of both breast cancer⁹ and colorectal cancer.^18,19 Our group has also observed an association between race and early termination of breast cancer treatment.¹⁰ However, other investigators have found inconsistent associations between treatment adherence and race or SES.^30,31 Although there was a trend toward more early discontinuation of chemotherapy among black patients (OR, 1.56; 95% CI, 0.98 to 2.48), race was not significantly associated with mortality.

The literature on the quality of colon cancer treatment in relation to survival is sparse. One study of treatment compliance in 139 patients who were to receive 12 cycles of adjuvant chemotherapy for stage III colon cancer found that, among patients who received six or more cycles, the recurrence rate was 7%; among those who received five or fewer cycles, the recurrence rate was 36%, suggesting that survival was associated with the cumulative dose of FU.³² In randomized clinical trials, in which adherence is known to be higher than in the community, 15% to 30% of patients also fail to complete all of the prescribed cycles of FU-based chemotherapy^33-35; dose reductions occurred frequently after the first two cycles.³⁴ Six months of chemotherapy appears to be as effective as 12 months of therapy.³ In a recent trial, 3 months of continuous-infusion FU appeared to be as effective as 6 months of bolus FU³⁶; however, the participants included both patients with stage II disease and patients who were treated with radiation therapy for rectal cancer. No other studies have analyzed the effects of limited bolus FU treatment with mortality.

Our findings in this population-based sample of patients with colon cancer are strikingly similar to our findings and those of others among patients with breast cancer.^4,10,37 We found that, like many breast cancer patients, many colon cancer patients failed to complete their adjuvant chemotherapy. Others have reported poor adherence to chemotherapy for lymphoma³⁸ and poor adherence to hormonal therapy for breast cancer.^39,40

Although we also found that early discontinuation of treatment was associated with poor survival, we cannot assume that that association is causal. Some patients may be at high risk for adverse outcomes because of the same factors that cause them to discontinue treatment: poor physical condition, performance status, psychological outlook, or health behaviors. In addition, some patients may have discontinued treatment early in response to toxicity. However, FU toxicity is unlikely to account for much of the mortality in our study sample; recent clinical trials have reported only a 0.5% therapy-related death rate among patients receiving FU therapy.⁴¹

Furthermore, we found that duration of treatment was more strongly associated with colon cancer–specific survival than with overall survival. This pattern reinforces the view that the duration of treatment is indeed contributing to a reduction in colon cancer mortality and does not represent merely selection bias.

Most studies of treatment discontinuation have focused on oral medications, such as those for the treatment of HIV,⁴² heart disease,^43,44 and psychiatric disorders.⁴⁵ In these settings, poor adherence accounts for worsening disease, death, and increased health care costs.^46,47 A decision to discontinue treatment may be based on such factors as the adverse effects of medications,⁴⁸ patient lack of knowledge about the illness or the potential benefits of the treatment,^49,50 financial barriers,³⁰ poor patient-physician communication,^49,51 and the presence of comorbid conditions.^43,52,53 Personal belief in the efficacy of the therapy may also play a significant role in adherence.⁵⁴ Our analysis could take few of these factors into account and could not determine what roles patients, physicians, families, and the health care system played in determining the duration of treatment. However, in a Medicare population, at least some financial barriers are absent, and we used Medicare data to control for comorbid conditions, which were indeed statistically significant predictors of treatment and early and later mortality.

Another limitation of our study was a lack of detailed information on chemotherapy dose and dose-intensity. Although dose reductions may contribute to suboptimal outcomes, especially among elderly patients, adjustment for dose is unlikely to account for the difference in survival between patients treated for 1 to 4 months and patients treated for 5 to 7 months. Our inability to take dose into account seems more likely to have biased our results toward the null than to account for the strong association we observed.

New treatments for colorectal cancer are superseding the FU-based regimens, but although these agents appear to improve survival, they are also more toxic than the FU-based regimens.^55,56 Patients who receive these new chemotherapeutic agents may therefore be even more inclined than the patients we studied to discontinue treatment. For example, in a clinical trial, adding oxaliplatin to FU resulted in a lower likelihood of completing all cycles of chemotherapy (75% v 86%) and a reduced total dose of FU administered (84% v 98%).⁴¹ Likewise, patients in a randomized trial of continuous-infusion FU were more likely to discontinue adjuvant therapy than those in the arm with bolus FU and leucovorin, due to the increased difficulties associated with administration.³⁵ Research is needed on ways to minimize the adverse effects of chemotherapeutic drugs and to facilitate adherence so that patients can receive in full whatever survival benefits the treatments can provide.

Our study is the first to explore factors associated with the duration of adjuvant FU chemotherapy in patients with colon cancer. We found that more than 30% of patients were treated for only 1 to 4 months, and that such patients had poorer survival than those who received 5 to 7 months of treatment. We do not know whether these differences in duration of treatment accounted for the observed differences in survival or reflected factors for which we were unable to control. Additional investigation is warranted to determine whether dose-intensity, cumulative dose, or other factors related to receipt of full adjuvant treatment for colon cancer are associated with survival.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Conception and design: Alfred I. Neugut, Matthew Matasar, Russell McBride, Judith S. Jacobson, Victor R. Grann, Dawn L. Hershman

Financial support: Alfred I. Neugut, Dawn L. Hershman

Collection and assembly of data: Matthew Matasar, Xiaoyan Wang, Russell McBride, Dawn L. Hershman

Data analysis and interpretation: Alfred I. Neugut, Matthew Matasar, Xiaoyan Wang, Russell McBride, Judith S. Jacobson, Wei-Yann Tsai, Victor R. Grann, Dawn L. Hershman

Manuscript writing: Alfred I. Neugut, Judith S. Jacobson, Dawn L. Hershman

Final approval of manuscript: Alfred I. Neugut, Xiaoyan Wang, Russell McBride, Judith S. Jacobson, Wei-Yann Tsai, Victor R. Grann, Dawn L. Hershman

	ACKNOWLEDGMENTS

 
We thank the Applied Research Branch, Division of Cancer Prevention and Population Science, National Cancer Institute; the Office of Information Services, the Office of Strategic Planning, HCFA; Information Management Services; and the Surveillance, Epidemiology, and End Results tumor registries in the creation of the SEER-Medicare database.

	NOTES

 
Supported by a K05 Award from the National Cancer Institute (NCI; Grant No. CA89155), a grant from the American Cancer Society (Grant No. RSGT-01-024-04-CPHPS), and a Department of Defense Breast Cancer Center of Excellence Award (Grant No. BC043120) to A.I.N; an R25 fellowship from the NCI (Grant No. CA94061) to M.M.; a T32 fellowship from NCI (Grant No. CA09529) to R.M.; and an American Society of Clinical Oncology Career Development Award and a K07 Award from the NCI (Grant No. CA95597) to D.L.H.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted October 6, 2005; accepted March 10, 2006.

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