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Influenza Vaccination in Elderly Patients With Advanced Colorectal Cancer

Craig C. Earle

From the Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Address reprint requests to Craig C. Earle, MD, Center for Outcomes and Policy Research, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: craig_earle{at}dfci.harvard.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To examine influenza vaccination use in patients undergoing chemotherapy for advanced cancer.

Methods: All Medicare patients treated for stage IV colorectal cancer between 1993 and 1998 while living in one of the regions monitored by the Survival, Epidemiology, and End Results Program who were alive in the fall months and who survived at least 4 months with their cancer were considered eligible to have received vaccination. Their medical bills were analyzed to determine receipt of influenza vaccination and subsequent outcomes.

Results: Eligibility criteria were met by 1,225 patients who were undergoing chemotherapy during 1,577 person-years of observation. Overall, 39.7% of patients received influenza vaccination, increasing from 26% in 1993 to 43% in 1998. When vaccination was administered, it was provided by primary care physicians 68% of the time. Vaccinated patients were more likely to be white, of higher socioeconomic status, and to have more comorbidity. Fewer diagnoses of influenza and pneumonia infections were made in vaccinated patients while undergoing treatment. Those patients who were immunized also had fewer chemotherapy interruptions and were more likely to survive through to the beginning of the next fall (hazard ratio, 0.88; 95% confidence interval, 0.77 to 0.99). There was a trend toward decreased resource use among immunized patients.

Conclusion: This study observed outcomes associated with influenza vaccination that are similar to those reported for patients without cancer. However, rates of immunization are relatively low, and disparities exist for vulnerable populations. As part of delivering high-quality care, oncologists should promote influenza vaccination for their patients who are undergoing treatment for advanced cancer.

	INTRODUCTION

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INFLUENZA AFFECTS approximately 15% of adults each year.¹ It is caused by the influenza A or B virus, resulting in such symptoms as fever, chills, sore throat, myalgias, and anorexia. The combination of influenza and pneumonia is the sixth leading cause of death in the United States and is responsible for 20,000 deaths per year, the vast majority of which occur in patients who are older than 65 years.² It also accounts for 114,000 hospitalizations^3,4 and has been estimated to result in a loss of 2 to 4 working days per episode.^1,5 At the peak of the last influenza season, in February 2002, influenza and pneumonia accounted for 3.6% of physician visits⁶ and 8.9% of deaths.⁷ The number of visits likely underestimates the burden of disease, however, because less than half of adults seek medical attention for influenza.¹ Infections are more severe in patients with significant comorbid conditions such as cancer.⁸ Consequently, influenza infection carries with it both significant human and economic costs.

The influenza vaccine is composed annually of antigens from the strains of influenza that are anticipated to dominate in the coming year. The vaccine is currently recommended for all persons 65 years of age or older,⁹ particularly those who are at increased risk from underlying chronic immunosuppressive disease, and has been covered for all Medicare part B beneficiaries since May 1, 1993. The only contraindications are for people who are allergic to hens’ eggs or who have had severe reactions to the vaccine in the past. Some controversy about this recommendation exists for cancer patients because of concerns that they may not be able to mount an appropriate antibody response, especially if they are taking chemotherapy, or concerns about possible immunosuppression from vaccination.¹⁰ Nevertheless, many studies have demonstrated that cancer patients can mount an immune response to influenza vaccination,^11–13 although it may be attenuated.¹⁴ Cancer patients may actually need higher titers for efficacy, and chemotherapy may exacerbate these effects,^15,16 leading some to even suggest that chemotherapy should be interrupted for immunization in certain situations.¹⁷

There are no published data on the use of influenza vaccination among cancer patients, and there have been no clinical studies to date examining the patterns of care and outcomes related to influenza vaccination in patients with advanced solid tumors. Therefore, this study was undertaken with a cohort of patients undergoing treatment for advanced colorectal cancer to observe vaccination practice patterns and the morbidity, mortality, and resource use corresponding to its use. Colorectal cancer was chosen because when the disease is metastatic, there is less variation in the clinical course than other common diseases such as breast cancer. In addition, because of the limited treatment options, especially during the study period, all treated patients would be likely to be undergoing similar therapy. The median expected survival time is at least a year, providing sufficient time during which to observe the patients.

	METHODS

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Data Sources
Two data sources were used: the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) and the Centers for Medicare and Medicaid Services (formerly the United States Health Care Finance Administration) Medicare database. The 11 tumor registries participating in the SEER program capture approximately 97% of their incident cases,¹⁸ covering a representative sample¹⁹ of approximately 14% of the American population.²⁰ Registries collect data on each patient’s age, sex, race and ethnicity, cancer site, stage, histology, date of diagnosis, and the date and cause of death. They also record initial treatment data on surgery and radiation received in the first 4 months after diagnosis. However, SEER does not provide information on later treatments. To follow these patients longitudinally, Medicare claims for patients older than 65 years have been linked to the SEER registry data. The Medicare data set includes files through 1998 for inpatient and outpatient care, physician and laboratory billings, and bills for home health and hospice care. Consequently, patients diagnosed before the end of 1996 but vaccinated as late as the fall of 1997 could be observed through to fall of 1998. For patients 65 years of age and older captured by the SEER registries, 94% have been linked to Medicare.²¹ Census-level sociodemographic data have also been linked to these cases, allowing the creation of socioeconomic deciles on the basis of the race and age-adjusted income, wealth, and education in each patient’s census tract in the 1990 census. Combining SEER data with Medicare data provides information about the initial diagnosis and later cancer treatment, as well as downstream medical care.

Cohort Selection
The study sample consisted of all patients diagnosed with advanced (distant SEER stage) colorectal (SEER sites 15 through 26) adenocarcinoma (SEER histology codes 1, 2, 5, 11, 26, and 27) between 1993 and 1996 while living in one of the SEER regions. Patients were excluded if they were enrolled in a health maintenance organization at any time during the study period or if they were not eligible for both parts of Medicare, because their Medicare files would not have complete treatment information.

Each year (from September 1 to August 31) was treated as a separate observation period. Because influenza infections peak between late December and early March and the vaccine takes at least 2 weeks to induce antibodies, early October to late November is the optimal vaccination period.⁹ Consequently, patients who were alive and survived the entire 4-month period of September through December were considered eligible to have received vaccination. To construct a cohort of patients with fairly good performance status, thereby avoiding the bias of observing patients who are extremely ill and consequently unlikely to receive vaccination, only those undergoing active chemotherapy during the September to December period, as determined by having Medicare claims for chemotherapy, were included for that year. The requirement that patients live at least 4 months also served as a landmark analysis, eliminating patients with rapidly declining courses. Consequently, to contribute an observation in a given year, patients had to be alive and undergoing chemotherapy between September and December and were then observed in the 8 subsequent months.

To estimate the proportion of vaccinations captured by Medicare claims, patients from a 5% random sample of Medicare beneficiaries living within the same SEER areas were selected and analyzed with the same criteria. Rates of influenza vaccination were calculated for each year of the study, which could be compared with survey data from the literature to estimate the rate of capture.

Definitions of Outcomes
The likelihood of hospitalization and number of days spent in hospital were also evaluated between January 1 and August 31 of each year, as were diagnoses of influenza and pneumonia (International Classification of Diseases, ninth revision, diagnostic codes 480 through 487). Diagnostic confirmation of influenza infection requires laboratory analysis, which is often not done. Consequently, an influenza-like illness may or may not be caused by they influenza virus. For these reasons, the Centers for Disease Control group influenza and pneumonia together for its statistical analyses.⁹ To explore whether developing influenza while receiving treatment resulted in interruption of therapy, episodes of influenza and pneumonia while receiving treatment were defined as those occurring between the first chemotherapy bill and 28 days after the last chemotherapy bill, because the developing illness may have resulted in cessation of treatment. The average interval between chemotherapy bills was calculated as the number of treatments divided by the time between the first and last claims.

Survival was examined between January 1 and August 31 of each year, such that the presence or absence of immunization in the autumn months was compared with each patient’s likelihood of surviving through to the next fall. Cause of death was determined from linked files of the National Center for Vital Statistics. Resource use from the perspective of the healthcare system was calculated for each patient in the cohort by summing their Medicare reimbursements as a proxy for cost in each year, adjusted for time and geographic factors into constant 1998 United States dollars as others have done.^21–23

Definitions of Explanatory Variables
Race and ethnicity were evaluated as non-Hispanic white, non-Hispanic black, Hispanic, Asian, and other categories. Socioeconomic deciles were developed on the basis of the availability of information from the linked census data as others have done,²⁴ according to the following hierarchy: (1) race- and age-specific median household income by census tract (91.3% of patients), (2) unadjusted median household income by census tract (5.5%), and (3) median household wealth (2.4%).²⁵ The remaining 0.8% unclassifiable patients were assigned to the lowest decile. Comorbidities were identified by examining diagnostic billing codes for various conditions during the year before diagnosis of cancer using the Deyo implementation²⁶ of the Charlson score²⁷ applied to both inpatient and outpatient claims, as suggested by Klabunde.²⁸ The use of chemotherapy and radiation was identified from billing claims.²⁹ A patient was considered to have received care in a teaching hospital if there was a bill for indirect medical education at one of their medical contacts during the study period. Influenza vaccination was identified by the International Classification of Diseases (ninth revision) procedure code 9952, the United States Health Care Finance Administration Common Procedure Coding System codes G0008 and Q0124, and Current Procedural Terminology codes 90657, 90658, 90659, and 90724.

Analytic Considerations
Patients’ medical bills were analyzed through the end of 1998 to determine whether they received influenza vaccination and to examine the medical care they received for their cancer and their overall healthcare resource use. The likelihood of survival through the subsequent year was then observed. Univariate analyses comparing the characteristics of patients who did and did not receive influenza vaccination were carried out using t tests for continuous variables and ² analyses for categorical variables. A Cox proportional hazards model was constructed on the basis of the univariate results to determine the effect of vaccination on survival when controlling for measurable explanatory covariates. In this model, vaccination status was considered a time-varying covariate. Vaccination status was re-evaluated each fall period through which the patient survived and received chemotherapy such that a patient could be, for example, analyzed in the nonvaccinated group in one year but then switched to the vaccinated group in a later year if they were immunized and still undergoing active chemotherapy. To explore practice patterns, multivariate logistic regression models were also constructed to examine which variables predict immunization. Significant explanatory variables were identified through stepwise elimination, and rational interaction terms between the significant variables were investigated further. All statistical analyses were performed with Statistical Analysis Software (version 8.01 for Windows; SAS Institute, Cary, NC).

	RESULTS

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A total of 4,618 eligible Medicare patients with advanced colorectal cancer were identified, 3,132 (68%) of whom lived at least 4 months after diagnosis. Of these, 1,991 (64%) received chemotherapy and 1,225 (62% of those receiving chemotherapy or 27% of the original patient pool) underwent chemotherapy in the fall months and survived through that fall. These patients comprised the final cohort for analysis, and because 23% were alive and still receiving chemotherapy for more than 1 year, they were observed for 1,577 person-years. Overall, influenza vaccination was administered in 39.7% (626) of these person-years. Rates of immunization increased steadily from 26% in 1993 to 43% in 1998 (Mantel-Haenszel ² P = .06 for trend). In comparison, among 35,959 Medicare beneficiaries without cancer, 41% were vaccinated in 1993, increasing to 50% in 1998. Only 2% of vaccinations were given outside the 4-month window of analysis.

The colorectal cancer patients who received vaccination were similar to those who did not in terms of age, sex, and proportion being cared for in a teaching hospital (Table 1). Nonwhite patients were less likely to be vaccinated, as were those of lower socioeconomic status and those living in an urban county. Of note, patients who were immunized had more comorbid conditions detected in their billing claims, particularly heart and lung disease. Multivariate analyses confirmed these associations, although race was no longer significantly associated with the likelihood of immunization when socioeconomic status was adjusted for in a logistic regression model. When vaccine administration could be linked to a specific provider, 68% of patients had vaccinations administered by a primary care physician (internist, family doctor, or general practitioner).

Survival
On multivariate analysis with vaccination status treated as a time-dependent covariate, influenza vaccination was associated with a hazard ratio for death of 0.88 (95% confidence interval, 0.77 to 0.99). Age was the only other predictor of survival in the Cox regression analysis, with a hazard ratio of 1.02 (95% confidence interval, 1.01 to 1.04) for each incremental year of life. Median survival was not reached, but the 75th percentile of vaccinated patients survived 260 days compared with 241 days for those not vaccinated. The 1-year survival rates were 60.2% and 55.3%, respectively. Survival analyses were repeated both looking only at the first year after diagnosis and measuring survival from the date of diagnosis rather than the date of immunization on the basis of whether the patient ever received influenza vaccination. The results of these analyses were similar to the main model and are not shown.

Eighty-six percent (1,054) of the patients were followed-up until death. However, because of data availability, the cause of death is only known for the 697 patients (56.9%) who died before 1997. Of these, 653 (93.7%) died of colorectal cancer. Heart disease claimed 18 lives (2.6%), two patients died of diabetic complications, and there was one death each from septicemia, thromboembolism, and chronic lung disease. The cause of death was unknown for 19 patients (2.7%). Only two deaths were attributed directly to influenza, both of which occurred in nonvaccinated patients for whom the diagnosis of influenza was captured in their claims before death.

Resource Use
There were weak trends indicating possible economic efficiency associated with immunization, but none reached statistical significance. As Table 2 indicates, annualized hospital use and cost measures were all slightly less for patients who had been vaccinated, but this did not reach statistical significance.

	DISCUSSION

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The benefits of influenza vaccination in the general population are well documented. It has been shown to be 70% to 90% effective in preventing a case of influenza caused by strains included in the vaccine and 31% to 45% effective in preventing hospitalization from any pneumonia.³⁰ In the general elderly population, it is associated with a 17% decrease in outpatient visits for influenza and pneumonia, a 6.4% decrease in visits for any respiratory condition, a 51.2% decrease in hospitalizations for influenza and pneumonia, a 32.5% decrease in hospitalization for any respiratory condition, a 28.6% decrease in hospitalizations for congestive heart failure, and a 45% decrease in all-cause mortality.³⁰

If influenza is more common among cancer patients than in the general population and tends to be more severe with a higher mortality rate,³¹ then why are rates of immunization so low among colorectal cancer patients? The Behavioral Risk Factor Surveillance System found that approximately 50% of people older than 65 years in the general population reported receiving influenza vaccination in 1993, a figure that increased to 67% by 1999.³² In this study, 40% of patients without cancer had claims for immunization in 1993, increasing to 50% in 1998, suggesting that vaccination may occur in settings in which Medicare would not be billed approximately 10% to 15% of the time. Still, the observed findings are important. An explanation may be that physicians do not vaccinate patients who are about to die, and this bias may have extended to patients within this cohort. However, restricting the analysis to patients receiving active chemotherapy (presumably with a reasonably good performance status) and who survived at least 4 months after diagnosis should have controlled for many such unmeasurable confounding characteristics.

Disparities have been noted previously in rates of influenza vaccination. The 1996 Medicare Current Beneficiary Survey found that only 46.1% of black patients were immunized, compared with 67.7% of white patients.³³ Those in managed care were more likely to be vaccinated than those with fee-for-service insurance, and people of low income or who were not high school graduates were less likely to receive the vaccine. Although it is possible that patients with these characteristics do not desire vaccination, when Medicare beneficiaries were surveyed about their reasons for not being vaccinated, there were no racial or socioeconomic correlates with the answers given (20.6% did not know it was needed, 18.4% thought vaccination could cause influenza, 15% thought it could have other adverse effects, 14.5% did not think it would prevent influenza, and 12.6% did not think about it or missed it).³³

Most of the sociodemographic predictors of influenza vaccination observed in this study were anticipated. Race has previously been shown to be significantly related to the likelihood of vaccination in an older noncancer population.³³ This analysis suggests that race may largely be a proxy for socioeconomic effects. The finding that rural patients were more likely to receive vaccination was unexpected but may reflect the racial and socioeconomic makeup of more urban counties. The finding that patients who received vaccination were more likely to have other comorbid illnesses has been documented previously in other populations³³ and makes sense, because many of these illnesses are specific indications for immunization. However, this entire cohort of elderly patients with significant underlying illness and immunosuppression from treatment would be expected to have sufficient indication for vaccination.

How could influenza vaccination lead to a survival advantage for cancer patients? Vaccination could prevent deaths either directly from influenza or from sequelae such as immunosuppression or superinfection. Alternatively, vaccination could prevent interruptions of therapy.^34,35 The data presented here seem to support both mechanisms. Although only two deaths were directly attributed to influenza, there may have been more. For patients debilitated by an underlying malignancy, it is considered appropriate to code the cancer as the principle cause of death on the death certificate. The mean interval between chemotherapy bills observed here would be expected from a cohort of patients largely receiving the so-called Mayo loading schedule of fluorouracil. The validity of using chemotherapy Medicare claims in colorectal cancer has been previously established.³⁶ These data suggest that treatment interruptions occur when patients become ill, which may have contributed to inferior survival. Despite restricting the analysis to only those patients who survived at least 4 months and were well enough to undergo chemotherapy, there may still be an element of confounding, with patients with poorer prognoses being less likely to be immunized.

Each dose of the influenza vaccine costs approximately $7. At a vaccination rate of 40%, influenza vaccination has been found to be cost-neutral in the Medicare population.³⁷ It is cost-saving at higher uptake rates because of decreased absenteeism in the young and lower medical care costs in the elderly, where it has been estimated to save $95 per person vaccinated (1991 United States dollars). Moreover, the cost effectiveness in the general population has been estimated at $145 per life-year gained, which is substantially less than the cost of most other widely accepted medical interventions. There was insufficient power in this analysis to detect statistically significantly lower health-related costs among the vaccinated population, but the trend was consistent with these previous findings. Options exist to prevent influenza infection by methods other than vaccination. Drugs such as amantadine, rimantadine, zanamivir, and oseltamivir can be 80% to 90% effective against influenza A, but only the latter two are active against influenza B, and some strains of influenza A have shown resistance to the former treatment. Furthermore, the use of these drugs may be accompanied by side effects such as anxiety, depression, insomnia, nausea, vomiting, or bronchospasm and medication costs as much as $10 per day. Because of these factors and the need to start treatment promptly in a disease that is difficult to quickly and accurately diagnose, these drugs have not been found to be cost effective.³⁸

There are several limitations to this study. As described, despite the steps taken in cohort selection, it is not possible to ensure that the vaccinated and nonvaccinated groups were alike in every way or that all of the differences between them can be controlled for in the analysis. Unmeasured confounding variables could have resulted in patients destined to live longer being more likely to receive immunization, such as the tumor burden, patient performance status, extent of pretreatment, and organ function. These factors could influence a doctor’s decision to recommend vaccination. Restriction of analysis to patients receiving active therapy was an attempt to control for much of this. Influenza vaccination could also be a marker for high-quality care in general, which could explain some of the survival benefit. The following factors should also be considered: (1) the extent to which patient preference for vaccination may have affected decision making could not be observed; (2) the conclusions are based on information gleaned from administrative data, which were not designed for research use; (3) as mentioned, it is possible that some patients received vaccinations that were not captured in Medicare claims; (4) this is an elderly population, with an average age approximately 4 years older than that of colon cancer patients in the general population, although this is also a population for whom immunization recommendations are quite clear; (5) it is likely that cases of influenza and pneumonia were missed — previous studies indicate that only half of adults seek medical care for these diagnoses¹ and that fatal cases only appear on the death certificate approximately half of the time³⁹; (6) the analysis was underpowered for resource use outcomes and would have required approximately 3,000 patients to detect the observed differences in cost; and (7) the results observed in elderly colorectal cancer patients who mostly received fluorouracil may not have the same outcomes as patients who underwent more immunosuppressive treatment, such as patients with breast, lung, or hematologic malignancies. However, this was a homogeneous, well-defined population with a relatively long life expectancy for whom immunization is clearly indicated according to practice guidelines. Other strengths of this analysis include a large, population-based sample of patients who are geographically distributed across the country and all of whom have uniform insurance, thus removing financial barriers to vaccination.

This study, the first to provide clinical information on the use of influenza vaccination in cancer patients, found that rates of immunization are quite low among elderly patients undergoing treatment for advanced colorectal cancer and that disparities exist, particularly along socioeconomic lines. These immunization rates are improving with time, however. Furthermore, vaccinated patients had better outcomes in the form of decreased rates of infection and treatment interruption, which possibly contributed to better survival. Although this study is unable to establish cause and effect between these observations, the findings are remarkably consistent with those of studies in the noncancer setting. Most patients who were immunized received their vaccination through a primary care physician, yet oncologists are often these patients’ most consistent medical contacts. As a result, it is critical that oncologists actively provide routine influenza vaccination to their patients with advanced cancer as part of delivering comprehensive, high-quality cancer care.

	NOTES

 
Supported in part by grants from the National Cancer Institute (grant no. CA 91753-02), Bethesda, MD, and the Lance Armstrong Foundation, Austin, TX.

	REFERENCES

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Submitted June 4, 2002; accepted November 27, 2002.

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