Testicular cancer is the most curable solid tumor, with an overall 10-year relative survival rate of more than 95% (1
). Given the young average age at diagnosis, it is estimated that successful treatment approaches, in particular, platinum-based chemotherapy (3
), have resulted in an average gain of several decades of life for patients with advanced disease. The high cure rate of patients with testicular cancer, however, is offset by the emergence of considerable long-term morbidity (6
). The late effects of testicular cancer and its treatment include second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, psychosocial disorders, and possibly cognitive impairment (3
). An international study of more than 40
000 testicular cancer survivors that included those diagnosed before the cisplatin era showed that the 40-year cumulative incidence of second malignant neoplasm may reach approximately one in three (7
). Moreover, second malignant neoplasms and cardiovascular disease are important causes of premature death in long-term testicular cancer survivors (8
A compelling need exists to expand the research base into the late effects of testicular cancer and its treatment, especially with regard to factors that confer an enhanced susceptibility to the long-term toxicities of cisplatin-based chemotherapy and radiotherapy. Furthermore, an understanding of the mechanisms that underlie the development of long-term adverse sequelae after cisplatin-based therapy has broader implications because platinating agents are now one of the most widely used groups of cytotoxic drugs worldwide. The persistence of platinum-DNA adducts in numerous tissues (eg, kidney or brain) (9
) for up to several years after treatment also causes concern. For example, whether platinum-DNA adducts in brain (11
) might result in premature cognitive impairment in survivors as they age has not been evaluated, although central nervous system progenitor cells are targeted by cisplatin-based therapy in preclinical studies (12
). Circulating platinum, which remains partly reactive (13
), is detectable for more than 10 years after treatment completion (11
), with urine and serum concentrations that are up to 1000 times higher in patients than in unexposed control subjects (14
). Whether platinum might have an impact on the actions of essential trace elements (eg, calcium, copper, magnesium, iron, and zinc) or result in chronic endothelial activation and vascular damage has not been comprehensively addressed.
Just as testicular cancer is the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors (15
) now provide the opportunity to pioneer new methodologies in survivorship research for all adult-onset cancers (16
). Given the current 5-year relative survival rate of 67% for all cancer patients (1
) and the new era of personalized medicine (19
), treatment approaches focused only on tumor eradication have given way to curative strategies that minimize toxicity (21
). This new approach involves the meticulous assessment of late effects, with risk estimation through large-scale epidemiological studies, and research that addresses the molecular mechanisms of susceptibility to late treatment sequelae (17
). Given the introduction of genome-wide association studies and next generation sequencing, opportune timing exists for the integration of molecular approaches into the identification of testicular cancer survivors at highest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies (15
The aim of this commentary is to provide perspective on the research agenda that is needed to understand the incidence and underlying mechanisms of the known and emerging late effects of testicular cancer and its treatment. The current perspective represents a summary of recommendations made during an international meeting devoted to testicular cancer survivorship that was held on May 9–10, 2009, in Rochester, NY. The main goals of this workshop were to 1) identify the major unresolved questions affecting testicular cancer survivors, starting with the long-term site-specific risks of the known and emerging adverse effects of therapy, including genetic modifiers and underlying mechanisms; 2) identify possible interventions; and 3) generate recommendations for future areas of research. Included in workshop discussions was a systematic assessment of reported medical and psychosocial issues in testicular cancer survivors and a comprehensive review of known underlying molecular mechanisms. The participants represented an interdisciplinary group of experts in molecular genetics, pharmacogenomics, bioinformatics, radiation biology, medical oncology, pediatric oncology, surgical oncology, radiation oncology, radiation physics, cardiology, nephrology, urology, reproductive endocrinology, surgical pathology, psychosocial oncology, heavy metal toxicology, environmental sciences, biostatistics, and epidemiology.
The late effects of testicular cancer and its treatment were categorized into two major groups: medical and psychosocial. The groups were recognized as not mutually exclusive because they influence each other (23
). Medically adverse effects in testicular cancer survivors were subdivided into the following categories: possibly life-threatening (eg, second malignant neoplasm or cardiovascular disease) and sequelae with impairment of single organ function. Psychosocial effects were similarly divided into several categories. We have reviewed current knowledge with regard to genetic susceptibility to the late effects of testicular cancer treatment. At the end of each section, we have provided recommendations for future research directions.