Has the time come for routine use of PET/CT for guiding treatment of biochemical recurrence after radical prostatectomy?

Clinical context: About one-third of men who undergo a radical prostatectomy for prostate cancer will experience recurrence, first noticed as rising PSA (prostate-specific antigen) values. Salvage radiotherapy offers a second chance for cure, but when the treatment decision is made the tumour burden is usually too small to be detected on standard imaging with CT, MRI or bone scan. The treatment decision and the definition of the radiotherapy target are therefore based on nomograms estimating the probability of where the recurrence is located [1]. Not surprisingly, a large proportion of the patients do not respond, i.e. their PSA values continue to rise after the radiotherapy course. Patients with a poorly differentiated cancer or a rapidly rising PSA would benefit most from effective salvage treatment but are the ones least likely to respond [1].

The new PSMA (prostate-specific membrane antigen)- and fluciclovine-targeting PET/CT (positron emission tomography/computed tomography) tracers have much higher sensitivity for localising recurrence at low PSA values than current standard imaging [2,3]. These new tracers give us hope of leaving the current ‘probability-guided’ treatment planning in favour of an ‘imaging-guided’ one with better outcomes. PET/CT-guided salvage radiotherapy may eradicate cancer recurrence at locations otherwise not included in the treatment field, and save some patients with distant metastasis from ineffective loco-regional radiotherapy. The path from hope to clinical routine must, however, be gradually built by pieces of solid evidence from well-designed trials.

News: The single-centre EMPIRE-1 trial randomly allocated 165 men to either ¹⁸F-fluciclovine-PET/CT-guided or conventional salvage radiotherapy to the prostate bed ± pelvic lymph nodes [4]. The men in the conventional group had a bone scan and a CT or MRI of the abdomen and pelvis. Primary outcome was 3-year event-free survival (essentially biochemical recurrence-free survival). Median PSA at the start of salvage radiotherapy was 0.3 ng/ml; one-fourth of the participants had a PSA ≥1.0 ng/ml. One-third received adjuvant androgen deprivation therapy for up to 2 years.

Of the 79 men who underwent ¹⁸F-fluciclovine-PET/CT imaging, 4 had extra-pelvic or skeletal uptake, 27 had uptake in pelvic lymph-nodes, 32 had uptake in the prostate bed only, and 16 had no uptake. The PET/CT findings affected the treatment planning for 35% of the men, including adjustment of the radiotherapy target. More men in the PET/CT group had radiotherapy to the pelvic nodes (46% vs 31%). After excluding the 4 men with extra-pelvic or skeletal uptake, 24% of men in the PET/CT group and 37% in the conventional imaging group had an event (PSA relapse) within 3 years (12.5 percentage points difference, 95% CI 4.3–21%, p = 0.003). Toxicity was similar in both groups.

View: Better methods to visualise cancer do not automatically lead to better patient outcomes. The use of high-sensitivity PET/CT tracers for planning treatment of biochemical prostate cancer recurrence could exclude patients from the chance of cure (in case of false-positive distant uptake) or lead to more side-effects only (if radiotherapy fields are expanded without improving oncological outcomes). The results of the EMPIRE-1 trial do, however, suggest that ¹⁸F-fluciclovine-PET/CT-guided salvage radiotherapy to the prostate bed and affected pelvic lymph nodes improves cancer control, without increasing side effects. This is clearly good news, but not enough to conclude that a ¹⁸F-fluciclovine-PET/CT scan should be offered to all patients for whom salvage radiotherapy is considered. First and foremost, the trial was small and did not evaluate tertiary treatment or distant metastasis, so more trials with longer follow-up are needed to corroborate the findings. Second, the optimal PET tracer is yet to be determined; PSMA may be better than fluciclovine [5]. Third, many patients in the EMPIRE-1 trial had higher PSA values than when the treatment decision is usually made; fewer patients may benefit at PSA values around 0.2 ng/ml. Fourth, the patient group is large and PET/CT resources limited, so identifying patients with a very low probability of metastasis would be valuable, as they are unlikely to benefit from a PET/CT-guided treatment. Fifth, there are many unanswered questions about treating oligometastatic recurrence: Who benefits from metastasis-directed treatment? Is radiotherapy better than surgery? If so, what are the optimal target volumes? When should hormonal treatment be added, and for how long?

Despite these concerns, the EMPIRE-1 trial is clearly the first solid piece of evidence on the path towards a new, imaging-based standard for the management of biochemical recurrence after radical prostatectomy.

Disclosure statement

No potential conflict of interest was reported by the author(s).