(UroToday.com) The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on biochemical recurrence, and a presentation by Dr. Nicholas James discussing imaging directed treatment for biochemical recurrence. Dr. James notes that in the pre-PSA era, data favored early versus deferred hormone therapy, given that many patients received treatment very late and ~10% of deferred patients died from prostate cancer and no treatment (with all patients having advanced disease at study entry).
The SAKK 08/88 trial1 determined if immediate hormonal therapy is advantageous compared with deferred treatment in newly diagnosed asymptomatic prostate cancer patients who were not candidates for curative local treatment. This trial randomized 197 men to either immediate or deferred orchiectomy for symptomatic progression. Median time to disease progression was 2.8 years less than for patients with immediate orchiectomy, however overall pain-free time from random assignment to symptomatic progression after immediate or deferred orchiectomy, and performance status, were identical in both groups. Cancer-specific survival tended to be longer in the immediate group (p = 0.09) but there was no difference in overall survival between the two groups (p = 0.96):
In 2012, Crook et al.2 assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Over a median follow-up of 6.9 years, there were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (HR for death 1.02, 95% CI 0.86 to 1.21), and the estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (p = 0.24):
For the timing of hormone therapy, Dr. James provided the following summary:
- There is probably no survival benefit to early versus late hormone therapy, even in advanced disease
- With better monitoring, later therapy is safe
- The harms of overtreatment with hormones are well known
When discussing if we can predict who is at risk of harm, Dr. James highlighted the classic Pound paper3 which delineated the natural history of progression after PSA elevation following radical prostatectomy. High Gleason score (8-10), PSA recurrence <= 2 years after surgery, and PSA doubling time <10 months were predictive of metastatic disease:
Androgen deprivation for these patients leads to increased risk of fracture. Shahinian et al.4 assessed risk of fracture after ADT among 50,613 men in the SEER-Medicare database. Of men surviving at least five years after diagnosis, 19.4% of those who received ADT had a fracture, as compared with 12.6% of those not receiving ADT (p < 0.001):
Dr. James notes that there are several implications for starting ADT:
- Many men will die from other causes before getting metastasis if left untreated
- Even if men develop metastasis, many will die from other causes
- All men are guaranteed to be harmed by ADT, including increased risk of cardiovascular disease, osteoporosis, loss of sexual function, sarcopenia, and diabetes
With regards to timing of starting radiotherapy, there are several key trials that have assessed adjuvant versus salvage radiotherapy, three of which were highlighted by Dr. James:
- SWOG 8794 trial: This trial showed an advantage of adjuvant versus salvage radiotherapy, but ~35% of patients had a PSA > 0.2 ng/mL at study entry, all were T3 disease, a lot of salvage radiotherapy was driven by clinical relapse, and only 65/211 patients had salvage radiotherapy (but 75% relapsed)
- EORTC 22911 trial: This trial tested adjuvant versus salvage radiotherapy with radiotherapy being initiated on PSA relapse > 0.2, only showing a benefit for PSA rPFS and suggestion of harm on overall survival
- RADICALS-RT:5 A multi-national trial of 1396 men with intermediate to high risk localized prostate cancer. Patients were included if they had undergone radical prostatectomy within 22 weeks of enrollment, had a post-operative PSA less than 0.2 ng/mL, and had one or more of the following “high risk criteria”: pT3/4 disease, Gleason 7-10, preoperative PSA >10 ng/mL, or positive surgical margins. Over a median follow-up of 5 years, there was no difference in biochemical progression free survival among patients who received adjuvant or early salvage radiotherapy (HR 1.10, 95% CI 0.81 to 1.49). Further, toxicity was higher in the adjuvant radiotherapy arm.
For the timing of radiotherapy, Dr. James provided the following summary:
- With newer data, it is hard to show benefit from early treatment
- This suggests that better imaging plus PSA monitoring keeps patients safe
- There is a side effect penalty from overtreatment
Dr. James notes that the best way to assess where relapses occur after radiotherapy is to look at the relapse patterns in the PET/CT era. Local relapse is rare highlighting that radiotherapy works and that out of field relapses are most common. Additionally, loco-regional relapse is reduced by pelvic radiotherapy. As follows is a Venn diagram of radiological patterns of failures’ distribution for patients and imaging tools (conventional imaging versus PET/CT) used to detect recurrence location:6
Discussing the impact of PET on SBRT recurrence rates, Dr. James discussed the ORIOLE trial,7 which randomized 54 men in a 2:1 ratio to receive stereotactic body radiotherapy or observation. The primary endpoint for this trial was progression at 6 months, defined as a PSA increase, radiographic or symptomatic progression, ADT initiation, or death. Progression at 6 months occurred in 7 of 36 patients (19%) receiving stereotactic body radiotherapy and 11 of 18 patients (61%) undergoing observation (p = 0.005). Furthermore, treatment with stereotactic body radiotherapy improved median progression-free survival (not reached vs 5.8 months; HR 0.30, 95% CI 0.11-0.81; p = 0.002):
For those patients in the stereotactic body radiotherapy arm that had a PSMA PET-CT scan, the proportion of men with disease progression at 6 months was 5% in those who did not have any untreated lesions, compared to 38% in those who did have some untreated PSMA avid lesions (p=0.03).
Dr. James concluded his presentation discussing imaging directed treatment for biochemical recurrence with the following take-home messages:
- PSA rises tell us about the presence of disease, PSA kinetics are prognostic, but PSA does not tell us the site of relapse
- Relapse patterns post-radiotherapy show that most relapses are outside the field
- Deferred treatment appears safe with more contemporary series, evidence of potential harm with early treatment, both hormonal and radiotherapeutic
- Radiotherapy works, but you don’t have to irradiate all the disease, with relapse inevitable
- Image directed treatment ensures better treatment decisions
Presented By: Nicholas D. James, BSc, MBBS, PhD, FRCP, FRCR, The Institute of Cancer Research, The Royal Marsden, London, UK
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.References:
- Studer UE, Hauri D, Hanselmann S, et al. Immediate versus deferred treatment for patients with prostate cancer who are not suitable for curative local treatment: Results of the randomized trial SAKK 08/88. J Clin Oncol 2004 Oct 15;22(20):4109-4118.
- Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367(10):895-903.
- Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999 May 5;281(17):1591-1597.
- Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005 Jan 13;352(2):154-164.
- 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.
- Gonazalez-Moya A, Supiot S, Seegers V, et al. Mapping of Recurrence Sites Following Adjuvant and Salvage Radiotherapy for Prostate Cancer Patients. Front Oncol. 2022; Jan 5.
- Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020 Mar 26;6(5):650-659.
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