Androgen deprivation therapy (ADT) has been an established and effective treatment for men with asymptomatic metastatic prostate cancer for decades. Randomized trials have shown significant survival benefits when ADT is used, coupled with radiotherapy, for patients with locally advanced disease; however it is often used in patients where the benefits are less clear, such as for a rising serum PSA level after radical prostatectomy, and among patients who elect to take a more conservative approach to treatment for low-risk disease. In addition to the absence of data proving benefit, there are a number of adverse consequences attached to androgen deprivation which should be given serious consideration before beginning treatment. Most of the side effects of ADT are linked to its induced hypo-androgenic, and consequently hypo-oestrogenic, state. These include fatigue, vasomotor flushing, loss of muscle mass, weight gain, hyperlipidaemia and insulin resistance.
Osteoporosis and fracture are additional known consequences of ADT with a trend toward greater fracture risk with a higher number of doses of a GnRH agonist and/or longer duration of use. Studies indicate that men with non-metastatic prostate cancer treated with ADT experience an annual loss in bone mineral density of up to nine times that of men in the general population. The use of intermittent ADT, as opposed to continuous use, as a strategy to reduce the negative cardiometabolic and osteoporotic effects is unresolved; however, a report indicating that more recent treatment was associated with a greater risk of fracture, irrespective of cumulative dose, suggests the potential for some reversibility in bone loss post-treatment.
In the present issue of the BJU International, Lu-Yao et al. add to the literature in this area. In a study of nearly 76 000 men with prostate cancer, using data gathered as part of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) cancer registry linked to Medicare claims data, the authors reported that patients at high risk for skeletal complications were, not surprisingly, more likely to experience a fracture associated with ADT use over a 12-year period compared with patients receiving ADT but at low risk for developing such complications. Furthermore, men who experienced a fracture were 40% more likely to die during follow-up than those without fracture. Patients were sorted into risk groups using an index which summed the number of known risk factors for incident fracture identified from Medicare claims in the 12 months before their prostate cancer diagnosis. Unfortunately, owing to the relatively small number of patients with more than one risk factor, the study was limited in its ability to establish a dose – response relationship between the baseline index and fracture risk. SEER-Medicare is an excellent resource to investigate both outcomes and treatment-related expense associated with cancer diagnoses in the USA; however, in this particular study, the reliability of behaviours included in the baseline index (i.e. smoking) is questionable as it would require both patient report of tobacco use as well as physician documentation as a billable claim. Still, one might argue that the heaviest smokers, whose behaviour would most likely be captured as part of a claim, would also be the most important group to capture in an index intended to predict fracture risk.
Interestingly, it was reported that patients at high risk for skeletal complications were significantly more likely to receive ADT than patients at low risk. This was driven in part by the use of primary ADT among elderly men (aged ≥80 years) with prostate cancer and consistent with the notion that when curative treatment is contraindicated (i.e. older patients and those with pre-existing comorbidities) treatment with ADT is more common. Lastly, these findings do not suggest any modification of fracture risk associated with ADT according to baseline risk index, which is consistent with reports of the impact of comorbid conditions and ADT on the risk of incident diabetes and cardiovascular events. This is an important observation in that it says, there is no group that is immune to the adverse effects of ADT – all men are at risk. In absolute terms, however, the men at the greatest risk of an ADT side effect (i.e. a fracture or diabetes) are the men who are at greatest risk of having that side effect even if they were not receiving ADT. The findings of Lu-Yao et al. reinforce the need for careful monitoring of all men receiving ADT. Moreover, when these data are combined with an earlier study that showed that primary ADT was associated with poorer survival than that for men with low-risk prostate cancer who were managed conservatively with observation alone, it should be a wake-up call for us to stop treating non-lethal cancer with lethal and toxic treatments, including ADT.
Jennifer L. Beebe-Dimmer*† and Stephen J. Freedland‡§
*Wayne State University School of Medicine, †Karmanos Cancer Institute, Detroit, MI, ‡Durham VA Medical Center, and §Duke University School of Medicine, Durham, NC, USA