The introduction of cisplatin-based chemotherapy has transformed germ cell tumors (GCTs), the most common malignancy to affect young adult men, into a highly curable cancer, even in the setting of advanced disease. However, over the past decade, the success of these chemotherapy regimens in curing GCTs has been temporized by an increasing recognition of their important late toxicities, such as cardiovascular disease. The relative risk of coronary artery disease in this population is particularly elevated within the first 10 years of follow-up, when patients are still in their 30s and 40s, which are age groups often considered too young to experience cardiovascular events. Two hypotheses have been proposed to explain the association between chemotherapy and cardiovascular disease in this population. The direct hypothesis asserts that chemotherapy causes diffuse endothelial damage, including in the coronary arteries, gradually leading to cardiovascular disease. In contrast, the indirect hypothesis proposes that chemotherapy leads to an increased incidence of cardiovascular disease risk factors, such as hypertension, hyperlipidemia, and the metabolic syndrome, which in turn enhance the risk of cardiovascular disease. This article summarizes the data on the association between chemotherapy (predominantly cisplatin-based) and the development of cardiovascular disease among GCT survivors, and reviews the evidence supporting both mechanistic hypotheses. In addition, recommendations are provided for the management of GCT survivors who received cisplatin-based chemotherapy and are therefore at risk for cardiovascular toxicity.
Darren R. Feldman, Wendy L. Schaffer, and Richard M. Steingart
Clair J. Beard, Shilpa Gupta, Robert J. Motzer, Elizabeth K. O'Donnell, Elizabeth R. Plimack, Kim A. Margolin, Charles J. Ryan, Joel Sheinfeld, and Darren R. Feldman
Testicular cancer is the most common cancer in men aged 15 to 40 years in the United States, Canada, and many European countries. Given the excellent prognosis of most men with testicular cancer, updates in care after treatment have become very important. This article provides a review of the available evidence, integrated with expert medical judgment, in the area of testicular cancer follow-up.
Mohammad Abu Zaid, Wambui G. Gathirua-Mwangi, Chunkit Fung, Patrick O. Monahan, Omar El-Charif, Annalynn M. Williams, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Ryan Cook, Sandra K. Althouse, Shirin Ardeshir-Rouhani-Fard, Paul C. Dinh Jr, Howard D. Sesso, Lawrence H. Einhorn, Sophie D. Fossa, Lois B. Travis, and for the Platinum Study Group
Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization.
Mohammad Abu Zaid, Paul C. Dinh Jr, Patrick O. Monahan, Chunkit Fung, Omar El-Charif, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Ryan Cook, Sandra Althouse, Shirin Ardeshir-Rouhani-Fard, Howard D. Sesso, Robert Huddart, Taisei Mushiroda, Michiaki Kubo, M. Eileen Dolan, Lawrence H. Einhorn, Sophie D. Fossa, Lois B. Travis, and for the Platinum Study Group
Background: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone–binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.
Timothy Gilligan, Daniel W. Lin, Rahul Aggarwal, David Chism, Nicholas Cost, Ithaar H. Derweesh, Hamid Emamekhoo, Darren R. Feldman, Daniel M. Geynisman, Steven L. Hancock, Chad LaGrange, Ellis G. Levine, Thomas Longo, Will Lowrance, Bradley McGregor, Paul Monk, Joel Picus, Phillip Pierorazio, Soroush Rais-Bahrami, Philip Saylor, Kanishka Sircar, David C. Smith, Katherine Tzou, Daniel Vaena, David Vaughn, Kosj Yamoah, Jonathan Yamzon, Alyse Johnson-Chilla, Jennifer Keller, and Lenora A. Pluchino
Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.