What is the optimal strategy for oligometastatic prostatic cancers?

This is part of the continuum of my focus on oligometastatic cancers. I won’t delve into “controversies” around metastatic prostate, but it calls into question- whether the sole basis of partin’s nomograms around nodal involvement has been understaged and pelvic dissection of nodes incomplete. Numerous contemporary studies fail to account for these two basic statements. Therefore, the confusion (and controversy) around the metastatic prostatic tumours. I am including a summary of the different studies around this for quick revision. As always, my summary appears below the paper.

Makino, Tomoyuki, Kouji Izumi, Hiroaki Iwamoto, and Atsushi Mizokami. 2021. “Treatment Strategies for High-Risk Localized and Locally Advanced and Oligometastatic Prostate Cancer.” Cancers 13 (17). https://doi.org/10.3390/cancers13174470.

[embeddoc url=”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430548/pdf/cancers-13-04470.pdf”%5D

• With the introduction of prostate cancer (PC) screening, more men are continuously being diagnosed with clinically nonmetastatic PC
• Despite the significant advances in the treatment of high-risk prostate cancer, patients with very high-risk features such as being locally advanced, having a high Gleason pattern, or with oligometastasis may still have a poor prognosis despite aggressive treatment
• Attempts to further enhance disease control by concomitant metastasis-directed therapy (MDT) have been made [11,12,13], and radical curing of oligometastatic PC may be expected in the future
• Sphan et al studied 712 PC patients with prostate-specific antigen (PSA) > 20 ng/mL and found that a combination of additional risk factors (e.g., Gleason score (GS) 8–10, clinical stage (c) T3–4) at presentation were associated with unfavorable histopathology and worse cancer-specific outcomes [16]
• Walz and Joniau showed that patients with two or more high-risk features (e.g., PSA > 20 ng/mL, GS 8–10, cT3–4) had worse biochemical recurrence-free survival (RFS) and prostate cancer-specific survival (CSS) than those with only one high-risk feature [17,18]
• The National Comprehensive Cancer Network (NCCN) defined very high-risk PC patients as those with cT3b–4 or primary Gleason pattern 5 or >4 cores with grade group ≥ 4 according to the International Society of Urological Pathology [20]
• Patients with a GS < 8 and ≤2 positive lymph nodes had relatively favorable outcomes at 10 years among patients with lymph node metastases treated with radical prostatectomy (RP) and extended pelvic lymphadenectomy [22]. These findings suggest that the current staging system of PC does not accurately reflect prognosis and treatment paradigms may need to be reconsidered for better outcomes
• Combining systemic treatment with androgen deprivation therapy (ADT) and local treatment has recently become more common, there is no standardized treatment for the choice of local treatment because it is unknown which is better between RP and RT; no direct comparison studies have been conducted
• In a report based on the Surveillance Epidemiology and End Results (SEER) database including 1093 patients with cT4 or cN1 PC, the five-year overall survival (OS) of patients treated with RP or combined ADT and RT was significantly better than that of patients treated with ADT alone or without treatment [30]
• In a randomized phase 3 trial of 1205 patients with locally advanced PC staged at cT3-4N0/NXM0, cT1–2 + PSA > 40 ng/mL, or cT1–2 + PSA 20–40 ng/mL + GS 8–10, the 10-year OS of patients treated with combined ADT and RT was significantly better than that of patients treated with ADT alone, at 55% and 49%, respectively (HR: 0.70; 95% CI: 0.57–0.85; p < 0.001), and the risk of death was reduced by 30% [5]
• This study reported that the five-year relapse-free survival was 80.5% for patients treated with hypofractionation and 77.1% for those treated with conventional fractionation
• This study found that the LDR boost improved PSA control compared to external beam RT (EBRT) alone, but at the cost of higher GU late toxicity [64]
• There has been an expansion of the indications for sealed small source therapy, which allows for high-dose local irradiation, and good results have been reported in high-risk PC patients, especially for trimodal therapy [65,66]
• The five-year metastasis-free survival (MFS) rates were 76% for RP, 76% for EBRT, and 92% for EBRT plus brachytherapy, which was associated with a significantly lower rate of distant metastasis (HR: 0.27 for RP and 0.30 for EBRT)
• It is considered as a metastatic carcinoma that lies between locally advanced carcinoma and widely metastatic carcinoma, and it should be treated separately from both in terms of prognosis and treatment [2]
• prostate-specific membrane antigen (PSMA)-PET has improved specificity and sensitivity compared to standard imaging (CT, MRI, and bone scintigraphy), and improves the detection of metastatic disease in biochemically recurrent PC with low serum PSA levels
• It is expected to reliably diagnose clinical stage, which would lead to early intervention in cases of locally advanced cancer with potential metastasis and in more extensive metastatic cancer, even in oligometastatic PC
• The efficacy of HDR brachytherapy, which delivers a high dose per instance of irradiation, has been recognized for the control of the primary disease; there are no reports of HDR brachytherapy against PC with oligometastasis
• These results suggest that the combined local irradiation is effective for patients with low metastatic volume
• RT delivery methods and protocols vary from study to study, which is an issue that remains unresolved
• It will be interesting to see the results of currently ongoing large-scale studies in this field which will be reported in the future

The condensed summary of the results

• The preoperative criteria of the National Comprehensive Cancer Network (NCCN) identifies those with primary Gleason pattern 5 on biopsy or ≥4 cores containing pattern 4 (odds ratio (OR): 3.17; p < 0.001) as the high-risk subgroup, who are most likely to experience early (within one year) biochemical recurrence after surgery [19]
• Patients with ≤2 positive lymph nodes treated with RP with extended pelvic lymph node dissection show significantly better CSS outcomes at 15-year follow-up compared to those with ≥2 positive lymph nodes (84% vs. 62%, respectively; p < 0.001) [21]
• A meta-analysis including 17 studies that used mpMRI to detect extracapsular invasion reported a sensitivity of 0.55 (95% confidence interval (CI): 0.43–0.66) and a specificity of 0.87 (95% CI: 0.82–0.91), suggesting the usefulness of mpMRI for diagnosing locally advanced PC [25]
• EBRT was associated with higher overall and prostate-specific mortality (hazard ratio (HR): 1.41; 95% CI: 1.09–1.82 vs. HR: 2.35; 95% CI: 1.85–2.98, respectively)
• On the other hand, in a randomized phase 3 trial of 1205 patients with locally advanced PC staged at cT3-4N0/NXM0, cT1–2 + PSA > 40 ng/mL, or cT1–2 + PSA 20–40 ng/mL + GS 8–10, the 10-year OS of patients treated with combined ADT and RT was significantly better than that of patients treated with ADT alone, at 55% and 49%, respectively (HR: 0.70; 95% CI: 0.57–0.85; p < 0.001), and the risk of death was reduced by 30% [5]
• The prospective randomized trial RTOG 85-31 evaluated the effectiveness of adjuvant ADT after definitive RT (a total dose of 65–70 Gy including a boost to the prostate) in patients with cT3 and/or regional lymph node involvement and showed the addition of ADT significantly improved 10-year OS (49% vs. 39%, p = 0.002) [3,4]
• The GETUG 12 trial evaluated the addition of docetaxel and estramustine to adjuvant ADT in RT or RP among patients with high-risk localized PC and showed that the combined group significantly improved the eight-year RFS (62% vs. 50%, p = 0.017) [7]
• Rusthoven et al reported that additional EBRT for prostate to ADT improved the 10-year estimated CSS (67% and 53%, respectively; p < 0.001) in 796 patients with cT1-4N1M0 PC [8]
• Evaluation of 3540 patients with clinically lymph node positive PC from the National Cancer Data Base also reported treatment with ADT plus RT was associated with a 50% reduction in five-year all-cause mortality when compared to treatment with ADT alone (HR: 0.5, 95% CI: 0.37–0.67; p < 0.001) [9]
• A well-conducted, non-randomized, propensity-matched retrospective analysis of 42,481 patients in the U.S National Cancer Database found IMRT to be beneficial in intermediate-risk (p < 0.001) and high-risk PC (p < 0.001), but not in low-risk PC (p = 0.54) [50]
• The results of high-dose RT (78 Gy in 92.5% of patients) with IMRT for cT3–4 PC showed eight-year RFS, CSS, and OS rates of 53.2% (95% CI: 43.4–62.1%), 96.6% (95% CI: 91.2–98.7%), and 89.1% (95% CI: 81.5–93.7%), respectively, at a median observation period of 97 months without grade 4 or higher side effects [51]
• This study reported that the five-year relapse-free survival was 80.5% (95% CI: 75.7–84.4%) for patients treated with hypofractionation and 77.1% (95% CI: 71.9–81.5%) for those treated with conventional fractionation (adjusted HR: 0.86; 95% CI: 0.63–1.16; log-rank p = 0.36)
• The biochemical disease-free rate at five years was 78.9% (95% CI: 69.8–87.9%) in the EBRT and HDR boost group compared to 66.5% (95% CI, 56.1–76.9%) in the conventional EBRT group treated with 70–72 Gy [73]
• The five-year MFS rates were 76% for RP, 76% for EBRT, and 92% for EBRT plus brachytherapy, which was associated with a significantly lower rate of distant metastasis (HR: 0.27 (95% CI: 0.17–0.43) for RP and 0.30 (95% CI: 0.19–0.47) for EBRT)
• The 7.5-year OS rates were 83% for RP, 82% for EBRT, and 90% for EBRT plus brachytherapy, which was associated with significantly lower all-cause mortality (HR: 0.66 (95% CI: 0.46–0.96) for RP and 0.61 (95% CI: 0.45–0.84) for EBRT)
• Although the two groups had no significant difference in OS (HR: 0.90; 95% CI: 0.70–1.14; p = 0.4), a subanalysis suggested that RT to the prostate improved OS in patients with low tumor volume (<5 bone lesions)
• Although survival was significantly prolonged in the standard treatment plus RT group (HR: 0.76, 95% CI: 0.68–0.84; p < 0.0001), OS was not prolonged in the standard treatment plus RT group (HR: 0.92, 95% CI: 0.80–1.06; p = 0.266)
• In the subanalysis by tumor volume, there was a significant difference in OS at three years in the low metastatic volume group (73% in the standard treatment group vs. 81% in the standard treatment plus radiation group; HR: 0.68, 95% CI: 0.52–0.90; p = 0.007), whereas combined radiation treatment had no prognostic effect in the high metastatic volume group
• The ORIOLE Trial, a randomized phase 2 study comparing observation and MDT, showed a significantly better PFS of MDT than observation (median, not reached vs. 5.8 months; HR: 0.30; 95% CI: 0.11–0.81; p = 0.002) [12]
• The proportion of patients who did not require treatment escalation (e.g., modification of ADT, introduction of chemotherapy, or palliative RT) was 51.7% (95% CI: 44.1–59.3%) at two years after SBRT, and the median survival without treatment escalation over the entire follow-up period was 27.1 months (95% CI: 21.8–29.4 months)
• PSA reduction was observed in 75% of patients