Cervical cancer is an important health problem. Although its incidence is decreasing, it remains the leading cause of death from cancer in women in Taiwan. Radiotherapy is an integral component of the standard treatment, particularly treatment of bulky tumors and advanced stage disease. The absolute survival benefit of platinum-based concurrent chemoradiation in locally advanced cervical cancer has been reported to be 12% . Although radiotherapy and chemotherapy could increase tumor control, they also increase local and systemic toxicity. Several investigators have mentioned the importance of recording therapy-related toxicity. However, the data are limited, particularly the data on late effects . Our study demonstrated that cervical cancer patients who received radiation therapy as part of their cancer treatments had a higher risk of VTE, AP, MI, and ischemic stroke compared with the general population.
Associations of stroke risk with treatment modalities in different cancers have recently been reported. Nilsson et al. reported a statistically significant increase in the risk of stroke in women with a history of breast cancer . Dorresteijn et al. showed that radiation to the neck was associated with a 5.6 times increased risk of ischemic stroke after a median follow-up time of 7.8 years . Julio et al. reported the later development of disseminated intravascular coagulation-mediated cerebral infarction in a patient with cervical cancer . However, there have been no population-based reports regarding the correlation of stroke and cervical cancer. This is the first large study to estimate the incidence of stroke in cervical cancer patients treated with radiotherapy.
Radiotherapy in cervical cancer patients not only has local but also systemic late effects. Vascular damages induced by radiation have been much investigated. Radiation could induce vascular damage directly and also result in various types of functional damage. The effects include degeneration of endothelium, decrease in intimal thickness, splitting of the basement membrane, lipid deposits, adventitial fibrosis, and occlusion . In addition, ovarian is very radiation-sensitive organ. Ovarian insufficiency caused by pelvic radiation has been well known . Ovarian insufficiency has a large effect on the health of women, in particular effects on bone density, and on cardiovascular and neurological systems . Furthermore, menopause, a manifestation of ovarian insufficiency, has been reported as a risk factor for stroke because of its potential for increasing blood pressure, obesity, insulin resistance, and accelerated changes of lipids and lipoproteins [16, 17]. All of these effects may lead to the development of vascular events. In this cohort study, increased risks for developing AP, MI, and ischemic stroke were observed. The mean age of women at menopause in our country is 50 to 51 years old . To define clearly clarify the systemic influence of menopause, patients were divided into ≥51 years and <51 years age groups. Interestingly, younger patients had 1.4, 3.4, and 2 times the risk of AP, MI, and ischemic stroke events, respectively, compared with older patients. In addition, there were no significantly different vascular events between surgery alone with oophorectomy and cervical cancer patients who received radiotherapy as a part of their treatment. These results suppose that radiotherapy in cervical cancer not only has local but also systemic effects, especially in younger patients. We supposed that ovarian insufficiency plays an important role in the development of these vascular diseases, especially in ischemic stroke. Recently, Gross et al. reported the surgical technique of ovarian transposition (moving the ovaries away from the field of irradiation) minimizes the radiation dose and damage to the ovary . In addition, although the “timing hypothesis” holds that estrogens have beneficial effects on young and healthy blood vessels of women, direct evidence showing the benefit of replacement therapy is scarce . Hormone replacement therapy or transposition of ovaries before radiotherapy should be considered as part of a multidisciplinary approach, especially in younger patients. However, these results and suggestions need further investigation.
Compared with the general population, cancer patients are often observed to have lower socioeconomic status . This has subsequently been associated with a higher prevalence of comorbidities, such as diabetes mellitus, hypertension, or hyperlipidemia. These factors exacerbate vascular disease. In our study, five stroke-related risk factors were used to stratify the cancer patients into three groups (low-, intermediate-, and high-risk groups). The 5-year stroke incidence was lower in the low risk group, 4%, than in the intermediate risk, 9%, and high risk groups, 15%. Patients with more comorbidity had higher risk of stroke. Therefore, interventions aimed at stroke prevention are extremely important. Complete survey of modifiable risk factors and intensive lifestyle modification are indicated in patients with multiple comorbidities. Further studies are recommended to determine the role of medications used in primary prevention of ischemic stroke.
Several limitations of this study should be mentioned. First, hospitalized or outpatients with a principal diagnosis of cervical cancer were chosen to avoid inclusion of patients with misdiagnosed cervical cancer, though some patients may have been missed. Second, in our multivariate analysis, increase in the incidence of stroke or any other vascular events was unrelated to the addition of platinum-based chemotherapy to radiotherapy. The relatively small size of the census populations and the relatively short follow-up period probably hindered the analysis, but we have found the significant different stroke rate in these two cohorts in this short period. Third, the NHIRD has no data on clinical characteristics, including staging, stroke severity, and biochemical data or other information, like tobacco use, dietary habits, body mass index, and activity level (ECOG) for further analysis. Smoking is the important factor for cervical cancer and vascular events. Tsai et al. reported the prevalence of smoking increased gradually from 3% in the normal group, 9% in the inflammation group and 13.6% in the intraepithelial neoplasm group in Taiwan . Strategies to reduce these risks should be considered, especially in younger patients. Although we had many limitations; however, these would not change our conclusion, given the magnitude and statistical significance of the observed effects in this study.