Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review and Meta-Analysis

Tam谩s Fazekas; Sung Ryul Shim; Giuseppe Basile; Michael Baboudjian; Tam谩s K贸i; Mikolaj Przydacz; Mohammad Abufaraj; Guillaume Ploussard; Veeru Kasivisvanathan; Juan G贸mez Rivas; Giorgio Gandaglia; Tibor Szarvas; Ivo G. Schoots; Roderick C. N. van den Bergh; Michael S. Leapman; P茅ter Nyir谩dy; Shahrokh F. Shariat; Pawel Rajwa

doi:10.1001/jamaoncol.2024.0734

Comment

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April 7, 2024

Clinical Significance of Screen-detected Prostate Cancer

Takeshi Takehashi, M.D, Ph.D | Kitakyushu city

The theoretical premise behind utilizing MRI in this context is to mitigate the harm of overdiagnosis by efficiently identifying clinically significant cancers while avoiding definitive treatment for clinically insignificant ones. However, there are inconsistencies within this rationale.
Here, clinically significant cancers refer solely to those deemed pathologically significant, as predicted by the Gleason score. Retrospective observations have shown the Gleason score to be somewhat prognostic in clinically detected cancers [1]. However, in screen-detected cancers, there has been no clinical validation utilizing meaningful endpoints such as cancer-specific or overall mortality, rather than biochemical recurrence [2,3]. If the Gleason score could precisely determine clinically significant cancer, MRI would be unnecessary for this purpose.
Furthermore, findings from the randomized controlled trial (RCT) ProtecT, focusing on screen-detected prostate cancer, indicated no significant difference in cancer-specific survival rates among the three arms: surgery, radiation therapy, and active surveillance (AS) [3]. This suggests that in all cases where cancer is diagnosed, AS should be the preferred approach. No need to stratify clinically significant cancers.
Can we confidently assert that the harm of overdiagnosis has been mitigated by shifting towards less invasive AS in some cases? It seems challenging to quantify or compare the extent of overdiagnosis [4]. Moreover, it is essential to verify that this shift does not compromise the uncertain benefits of PSA screening. Perhaps a RCT of comparable size to the European Randomized Study of Screening for Prostate Cancer (ERSPC) or ProtecT would be necessary [2].
In contrast to the ProtecT trial, results from the SPCG4 trial, which focused on clinically detected cancers, suggest the superiority of surgery in terms of cancer-specific and overall mortality [2]. Therefore, interpreting the ProtecT results as indicative of equal effectiveness among all three treatments would be erroneous. Instead, considering the AS arm akin to no treatment and recognizing radiotherapy's limited impact on indolent cancers, such as screen-detected ones, provides a more nuanced perspective. The cancer-specific survival curves in the ProtecT trial illustrate the natural history of screen-detected cancers, which essentially resemble normal cells rather than cancerous ones, initially excluding clinically significant cancers.
Furthermore, PSA screening, along with subsequent tests and treatments, should not be covered by publicly-funded health insurance, and of course MRI [5]. Public funding of medical procedures may create a misconception that they are endorsed by authorities, hindering individuals' ability to assess the balance of benefits and harms themselves. This falls short of achieving adequate shared decision-making. Caution should be exercised in countries like Japan, Australia, and various European nations, including Sweden, Norway, and Germany.

REFERENCE
Albertsen PC JAMA. 1998 Sep 16;280(11):975-80.
US Preventive Services Task Force Recommendation Statement. JAMA. 2018 May 8;319(18):1901-1913.
Catalona WJ. Med Clin North Am. 2018 Mar;102(2):199-214.
Welch HG, J Natl Cancer Inst. 2010 May 5;102(9):605-13.
Takahashi T. JAMA Oncol. 2023 Jun 1;9(6):867-868.

CONFLICT OF INTEREST: None Reported

April 5, 2024

Clinical Significance of Screen-detected Prostate Cancer

Takeshi Takehashi, M.D, Ph.D | Kitakyushu city

The theoretical premise behind utilizing MRI in this context is to mitigate the harm of overdiagnosis by efficiently identifying clinically significant cancers while avoiding definitive treatment for clinically insignificant ones. However, there are inconsistencies within this rationale.
Here, clinically significant cancers refer solely to those deemed pathologically significant, as predicted by the Gleason score. Retrospective observations have shown the Gleason score to be somewhat prognostic in clinically detected cancers [1]. However, in screen-detected cancers, there has been no clinical validation utilizing meaningful endpoints such as cancer-specific or overall mortality, rather than biochemical recurrence [2,3]. If the Gleason score could precisely determine clinically significant cancer, MRI would be unnecessary for this purpose.
Furthermore, findings from the randomized controlled trial (RCT) ProtecT, focusing on screen-detected prostate cancer, indicated no significant difference in cancer-specific survival rates among the three arms: surgery, radiation therapy, and active surveillance (AS) [3]. This suggests that in all cases where cancer is diagnosed, AS should be the preferred approach. No need to stratify clinically significant cancers.
Can we confidently assert that the harm of overdiagnosis has been mitigated by shifting towards less invasive AS in some cases? It seems challenging to quantify or compare the extent of overdiagnosis [4]. Moreover, it is essential to verify that this shift does not compromise the uncertain benefits of PSA screening. Perhaps a RCT of comparable size to the European Randomized Study of Screening for Prostate Cancer (ERSPC) or ProtecT would be necessary [2].
In contrast to the ProtecT trial, results from the SPCG4 trial, which focused on clinically detected cancers, suggest the superiority of surgery in terms of cancer-specific and overall mortality [2]. Therefore, interpreting the ProtecT results as indicative of equal effectiveness among all three treatments would be erroneous. Instead, considering the AS arm akin to no treatment and recognizing radiotherapy's limited impact on indolent cancers, such as screen-detected ones, provides a more nuanced perspective. The cancer-specific survival curves in the ProtecT trial illustrate the natural history of screen-detected cancers, which essentially resemble normal cells rather than cancerous ones, initially excluding clinically significant cancers.
Furthermore, PSA screening, along with subsequent tests and treatments, should not be covered by publicly-funded health insurance, and of course MRI [5]. Public funding of medical procedures may create a misconception that they are endorsed by authorities, hindering individuals' ability to assess the balance of benefits and harms themselves. This falls short of achieving adequate shared decision-making. Caution should be exercised in countries like Japan, Australia, and various European nations, including Sweden, Norway, and Germany.

REFERENCE
1. Albertsen PC, et al. JAMA. 1998 Sep 16;280(11):975-80.
2. US Preventive Services Task Force; JAMA. 2018 May 8;319(18):1901-1913.
3. Catalona WJ. Med Clin North Am. 2018 Mar;102(2):199-214.
4. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010 May 5;102(9):605-13.
5. Takahashi T. JAMA Oncol. 2023 Jun 1;9(6):867-868

CONFLICT OF INTEREST: None Reported

June 13, 2024

Re: Takehashi T. Clinical Significance of Screen-detected Prostate Cancer

Tamás Fazekas, MD | Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

Authors: Tam谩s Fazekas, Michael S. Leapman, Shahrokh F. Shariat, Pawel Rajwa

We are grateful for the opportunity to respond to Dr. Takahashi鈥檚 remarks on our recent publication on the role of prostate magnetic resonance imaging (MRI) in prostate cancer screening. The author鈥檚 points that Gleason score are incomplete representations of cancer risk are well-taken. It is clear that considerable biologic heterogeneity exists within Gleason grade group (GG) classifications, and designations between 鈥渃linically significant鈥� and 鈥渋nsignificant鈥� cancers should reasonably include a host of factors including cancer risk, life expectancy, comorbidities and patient preferences [1]. A more holistic view of prostate cancer risk to an individual patient stands to improve decisional quality and outcomes.

However, the limitations of our current systems to ideally predict outcomes, should neither lead us to dismiss the progress in cancer mortality attributable to screening and treatment of aggressive prostate cancer, or fail to recognize the substantial progress towards personalizing management of the disease.

Until a better strategy replaces it, histological grading will remain a backbone of clinical risk stratification due to the reliability and reproducibility of this system [2-4]. Importantly, the performance of GG for estimating disease outcome and treatment benefit differs between biopsy and radical prostatectomy assessments. In the latter, full evaluation of the prostate gland reduces under-sampling associated with biopsy [5,6]. To this end, prostate MRI is associated with improved concordance between biopsy and RP, towards a ground truth standard that can reduce concerns associated with under-sampling aggressive prostate cancer that has been used to justify treatment of GG1 disease [7].

From this perspective, we also urge caution in over-generalizing the results of the ProtecT study, a landmark trial that compared observation to immediate treatment in patients with primarily low-grade (GG1) prostate cancer [8]. Indeed, a high level of evidence supports the value of treating aggressive prostate cancer as assessed by Gleason score and other clinical factors. For example, in the SPCG4 study that evaluated the effect of radical prostatectomy versus watchful waiting among those with higher risk features, treatment was associated with improved survival - an average of nearly 3 years of life gained [9].

The findings from our systematic review and meta-analysis highlight the ways in which prostate cancer detection and risk assessment continue to evolve. Notably, wide-spread use of prostate MRI has been associated with increased detection of high-grade prostate cancer and less use of invasive diagnostic biopsy for lower-suspicion lesions. Yet continued study is needed to determine whether the promise of MRI will be realized in terms of empirically improved quality and length of life for individuals screened for prostate cancer. Towards this goal, these findings can provide greater clarity about the role of prostate MRI in balancing risks and benefits associated with screening.

References
1.F眉tterer JJ et al. Eur Urol. 2015;68(6):1045-1053
2.Epstein JI et al. Eur Urol. 2016;69(3):428-435
3.EAU Guidelines on Prostate Cancer-2024
4.Eastham JA et al. Journal of Urology. 2022;208(1):10-18
5.M眉ntener M et al. Eur Urol. 2008;5
6.D'Amico AV et al. The Journal of Urology. 1995;154(1):131-138
7.Ahdoot M et al. N Engl J Med. 2020;382(10):917-928
8.Hamdy FC et al. N Engl J Med. 2023;388(17):1547-1558
9.Bill-Axelson A et al.N Engl J Med. 2018;379(24):2319-2329

CONFLICT OF INTEREST: None Reported

June 22, 2024

Level of evidence for screen-detected prostate cancer

Takeshi Takehashi, M.D, Ph.D | Health and welfare bureau, Kitakyushu city

Thank you for considering my comments and your sincere response. It appears that the authors may have some confusion regarding the differences between screen-detected and clinical prostate cancer, as well as the classifications of clinical studies and levels of evidence.
Screen-detected prostate cancer refers to diagnoses based solely on histopathology in asymptomatic individuals. In contrast, clinical prostate cancer manifests in patients with symptoms, often due to metastasis, detected before the introduction of screening. The biological nature, or natural history, of screen-detected prostate cancer has not been definitively established, similar to latent or incidental prostate cancers.

A previous review on prostate cancer screening and surgery, conducted before the introduction of PSA testing, emphasized the lack of validated natural history for screen-detected cancers.[1] It highlighted the necessity for long-term observational studies comparing treated and untreated cases to clarify this natural history. However, conclusive results await randomized controlled trials (RCTs) [2]. In 2012, the United States Preventive Services Task Force (USPSTF) initially viewed the RCT results as negative evidence but revised this perspective in 2018, clarifying that they did not constitute positive evidence. Thus, scientific validation remains inconclusive [3].

Among PSA screening studies, only three RCTs on efficacy and the ProtecT trial on treatment, reviewed by the USPSTF, provide substantial evidence. Without a validated natural history, the T1c classification in TNM staging lacks a foundation, and clinical data on screen-detected cancers鈥攊ncluding Gleason scores, MRI imaging, and treatment outcomes鈥攁re predominantly based on descriptive case series. Such evidence carries limited weight, particularly when supported by mathematical models with restricted statistical reliability. Similarly, MRI studies included in this review mainly consist of case series, lacking established endpoints for screen-detected cancer like Gleason scores. Caution should be exercised to avoid misinterpreting these results as evidence, especially in contrast to the generalizability of the ProtecT trial. ProtecT, which focused solely on screen-detected prostate cancer, primarily assigned patients to three treatment arms, with a higher proportion in Gleason Group 1. Conversely, SPCG4 primarily investigated clinically detected cancers through RCTs, revealing surgical advantages absent in ProtecT, possibly because screen-detected cancers may not be ideal candidates for surgery. Furthermore, ProtecT demonstrated that surveillance therapy was comparable to no treatment or active intervention, with favorable 10-year cancer-specific survival rates approaching 99%. These outcomes suggest that screen-detected prostate cancers may exhibit characteristics similar to normal tissue [4].

Despite over four decades of empirical use in prostate cancer screening, its pathological diagnosis lacks scientific grounding, leading to unfavorable comparisons with speculative practices. The authors' conclusions, heavily reliant on case series, highlight unmet scientific benchmarks in prostate cancer screening. In conclusion, prostate cancer screening has yet to establish definitive starting points. Therefore, it remains challenging to achieve 鈥渢he goals鈥� to which the authors refer.

1. Chodak GW, Schoenberg HW. World J Surg. 1989 Jan-Feb;13(1):60-4.

2. Swanson G. JAMA. 1996 Jan 3;275(1):31

3. Takahashi T. Jpn J Clin Oncol. 2023 Mar 7;53(3):280-283.

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CONFLICT OF INTEREST: None Reported

Original Investigation

April 5, 2024

Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review and Meta-Analysis

罢补尘谩蝉听贵补锄别办补蝉,听惭顿^1,2,3; Sung Ryul听Shim,听MPH, PhD⁴; 骋颈耻蝉别辫辫别听叠补蝉颈濒别,听惭顿⁵; et al 惭颈肠丑补别濒听叠补产辞耻诲箩颈补苍,听惭顿⁶; 罢补尘谩蝉听碍贸颈,听笔丑顿^3,7; Mikolaj听Przydacz,听MD, PhD, DSc⁸; 惭辞丑补尘尘补诲听础产耻蹿补谤补箩,听惭顿^9,10; Guillaume听Ploussard,听MD, PhD¹¹; Veeru听Kasivisvanathan,听MD, PhD¹²; Juan G贸mez听Rivas,听MD, PhD¹³; 骋颈辞谤驳颈辞听骋补苍诲补驳濒颈补,听惭顿⁵; Tibor听Szarvas,听PhD, DSc^2,14; Ivo G.听Schoots,听MD, PhD^15,16; Roderick C. N.听van den Bergh,听MD, PhD^17,18; Michael S.听Leapman,听MD, MHS¹⁹; P茅ter听Nyir谩dy,听MD, PhD, DSc^2,3; Shahrokh F.听Shariat,听MD, DDr(hc)^{1,20,21,22,23,24}; Pawel听Rajwa,听MD, PhD^1,25

Author Affiliations Article Information

¹Comprehensive Cancer Center, Department of Urology, Medical University of Vienna, Vienna, Austria
²Department of Urology, Semmelweis University, Budapest, Hungary
³Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
⁴Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Republic of Korea
⁵Unit of Urology, Urological Research Institute, Division of Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
⁶Department of Urology, Assistance Publique des H么pitaux de Marseille, North Academic Hospital, Marseille, France
⁷Institute of Mathematics, Department of Stochastics, Budapest University of Technology and Economics, Budapest, Hungary
⁸Department of Urology, Jagiellonian University Medical College, Krakow, Poland
⁹Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan
¹⁰The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan
¹¹Department of Urology, La Croix du Sud Hospital, Quint Fonsegrives, France
¹²Division of Surgery and Interventional Science, University College London, London, England
¹³Department of Urology, Hospital Universitario La Paz, Madrid, Spain
¹⁴Department of Urology, University of Duisburg-Essen and German Cancer Consortium鈥揢niversity Hospital Essen, Essen, Germany
¹⁵Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, University Medical Centre, Rotterdam, the Netherlands
¹⁶Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
¹⁷Department of Urology, St Antonius Hospital, Utrecht, the Netherlands
¹⁸Department of Urology, Erasmus MC, Rotterdam, the Netherlands
¹⁹Department of Urology, Yale School of Medicine, New Haven, Connecticut
²⁰Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan
²¹Department of Urology, University of Texas Southwestern Medical Center, Dallas
²²Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
²³Department of Urology, Weill Cornell Medical College, New York, New York
²⁴Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria
²⁵Department of Urology, Medical University of Silesia, Zabrze, Poland

JAMA Oncol. 2024;10(6):745-754. doi:10.1001/jamaoncol.2024.0734

Key Points

Question听 Do prostate cancer screening pathways that incorporate magnetic resonance imaging (MRI) and targeted biopsies outperform strategies that rely solely on prostate-specific antigen testing and systematic biopsy?

Findings听 In this systematic review and meta-analysis of 80鈥�114 screened men from 12 studies, MRI-based screening was found to be associated with a reduced number of unnecessary prostate biopsies and detection of clinically insignificant prostate cancer while maintaining the detection of clinically significant prostate cancer compared with prostate-specific antigen鈥搊nly strategies.

Meaning听 The findings of this meta-analysis support the integration of prostate MRI in prostate cancer screening to improve the balance of patient harms and benefits.

Abstract

Importance听 Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway.

Objective听 To systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)鈥揵ased screening with systematic biopsy strategies.

Data Sources听 PubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023).

Study Selection听 Randomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening.

Data Extraction听 Number of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted.

Main Outcomes and Measures听 The primary outcome was csPCa detection rate. Secondary outcomes included clinical insignificant PCa detection rate, biopsy indication rates, and the positive predictive value for the detection of csPCa.

Data Synthesis听 The generalized mixed-effect approach with pooled odds ratios (ORs) and random-effect models was used to compare the MRI-based and PSA-only screening strategies. Separate analyses were performed based on the timing of MRI (primary/sequential after a PSA test) and cutoff (Prostate Imaging Reporting and Data System [PI-RADS] score 鈮�3 or 鈮�4) for biopsy indication.

Results听 Data were synthesized from 80鈥�114 men from 12 studies. Compared with standard PSA-based screening, the MRI pathway (sequential screening, PI-RADS score 鈮�3 cutoff for biopsy) was associated with higher odds of csPCa when tests results were positive (OR, 4.15; 95% CI, 2.93-5.88; P鈥夆墹鈥�.001), decreased odds of biopsies (OR, 0.28; 95% CI, 0.22-0.36; P鈥夆墹鈥�.001), and insignificant cancers detected (OR, 0.34; 95% CI, 0.23-0.49; P鈥�=鈥�.002) without significant differences in the detection of csPCa (OR, 1.02; 95% CI, 0.75-1.37; P鈥�=鈥�.86). Implementing a PI-RADS score of 4 or greater threshold for biopsy selection was associated with a further reduction in the odds of detecting insignificant PCa (OR, 0.23; 95% CI, 0.05-0.97; P鈥�=鈥�.048) and biopsies performed (OR, 0.19; 95% CI, 0.09-0.38; P鈥�=鈥�.01) without differences in csPCa detection (OR, 0.85; 95% CI, 0.49-1.45; P鈥�=鈥�.22).

Conclusion and relevance听 The results of this systematic review and meta-analysis suggest that integrating MRI in PCa screening pathways is associated with a reduced number of unnecessary biopsies and overdiagnosis of insignificant PCa while maintaining csPCa detection as compared with PSA-only screening.

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Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review and Meta-Analysis