Hospitalization outcomes among brain metastasis patients receiving radiation therapy with or without stereotactic radiosurgery from the 2005–2014 Nationwide Inpatient Sample

In this cross-sectional study of hospitalization records from the 2005–2014 AHRQ HCUP NIS database, we applied TMLE and Super Learner algorithms to compare distinct types of radiation therapies (SRS and/or non-SRS) on length of stay and discharge destination among US inpatients diagnosed with brain metastases. To date, SRS utilization and its outcomes have rarely been examined using the NIS—a nationally representative sample of hospitalized US patients—and most previously published studies were not focused on the treatment of brain metastases^{9,16,17,18,19,20}. Study results suggested disparities in treatment selection according to patient and hospital characteristics, which did not fully explain the observed treatment outcome differences. Specifically, recipients of SRS alone or SRS + non-SRS therapies were more frequently admitted on an emergency basis to teaching hospitals, whereas patients who received SRS alone were often younger, with fewer comorbidities and more likely to have Medicare or private insurance. Whereas SRS alone and SRS + non-SRS therapies were less frequent among African Americans, SRS + non-SRS therapies were more frequent among Hispanics. Compared to those patients who received SRS alone or SRS + non-SRS therapies, recipients of non-SRS therapies alone were at higher risk for prolonged hospitalization and non-routine discharge. In addition, patients who underwent SRS alone had lower rates for prolonged hospitalization and similar rates of non-routine discharge as compared to those who underwent SRS + non-SRS therapies.

Whereas the indication for neurosurgical treatment is clear-cut, the choice between SRS alone or in combination with non-SRS therapies remains controversial given quality of life and cost considerations¹⁰. Recent studies have examined the cost-effectiveness of SRS among patients with brain metastases^{3,4,7,8,21,22,23,24,25}. Despite evidence supporting the cost-effectiveness of SRS, previous studies have also suggested that only a small percentage of eligible US patients were selected to undergo this procedure, with clear disparities according patient and hospital characteristics, as suggested in this study. In one study, secondary analyses of existing SEER-Medicare data were performed on 7,684 elderly patients who were diagnosed with brain metastases resulting from non-small cell lung cancer (NSCLC) and treated with radiation therapy between 2000 and 2007 within two months of their diagnosis²⁶. Whereas 469 (6.1%) patients had billing codes for SRS, characteristics that predicted SRS utilization included year of diagnosis, SEER registry, higher socioeconomic status, admission to a teaching hospital, no participation in low-income state buy-in programs, no extracranial metastases, and longer interval from NSCLC diagnosis²⁶. Another study involving 2312 patients (813 SRS and 1499 non-SRS) from 2005 to 2014 National Cancer Database (NCD) evaluated utilization of intracranial radiotherapy for renal cell carcinoma²⁷. SRS utilization increased from 27% in 2005 to 44% in 2014, and was more often reported among individuals whose place of residence was away from the facility, those who were treated at academic centers and/or those who had chemotherapy or nephrectomy²⁷. By contrast, SRS was less common among individuals with lower income and those who were uninsured/had Medicaid²⁷. Finally, 11,000 hospital discharge records from the 1998–2011 NIS database corresponding to patients who underwent primary or adjuvant SRS were analyzed to examine SRS trends and outcomes (in-hospital complications, mortality and resource utilization)⁹. Their results suggested that the most frequent indication for SRS remained brain metastasis (36.7%), with the complexity and severity of illness increasing over time as SRS became increasingly less frequent as a primary treatment but remained stable as an adjuvant treatment among hospitalized patients⁹. In recent years, those who received SRS while hospitalized were mostly high-risk patients who were more likely to experience poor outcomes in terms of mortality and resource utilization whereas stable patients often received SRS at outpatient centers⁹.

A causal link between treatment selection and hospitalization outcomes is ideally established in the context of randomized controlled trials, whereby random allocation of patients to various treatments aids in balancing both measured and unmeasured confounders at baseline. Statistical techniques such as TMLE are useful for dealing with confounding bias in the context of observational studies that aim to approximate randomized controlled trials. Current evidence suggests that selection of SRS and/or non-SRS therapies may be influenced by a wide range of prognostic factors, which in turn may influence healthcare utilization outcomes of hospitalized US patients diagnosed with brain metastases. For instance, patients undergoing SRS often have lower intracranial disease burden, receive fewer treatments and are more likely to be discharged routinely and earlier than patients who receive WBRT which can take 5–10 fractions and is more frequently used among patients with more extensive disease and poorer performance. Therefore, the observed associations between treatment selection and hospitalization outcomes may or may not be causal in nature since they could be explained, in part, by unmeasured prognostic factors that are amenable to SRS selection rather than to SRS itself. In this observational study, we applied TMLE, a double-robust semiparametric estimator which is superior to propensity scoring methodology in terms of disentangling the effects of treatment from those of prognostic factors. To our knowledge, this study is the first to apply Super Learner algorithms while estimating ATE using TMLE among hospitalized US patients who underwent SRS and/or non-SRS therapies for brain metastases. It has already been established that SRS is two to sixfold more expensive than non-SRS therapies¹⁰. However, additional research is needed to elucidate shorter hospital stays and fewer non-routine discharges among patients who underwent SRS with or without non-SRS therapies, although fewer neurological complications may be partly responsible for improved clinical outcomes among individuals treated with SRS.

Study results should be interpreted with caution in light of several limitations. First, we relied on an administrative database, which has limited scope and granularity. Unlike the SEER-Medicare and NCD databases, the NIS database does not collect detailed information on cancer diagnosis, staging and treatment. Second, complete subject analysis was performed with the potential for selection bias because of missing data. Third, many study variables, including cancer diagnosis and treatment, were defined using ICD-9 codes, potentially leading to misclassification bias. Fourth, residual confounding could not be ruled out as an alternative explanation given the observational study design and the limited availability of data elements within the NIS database, including intracranial disease burden and patient performance which can influence SRS treatment selection. Similarly, the role of chance could not be ruled out given the limited number of patients who underwent SRS during their hospital stays. Fifth, the cross-sectional design does not allow the establishment of temporality between variables of interest. Finally, study results could only be generalized to hospitalized patients within the period of interest. The demographic, socioeconomic and health characteristics of hospitalized patients may differ from those who sought outpatient care for SRS and/or non-SRS therapies at later time points.