Chunkit Fung

Solid Tumors After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study

PURPOSE Increased risks of solid tumors after older radiotherapy strategies for testicular cancer (TC) are well established. Few population-based studies, however, focus on solid cancer risk among survivors of TC managed with nonradiotherapy approaches. We quantified the site-specific risk of solid cancers among testicular nonseminoma patients treated in the modern era of cisplatin-based chemotherapy, without radiotherapy. PATIENTS AND METHODS Standardized incidence ratios (SIRs) for solid tumors were calculated for 12,691 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2008) and treated initially with either chemotherapy (n = 6,013) or surgery (n = 6,678) without radiotherapy. Patients accrued 116,073 person-years of follow-up. RESULTS Two hundred ten second solid cancers were observed. No increased risk followed surgery alone (SIR, 0.93; 95% CI, 0.76 to 1.14; n = 99 solid cancers), whereas significantly increased 40% excesses (SIR, 1.43; 95% CI, 1.18 to 1.73; n = 111 solid cancers) occurred after chemotherapy. Increased risks of solid cancers after chemotherapy were observed in most follow-up periods (median latency, 12.5 years), including more than 20 years after treatment (SIR, 1.54; 95% CI, 0.96 to 2.33); significantly increased three- to seven-fold risks occurred for cancers of the kidney (SIR, 3.37; 95% CI, 1.79 to 5.77), thyroid (SIR, 4.40; 95% CI, 2.19 to 7.88), and soft tissue (SIR, 7.49; 95% CI, 3.59 to 13.78). CONCLUSION To our knowledge, this is the first large population-based series reporting significantly increased risks of solid cancers among patients with testicular nonseminoma treated in the modern era of cisplatin-based chemotherapy. Subsequent analytic studies should focus on the evaluation of dose-response relationships, types of solid cancers, latency patterns, and interactions with other possible factors, including genetic susceptibility.

Complications associated with chemotherapy in testicular cancer management

Testicular cancer is the most common solid tumor among men aged 15–35 years. The introduction of cisplatin-based chemotherapy has resulted in a cure rate of over 95% for men with testicular cancer, which has put increased emphasis on understanding the morbidity associated with chemotherapy. Hematological, gastrointestinal, gonadal, otological, renal, neurological, and pulmonary toxicities are the most common acute adverse effects. Although most patients recover, some of these effects can persist after the chemotherapy regimen has been completed and can become chronic problems. The late complications associated with cisplatin-based chemotherapy include secondary malignancies, cardiovascular disease, avascular necrosis, and cognitive impairment. Late complications can have considerable effects on survival and quality of life, so close monitoring of patients is critical for the early diagnosis of late adverse effects and to limit associated damage. All patients should adopt a healthy lifestyle and follow age-appropriate cancer screening programs. Hormonal supplementation should be considered for those with a low testosterone level, in order to reduce the risk of sexual dysfunction and metabolic syndrome. Prompt diagnosis of avascular necrosis is essential, and it should be considered in the differential diagnosis for any long-term testicular cancer survivor complaining of hip pain. Finally, sperm cryopreservation should be discussed with all patients before chemotherapy is initiated.

Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study

PURPOSE Increased risks of incident cardiovascular disease (CVD) in patients with testicular cancer (TC) given chemotherapy in European studies were largely restricted to long-term survivors and included patients from the 1960s. Few population-based investigations have quantified CVD mortality during, shortly after, and for two decades after TC diagnosis in the era of cisplatin-based chemotherapy. PATIENTS AND METHODS Standardized mortality ratios (SMRs) for CVD and absolute excess risks (AERs; number of excess deaths per 10,000 person-years) were calculated for 15,006 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2010) who initially received chemotherapy (n=6,909) or surgery (n=8,097) without radiotherapy and accrued 60,065 and 81,227 person-years of follow-up, respectively. Multivariable modeling evaluated effects of age, treatment, extent of disease, and other factors on CVD mortality. RESULTS Significantly increased CVD mortality occurred after chemotherapy (SMR, 1.36; 95% CI, 1.03 to 1.78; n=54) but not surgery (SMR, 0.81; 95% CI, 0.60 to 1.07; n=50). Significant excess deaths after chemotherapy were restricted to the first year after TC diagnosis (SMR, 5.31; AER, 13.90; n=11) and included cerebrovascular disease (SMR, 21.72; AER, 7.43; n=5) and heart disease (SMR, 3.45; AER, 6.64; n=6). In multivariable analyses, increased CVD mortality after chemotherapy was confined to the first year after TC diagnosis (hazard ratio, 4.86; 95% CI, 1.25 to 32.08); distant disease (P<.05) and older age at diagnosis (P<.01) were independent risk factors. CONCLUSION This is the first population-based study, to our knowledge, to quantify short- and long-term CVD mortality after TC diagnosis. The increased short-term risk of CVD deaths should be further explored in analytic studies that enumerate incident events and can serve to develop comprehensive evidence-based approaches for risk stratification and application of preventive and interventional efforts.

Prostate Cancer in the Elderly Patient

Treatment for prostate cancer (PCa) has evolved significantly over the last decade. PCa is the most prevalent non-skin cancer and the second leading cause of cancer death in men, and it has an increased incidence and prevalence in older men. As a result, physicians and patients are faced with the challenge of identifying optimal treatment strategies for localized, biochemical recurrent, and advanced PCa in the older population. When older patients are appropriately selected, treatment for PCa results in survival benefits and toxicity profiles similar to those experienced in younger patients. However, underlying health status and age-related changes can have an impact on tolerance of hormonal therapy and chemotherapy in men with advanced disease. Therefore, the heterogeneity of the elderly population necessitates a multidimensional assessment to maximize the benefit of medical and/or surgical options. Providing clinicians with the requisite health status data on which to base treatment decisions would help ensure that older patients with PCa receive optimal therapy if it will benefit them and/or active surveillance or best supportive care if it will not. We provide a review of the existing evidence to date on the management of PCa in the older population.

Gonadotropin-releasing hormone agonists for the preservation of ovarian function among women with breast cancer who did not use tamoxifen after chemotherapy: a systematic review and meta-analysis

OBJECTIVE To determine whether concurrent use of GnRH agonists with chemotherapy preserves ovarian function in women with breast cancer who did not use tamoxifen. DESIGN Systematic review and meta-analysis. SETTING University-based hospitals. PATIENT(S) Premenopausal women with breast cancer treated with chemotherapy who did not receive tamoxifen. INTERVENTION(S) Randomization to concurrent GnRH agonists with chemotherapy or chemotherapy alone. MAIN OUTCOME MEASURE(S) Odds ratio (OR) of resumption of menses 1 year or more after chemotherapy. RESULT(S) Searches were conducted in PubMed, Scopus, Cochrane Trials Register, and the National Research Register through March 2014, and all randomized trials that reported resumption of menses 1 year or more after GnRH agonist with chemotherapy or chemotherapy alone among women with breast cancer who did not receive tamoxifen were included. Four studies were analyzed in the meta-analysis and included 252 patients (GnRH agonist with chemotherapy, n=131; chemotherapy alone, n=121). There was no significant difference in the rate of return of menses between the two groups (OR, 1.47; 95% confidence interval [0.60-3.62]). Heterogeneity among the trials was not significant (I2=16.6%). CONCLUSION(S) Concurrent GnRH agonists with chemotherapy may not preserve ovarian function in women with breast cancer. Furthermore, randomized data are limited regarding fertility after concurrent use of GnRH agonists with chemotherapy.

Bladder cancer in the elderly patient: challenges and solutions

Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC.

Adjuvant and neoadjuvant therapies in high-risk renal cell carcinoma.

The standard of care for renal cell carcinoma (RCC) is surgical resection as a monotherapy or as part of a multimodal approach. A significant number of patients undergoing surgery for localized RCC experience recurrence, suggesting that there are some individuals in whom surgical excision is necessary but insufficient because of the presence of micrometastatic disease at diagnosis. This review summarizes current algorithms used to identify patients at high risk for disease recurrence following the surgical resection of RCC, the outcomes of contemporary adjuvant systemic therapy trials, and the rationale supporting the use of neoadjuvant therapy.

Long-term Morbidity of Testicular Cancer Treatment

Second malignant neoplasms, cardiovascular disease, neurotoxicity and ototoxicity, pulmonary complications, hypogonadism, and nephrotoxicity are potentially life-threatening long-term complications of testicular cancer and its therapy. This article describes the pathogenesis, risks, and management of these late effects experienced by long-term testicular cancer survivors, who are defined as individuals who are disease free 5 years or more after primary treatment. Testicular cancer survivors should follow applicable national guidelines for cancer screening and management of cardiovascular disease risk factors. In addition, health care providers should capitalize on the time of cancer diagnosis as a teachable moment to introduce and promote lifestyle changes.

Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity

Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048). Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325–33. ©2016 AACR.

Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study

To describe the management strategies and outcomes of patients with renal medullary carcinoma (RMC) and characterise predictors of overall survival (OS).