Treatment-related cardiovascular toxicity in long-term survivors of testicular cancer

Hanks et al. reported on elevated cardiac mortality after 15-years follow up in 387 testicular cancer survivors treated with radiotherapy in 1973 and 1974. Seventy-nine percent of patients with stage II and 27% of patients with stage I had mediastinal irradiation. A significant, 3.1-fold increase in non-cancer mortality was observed compared to general male population. Further analysis of causes of death revealed a 2.3-fold increase in cardiac deaths. Eight out of ten patients, who died due to cardiac disease, received mediastinal irradiation.22

In Zagars’ study only minority of patients (71 of 477) received mediastinal irradiation. The cardiac mortality rate was significantly elevated only beyond 15 years of follow-up with standardized mortality ratio (SMR) 1.95 (95% CI, 1.24 to 2.94). Cardiac mortality rate was not significantly elevated during the first 15 years of follow up for the whole group of patients, except for the subgroup of patients treated with mediastinal irradiation (SMR = 1.63, 95% CI, 0.44 to 4.17).23

Fossa et al. was the first author reporting on cardiac mortality among testicular cancer survivors treated with combination of radiotherapy and chemotherapy. They found slightly, but significantly increased risk of dying from circulatory disease (SMR = 1.20, 95% CI, 1.0 to 1.5). A comparison according to the diagnostic periods failed to show increase of mortality after the introduction of cisplatin, probably due to other treatment modifications that happened in that period: omission of mediastinal irradiation, confinement of subdiaphragmatic fields and introduction of modern radiotherapy planning and delivery facilities.24

In another large international study by Fossa et al., there was no significant increase in overall mortality from circulatory disease in whole study population of 38 907 patients treated for testicular cancer with only surgery, chemotherapy or radiotherapy or with combination of chemotherapy and radiotherapy. However, a significantly increased mortality due to hypertensive disorder (SMR = 1.39, 95% CI, 1.01 to 1.89) was documented. Mortality caused by all circulatory diseases was significantly higher in testicular cancer survivors treated with chemotherapy (SMR = 1.44, 95% CI, 1.06 to 1.91) compared to group of patients treated with radiotherapy or surgery only. The risk was even higher in testicular cancer survivors treated with radiotherapy and chemotherapy (SMR = 2.06, 95% CI, 1.27 to 3.14). In comparision with the general population, mortality from circulatory disease was significantly increased in patients treated with radiotherapy at the age under 35 years (SMR = 1.7, 95% CI, 1.21 to 2.31), as well as in patients treated with chemotherapy (with or without radiotherapy) at the age under 35 years after 1975 (SMR = 1.58, 95% CI, 1.25 to 2.01). The latter coincides with introduction of cisplatin based chemotherapy.5

Although mechanisms that would explain an increased risk of CVD after cisplatin based chemotherapy are not completely clarified, endothelial damage is considered to play a main role in pathogenesis. Microalbuminuria, thought to be an early sign of endothelial damage, was reported by Meinardi et al. in 22% of patients treated with cisplatin based chemotherapy.19 Patients with micro-albuminuria had a tendency of higher blood pressure, which could be a consequence of systemic endothelial damage as well.30 Moreover, microalbuminuria was shown to be a predictor of cardiac events.31,32 Nuver et al. observed microalbuminuria in 12% of patients treated with cisplatin based chemotherapy for testicular cancer after median follow up of 7 years, compared to 0% in surgery only group and 4.6% in a larger group of healthy men from general population.33

Nuver et al. proposed other endothelial and inflammatory markers as potential early indicators of endothelial damage and atherosclerosis, which is essentially an inflammatory proces.33 Namely, they found significantly higher levels of von Willebrandt factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), fibrinogen and high sensitivity C-reactive protein (hs-CRP) in patients treated with chemotherapy compared to healthy men. Elevated levels of endothelial and inflammatory markers were shown to be associated with higher risk for coronary artery disease.34,35 In addition, elevated levels of inflammatory proteins were associated with more pronounced atherosclerosis as well.36 Moreover, according to the available data from the literature, hs-CRP could be a predictive marker for CVD.36-39 In the same study by Nuver et al. evaluation of vascular structure and function of common carotid artery was performed. Irrespective of high levels of endothelial and inflammatory markers, this evaluation failed to show any significant changes in wall structure or function of blood vessel, except a small, but statistically significant increase in carotid wall stiffness. Explanation for this could be impairment of microvasculature at the early stages, with later impairment of the macrovasculature. The same author in another study also reported on small, but statistically significant increase in carotid intima media thickness in patients treated with cisplatin based chemotherapy, which was shown to be associated with higher myocardial infarction incidence.40

Gietema et al. showed a presence of circulating platinum in plasma up to 20 years after treatment with cisplatin based chemotherapy in testicular cancer survivors, which, together with the awareness of signs for endothelial damage, led to the theory that cisplatin may chronically stimulate the endothelium, eventually resulting in vasculature impairment.41,42 Correlation between cisplatin plasma levels and severity of neurotoxicity was recently shown, indicating that cisplatin level may serve as a putative marker for long-term toxicity, perhaps even for CVD.43

CVD following cisplatin based chemotherapy could, on the other hand, be caused by a gradual development of unfavourable cardiovascular risk profile. Namely, several studies reported significantly higher prevalence of hypertension in testicular cancer survivors treated with platinum based chemotherapy.14,16,19 Another cause of hypertension in testicular cancer survivors could be abdominal radiotherapy. Namely, some studies with patients treated with abdominal radiotherapy for malignant disease in abdomen reported on increased risk of hypertension. Possible explanation for this is development of radiation nephropathy with resulting hypertension, probably through a renovascular mechanism with activation of the reninangiotensin-aldosteron system.44-46 Furthermore, a few studies reported on increased risk for hypercholesterolemia, as well as increased prevalence of obesity following cisplatin based chemotherapy in testicular cancer survivors, which was, on the other hand, not confirmed by others.14-19,21 Haugnes et al. found significantly higher levels of HbA1c in all chemotherapy and radiotherapy treated testicular cancer patients compared to surgery only group, moreover, patients treated with radiotherapy were at a greater risk of being diagnosed with diabetes as well. Namely, the prevalence of diabetes for the whole study group was 7.3%, while it was 10.2% and 15.6% for radiotherapy and radiotherapy/ chemotherapy group, respectively. The most likely explanation for this is radiation damage of pancreatic gland tissue, as the large part of the gland is included in subdiaphragmatic radiation field. Insulin resistance in testicular cancer patients treated with chemotherapy could be a consequence of persistent hypomagnesemia, caused by cisplatininduced damage of proximal renal tubules. In Haugnes´ study it was found that the prevalence of other unfavourable risk factors for CVD was the highest in radiotherapy/chemotherapy group as well, suggesting a possibility of synergistic effect.14

Hypertension, dyslipidaemia, obesity and insulin resistance are all components of the metabolic syndrome. Considering that testicular cancer survivors are at greater risk to have one or more of these components, the metabolic syndrome could be a possible causal link between cytotoxic treatment and CVD.47,48 The prevalence rates of metabolic syndrome in testicular cancer survivors range from 8% to 40%, depending on applied criteria for diagnosis of this syndrome. Patients treated with chemotherapy are at higher risk for development of metabolic syndrome, compared to controls and to radiotherapy or surgery only group. This is especially true for patients receiving higher cumulative dose of cisplatin – 850 mg or more. Beside association with cumulative dose of cisplatin, a positively correlation was demonstrated between prevalence of metabolic syndrome and cumulative doses of bleomycin and etoposide as well.48 The aetiology of the metabolic syndrome is not entirely clear. Gietema et al. were the first authors reporting on the possible association of metabolic syndrome with low serum testosterone levels in patients who received chemotherapy.49 Nuver et al. proposed that low serum testosterone level and metabolic syndrome could be associated through increased body mass index.48

It’s well known that hypogonadism increases risk for CVD and correlates with the severity of atherosclerosis, even in a healthy male population. In addition, it was shown that gonadal dysfunction is associated with obesity, dyslipidaemia and insulin resistance, as well as with higher levels of markers of endothelial damage. A middle aged men from general population with free testosterone levels in the lower third of normal range were at a 2.7-fold (95% CI, 2.0 to 3.7-fold) increased risk for metabolic syndrome in age-adjusted analyses. After further adjusting for body mass index, low free testosterone level was associated with 1.7-fold (95% CI, 1.2 to 2.4-fold) increased risk for metabolic syndrome. This correlation was even more pronounced for total testosterone levels and sex-hormone binding globulin levels.50 In testicular cancer survivors, gonadal dysfunction may be result of prior treatment with chemotherapy, subdiaphragmatic radiotherapy and with surgery as well.51

However, it is still ongoing debate, whether metabolic syndrome is a consequence of hypogonadism or intrinsic feature of testicular cancer survivors, as a part of testicular dysgenesis syndrome. If the first assumption is true, the testosterone substitution therapy could have a favourable impact on metabolic syndrome and development of CVD in testicular cancer survivors. To date, there is no evidence for that. According to the literature, substitution therapy with testosterone might be useful in men with significantly reduced testosterone levels, while its benefit is questionable in a case of modest hypogonadism.48

Increased risk for CVD after mediastinal radiotherapy in patients treated for testicular cancer is a consequence of a direct exposure of the heart to irradiation.52-54 Data from the literature indicate that irradiation of the heart leads to the tissue damage through microvasculopathy and eventually macrovasculopathy. Endothelial damage of small blood vessels is due to radiation induced generation of reactive oxygen species. Typically, irregularities of the endothelial cell membranes, cytoplasmic swelling, thrombosis and rupture of the walls are present in early phase. This eventually results in reduced ratio of capillaries to myocytes by approximately 50%, leading to ischaemia and fibrosis in late phase.55

Less is known about pathologic association between subdiaphragmatic radiotherapy and CVD. According to the physical model, in series of Huddart et al., the expected mean dose to the heart in a case of “dog leg” radiation field, extending upwards to the bottom of tenth thoracic vertebra, was approximately 2.5% of the total dose, which is unlikely to cause any serious damage.26 Possible mechanism of CVD in patients treated with abdominal radiotherapy could be radiation nephropathy, as well as hypogonadism, as mentioned above. A direct endothelial damage, eventually resulting in atherosclerosis, is another possible mechanism, supported by increased levels of hs-CRP in patients treated with radiotherapy.56

Up to 1980's, total dose of subdiaphragmatic radiotherapy was 36 to 40 Gy and even more. After that, radiation dose was gradually reduced, being 20 Gy for stage I seminoma, 30 Gy for stage II A and 36 Gy for stage II B. In case of prophylactic mediastinal irradiation, testicular cancer survivors usually received 30 Gy. Fractionation, mainly used in subdiaphragmatic, as well as in mediastinal irradiation, is 2 Gy daily fractions 5 days per week.

Current knowledge about long-term treatment-related toxicity in testicular cancer survivors is based on treatment modalities administered years to decades ago. Optimization of treatment, including omission of mediastinal irradiation, confinement of subdiaphragmatic fields, use of modern radiotherapy planning and delivery techniques, lowering the cumulative doses of cytotoxic drugs and preferential use of active surveillance will probably all reduce risk for cardiac toxicity.7-12 However, as data from newer studies are not yet available, we do not have confirmation for this and further research is essential.57

Following successful treatment, most of the testicular cancer survivors are under the medical surveillance of their oncologists for subsequent 5 to 10 years. Obviously, these patients need a longer, probably life-long follow-up with special attention to modifiable CVD risk factors. Patients should be treated for hypertension, diabetes, hyperlipidaemia and dyslipidaemia and advised about healthy lifestyle. A smoking cessation is highly recommended, along with regular physical activity and maintaining of optimal body weight. At the moment, no guidelines concerning CVD risk in testicular cancer survivors are available and several study groups proposed their development.25