Platinum Study Finds High Risk of Metabolic Syndrome in Testicular Cancer Survivors



A multicenter study of North American testicular cancer survivors treated with platinum-based chemotherapy has found a high prevalence of metabolic syndrome, a cluster of cardiovascular risk factors that doubles the risk of cardiovascular disease.1

According to the results of this trial, approximately one in five testicular cancer survivors had metabolic syndrome, with age and hypogonadism being statistically significant risk factors. The researchers also examined the reported association of genetic variation and metabolic syndrome but found no validity.


There is a high prevalence of metabolic syndrome among testicular cancer survivors treated with modern-day chemotherapy. Given these data, providers are encouraged to screen survivors for hypertension, dyslipidemia, and hypogonadism.
— Mohammad Abu Zaid, MD

“There is a high prevalence of metabolic syndrome among testicular cancer survivors treated with modern-day chemotherapy,” said Mohammad Abu Zaid, MD, Assistant Professor of Medicine, Division of Hematology and Oncology, Indiana University. “This comes at a relatively young age and shortly after completion of cancer treatment. Given these data, providers are encouraged to screen survivors for hypertension, dyslipidemia, and hypogonadism.”

As Dr. Abu Zaid reported at the 2017 Cancer Survivorship Symposium, although testicular cancer is the most common cancer in young men,2 since the introduction of platinum-based chemotherapy, the disease is “highly curable,” with a 10-year survival rate of over 95%.3 Despite this “excellent, long-term survival profile,” however, survivors are at high risk of developing adverse health outcomes, including cardiovascular disease.4

“Several European studies have reported up to a sevenfold increased risk of cardiovascular disease, especially after chemotherapy,” said Dr. Abu Zaid. The prevalence of metabolic syndrome ranges from 13% to 39% in European studies of testicular cancer survivors, he added.

In addition, a study by Boer et al reported that metabolic syndrome is more prevalent in testicular cancer survivors treated with chemotherapy who were homozygous or heterozygous for a single nucleotide polymorphism, rs523349, when compared with the wild-type of the single nucleotide ­polymorphism.5

“There is logical plausibility to this finding, as the variant SNP was shown by others to decrease the conversion of testosterone to the more active metabolite dihydrotestosterone,” Dr. Abu Zaid explained. “The prevalence of metabolic syndrome was 67% in survivors carrying the variant genotype who had low testosterone levels.”

Study Design

For the ongoing platinum study, Dr. Abu Zaid and colleagues enrolled 486 testicular cancer survivors from 8 cancer centers in the United States and Canada. Survivors were 55 years or younger at the time of diagnosis and had received first-line chemotherapy only.

Metabolic Syndrome and Platinum-Based Chemotherapy

  • A multicenter study detected metabolic syndrome in approximately one in five North American testicular cancer survivors treated with platinum-based chemotherapy.
  • The median age at clinical evaluation was 38 years, and the onset of metabolic syndrome occurred shortly after completion of cancer treatment.

Participants completed questionnaires and underwent a brief physical examination to measure height, weight, waist circumference, and blood pressure. Lipid panels, testosterone, and serum levels of soluble cell-adhesion molecule-1 (sICAM-1) were measured at a central laboratory. The researchers also genotyped the variant single nucleotide polymorphism, which was implicated in increasing risk of metabolic syndrome.

Per the National Cholesterol Education Program Adult Treatment Panel III Guidelines, metabolic syndrome was defined as the presence of three or more of the following: hypertension, obesity, diabetes mellitus, decreased high-density lipoprotein (HDL) levels, and high serum triglyceride levels.

Survivors were then matched to controls by race, age, and educational status and compared with respect to different components of metabolic syndrome.

Key Outcomes

As Dr. Abu Zaid reported, the median age of participants at clinical evaluation was 38.1 years, and the median time since chemotherapy completion was 4.7 years. The majority of survivors received either bleomycin, etoposide, and cisplatin or etoposide and cisplatin chemotherapy regimens.

Overall, the prevalence of metabolic syndrome in survivors (21%) was similar to controls (22.4%), said Dr. Abu Zaid, but differences were found in the prevalence of individual components. When compared with controls, survivors were more likely to be hypertensive (43% vs 31%) but less likely to have low HDL levels (24% vs 35%) or abdominal obesity (28% vs 40%).

In the multivariate model, age, low serum testosterone, and serum levels of sICAM-1 were significantly associated with metabolic syndrome. In fact, low testosterone levels (≤ 300 ng/dL) were associated with more than double the risk of metabolic syndrome when compared with normal levels. Regardless of serum testosterone level, however, the variant genotype did not correlate with the diagnosis of metabolic syndrome (P = .61).

“Although our cohort is more than twice the size of the prior cohort, we do not validate their findings,” said Dr. Abu Zaid, who noted that metabolic syndrome is a complex phenotype with many genetic and environmental factors contributing to its pathogenesis.

“An approach that takes into account multiple genes involved in relevant pathways would be more promising in terms of finding clinically actionable results that would provide risk-adapted replacement of low testosterone levels,” he observed. It is possible that chemotherapy predisposes patients to cardiovascular disease through mechanisms other than metabolic syndrome (eg, through direct vascular damage), the authors reported. ■

Disclosure: This study was funded by the National Cancer Institute. Dr. Abu Zaid reported no potential conflicts of interest.

References

1. Abu Zaid MI, Gathirua-Mwangi WG, Williams AL, et al: Metabolic syndrome after platinum-based chemotherapy: A multicenter study of North American testicular cancer survivors. 2017 Cancer Survivorship Symposium. Abstract 102. Presented January 27, 2017.

2. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000.

3. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003.

4. Haugnes HS, Wethal T, Aass N, et al: Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: A 20-year follow-up study. J Clin Oncol 28:4649-4657, 2010.

5. Boer H, Westerink ND, Altena R, et al: Single-nucleotide polymorphism in the 5-α-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors. Eur J Cancer 54:104-111, 2016.


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Expert Point of View: Kevin C. Oeffinger, MD


Although an easy-to-use tool in the clinician’s office, metabolic syndrome is not an ideal set of criteria for research. Are you capturing data other than waist circumference, which may not be applicable in this group, to analyze fat mass and muscle mass?
— Kevin C....


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