Cardiovascular Mortality in Testicular Nonseminomatous Germ Cell Tumors: Does Statistical Significance Imply Clinical Significance?

Testicular germ-cell tumors (GCTs) represent one of the few solid tumors in which the majority of patients with metastatic disease are cured. In 2015, it is estimated that there will be 8,430 new occurrences and only 380 deaths as a result of testicular cancer. Treatment for testicular GCTs involves radical orchiectomy in almost all patients, regardless of the extent of disease. Subsequent treatment options, which depend on disease stage, include active surveillance, retroperitoneal lymph node dissection (RPLND), and cytotoxic chemotherapy. Radiation therapy is also an option in patients diagnosed with pure seminoma. With the implementation and refinement of cisplatin-based combination chemotherapy in the late 1970s and 1980s, approximately 80% of all patients with metastatic GCTs now are cured. Therefore, understanding the acute and long-term effects associated with treatment for a largely curable disease is important to optimize the care of this patient population. In the article accompanying this editorial, using the SEER database, Fung et al compared the cardiovascular disease (CVD) mortality risk in 15,006 patients with nonseminomatous germ-cell tumors (NSGCTs) who either received chemotherapy as part of their initial treatment plan (n 6,909) or underwent surgery alone (n 8,097) with the CVD mortality risk in the general population. Compared with the general population, there was an increased risk in CVD mortality in patients who were treated with chemotherapy; however, there was no difference in CVD mortality in the surgery-alone group. In total, 54 cardiovascular deaths occurred in the chemotherapy group, and 50 occurred in the surgery-only group. Of interest, the statistically significant increase in CVD mortality in the chemotherapy group compared with the general population was limited to the first year after the diagnosis of testicular NSGCT. In the first year after diagnosis, 11 patients who received chemotherapy for the treatment of testicular NSGCT, versus two patients in the surgery-only group, had a cardiovascular cause of death. Several population-based, observational studies have shown an increased long-term risk of developing CVD in testicular GCT survivors. The most likely explanation for the increased incidence of CVD seen in this patient population is the early development of atherosclerotic disease, possibly secondary to metabolic syndrome. Willemse et al demonstrated a 1.9-fold increased risk of developing metabolic syndrome in testicular GCT survivors and a 2.3-fold higher risk in the subgroup that received chemotherapy compared with healthy men as controls. The mechanism for the development of metabolic syndrome in long-term survivors is not completely understood but may be associated, in part, with hypogonadism that results from cytotoxic chemotherapy. Conversely, Fung et al hypothesize that their novel finding of early CVD mortality may at least partially occur through the direct toxic effect of cisplatin on the vascular system and the resultant endothelial dysfunction. SEER is a large, population-based cancer database that provides extensive information on demographics, tumor characteristics, and initial treatment modalities. The SEER registries also collect and report data on vital status and cause of death, which allow for the study of cancer incidence, survival, and trends in care over time. However, it is important to be aware of some pitfalls when analyses are conducted with the SEER database. First, analyses from SEER are limited by the potential inherent confounders and bias associated with any retrospective analysis. In addition, the heterogeneity and lack of granularity in the SEER-coded causes of death may make the true etiology less clear. In the study by Fung et al, the SEER-coded diseases of heart account for six of the 11 deaths in the chemotherapy group in the first year after testicular NSGCT diagnosis, which suggests an arterial thrombotic event as the cause of death. However, this SEER category also includes the International Classification of Diseases 9th and 10th revisions codes for acute pulmonary embolism, a venous thromboembolic event (VTE). There is abundant evidence that cisplatin increases the risk of VTE in a multitude of malignancies. In testicular GCTs, the estimated thromboembolic (arterial and venous) rate has ranged from 8.4% to 18% in patients who received cisplatin-based chemotherapy. Greater than 80% of the events were VTE in these studies. It is also established that VTE leads to increased mortality in patients with cancer. Because there is a known predominance of VTE associated with cisplatin, the inclusion of pulmonary embolism in the analysis may have contributed significantly to the CVD mortality seen in the chemotherapy group in the study by Fung et al. In addition to the aforementioned six deaths as a result of diseases of heart, the remaining five deaths in the first year resulted from cerebrovascular diseases. This SEER-coded category also is heterogeneous, because it is not possible to discern whether the deaths as a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 28 OCTOBER 1 2015