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Second Malignant Neoplasms in Testicular Cancer Survivors

Chunkit Fung, Sophie D. Fossa, Clair J. Beard, and Lois B. Travis

Second malignant neoplasms (SMNs) are a potentially life-threatening late effect of testicular cancer (TC) and its therapy. Although the increased risk for developing solid tumors among TC survivors is largely attributed to radiotherapy, chemotherapy may also be associated with excess risks. However, the baseline risks of developing site-specific SMNs in TC survivors have not yet been quantified, nor have interactions between treatments and other risk factors been elucidated. Studies to date report overall relative risks ranging from 1.4- to 2.8-fold for SMN in TC survivors, with significantly elevated risks apparent for more than 35 years. Analytic investigations show relationships between increasing radiation dose and/or field size and solid tumor risk. Small excess risks of leukemia follow treatment with either chemotherapy or radiotherapy. Recently, concern has been expressed about the increased risk of SMN from radiation exposure during imaging surveillance for recurrence. A small number of studies have examined this issue, generating inconclusive results. Given the current changes in TC treatment that result in lower radiation doses, in the future solid tumors will likely have a considerably lower impact on the lives of TC survivors, although diligent follow-up will be required to accurately quantify long-term risks and to ascertain risks associated with chemotherapy.

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Follow-Up Management of Patients With Testicular Cancer: A Multidisciplinary Consensus-Based Approach

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.

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Variation in National Use of Long-Term ADT by Disease Aggressiveness Among Men With Unfavorable-Risk Prostate Cancer

Vinayak Muralidhar, Paul J. Catalano, Gally Reznor, Brandon A. Mahal, Toni K. Choueiri, Christopher J. Sweeney, Neil E. Martin, Clair J. Beard, Yu-Wei Chen, Michelle D. Nezolosky, Karen E. Hoffman, Felix Y. Feng, Quoc-Dien Trinh, and Paul L. Nguyen

Background: The current NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer treated with external-beam radiation therapy (EBRT). We determined whether the use of long-term ADT varied by the recently defined subcategories of high-risk disease (favorable, other, and very high) versus unfavorable intermediate-risk disease. Methods: We identified 5,524 patients with unfavorable-risk prostate cancer diagnosed from 2004 to 2007 and managed with EBRT using the SEER-Medicare linked database. Patients were stratified by risk group: unfavorable intermediate-risk, favorable high-risk (previously defined and validated as clinical stage T1c, Gleason score of 4 + 4 = 8, and prostate-specific antigen [PSA] level <10 ng/mL, or clinical stage T1c, Gleason score of 6, and PSA level >20 ng/mL), very-high-risk (clinical stage T3b–T4 or primary Gleason pattern 5), or other high risk (ie, neither favorable nor very high). We used multivariable competing risks regression to estimate the rates of long-term (≥2 years) ADT by group. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive long-term ADT than those with other high-risk disease (15.4% vs 24.6%, adjusted hazard ratio [AHR], 0.68; 95% CI, 0.60–0.76; P<.001), and similarly likely as those with unfavorable intermediate-risk disease (AHR, 1.10; 95% CI, 0.99–1.23; P=.087). Other high-risk disease was less likely to receive long-term ADT than very high-risk cancer (24.6% vs 30.8%; AHR, 0.83; 95% CI, 0.74–0.93; P=.002). Conclusions: Despite current guidelines, patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Our results suggest that oncologists view these patients as a heterogeneous group with favorable high-risk cancer warranting less aggressive therapy than other high-risk or very high-risk disease.

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Models of Care and NCCN Guideline Adherence in Very-Low-Risk Prostate Cancer

Ayal A. Aizer, Jonathan J. Paly, Anthony L. Zietman, Paul L. Nguyen, Clair J. Beard, Sandhya K. Rao, Irving D. Kaplan, Andrzej Niemierko, Michelle S. Hirsch, Chin-Lee Wu, Aria F. Olumi, M. Dror Michaelson, Anthony V. D’Amico, and Jason A. Efstathiou

NCCN Guidelines recommend active surveillance as the primary management option for patients with very-low-risk prostate cancer and an expected survival of less than 20 years, reflecting the favorable prognosis of these men and the lack of perceived benefit of immediate, definitive treatment. The authors hypothesized that care at a multidisciplinary clinic, where multiple physicians have an opportunity to simultaneously review and discuss each case, is associated with increased rates of active surveillance in men with very-low-risk prostate cancer, including those with limited life expectancy. Of 630 patients with low-risk prostate cancer managed at 1 of 3 tertiary care centers in Boston, Massachusetts in 2009, 274 (43.5%) had very-low-risk classification. Patients were either seen by 1 or more individual practitioners in sequential settings or at a multidisciplinary clinic, in which concurrent consultation with 2 or more of the following specialties was obtained: urology, radiation oncology, and medical oncology. Patients seen at a multidisciplinary prostate cancer clinic were more likely to select active surveillance than those seen by individual practitioners (64% vs 30%; P<.001), an association that remained significant on multivariable logistic regression (odds ratio [OR], 4.16; P<.001). When the analysis was limited to patients with an expected survival of less than 20 years, this association remained highly significant (72% vs 34%, P<.001; OR, 5.19; P<.001, respectively). Multidisciplinary care is strongly associated with selection of active surveillance, adherence to NCCN Guidelines and minimization of overtreatment in patients with very-low-risk prostate cancer.

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Practice Patterns and Outcomes Among Patients With N0M0 Prostate Cancer and a Very High Prostate-Specific Antigen Level

Vinayak Muralidhar, Paul L. Nguyen, Brandon A. Mahal, David D. Yang, Kent W. Mouw, Brent S. Rose, Clair J. Beard, Jason A. Efstathiou, Neil E. Martin, Martin T. King, and Peter F. Orio III

Background: Management of patients with a very high prostate-specific antigen (PSA) level (≥98.0 ng/mL) but clinically localized (N0M0) prostate cancer is challenging. This study sought to determine practice patterns and outcomes among these patients. Patients and Methods: A total of 748,825 patients with prostate cancer from 2004 through 2012 were identified using the National Cancer Database. These patients were subdivided by PSA level (0–9.9, 10.0–19.9, 20.0–39.9, 40.0–59.9, 60.0–79.9, 80.0–97.9, and ≥98.0 ng/mL), nodal status (N0 vs N1), and distant metastases (M0 vs M1). Rates of locoregional treatment and 5-year overall survival (OS) in each group were determined. Survival was compared using Cox regression after adjusting for multiple patient-specific factors. Results: The rate of locoregional treatment for patients with N0M0 disease and PSA level ≥98.0 ng/mL was significantly lower than for those with N1M0 disease (52.6% vs 60.4%; P<.001) or N0M0 disease and PSA level <98.0 ng/mL (52.6% vs 86.6%; P<.001). The 5-year OS rate was similar for patients with N1M0 disease and those with N0M0 disease and a very high PSA level (63.2% vs 59.1%; adjusted hazard ratio [aHR], 0.91; P=.063). The survival benefit associated with locoregional treatment was higher among those with N0M0 disease and a very high PSA level than among those with N1M0 disease (aHR, 0.28 vs 0.44; P<.001). Conclusions: Patients with clinical N0M0 disease and a very high PSA level (≥98.0 ng/mL) have outcomes similar to those with N1 disease but receive locoregional treatment at a lower rate. Future work is needed to investigate the utility of locoregional treatment in this population.

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Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors

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.

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Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

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.

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Testicular Cancer, Version 2.2015

Robert J. Motzer, Eric Jonasch, Neeraj Agarwal, Clair Beard, Sam Bhayani, Graeme B. Bolger, Sam S. Chang, Toni K. Choueiri, Brian A. Costello, Ithaar H. Derweesh, Shilpa Gupta, Steven L. Hancock, Jenny J. Kim, Timothy M. Kuzel, Elaine T. Lam, Clayton Lau, Ellis G. Levine, Daniel W. Lin, M. Dror Michaelson, Thomas Olencki, Roberto Pili, Elizabeth R. Plimack, Edward N. Rampersaud, Bruce G. Redman, Charles J. Ryan, Joel Sheinfeld, Brian Shuch, Kanishka Sircar, Brad Somer, Richard B. Wilder, Mary Dwyer, and Rashmi Kumar

Germ cell tumors (GCTs) account for 95% of testicular cancers. Testicular GCTs constitute the most common solid tumor in men between the ages of 20 and 34 years, and the incidence of testicular GCTs has been increasing in the past 2 decades. Testicular GCTs are classified into 2 broad groups—pure seminoma and nonseminoma—which are treated differently. Pure seminomas, unlike nonseminomas, are more likely to be localized to the testis at presentation. Nonseminoma is the more clinically aggressive tumor associated with elevated serum concentrations of alphafetoprotein (AFP). The diagnosis of a seminoma is restricted to pure seminoma histology and a normal serum concentration of AFP. When both seminoma and elements of a nonseminoma are present, management follows that for a nonseminoma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer outline the diagnosis, workup, risk assessment, treatment, and follow-up schedules for patients with both pure seminoma and nonseminoma.

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Kidney Cancer

Robert J. Motzer, Neeraj Agarwal, Clair Beard, Sam Bhayani, Graeme B. Bolger, Michael A. Carducci, Sam S. Chang, Toni K. Choueiri, Steven L. Hancock, Gary R. Hudes, Eric Jonasch, David Josephson, Timothy M. Kuzel, Ellis G. Levine, Daniel W. Lin, Kim A. Margolin, M. Dror Michaelson, Thomas Olencki, Roberto Pili, Thomas W. Ratliff, Bruce G. Redman, Cary N. Robertson, Charles J. Ryan, Joel Sheinfeld, Philippe E. Spiess, Jue Wang, and Richard B. Wilder

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Testicular Cancer

Robert J. Motzer, Neeraj Agarwal, Clair Beard, Sam Bhayani, Graeme B. Bolger, Mark K. Buyyounouski, Michael A. Carducci, Sam S. Chang, Toni K. Choueiri, Shilpa Gupta, Steven L. Hancock, Gary R. Hudes, Eric Jonasch, Timothy M. Kuzel, Clayton Lau, Ellis G. Levine, Daniel W. Lin, Kim A. Margolin, M. Dror Michaelson, Thomas Olencki, Roberto Pili, Thomas W. Ratliff, Bruce G. Redman, Cary N. Robertson, Charles J. Ryan, Joel Sheinfeld, Jue Wang, and Richard B. Wilder