Clinical Investigation
Risk of Cerebrovascular Events in Elderly Patients After Radiation Therapy Versus Surgery for Early-Stage Glottic Cancer

https://doi.org/10.1016/j.ijrobp.2013.06.009Get rights and content

Purpose

Comprehensive neck radiation therapy (RT) has been shown to increase cerebrovascular disease (CVD) risk in advanced-stage head-and-neck cancer. We assessed whether more limited neck RT used for early-stage (T1-T2 N0) glottic cancer is associated with increased CVD risk, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database.

Methods and Materials

We identified patients ≥66 years of age with early-stage glottic laryngeal cancer from SEER diagnosed from 1992 to 2007. Patients treated with combined surgery and RT were excluded. Medicare CPT codes for carotid interventions, Medicare ICD-9 codes for cerebrovascular events, and SEER data for stroke as the cause of death were collected. Similarly, Medicare CPT and ICD-9 codes for peripheral vascular disease (PVD) were assessed to serve as an internal control between treatment groups.

Results

A total of 1413 assessable patients (RT, n=1055; surgery, n=358) were analyzed. The actuarial 10-year risk of CVD was 56.5% (95% confidence interval 51.5%-61.5%) for the RT cohort versus 48.7% (41.1%-56.3%) in the surgery cohort (P=.27). The actuarial 10-year risk of PVD did not differ between the RT (52.7% [48.1%-57.3%]) and surgery cohorts (52.6% [45.2%-60.0%]) (P=.89). Univariate analysis showed an increased association of CVD with more recent diagnosis (P=.001) and increasing age (P=.001). On multivariate Cox analysis, increasing age (P<.001) and recent diagnosis (P=.002) remained significantly associated with a higher CVD risk, whereas the association of RT and CVD remained not statistically significant (HR=1.11 [0.91-1.37,] P=.31).

Conclusions

Elderly patients with early-stage laryngeal cancer have a high burden of cerebrovascular events after surgical management or RT. RT and surgery are associated with comparable risk for subsequent CVD development after treatment in elderly patients.

Introduction

Laryngeal cancer is the most prevalent cancer of the head and neck in the United States, with approximately 89,142 laryngeal cancer survivors on January 1, 2009 (1), the combined result of a relatively high incidence and a favorable prognosis compared with other head-and-neck malignancies. Patients with early-stage (T1-T2) glottic laryngeal cancer routinely undergo surgery or radiation therapy (RT). Multiple reports identify comparable disease control, survival, and laryngeal preservation rates when comparing surgery and RT 1, 2, 3, 4. Given the excellent oncologic outcomes with either surgery or RT, long-term toxicities of therapy warrant evaluation.

Prior studies have suggested that patients who have undergone RT for cancer of the head and neck are subject to an increased risk of cerebrovascular disease (CVD) 2, 5, 6, 7, 8, 9. However, many of these reports make comparisons of CVD rates with those of healthy historical controls without head-and-neck cancer, which introduces bias, as numerous studies have shown that head-and-neck cancer patients have an elevated risk of CVD at baseline 5, 10, 11, 12, 13. Moreover, these studies are confounded by heterogeneity in head-and-neck subsite and RT dose, technique, and volume treated. To more rigorously query the potential contribution of head-and-neck RT to subsequent CVD development in head-and-neck cancer patients, Smith et al recently analyzed the Surveillance, Epidemiology, and End Results (SEER)—Medicare cohort of head-and-neck cancer patients and observed higher rates of subsequent CVD in patients receiving RT as compared to surgery alone (5). Importantly, this study did not include patients with laryngeal cancer.

Furthermore, few studies have analyzed CVD rates in patients with early-stage glottic laryngeal cancer, for which RT is typically delivered using small-volume treatment fields, thereby affecting only a limited segment of the carotid arteries, rather than the more comprehensive radiation fields used in the majority of more advanced-stage head-and-neck cancer cases. In one of the few studies examining CVD rates in laryngeal cancer patients, Dorresteijn et al described 162 T1-T2 laryngeal cancer cases and found a relative risk (RR) of stroke of 5.1 (95% confidence interval 2.2-10.1) associated with laryngeal RT. However, this RR was calculated as compared to that in a general population stroke-incidence registry (8). Therefore, the contribution of RT as compared to surgical management in patients with known early-stage laryngeal cancer remains unclear. We thus analyzed the SEER-Medicare database to address this potential toxicity in early-stage glottic cancer.

Section snippets

SEER-Medicare database

The SEER-Medicare database links a national population-based cohort of patients diagnosed with cancer with Medicare claims data (14). The SEER database is managed by the National Cancer Institute and currently aggregates data from 20 sites, encompassing 28% of the United States population. SEER collects a broad range of data, covering patient demographics, cancer details, RT and surgery information, and date of death (2).

Data for all enrolled patients with laryngeal cancer from 1990 to 2007

Results

The final eligible study cohort included 1413 patients (RT, n=1055; surgery, n=358). Patient characteristics are presented in Table 2. Median age at diagnosis was 72.6 years, and median follow-up was 4.2 years (range, 0-17.3 years). Patients treated with RT were more likely to reside in an urban setting (RT 90% vs surgery 86%, P=.04) and less likely to have either a moderate or severe Charlson comorbidity score (RT 28% vs surgery 34%, P=.03).

Discussion

Patients with early-stage (T1-2) glottic laryngeal cancers routinely undergo surgery or RT for definitive treatment, with similarly excellent oncologic success rates. As such, given the similar efficacy, potential toxicities are perhaps even more worthy to consider than in patients with more locally advanced disease, for whom treatment often requires surgery and radiation in an effort to augment the likelihood of long-term tumor control. In this context, the potentially excess CVD that has been

Conclusion

In conclusion, elderly patients with early-stage glottic laryngeal cancer have high rates of CVD and PVD in the years after their cancer management. However, we were unable to ascertain an association with elevated risk of subsequent CVD with RT, as compared to surgery, in this patient population. Whether RT is associated with elevated CVD risks in patients younger than 65 years of age is unclear to date, and efforts to minimize carotid RT dose, such as carotid-sparing IMRT, may be more

Acknowledgments

This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.

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  • Cited by (30)

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      Several population-based series have evaluated patients treated with early stage glottic cancers and compared the resultant cerebrovascular event rates for those patients treated with radiation vs. surgery. In Hong et al., the authors identify a cohort of 1413 patients from the SEER-Medicare database, in which 1055 were treated with radiation and 358 were treated with surgery [60]. There was a high-burden of all cerebrovascular events in this population; however, there was no statistically significant difference between patients treated with the two modalities (56.5% RT vs. 48.7% surgery; p = 0.27).

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      RT correlated with high rates of stroke in two retrospective series comparing HNC patients to matched controls from population-based stroke registries (relative risk 2.1–10.1) [10,11]. Several Surveillance, Epidemiology, and End Results analyses of HNC patients showed that, compared to surgery alone, RT use was associated with an increased 10-year risk of stroke [12,13], and 15-year risk of fatal stroke [14]. RT also correlated with high rates of asymptomatic stenosis in multiple cross-sectional studies of HNC patients, with CAS prevalence ranging from 11.7% at a mean of 72 months post-RT to 19.8% at a mean of 24 months post-RT [15–19].

    • Stroke After Radiation Therapy for Head and Neck Cancer: What Is the Risk?

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      The magnitude of the risk of ischemic stroke as a late effect of RT to the head and neck, however, remains unclear from the evidence. The current literature reports risks ranging from 1.1 to 10.1, from studies varying in their designs and patient samples (10-13). In a study by Smith et al (11), the hazard of ischemic stroke was estimated (hazard ratio [HR] = 1.5; 95% confidence interval [CI]:1.18-1.9) in HNSCC patients treated with RT.

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      A recent Surveillance, Epidemiology, and End Results (SEER) report investigating the risk of fatal cerebrovascular accidents (CVA) after RT vs surgery for T1 glottic cancer showed that the 15-year risk of fatal CVA increased from 1.5% with surgery to 2.8% with RT (n = 8721, hazard ratio = 1.75, 95% CI: 1.04 to 2.96; p = 0.0437).21 Another SEER analysis including a more broad definition of CVA showed that the 10-year risk increased with the use of RT, although the difference was not statistically significant (56.5% with RT vs 48.7% with surgery, p = 0.27).22 Although these are the only data specific to early-stage glottic cancer, an additional SEER analysis compiling multiple head and neck sites showed that definitive RT increases the 10-year risk of cerebrovascular disease from 26% in those treated with surgery alone to 34% in those treated with definitive RT.23 Other series investigating carotid stenosis have agreed with these results and established a dose-response relationship.24,25

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    This report is not supported by specific funding.

    V.G. acts as a consultant for Novocure TTF and Philips Healthcare, has a grant pending from Elekta, is paid for development of educational presentations from the American Board of Medical Specialties, and is an external grant reviewer for the University of California San Diego Cancer Center. None of these relate to this work.

    PMH has laboratory research contracts paid to the institution from Amgen, Inc, and Genentech, Inc, neither of which relate to this work.

    Conflict of interest: none.

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