The first paper presented by Dr. Mathieu was “MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis” published in the New England Journal of Medicine.1 This paper assessed whether performing biopsies magnetic resonance imaging (MRI) targeting may reduce the misclassification of prostate cancer in men with MRI-visible lesions. There were 2,103 men with MRI-visible prostate lesions who underwent both MRI-targeted and systematic biopsy with a primary outcome of cancer detection according to grade group. Additionally, among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens were recorded. The authors found that cancer was diagnosed in 1,312 (62.4%) by a combination of the two methods, and 404 (19.2%) men underwent radical prostatectomy. Cancer detection rates on MRI-targeted biopsy were significantly lower than on systematic biopsy for grade group 1 cancer and significantly higher for grade groups 3 through 5 (p<0.). Combined biopsy led to cancer diagnoses in 208 more men (9.9%) than with either method alone and to upgrading to a higher grade group in 458 men (21.8%). However, if only MRI-target biopsies had been performed, 8.8% of clinically significant cancers (grade group ≥3) would have been misclassified:
Among the 404 men who underwent subsequent radical prostatectomy, combined biopsy was associated with the fewest upgrades to grade group 3 or higher on histopathological analysis of surgical specimens (3.5%), as compared with MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%):
A second paper, complementary to the aforementioned paper, was published by Gandaglia et al. “The Key Combined Value of Multiparametric Magnetic Resonance Imaging, and Magnetic Resonance Imaging-targeted and Concomitant Systematic Biopsies for the Prediction of Adverse Pathological Features in Prostate Cancer Patients Undergoing Radical Prostatectomy” published in European Urology.2 The objective of this study was to develop novel models to predict extracapsular extension (ECE), seminal vesicle invasion (SVI), or upgrading in patients diagnosed with MRI-targeted and concomitant systematic biopsies. Among 614 men with clinical stage ≤T2 at DRE who underwent MRI-targeted biopsy with concomitant systematic biopsy, 333 (54%) had ECE, 88 (14%) had SVI, and 169 (27%) patients had upgrading at RP. Models including mpMRI, and MRI-targeted and concomitant systematic biopsy information achieved the highest AUC at internal validation for ECE (73%), SVI (81%), and upgrading (73%). As such, although omitting systematic prostate sampling at the time of MRI-targeted biopsy might be associated with a reduced risk of detecting insignificant prostate cancer, it reduces the ability to accurately predict pathological features.
The third influential paper discussed by Dr. Mathieu was “Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomized, multicenter study” published in The Lancet.3 The objective of this study was to assess prospectively the use of PSMA PET-CT among patients with high-risk prostate cancer before curative-intent surgery or radiotherapy. To be eligible for inclusion in this trial, men must have had at least one high-risk factor including PSA >= 20 ng/mL, ISUP grade group 3-5, or clinical stage T3 or greater. Patients who had undergoing staging investigations (apart from prostate MRI) within eight weeks prior to randomization were excluded. Following enrollment, patients were randomly assigned in a 1:1 ratio to either conventional imaging performed using bone scan and CT or PSMA PET/CT. Patients who were randomized to conventional imaging underwent an abdominopelvic CT scan with contrast as well as a technetium-99m bone scan with SPECT CT of chest, abdomen, and pelvic in keeping with the standard of care. For patients randomized to PET/CT, gallium-68 PSMA-11 PET/CT was performed. In patients who had fewer than three unequivocal sites of metastasis, cross-over imaging for confirmation was performed within 14 days. There were 300 men that received assigned first-line imaging, showing that PSMA PET-CT had a 27% absolute greater AUC for accuracy compared to conventional imaging (95% CI 23-31): 92% (95% CI 88-95%) vs. 65% (60-69%). Conventional imaging had both a lower sensitivity (38% vs. 85%) and also a lower specificity (91% vs. 98%):
Prior to treatment, the results of conventional imaging studies resulted in treatment change for 23 men (15%, 95% CI 10-22) while the results of PSMA PET-CT resulted in treatment change for 41 (28%, 95% CI 21-36). These changes included both a transition from curative intent to palliative intent treatment in 20 patients (14%) and also a change in treatment approach in 22 (14%). Additionally, conventional imaging was associated with a higher radiation dose (19.2 mSv compared to 8.4 mSv; absolute difference 10.9 mSv, 95% CI 9.8-12.0 mSv0. PSMA PET-CT was not associated with any adverse events and reporter agreement was high for both nodal (kappa 0.87, 95% CI 0.81-0.94) and distant metastatic disease (kappa 0.88, 95% CI 0.94-0.92).
The fourth paper of importance discussed by Dr. Mathieu was from Strom et al. “Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: A population-based, diagnostic study” published in Lancet Oncology.4 The objective of this study was to develop an artificial intelligence system with clinically acceptable accuracy for prostate cancer detection, localization, and Gleason grading. The authors digitized 6,682 slides from needle core biopsies from 976 randomly selected participants aged 50-69 in the Swedish prospective and population-based STHLM3 diagnostic study, and another 271 from 93 men from outside the study. Impressively, the artificial intelligence system achieved an area under the receiver operating characteristics curve of 0.997 (95% CI 0.994-0.999) for distinguishing between benign and malignant biopsy cores on the independent test dataset and 0.986 (0.972-0.996) on the external validation dataset. Additionally, the artificial intelligence system achieved a mean pairwise kappa of 0.62 for assigning Gleason grades, which was within the range of the corresponding values for the expert pathologists (0.60-0.73). The authors note that this clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores.
2020 also saw the publication of three randomized control trials assessing adjuvant or early salvage radiotherapy for the treatment of localize or locally advanced prostate cancer. Dr. Mathieu’s fifth article he discussed was by Vale et al. “Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data” published in The Lancet5 – a meta-analysis of these three trials. There were 2,153 patients recruited between November 2007 and December 2016, with a median follow-up ranging from 60 months to 78 months, with a maximum follow-up of 132 months. There were 1,075 patients were randomly assigned to receive adjuvant radiotherapy and 1,078 to early salvage radiotherapy, of whom 421 (39.1%) had commenced treatment at the time of analysis. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (HR 0.95, 95% CI 0.75-1.21), with only a 1 percentage point (95% CI -2 to 3) change in 5-year event-free survival (89% vs 88%):
These three trials and the meta-analysis suggest that adjuvant radiotherapy does not improve event-free survival in men with localized or locally advanced prostate cancer.
Finally, Dr. Mathieu discussed the story of olaparib in men with mCRPC which included an initial the publication by de Bono et al. “Olaparib for Metastatic Castration-Resistant Prostate Cancer,”6 followed later in the year by Hussain et al. “Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer”7 – both published in The New England Journal of Medicine. In the first publication, it was shown that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent.6 Subsequently, the authors published overall survival benefit.7 This trial was an open-label, phase 3 trial, in which patients were randomly assigned in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (HR for death 0.69, 95% CI 0.50 to 0.97; p = 0.02):
This trial concluded that the overall survival benefit for olaparib versus next-generation hormonal agents was observed despite substantial crossover from control therapy to olaparib.
Presented by: Romain Mathieu, MD, PhD, Rennes University Hospital Rennes, France
Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 18th Meeting of the EAU Section of Oncological Urology (ESOU21), January 29-31, 2021
References:
- Ahdoot M, Wilbur AR, Reese SE, et al. MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis. N Engl J Med. 2020 Mar 5;382(10):917-928.
- Gandaglia G, Ploussard G, Valerio M, et al. The Key Combined Value of Multiparametric Magnetic Resonance Imaging, and Magnetic Resonance Imaging-targeted and Concomitant Systematic Biopsies for the Prediction of Adverse Pathological Features in Prostate Cancer Patients Undergoing Radical Prostatectomy. Eur Urol 2020 Jun;77(6):733-741.
- Hofman MS, Lawrentschuk N, Francis, RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomized, multicentre study. Lancet 2020 Apr 11;395(10231):1208-1216.
- Strom P, Kartasalo K, Olsson H, et al. Artificial intelligence for diagnosis and grading of prostate cancer in biopsies: A population-based, diagnostic study. Lancet Oncol 2020 Feb;21(2):222-232.
- Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localized and locally advanced prostate cancer: A prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020 Oct 31;396(10260):1422-1431.
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020 May 28;382(22):2091-2102.
- Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357.