APCCC 2022: Debate: PSA Directed Treatment for BCR

(UroToday.com) The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on biochemical recurrence, and a presentation by Dr. Neha Vapiwala discussing PSA directed treatment for biochemical recurrence.

 Dr. Vapiwala started her talk by emphasizing that it’s all about timing and noting that there are several instances when there is a problem: (i) locally advanced disease on initial staging (planned trimodal approach), (ii) high-risk features discovered on surgical pathology (adjuvant versus salvage radiation), and (iii) all of the above, but only if there is a concerning genomic classifier score (incorporating routine, tissue-based genomics such as Decipher or PAM50). Furthermore, we may detect ‘evidence of abnormality’ on imaging (conventional versus molecular) or physical exam, or the first signs of symptoms.

 For early salvage radiotherapy, how early is enough? At the first sign of PSA rise (ultrasensitive PSA) +/- high-risk genomic classifier score versus AUA definition? What about persistent PSA levels, even if they are low? Dr. Vapiwala suggests that we should give radiotherapy at the earliest sign of PSA rise, especially if the patient has adverse pathological findings, such as pT3b/pT4, Gleason score >8 or positive surgical margins. As follows is a helpful nomogram for assessing risk/timing of radiotherapy for these patients:

 Dr. Vapiwala notes that taking the absolute PSA aside, there is greater risk of distant metastasis and cancer-specific mortality with bad PSA kinetics (doubling time < 10 months) and a short interval after surgery. The ASTRO/AUA guidelines reinforce the importance of early intervention, noting that post-operative PSA recurrence (>= 0.2 ng/mL) is associated with higher risk of metastatic prostate cancer or death, and that we should “monitor PSA to enable early administration of salvage therapies if appropriate.” Furthermore, the EAU-EANM-ESTRO-ESUR-SIOG guidelines recommend early salvage radiotherapy to the prostate bed at PSA levels of < 0.5 ng/mL, even in the absence of a specific target.

Dr. Vapiwala highlighted the findings of the contemporary adjuvant versus salvage radiotherapy trials, RADICALS-RT [1], GETUG-AFU 17 [2], and RAVES [3], with the following summary table:

In theory, better staging and patient selection with imaging leads to better outcomes, but Dr. Vapiwala emphasized the inverse relationship of pre-salvage radiotherapy PSA and outcome due to unappreciated, undertreated, and macroscopic disease. For CT imaging in the salvage setting, the sensitivity is only 42% (specificity 82%) and for MRI the sensitivity is 39% (specificity 82%). Furthermore, the detection rates of macroscopic disease are low, even with PSMA PET/CT, noting a 45% detection rate at PSA levels ranging from 0.20 to 0.49 ng/mL. In intermediate and high-risk prostate cancer, PET/CT has a sensitivity of 40% versus pelvic nodal sampling at surgery. Dr. Vapiwala cautions that waiting until disease can be seen increases the risk of spread beyond the salvage radiotherapy field (prostate bed/pelvic lymph nodes).

 The EMPIRE-1 trial [4] published in The Lancet in 2021 evaluated the role of ¹⁸F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage post-prostatectomy radiotherapy. There were 165 patients randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus ¹⁸F-fluciclovine-PET/CT. Importantly, 3-year event-free survival was 63.0% (95% CI 49.2-74.0) in the conventional imaging group versus 75.5% (95% CI 62.5-84.6) for ¹⁸F-fluciclovine-PET/CT (difference 12.5; 95% CI 4.3-20.8; p=0.0028). However, Dr. Vapiwala emphasized that the absence of PET-defined involvement does not equal proof of disease absence, and there is unknown clinical significance of PET-detected disease lacking conventional imaging correlation.

To resolve the debate of PSA or imaging to guide treatment for biochemical recurrence, Dr. Vapiwala states that we should use both. For the patients that have biochemical recurrence and a negative PET/CT, these patient should have salvage radiotherapy alone, using PSA response as a surrogate measure of potential subclinical extraprostatic disease.

Dr. Vapiwala concluded her presentation by arguing for PSA directed treatment for biochemical recurrence emphasizing that an imaging detection threshold is not equal to the clinical relevance threshold in all cases. The dilemma comes down to salvage +/- ADT to reduce distant metastasis from suspected localized disease based on clinicopathologic data, genomic classifier score, PSA, +/- imaging evidence, versus awaiting imaging evidence while at risk of distant metastasis from untreated, undetected disease.

Presented By: Neha Vapiwala, MD, FACR, FASTRO, Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Annual Hybrid Meeting, Lugano, Switzerland, Thurs, Apr 28 – Sat, Apr 30, 2022.

1. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): A randomized, controlled phase 3 trial. Lancet 2020;396(10260):1413-1421.
2. Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): A randomized, phase 3 trial. Lancet Oncol 2020;21(10):1341-1352.
3. Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): A randomized, controlled, phase 3, non-inferiority trial. Lancet Oncol. 2020;21(10):1331-1340.
4. Jani AB, Schreibmann E, Goyal S, et al. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): A single centre, open-label, phase 2/3 randomized controlled trial. Lancet. 2021 May 22;397(10288):1895-1904.