Marieke van Son

14 CHAPTER 1 (pN+) or image-suspected (iN+M+) metastatic disease represent a heterogeneous and complex group (often referred to as “very high risk”), for whom a clear consensus re- garding optimal treatment is lacking. A subdivision based on metastatic volume (low- or high-volume) has been adopted as a predictor for survival and as a guideline for treatment decisions(64). ADT, which lowers androgen levels to prevent prostate cancer cells from growing, has been the standard of care for disseminated disease for over 50 years(65). However the timing of initiation, type of androgen blockade and its role in asymptomatic stages remains poorly defined. ADT has a temporary suppressive effect on the disease, halting its progression for a mean of 2-3 years before the tumor becomes hormone-resis- tant(66). It is therefore a palliative treatment with no potential of cure. Moreover, ADT is associated with significant side-effects, including impotence, fatigue, gynecomas- tia, breast pain, hot flushes, metabolic and cardiovascular events and psychological distress(67). ADT is therefore usually deferred until the patient suffers symptoms of metastatic prostate cancer or has evident radiological tumor progression. However the ideal timing remains controversial, with a recent Cochrane review concluding that early ADT may extend time to death(68). Further research in the field of systemic palliative treatments has led to the adoption of novel therapeutic approaches, particularly the wide-spread use of combination therapies (ADT with chemotherapy or second gener- ation antiandrogens)(69) and the concept of adding local treatment for cytoreductive purposes in patients with “low volume” metastatic disease(70). Recurrence of disease Although the average 10-year overall survival rate is as high as 98%(8), prostate cancer recurrences are quite common after local treatment. Depending on the primary risk group, 10-40% of patients have recurrence of disease within 10 years after radiotherapy or surgery(71, 72). A relapse is diagnosed based on rising PSA, with different definitions of biochemical failure after RP (PSA >0.4 ng/mL and rising) and radiotherapy (PSA increase >2 ng/mL above nadir value)(73). The management of recurrent disease is controversial since its natural history is very heterogeneous, ranging from indolent cancer that remains clinically undetectable to aggressive recurrences that are rapidly lethal(74). Nonetheless, on average, biochemical failure precedes progression to distant metastases by ±5 years and prostate cancer-specific mortality by ±10 years(75). As concluded in a recent review, the impact of biochemical recurrence on survival seems most outspoken in a subgroup of patients with specific clinical risk factors (short PSA doubling time, short interval to biochemical failure, high Gleason score)(76). Just as in the primary setting, the decision to initiate salvage treatment should be carefully balanced between the risk of disease progression and the risk of treatment morbidity. For patients with a localized recurrence after radiotherapy (“radiorecurrent” disease), there is potential to re-treat the prostate gland. In this setting, modern imaging has a more established role in staging the disease and guiding local salvage treatment. PSMA/ PET-CT is the most sensitive tool for the detection of distant metastases(77), while