Treatment-related cardiovascular late effects and exercise training: countermeasures in testicular germ cell cancer survivorship - Beyond the Abstract

Testicular germ cell cancer is a relatively rare disease comprising approximately 1% of all solid tumors in men, but despite its low incidence, it is a very important malignancy for several reasons.

First, it is the most common male cancer in the age group 15-40 years, and given the relatively young age at diagnosis, the disease potentially accounts for a very high number of productive years of life lost. Second, within germ cell cancer, no strong behavioral risk factors/predictors have been identified, and no competing morbidities generally coincide with the onset of diagnosis. Therefore no confounding factors are considered to influence the patho-physiological state of a germ cell cancer patient, other than the cancer and subsequently its treatment. Finally, prognostic advances have resulted in a substantial number of long-term survivors, which has provided important insight into incidence and severity of late adverse events following successful cancer therapy, and their overall impact on cancer survivorship. It was the induction of platinum-based chemotherapy more than three decades ago which led germ cell cancer to be labeled as “a model for curable neoplasms”, and today accordingly, 5-year relative survival rates surpasses 95%. However, the therapeutic advances, particularly platinum-based chemotherapy, and subsequent high survival rates have led to increased awareness of long-term adverse effects with several studies showing that germ cell cancer survivors are presented with increased risk of developing serious late-occurring disorders including cardiovascular morbidities. Today, germ cell cancer therefore arguably constitutes “a model for cancer survivorship” as an intriguing entity for in-depth exploration of the challenges associated with a curable cancer diagnosis: acute therapy toxicities and organ-dysfunction, disturbance of endocrine and metabolic homeostasis, and elevated risk of long term morbidities and mortality.

In the present review-paper, we highlight the persuasive evidence describing, that the excellent cancer specific outcomes associated with germ cell cancer treatment comes with a backside in the form of several acute and chronic toxicities, which individually and synergistically can lead to cardiovascular dysfunction and leave patients more susceptible to clinical and sub-clinical cardiovascular disease. Based on the current evidence, we propose that orchiectomy-derived subclinical hypogonadism, and chemotherapy-induced cardiovascular injury and/or disturbance of metabolic homeostasis constitute the primary candidates as causal drivers of late occurring cardiovascular disease in germ cell cancer survivors. Importantly, these physiological impairments are, under normal circumstances, modifiable by structured exercise-training providing researchers and clinicians (and patients) with a strong rationale for exploring whether this well-known sequealae can be prevented and/or reversed by interventions with physical exercise.

Unfortunately, patients with a history of germ cell cancer are almost none-existing in the ‘exercise-oncology’ literature; that is, clinical research trials exploring the safety, feasibility and efficacy of exercise training to improve physical, psycho-social and clinical outcomes in individuals with a history of cancer. Our group recently performed the “PROgressive resistance TRAining and Cancer Testis (PROTRACT)” study, which was first (and so far only) training study in germ cell cancer patients. Our findings suggested that while resistance training may have the potential to ameliorate the considerable loss of muscle function (e.g. myofiber atrophy, loss of lean body mass and isometric muscle strength) observed during 9 weeks of chemotherapy, we found no indication that this translated into improved systemic metabolic or inflammatory profile. Thus despite a strong rationale and to some extend obvious needs, virtually no available evidence exists from which to prescribe germ cell cancer survivors with exercise recommendations during and after treatment.

We therefore strongly propose that future exercise-oncology research should be performed in the germ cell cancer setting with the dual aim of gaining a better understanding of candidate mechanisms responsible of anti-cancer treatment-related late-morbidities and developing effective exercise-based countermeasures. This work may have profound implications in both germ cell cancer survivorship, as well as within other malignancies striving towards similar success in cancer-specific outcomes and the increasing number of individuals who survive their primary cancer but subsequently has to battle treatment-related late-morbidities in the years to come.

Written by:
Jesper Frank Christensen, PhD, Post Doctoral Fellow
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (CIM/CFAS)
Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark

Abstract: Treatment-related Cardiovascular Late Effects and Exercise Training
Countermeasures in Testicular Germ Cell Cancer Survivorship