Exposure to ionizing radiation has clearly been established as one of the risk factors for the development of breast cancer. Much data on the relationship between radiation exposures and subsequent breast cancer are derived from atomic bomb survivors and women who received medical exposures either for diagnostic or therapeutic purposes. Although these populations differ in background breast cancer risks and the dose, quality, and timing of radiation, consistent findings include an increased risk with younger age at exposure, long latency to breast cancer development, and increasing risk with increasing radiation dose. Although therapeutic radiation is rarely used to treat benign conditions, it remains an important and effective treatment modality for a wide range of cancers. Increased knowledge of radiation-related breast cancer and modifying influences plays an important role in guiding the initial treatment approach for young women and optimizing long-term follow-up care.
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Andrea K. Ng and Lois B. Travis
Chunkit Fung, Paul C. Dinh Jr, Sophie D. Fossa, and Lois B. Travis
Testicular cancer (TC) is the most common cancer among men aged 18 to 39 years. It is highly curable, with a 10-year relative survival approaching 95% due to effective cisplatin-based chemotherapy. Given the increasing incidence of TC and improved survival, TC survivors (TCS) now account for approximately 4% of all US male cancer survivors. They have also become a valuable cohort for adult-onset cancer survivorship research, given their prolonged survival. Commensurately, long-term treatment-related complications have emerged as important survivorship issues. These late effects include life-threatening conditions, such as second malignant neoplasms and cardiovascular disease. Moreover, TCS can also experience hearing loss, tinnitus, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, infertility, anxiety, depression, cognitive impairment, and chronic cancer-related fatigue. Characterization of the number and severity of long-term adverse health outcomes among TCS remains critical to develop risk-stratified, evidence-based follow-up guidelines and to inform the development of preventive measures and interventions. In addition, an improved understanding of the long-term effects of TC treatment on mortality due to noncancer causes and second malignant neoplasms remains paramount. Future research should focus on the continued development of large, well-characterized clinical cohorts of TCS for lifelong follow-up. These systematic, comprehensive approaches can provide the needed infrastructure for further investigation of long-term latency patterns of various medical and psychosocial morbidities and for more in-depth studies investigating associated etiopathogenetic pathways. Studies examining premature physiologic aging may also serve as new frontiers in TC survivorship research.
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.
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.
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.