Cardiovascular Risk Factors

In addition to the studies mentioned earlier that documented increased mortality from cardiovascular disease in the survivors of testicular cancer after treatment with radiotherapy or chemotherapy, numerous reports have investigated the cardiovascular disease risk factors and cardiovascular events in the survivors of testicular cancer. Early investigations of cardiovascular complications of the treatment of testicular cancer revealed that serum cholesterol increased after cisplatin-based chemotherapy for germ cell tumors. Subsequent investigations have documented hyperlipidemia and other components of the metabolic syndrome in the survivors of testicular cancer. A Norwegian study of 1289 survivors of testicular cancer reported that 11 years after treatment, chemotherapeutically treated patients had higher systolic and diastolic blood pressure and an increased risk of hypertension (odds ratio, 2.4; 95% CI, 1.4–4.0) compared with those treated with surgery alone. Compared with healthy controls, those receiving either radiotherapy or chemotherapy had an increased risk of hypertension. An analysis of 62 patients treated with chemotherapy at least 10 years previously compared with 40 patients treated with orchiectomy alone and with similarly long follow-up reported that the patients treated with chemotherapy had higher blood pressure, total cholesterol, and triglyceride levels. A subsequent study of 86 chemotherapeutically treated patients, 44 patients with stage I disease treated with orchiectomy only, and 47 healthy controls reported that the total cholesterol and total cholesterol/high-density lipoprotein (HDL) cholesterol ratio were elevated in patients treated with chemotherapy compared with the controls. Moreover, the incidence of metabolic syndrome was higher in patients treated with chemotherapy (26%, P = .017) and also in those with stage I disease (36%, (36%, P = .002) compared with the controls (9%).

One of the many Norwegian studies in this area compared 140 patients treated with surgery alone, 231 who received infradiaphragmatic radiotherapy, and 218 treated with chemotherapy. Patients treated with radiotherapy had elevated C-reactive protein and soluble CD40 ligand, whereas those treated with chemotherapy had lower HDL cholesterol and a higher prevalence of metabolic syndrome. These findings suggested that radiotherapy resulted in chronic inflammation and endothelial dysfunction, whereas chemotherapy resulted in increased risk factors for atherosclerosis. In contrast, Dutch investigators had previously reported that, compared with healthy controls and survivors treated with orchiectomy alone, chemotherapeutically treated patients with testicular cancer had higher levels of C-reactive protein and von Willebrand factor and other plasma markers of inflammation and endothelial stimulation. Supporting the relevance of these findings, a Norwegian study of 586 survivors of testicular cancer found that those with higher C-reactive protein levels (≥1.5 mg/L) had a 2.79 times higher risk of cardiovascular disease compared with the survivors with lower levels (95% CI, 1.22–6.34). In a different study, carotid artery intima-media thickness and plasma von Willebrand factor increased in patients with testicular cancer after chemotherapy compared with pre-chemotherapy values, supporting a causative role for chemotherapy.

A 2010 Norwegian study of 990 patients with testicular cancer treated between 1980 and 1994 reported that compared with age-matched controls, patients with testicular cancer were more likely to be using lipid-lowering medication regardless of whether they had received chemotherapy. Patients treated with radiotherapy and/or chemotherapy were more likely than controls to be using antihypertensive medications, but patients treated with surgery alone were not. Men treated with radiotherapy were also more likely to be taking medication for diabetes.

Although the strongest evidence regarding elevated risk factors for cardiovascular disease points to chemotherapy and radiotherapy as the contributing causes, hypogonadism after orchiectomy may also contribute. Among the survivors of testicular cancer, hypogonadism has been documented in about 10% after surgical treatment alone and 13% to 26% after chemotherapy or radiotherapy. In turn, there is compelling evidence that hypogonadism may be a risk factor for cardiovascular disease. A group studying the survivors of testicular cancer found that hypogonadism was associated with a higher body mass index, higher systolic and diastolic blood pressure (140/90 vs 130/85, P <.016), and cardiovascular events. Moreover, numerous studies have reported that hypogonadism is associated with metabolic syndrome, both generally and in survivors of testicular cancer specifically. In support of this association, androgen deprivation has been shown to result rapidly in increased insulin resistance before any changes in body mass index. If hypogonadism leads to the development of metabolic syndrome, it would explain part of the increased risk of cardiovascular morbidity and mortality in patients with testicular cancer.

Cardiovascular Events

The literature documenting that the survivors of testicular cancer have increased risk factors for cardiovascular disease is paralleled by numerous studies reporting an increased incidence of cardiovascular events. Dutch investigators reported a 7.1 observed-to-expected ratio for cardiac events among 87 ten-year survivors who had received chemotherapy, whereas British researchers reported a more than 2-fold increased risk of cardiovascular events in a study of 992 ten-year survivors of testicular cancer after radiotherapy, chemotherapy, or both.

A much larger Dutch study of 2512 five-year survivors treated between 1965 and 1995 reported an increased incidence of cardiovascular events (standardized incidence ratio [SIR], 1.17; 95% CI, 1.04–1.31) compared with men in the general population matched for age and calendar period, although the difference was only seen if angina pectoris and myocardial infarction (MI) in the same person were counted as separate events. Moreover, although the risk of MI was roughly doubled among young survivors of nonseminoma , it was reduced by 50% among survivors of nonseminoma aged 55 years or older, and there was no significant change in the risk of MI among patients with seminoma of any age. Broken down by treatment, a significantly increased incidence of MI was seen only among survivors who had been treated with both radiotherapy and chemotherapy (SIR, 2.06; 95% CI, 1.17–3.35), although a clinically significant increased incidence was also reported after chemotherapy alone (SIR, 1.46; 95% CI, 0.91–2.21). In this study, radiotherapy was only associated with an increased risk of MI if mediastinal irradiation was included. Among men treated with surgery alone, there was no increased risk of MI (SIR, 0.95).

The 2010 Norwegian study of 990 survivors discussed earlier reported that in addition to increased risk factors for cardiovascular events, the incidence of coronary artery disease and atherosclerotic disease events was higher after chemotherapy and/or radiotherapy, although not all the differences were statistically significant. Compared with survivors treated with surgery alone, diagnosis with coronary artery disease was more common in patients treated with radiotherapy and chemotherapy (hazard ratio [HR], 5.3; 95% CI, 1.5–18.5), whereas the risk of cardiovascular events was higher after radiotherapy (HR, 2.3; 95%, CI 1.04–5.3), chemotherapy (HR, 2.6; 95% CI, 1.1–5.9), or both (HR, 4.8; 95% CI, 1.6–14.4). The risk of coronary artery disease was nonsignificantly increased after radiotherapy alone (HR, 2.1; 95% CI, 0.78–5.5) and chemotherapy alone (HR, 2.6; 95% CI, 0.96–6.9).

Prevention

As discussed earlier, risk factors for cardiovascular disease as well as cardiovascular morbidity and mortality are all increased in the survivors of testicular cancer or at least within certain subgroups of these men. Chemotherapy and radiotherapy have both been implicated as contributing to this risk. Hypogonadism because of the underlying cancer and/or orchiectomy may also contribute. Risk modification has proved highly effective for cardiovascular disease, although not specifically among the survivors of testicular cancer. Because these men are at elevated risk of cardiovascular disease, it is logical to be rigorous about following the standard preventive guidelines addressing screening for and treating conditions and behaviors associated with cardiovascular disease, including hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking. Regular aerobic exercise, a healthy diet, and maintenance of a healthy body weight are also logical recommendations, although there are little data to guide such advice in this patient population. Research is needed regarding whether the standard guidelines should be modified, intensified, or initiated at a younger age for the survivors of testicular cancer based on their increased risk.

Second Primary Germ Cell Tumors

The increased risk of a second primary contralateral testis germ cell tumor is well established. A population-based study of 29,515 US men diagnosed with testicular cancer reported that the 15-year cumulative risk was 2.5% (95% CI, 1.7–2.1), including a 0.6% risk of having synchronous tumors and a 1.9% risk of diagnosis with a metachronous tumor. Of 462 contralateral tumors, 62% were metachronous and 38% were synchronous. The median time to diagnosis of the second cancer was 5 years, and the risk of death from it was 0.3%. Risk factors for a contralateral cancer included an initial cancer that was pure seminoma and age below 30 years at diagnosis of the first cancer. Several smaller contemporary studies have reported roughly similar results. Because of the increased risk of developing a second germ cell tumor, the survivors of testicular cancer are often advised to perform a regular self-examination of their remaining testis.

Secondary contralateral testis germ cell tumors have a better prognosis than primary testicular cancers but represent a problem nonetheless because of the impact of bilateral orchiectomy on fertility, sex hormone levels, and body image. Testosterone replacement therapy can effectively treat hypogonadism, and sperm banking before treatment often provides a way to make procreation possible.

Secondary Non–Germ Cell Cancers

Non–germ cell cancers represent a much bigger threat to the long-term health of the survivors of testicular cancer who have been treated with radiotherapy and/or chemotherapy. Numerous studies have linked both the treatment modalities to an increased risk of cancer and cancer-related mortality, but there is no strong evidence of an increased risk among men treated with surgery alone (orchiectomy with or without retroperitoneal lymph node dissection [RPLND]). Thus, the risk seems to derive primarily from the treatment rather than from an inherent predisposition to develop malignancies. A population-based cancer registry study of more than 29,000 survivors of testicular cancer reported that a survival analysis of the 621 who developed a second cancer with known stage revealed that cancer-specific and overall survival were similar among these men and controls matched for a cancer site, stage, year of diagnosis, and age.

The 2 biggest studies of non–germ cell cancers in the survivors of testicular cancer evaluated 2 largely overlapping population-based data sets. The first studied 40,576 men in the US and Nordic cancer registries and reported that a man diagnosed with testicular cancer at 35 years of age had twice the risk of being diagnosed with a second non–germ cell solid tumor over the subsequent 10 years compared with men of the same age in the general population (relative risk [RR], 1.9; 95% CI, 1.8–2.1). Forty years after diagnosis, his risk of being diagnosed with a second cancer was 36% if the testicular cancer was seminoma and 31% if it was nonseminoma, compared with 23% for a man in the general population. There were 13 and 8 additional cancers diagnosed per 100 men treated for seminoma and nonseminoma, respectively. The RR for second cancer was similar for radiotherapy alone (RR, 2.0; 95% CI, 1.9–2.2) and chemotherapy alone (RR, 1.8; 95% CI, 1.3–2.5) and was highest among men who had received both (RR, 2.9; 95% CI, 1.9–4.2). Significantly increased risks were reported for melanoma and for cancers of the pleura, esophagus, lung, colon, bladder, pancreas, stomach, prostate, kidneys, thyroid, and connective tissue.

The second study evaluated both solid and liquid tumors in 29,511 survivors, 65% of whom were included in the same Nordic databases used in the first study, supplemented with patients from Australia, Canada, Scotland, and several other countries. The SIR for all non–germ cell malignancies was 1.65 (95% CI, 1.57–1.73) overall and was not significantly different for seminomas and nonseminomas. In addition to the increased risk of many solid tumors, the study also reported an increased risk of myeloid leukemia (SIR, 3.62; 95% CI, 2.56–4.97) and other nonlymphoid leukemia (SIR, 3.47; 95% CI, 2.20–5.21). The risk of myeloid leukemia was greater for nonseminomas (SIR, 6.77; 95% CI, 4.14–10.5) compared with seminomas (SIR, 2.39; 95% CI, 1.41–3.77). Twenty-year survivors of seminoma had a 9.6% cumulative risk of a second cancer, compared with 6.5% in the age-matched general population. Twenty-year survivors of nonseminoma had a 5.0% risk, compared with 3.1% in the general population (patients with nonseminomas are younger on average and hence the lower expected rate of cancer). Neither of these 2 studies provided strong evidence that men treated with radiotherapy or chemotherapy recently have a lower risk than those treated long ago.

Although the ability of radiotherapy and chemotherapy to cause cancer is clearly established, it is less precisely clear which chemotherapeutic drugs are responsible. Cisplatin, carboplatin, and etoposide have each been linked to a dose-dependent increased risk of nonlymphoid leukemia, but the increased risk of second cancers is documented in patients treated before the use of any of these drugs. The primary implication of the data on second cancers is that unnecessarily aggressive treatment should be avoided when considering and planning treatment with chemotherapy or radiotherapy. Treatment plans that include both chemotherapy and radiotherapy should be avoided whenever possible and are generally only appropriate in patients with seminoma who had disease relapse after radiotherapy for early-stage disease.

Additional screening beyond the standard guidelines for the general population cannot be recommended for patients with testicular cancer at this time because there are no data to support such a recommendation. Indeed, some part of testicular-cancer survivors’ increased risk of being diagnosed with a second cancer is likely because of the incidental detection of second cancers on surveillance imaging studies, and the potential risk of overdiagnosis cannot be ignored. Helping patients to identify and change behaviors, such as smoking, that are associated with a higher risk of cancer represents the most promising preventive strategy currently available.