Using data from SEER-Medicare, we compared survival outcomes for advanced NSCLC patients, non-squamous cell subtype, treated with carboplatin and paclitaxel, the prevailing standard chemotherapy regimen, with or without bevacizumab. We found that in the wake of the 2006 FDA approval decision, adoption of bevacizumab was by no means universal. For patients diagnosed in 2006 only 20% and among those diagnosed in 2007, only 22% received bevacizumab as a component of their first-line chemotherapy regimen. Second, we found no evidence that bevacizumab conferred a survival advantage on recipients in multivariable models that controlled for observable demographic and clinical patient attributes.
Our patterns of care findings in the Medicare population suggest that the medical oncology community requires therapeutic evidence specific to a particular disease prior to adoption. Medical oncologists, particularly those in private practice may have financial incentives to administer new expensive treatment agents if they can purchase them for less money than CMS reimburses. Because bevacizumab is expensive30–32
and was covered by CMS, if indeed, oncologists were subject to powerful treatment incentives as some have suggested,33
we would have expected to observe them in this context. That we did not observe rapid or complete uptake of bevacizumab provides some measure of reassurance that oncologists are circumspect and judicious in their use of new agents with uncertain benefit in the Medicare population.
The magnitude of the survival benefit we describe is lower than that observed for clinical trial participants. In our study, the median survival for BCP-treated patients was 9.7 months versus 12.3 months for participants in the ECOG 4599 trial. The CP patients in our study had median survival of 8.9 (2006–2007 diagnoses) versus 8.1 months (2002–2005 diagnoses) whereas those in ECOG 4599 were 10.3 months. The difference in median survival between BCP and CP 2006–7 was 0.8 and between BCP and CP 2002–5 was 1.6 months in our observational study which is 40–80% of the 2 months survival advantage obtained in ECOG 4599. This is not entirely surprising given that only 44% of CP and 42% of BCP trial participants were at age 65 or older at diagnosis6
whereas in our Medicare cohort, 100% were over age 65 and indeed over 1/3 were over age 75 at diagnosis. The marginally lower median survival rates in our observational cohort as compared to either the complete or elderly subgroup of the efficacy cohort may also be attributed to differences in clinical factors such as performance status and baseline lung function that cannot be ascertained from SEER-Medicare data.
Researchers have called for prospective trials specifically designed for the elderly to better define the role of intensive cancer treatments that are routinely demonstrated to have superiority in clinical trials that recruit patients who are younger and/or healthier than the general population of patients with the index malignancy.34–36
However, elderly-specific trials with bevacizumab face practical barriers. For example, Merza and colleagues studied 106 male elderly patients diagnosed with advanced NSCLC at a Veteran’s Administration medical center, and found that only 10% of patients were candidates for bevacizumab after applying exclusion criteria used in ECOG 4599 and another bevacizumab combination trial.37
Our study helps to determine if the insignificant results from the subset analyses of older patients in ECOG 45996,9
can be extended to broader elderly NSCLC patients treated in real world contexts.
Our study must be interpreted in the context of limitations inherent to all observational studies as well as those that rely on administrative data sources such as Medicare. First, the study was limited to Medicare fee-for-service beneficiaries who were aged 65 years or older and living in a SEER region at diagnosis. This cohort may not be representative of all non-squamous NSCLC patients in the United States12
although it is likely to be more representative than the sample of clinical trial participants. Second, SEER-Medicare lacks essential clinical details, such as the presence of molecular biomarkers, performance status, and baseline pulmonary function which may be associated with the selection of chemotherapy agents, survival, or both. However, the inability to identify patients with poor baseline lung function and limited performance status or other clinical contraindications to bevacizumab such as significant hemoptysis and brain metastases would be expected to widen rather than narrow the apparent gap in survival between BCP and CP patients. In an observational cohort, patients with relative contraindications to bevacizumab are more likely to be included in the CP cohort and this should increase the survival advantage of BCP relative to CP. The fact that we did not observe this lends credence to our finding that there is no sizeable benefit from adding bevacizumab to CP in the Medicare population. Third, because we only have NSCLC diagnoses through 2007, the sample size for BCP-treated patients was small and we cannot exclude the possibility that more recent data and/or larger sample would yield different results. Fourth, differences in second- and third-line chemotherapy between study groups may have contributed to survival outcomes; the overall survival might favor the group which had a higher percentage of patients receiving further lines of chemotherapy. Finally, although we used statistical techniques to mitigate the potential for imbalance between our cohorts based on measured prognostic factors, the potential for selection bias based on unmeasured factors that predisposed patients to be included in a particular treatment group cannot be excluded.
In conclusion, our analyses suggest that the addition of bevacizumab to carboplatin and paclitaxel is not associated with demonstrable improvement in overall survival in the Medicare population. In the future, for malignancies like NSCLC that disproportionately affect the elderly or where CMS covers a large proportion of treatment costs, negotiations with pharmaceutical sponsors of pivotal trials might mandate adequate representation of the elderly and/or preplanned subgroup analyses relevant to the Medicare population. Absent this information, clinicians will need to rely on efficacy data from subgroup analysis or randomized trials, observational data such as this report and their clinical judgment to make treatment recommendations. Given that neither subgroup analyses from efficacy studies nor observational data analyses identify a benefit for adding bevacizumab to standard carboplatin-paclitaxel therapy, bevacizumab should not be considered standard of care in this context. Clinicians should exercise caution in making treatment recommendations and should use bevacizumab judiciously for their older patients.