Summary
Stage I non–small cell lung cancer (NSCLC) is a disease of the elderly, with two third of patients diagnosed at age 65 years or above.1 Although the majority of NSCLC is detected late in its course with locally advanced or metastatic disease,2 early-stage lung cancer portends a favorable outcome with surgical resection as the standard of care. Five-year overall survival (OS) rates range from 70% to 80%, depending on tumor size with surgical management.3 Although recent studies suggest that sublobar resection is associated with fewer severe postoperative complications compared with lobar resection, there is conflicting data whether OS is equivalent.4,5 As such, lobectomy remains as the current standard of care for standard operative risk patients.6
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Original Article
A Matter of Comprehensive Informed Conset: Short-Term Mortality Rates With Definitive Treatment Options in Elderly Stage I NSCLC
American Journal of Clinical Oncology
Shraddha M. Dalwadi, MD, MBA, Ricky R. Savjani, BS, Eric H. Bernicker, MD, Edward B. Butler, MD, Bin S. Teh, MD, and Andrew M. Farach, MD
Background: Although lobectomy is the standard of care in stage I non–small cell lung cancer (NSCLC), medical comorbidities increase surgical risk in elderly patients. No population-based studies compare short-term mortality (STM) for surgery (STM-S), radiation (STM-R), and observation (STM-O) in elderly patients with stage I NSCLC.
Methods: A total of 60,466 biopsy-proven stage I NSCLC cases diagnosed between 2004 and 2012 were retrieved from the Surveillance, Epidemiology, and End Results Program. Patient characteristics were compared using χ2 test. Age was divided into 5-year subsets (60 to 64 to 90+ y) for analysis. Similar to other series, STM was defined as death within 2 months of diagnosis. Univariate and multivariate analysis for STM was performed using odds ratio, Kaplan-Meier actuarial method, and Cox proportional hazard ratio.
Results: In younger patients, STM-S rates are lower compared with STM-R (1.6% vs. 3.4% in patients 60 to 64 y, P<0.001). However, STM-S rates surpass STM-R with increasing age (up to 8.1% vs. 2.3% in patients 90+ y, P<0.001) becoming significant in the 75- to 79-year age group (4.7% vs. 2.2%, P<0.001). There is an inflection point in the 65- to 69-year age group where STM-S and STM-R rates are similar (2.6% vs. 3.0%, P=0.090). STM for observation reflected the poor health of this cohort with high STM rates in all age groups (19.5% for age 60 to 64 y to 25.3% for age 90+ y, P=0.005). Sex, race, Hispanic ethnicity, age group, and treatment were associated with higher STM on the multivariable analysis (all P<0.001).
Conclusion: STM in elderly stage I NSCLC patients treated with surgery increases with advancing age but remains stable for patients receiving radiation. Given the success of stereotactic body radiation therapy, radiation should be considered for patients with high STM risk associated with surgery.
Stage I non–small cell lung cancer (NSCLC) is a disease of the elderly, with two third of patients diagnosed at age 65 years or above.1 Although the majority of NSCLC is detected late in its course with locally advanced or metastatic disease,2 early-stage lung cancer portends a favorable outcome with surgical resection as the standard of care. Five-year overall survival (OS) rates range from 70% to 80%, depending on tumor size with surgical management.3 Although recent studies suggest that sublobar resection is associated with fewer severe postoperative complications compared with lobar resection, there is conflicting data whether OS is equivalent.4,5 As such, lobectomy remains as the current standard of care for standard operative risk patients.6
Without treatment, the prognosis of NSCLC is dismal, even for patients with T1 disease for whom 5-year OS is 9% with a median survival of 13 months.7 This mortality makes noninvasive options like stereotactic body radiation therapy (SBRT) particularly alluring in patients who refuse or are not candidates for surgery. Further, treatment schedules for SBRT can be delivered in short regimens, sometimes even with a single fraction, making treatment much more convenient and tolerable for the elderly.
Several meta-analyses have indicated a better OS and disease-free survival with surgical resection compared with SBRT in medically operable patients.8–10 However, when patients are matched more closely, SBRT may approach OS rates to those of surgery, especially in elderly patients with multiple comorbidities.11 A recent single-institution review at MD Anderson Cancer Center revealed that SBRT was as effective in the elderly (aged 75 y or above) as in patients aged below 75 years with no difference in time to progression, lung cancer-specific survival, or toxicity, indicating that SBRT is safe and efficacious in the elderly.12 Since the introduction of SBRT as a treatment option for the elderly, the number of untreated patients has declined and OS has increased as SBRT has become more widely available. Although small, single-institution prospective randomized studies also have shown SBRT to be considered comparable to lobectomy,13 large multi-intuition prospective phase III randomized controlled trials in operable patients comparing SBRT and surgery are still needed and are currently ongoing. Nonetheless, SBRT has shown to have excellent local control and low toxicity rates, positioning itself as a strong treatment alternative to surgery.14 The temporal study has shown that survival in patients treated with radiation continues to improve as SBRT adoption disseminates into the community, even in elderly patients.15
Informed consent plays an important role in elderly patients where the goals of care and preferences can dictate therapy. As data are emerging as having 2 viable options for definitive treatment of stage I NSCLC, patients should be integrally involved in the treatment decision with their preferences weighed significantly. A recent study examining patient preferences found that patients preferred minimally invasive operations over thoracotomies.16
Equally important in shared decision-making, patients should be made aware of the medical risk associated with surgery. In those undergoing lobectomy, postoperative atrial fibrillation has been associated with higher in-hospital mortality and poorer long-term survival.17 Elderly patients also take longer to recover after surgery, with increased rates of delirium and postoperative cognitive dysfunction, which can last weeks to years.18 Furthermore, anesthesia in the elderly is associated with a higher risk profile, as these patients harbor unique physiology with difficult-to-predict pharmacodynamics.19 Comprehensive geriatric assessment is helpful in identifying optimal candidates,20 but no standard criteria exist in the selection of appropriate surgical candidates. Herein, we examined short-term mortality (STM) in 5-year age cohorts from 60 to 90+ years in both SBRT-treated and surgically treated patients. We sought to determine if and in which patient age groups radiation could be associated with lower STM than resection.
Methods
The Surveillance, Epidemiology, and End Results (SEER) database was used to draw a case list of biopsy-proven stage I NSCLC patients over the age of 60 years diagnosed between 2004 and 2012. Patients for which treatment was unknown and patients receiving both radiation and surgery were excluded due to the unknown significance of these cohorts. The remaining cases were divided into radiation, surgery, and observation groups based on treatment within 4 months of diagnosis as coded by SEER. Radiation treatment modality/dose and chemotherapy were not available in this dataset. Patients were divided into 5-year age cohorts using a sensitivity analysis. The Medicare population (ie, patients over 65) were defined as elderly for the purpose of this study; patients aged 60 to 64 years were included for comparison.
Race and ethnicity are reported in our study per SEER guidelines without modification (ie, relabeling or splitting). Racial categories are based on the United States Census 2010 data; these categories are as follows: white, black, other (Asian and Pacific Islander, etc.), and unknown. Ethnicity was reported as Hispanic or non-Hispanic based on the American North American Association of Central Cancer Registries (NAACCR) Hispanic/Latino Identification Algorithm, version 2.2.1.
STM was defined as death within 2 months of diagnosis as an actual time to death after treatment is not discernible from the SEER data alone. Although not an exact proxy for perioperative mortality, this is similar to how previous studies have investigated death within treatment-related mortality using SEER as it represents death within 2 months of therapeutic determination.
χ2 and t tests were used to analyze and report differences in patient characteristics. Kaplan-Meier and Cox proportional hazard ratio (HR) was used for univariable and multivariable survival analysis, respectively. All tests performed were 2 sided and P-values were considered significant at an α at 5%. Statistical Analysis System JMP 13 (SAS-JMP 13) software was used for statistical accuracy.
Results
The majority of our patients were male, white, and non-Hispanic (Table 1). Females were more likely to receive surgery (P<0.0001). Compared with other races, black patients were more likely to be observed or receive radiation than receive surgery (P<0.0001). Younger patients were more likely to receive surgery, whereas older patients were more likely to be observed or receive radiation (P<0.0001).
On multivariable analysis; sex, age, year, race, Hispanic ethnicity, and treatment were associated with OS (P<0.0001, Table 2). Male sex was associated with worse OS (HR=1.43, P<0.0001). Age 90+ years was associated with the worst OS when using patients aged 60 to 64 years as a reference (HR=2.10, P<0.0001). OS improved with each incremental year of diagnosis within the range of our study (HR=0.97/y, P<0.0001). Black patients fared worst when compared with white patients as a reference (HR=1.05, P<0.0001). Hispanic patients had improved survival compared with non-Hispanics (HR=0.92, P=0.0012). Receiving treatment significantly improved survival (surgery HR=0.21 and radiation HR=0.55, P<0.0001).
STM by treatment was significantly related to age group (Fig. 1). In younger patients, STM rates with surgery are lower compared with STM rates with radiation (1.6% vs. 3.4% in patients aged 60 to 64 y, P<0.0001). However, STM rates with surgery surpass STM rates with radiation with increasing age (up to 8.1% vs. 2.3% in patients 90+ y, P<0.0001) becoming significant in the 75- to 79-year age group (4.7% vs. 2.2%, P<0.0001). There is an inflection point in the 65- to 59-year age group where STM rates with surgery and radiation are similar (2.6% vs. 3.0%, P=0.090). STM of the observation group reflected the poor health status of this cohort with high STM rates in all age groups (19.5% for age 60 to 64 y to 25.3% for age 90+ y, P=0.005).
Discussion
Our data describes the highly variable short-term risk associated with radiation, surgery, and observation only in elderly patients. In the past, inoperable elderly patients with early-stage lung cancer were likely to succumb to their disease given the lack of definitive treatment options. However, in the era of well-validated SBRT techniques, definitive treatment for early-stage lung cancer can and should be extended as an option to all patients at increased surgical risk.
For patients who are surgical candidates, lobectomy is unequivocally the preferred treatment and is endorsed by the National Comprehensive Cancer Network, regardless of age.21 Anatomic resection (eg, lobectomy) is the preferred treatment modality, with video-assisted techniques significantly improving STM for an otherwise morbid procedure.22,23 Sagwada et al24 showed that perioperative mortality rates are equivalent between younger and older patients when controlling for performance status and comorbidity, suggesting advanced age alone should not disqualify patients from the standard of care. One retrospective report found male sex, age above 60 years, heart or lung disease, extended resection, diabetes, and treatment at low-volume center are factors associated with high perioperative mortality. High-risk cases may benefit from referral to high-volume centers.25
For elderly patients who are fragile with multiple comorbidities, operability may not be as clear. Our data suggest shared decision-making would be most beneficial in patients aged 75+ years, where surgery harbors higher perioperative mortality compared with radiation. Similar data have been published using a propensity-matched National Cancer Database cohort, where patients over age 70 years showed worse 30- and 90-day mortality rates when surgery26 was compared with SBRT. Comorbidity is a significant factor in determining operability, but evidence points towards good safety profile of SBRT even in patients with very high comorbidity scores.27,28 Spirometry does not significantly differ pre-SBRT and post-SBRT, indicating preservation of pulmonary function.29 One theoretical concern is dose to heart and its substructures in patients with preexisting cardiac comorbidity. However, a dedicated study by Reshko et al30 showed that while preexisting cardiac history is associated with increased cardiac events, radiation to the heart or cardiac substructures was not related to subsequent cardiac events or overall mortality. Further, elderly patients achieve similar long-term outcomes compared with younger patients with definitive SBRT for early-stage NSCLC.31
Many limitations of this study exist due to its retrospective population-based design. We used death within 2 months of diagnosis as a proxy for STM (similar to other SEER-based studies on this topic), whereas most surgeons use 30- or 90-day measures of mortality. We did not report the extent of resection (ie, lobar vs. sublobar), as 50% to 70% of patients in our SEER dataset did not have this data available. Exclusion of these patients may have introduced bias. In addition, we chose to focus on the age-based impact of surgical risk, regardless of technique. Last, we admit SEER-based mortality rates may not be representative of individual or institution mortality rates but still hold value in understanding the statistical risk for a typical patient especially in the community where such data is not routinely collected.
Ultimately, medical recommendations (including operability) only play a framework for autonomous patient decision-making (Fig. 2). Discussion from radiation oncology, medical oncology, and surgical oncology is likely to facilitate the process. However, many socioeconomic factors also play into the patient’s care, such as caregiver input, financial barriers, and social responsibilities. Elderly patients also have unique preferences when making medical decisions which should32–34 be assessed at the individual level. Although it is difficult to directly compare definitive surgery versus radiation for elderly early-stage lung cancer without placing importance on STM and quality of life outcomes, 1 Markov model shows comparable OS and quality-adjusted life expectancy in operable patients with early-stage lung cancer.35 For this reason, treatment in elderly early-stage lung cancer patients cannot be algorithmic. Autonomous patient decisions in elderly patients require multidisciplinary input and comprehensive informed consent, including the high short-term risk associated with treatment in the very elderly.
Conclusions
STM in elderly stage I NSCLC patients treated with surgery increases with advancing age but remains stable for patients receiving radiation. Multidisciplinary approach and comprehensive informed consent are a key to facilitating patient decision-making.
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