Despite reporting better lifestyle factors overall, testicular cancer survivors have a higher risk of metabolic syndrome (MetS) leading to cardiovascular disease (CVD) than matched controls, according to an article appearing in the Journal of the National Comprehensive Cancer Network (JNCCN) by Lois B. Travis of Indiana University, Melvin and Bren Simon Cancer Center, Indianapolis, US.
Investigators in the Platinum Study Group are studying the long-term effects of platinum-based chemotherapy in testicular cancer survivors (TCS). Cisplatin-based chemotherapy has provided a 5-year relative survival rate of 95% among patients with TC, the most common cancer among men aged 18 to 39 years. TCS comprise a unique population for studying the long-term adverse effects of cancer treatment, specifically TCS treated with chemotherapy, who have up to a 7-fold increased long-term risk for CVD, according to the authors who noted that MetS is an established risk factor for CVD.
The authors cited a lack of information in North America and the variation in the prevalence of MetS provided by European studies as prompting this evaluation of the prevalence of MetS and associated risk factors among a large cohort of North American TCS.
This study included 486 TCS participating in the Platinum Study. Participants had been diagnosed with a germ cell tumour prior to age 55 and received treatment with first-line platinum-based chemotherapy but no salvage chemotherapy, radiotherapy, or antecedent chemotherapy for another primary cancer. TCS were disease-free at the time of clinical evaluation. This evaluation comprised a physical examination and an evaluation of lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) levels. Genotyping was done for the single nucleotide polymorphism in the rs523349 (5-α-reductase gene, SRD5A2), which has recently been implicated in MetS risk. In addition, all TCS (median age, 38.1 years) completed a questionnaire regarding health outcomes, lifestyle behaviours, current prescription medications, demographic information, smoking status and physical activity.
MetS was defined by standard criteria as having ≥3 risk factors, including hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, or diabetes. Matched controls were derived from the US National Health and Nutrition Examination Survey.
The analysis uncovered similar rates of MetS in TCS and controls but different risk factors
In the TCS cohort, the median time from completing chemotherapy to study entrance was 4.7 years (range 0.4, 23.9) years. The 102 TCS with MetS were significantly older at evaluation compared than the 384 TCS without MetS; the median age was 44.4 compared to 36.6 years, respectively (p < 0.001).
The investigators found that the frequency of MetS was similar in TCS and controls at 21.0% versus 22.4% (p = 0.59). The frequency of MetS did not differ by the treatment received for testicular cancer (p= 0.20).
Although TCS had a higher prevalence of hypertension 43.2% compared to 30.7% in controls (p < 0.001), decreased HDL levels and abdominal obesity occurred less often in TCS than controls, 23.7% versus 34.8% (p < 0.001) and 28.2% versus 40.1% (p < 0.001), respectively.
An evaluation of risk factors for CVD revealed that TCS were significantly more likely than controls to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% versus 9.3%; p < 0.001), total cholesterol levels (26.3% versus 11.1%; p < 0.001), and a body mass index ≥25 kg/m2 (75.1% versus 69.1%; p = 0.04).
Significant associations were observed by multivariate analysis between MetS and the patient´s age at evaluation (p < 0.001), and the presence of hypogonadism indicated by a testosterone level ≤3.0 ng/mL (odds ratio [OR] 2.06; p = 0.005), and/or having an elevated sICAM-1 level (ORhighest vs lowest quartile 3.58; p = 0.001).
No association to rs523349 was determined (p = 0.61).
TCS reported better lifestyle factors than controls
A larger proportion of TCS reported being physically active; 93.8% of TCS reported participating in moderate-intensity activity compared to 42.4% of controls (p < 0.001), and 66.7% versus 33.5% of the respective groups reported vigorous-intensity physical activity (p < 0.001). TCS were also less likely to be current smokers versus controls (9.3% versus 25.9%; p < 0.001).
The risk of MetS increased in TCS with age and factors associated with hypogonadism
Using univariate analysis with factors incorporated into a multivariate model, age, low serum testosterone, and sICAM levels showed a significant association with MetS risk. The MetS risk increased by 1.7-fold for every 10-year increase in TCS age at clinical evaluation, (95% confidence interval [CI] 1.33, 2.30; p < 0.001). Having a testosterone level ≤3.0 ng/ mL was associated with a significant 2-fold increased risk of MetS compared with higher levels (p = 0.005). In addition, MetS risk increased monotonically with increasing sICAM levels (odds ratio [OR] 3.58 for highest versus lowest quartile; (p= 0.001).
In the multivariate model, neither educational level, marital status, alcohol intake, nor vigorous-intensity physical activity was associated with MetS risk.
The authors concluded that a high prevalence of metabolic abnormalities was found in this cohort of TCS treated with chemotherapy at a relatively young age. They encouraged health providers to screen and adequately treat TCS for hypertension, dyslipidemia, and hypogonadism.
The authors noted that, in TCS, metabolic abnormalities were characterised by hypertension, increased LDL and total cholesterol levels but also by lower rates of decreased HDL levels and abdominal obesity, which possibly signified shifts in fat distribution and fat metabolism, as compared with controls. These changes were accompanied by hypogonadism and inflammation.
They hypothesized that TCS may have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. In this study, approximately one-third of survivors were hypogonadal, which is higher than reported in the general population, but not unexpected due to orchiectomy in this cohort; TCS with hypogonadism were twice as likely to have MetS in multivariate analysis. Hypogonadism also was found to associate with obesity, hypertension, and high LDL and total cholesterol levels in univariate analysis.
The authors urged further characterisation of cancer treatment–associated MetS, as the etiology of MetS in TCS likely differs from the general population. They pointed out that the use of criteria developed for the general population to TCS may underestimate the risk of CVD and the need for longitudinal cohort studies in TCS that develop more accurate risk prediction models for CVD.
No external funding was disclosed.
Zaid MA, Gathirua-Mwangi WG, Fung C, et al. Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors. J Natl Compr Canc Netw 2018; 16:257-265. Doi: 10.6004/jnccn.2017.7046