Cancer Survivors have Double the Risk of Suffering a Later Stroke

Surviving cancer comes with a well known loss of remaining life expectancy, roughly the same as being obese or a lifelong smoker. It is plausible that this is a consequence of the generation of large numbers of lingering senescent cells, resulting from radiotherapy and chemotherapy, still the dominant forms of cancer treatment. An increased burden of cellular senescence is certainly preferable to death by cancer, but these cells secrete a potent mix of inflammatory signals that disrupt tissue maintenance and immune function, encourage fibrosis, and increase the risk of numerous age-related conditions. Given that the accumulation of senescent cells is a cause of aging, increasing their presence might rightfully be regarded as an acceleration of aging.

Researchers here note one of the specific consequences of surviving cancer, its present day therapies, and continuing forward with an increased burden of senescent cells, which is a greatly increased risk of stroke. This and numerous other consequences might be alleviated in large part via the use of senolytic drugs to clear out senescent cells. The development of senolytics is still in its comparative infancy, but some of the existing senolytics compounds are in human trials, are cheap and readily available, have been shown to clear senescent cells in human patients, and there is little other than regulatory barriers to prevent their wider adoption as a treatment for a range of age-related conditions. Consequently, testing their ability to reduce the impact of cancer therapy on patients only requires a trial sponsor, the funds, and the will to get started.

Notably, the authors of this open access paper do not mention cellular senescence in their discussion of potential mechanisms by which cancer might increase risk of stroke, which I think an oversight - senescent cells are known to influence many of the mentioned mechanisms. While much of the research community is embracing the contribution of cellular senescence to aging and age-related disease, there is still a way to go yet.

Stroke among cancer patients

We present a contemporary analysis of risk of fatal stroke among more than 7.5 million cancer patients and report that stroke risk varies as a function of disease site, age, gender, marital status, and time after diagnosis. The risk of stroke among cancer patients is two times that of the general population and rises with longer follow-up time. The relative risk of fatal stroke, versus the general population, is highest in those with cancers of the brain and gastrointestinal tract. The plurality of strokes occurs in patients older than 40 years of age with cancers of the prostate, breast, and colorectum. Patients of any age diagnosed with brain tumors and lymphomas are at risk for stroke throughout life.

Most cancer patients now die of non-cancer causes. The results of the current work suggest that stroke prevention strategies may be aimed at patients treated for brain tumors and lymphomas (particularly children) and older patients (i.e., older than 40 years) diagnosed with cancers of the prostate, breast, and colorectum. Though relatively less common, patients with cancers of the gastrointestinal tract (especially the pancreas, liver, esophagus) are at a relatively high risk to die of stroke at any time after diagnosis. We encourage individual guideline and survivorship committees to incorporate these data into their stroke prevention statements.

Relatively few studies have examined the risk of stroke among cancer patients, and the current analysis is the largest of its kind. Similar to previous analyses, we found that lung, prostate, breast, and colorectal patients experience the plurality of strokes. Although the current analysis does not include patient comorbidities or biomarkers, other studies suggest that D-dimer levels and classic risk factors for stroke (e.g., hypertension) put patients at greatest risk.

The risk factors for stroke in cancer patients are under investigation. A systemic review reported that patients with cancer are subject to the same stroke risk factors as the general population, and atherosclerosis remains the most common cause of stroke in cancer patients. Further, the authors noted that if stroke in cancer patients was caused by the same pathophysiologic mechanisms as in the general population, the distribution of stroke should be identical to the population at large, and there would be a distribution of primary neoplasms proportional to the most common cancers (i.e., lung, breast, and prostate). In their review, there was a relatively wide variability of stroke among tumor types.

Several pathways for increased risk of stroke in cancer patients have been proposed, and there are several cancer-specific types and causes of stroke in cancer patients. Cancer may lead to stroke via several mechanisms. First, certain cancers cause occlusive disease from emboli, compression, or meningeal extension of tumor. Tumor dissemination into the leptomeningeal space can lead to vascular compromise. Patients with leukemia and elevated leukocyte counts may develop intravascular leukostasis, leading to hemorrhagic infarct. Brain tumor metastases may also cause hemorrhage, and this is more common in cancers of the kidneys, thyroid, germ cells, melanoma, and choriocarcinoma. Second, coagulopathies, including non-bacterial thrombotic endocarditis (NBTE), may cause stroke. NBTE, or marantic endocarditis, is characterized by the presence of relatively acellular aggregates of fibrin and platelets attached to normal heart valves. Third, stroke may occur from therapy, such as radiation therapy-induced atherosclerosis, drug-induced thrombocytopenia, and hypercoagulability.

Comments

Just an anecdotal comment. Since I gave my 80 year old aunt who had breast cancer with chemo and radiation fisetin several times last summer using the Mayo Clinic protocol she seems stronger and healthier now and hasn't had to return to her hospital for other health complications as often.

Posted by: Corbin at December 9th, 2019 5:51 PM

Despite the fact that increased risk of stroke in people who underwent intensive chemo- and radiotherapy may be associated with a large number of senescent cells accumulated after such therapy, one should not forget the alternative explanation of this phenomenon. The reason for this may also be the depletion of stocks of progenitor cells, which are laid during embryogenesis and are no longer replenished after birth. In this case, monotherapy with senolytics will only further increase the likelihood of a stroke.
Obviously, it is desirable not only to get rid of senescent cells, but also to replenish the reserves of progenitor cells either by cell therapy, or by stimulating the proliferation of these cells. For example, the deficiency created by the senolytic dasatinib can be suppressed using ROCK inhibitors. See: "Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749/

Posted by: Dmitry Dzhagarov at December 9th, 2019 11:58 PM

As a prevention of stroke, I would recommend the ROCK inhibitor, the Japanese drug fasudil (trade name ErilĀ®), to such patients. See: Systematic assessment and meta-analysis of the efficacy and safety of fasudil in the treatment of cerebral vasospasm in patients with subarachnoid hemorrhage. https://link.springer.com/article/10.1007%2Fs00228-011-1100-x

Posted by: Dmitry Dzhagarov at December 10th, 2019 12:21 AM

@Corbin that sounds promising

Posted by: scott at December 10th, 2019 2:53 PM

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