Prostate-cancer: MRI and targeted biopsies could potentially cut overdiagnoses by half

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Most countries have not introduced nationwide prostate-cancer screening, as current methods result in overdiagnoses and excessive and unnecessary biopsies.

A new study by researchers at Karolinska Institutet in Sweden, which is published in the New England Journal of Medicine, indicates that screening by magnetic resonance imaging (MRI) and targeted biopsies could potentially cut overdiagnoses by half.

The results were presented today at the European Association of Urology Congress.

“Our results from a large, randomized study show that modern methods for prostate cancer screening maintain the benefits of screening, while decreasing the harms substantially. This addresses the greatest barrier to the introduction of nationwide screening,” explains Tobias Nordström, associate professor of Urology at the Department of Clinical Sciences, Danderyd Hospital at Karolinska Institutet, who is in charge of the STHLM3MRI study.

Yearly, approximately 1.4 million men get a prostate cancer diagnosis and 375,000 men die from the disease. Previous studies have shown that organized screening can result in earlier detection and thereby reduce the risk of prostate-cancer deaths.

Current screening methods – PSA (prostate-specific antigen) tests combined with traditional biopsies – result in unnecessary biopsies, and the detection of numerous minor low-risk tumors.

Consequently, no country except Lithuania has chosen to introduce a nationwide prostate-cancer screening program, as the benefits do not exceed the disadvantages.

“Refined screening methods are required to reduce overdiagnosis and overtreatment of low-risk tumors, and prevent unnecessary biopsies and biopsy-related side-effects,” explains Martin Eklund, associate professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, with joint responsibility for the STHLM3MRI study.

The results of the STHLM3MRI study indicate that overdiagnoses can be halved by substituting traditional prostate biopsies with magnetic resonance imaging (MRI) and targeted biopsies. The number of unnecessary biopsies and the identification of minor low-risk tumors is reduced, while the new method can detect just as many clinically significant tumors.

STHLM3MRI is a randomized study conducted between 2018 and 2021 with participants from Stockholm County, which included 12,750 men. The participants first provided a blood sample for PSA analysis, as well as analysis by the new Stockholm3 test, developed by researchers at Karolinska Institutet. Men whose tests showed elevated levels were then randomly selected for traditional biopsies or MRI. In the MRI group, biopsies were conducted strictly on suspected tumors identified by MRI.

The study proceeded thereafter by investigating how the Stockholm3 test could be combined with MRI to further improve the method for prostate-cancer screening.

“We will soon present the second of the two main reports from the STHLM3MRI trial where we assess the role of a novel blood test as adjunct to MRI in prostate cancer screening. The future of prostate cancer diagnostics probably includes both improved blood tests and MRI.

Nationwide screening for breast and cervical cancer among women has been available in the Western world for some time. We are finally able to show that men can also reduce their risk of malignant cancer through nationwide prostate-cancer screening that utilizes modern methods,” Nordström concludes.

Professor Hendrik Van Poppel, adjunct secretary general of the European Association of Urology (EAU), said, “It is exciting to see breakthroughs such as this in the field of early detection of prostate cancer. An innovation such as STHLM3MRI makes an even more compelling case for the European Commission to ensure a risk stratified approach to early detection of prostate cancer is adopted across the whole of Europe.

The EAU is working hard to ensure that early detection of prostate cancer is addressed in the implementation of Europe’s Beating Cancer Plan in order to reduce mortality of Europe’s most common male cancer while also dealing with the challenges of overdiagnosis and overtreatment. We are really looking forward to seeing how STHLM3MRI can continue to contribute to this aim.”


The aggressiveness of prostate cancers ranges from indolent to highly lethal. Low-grade prostate cancer (i.e., grade group 1) has been shown in large trials to be associated with a very low risk of cancer-specific death.1-5 In contrast, cancers of grade groups 3 through 5 have significantly higher metastatic potential and were responsible for the majority of the predicted 31,620 deaths from prostate cancer in the United States in 2019.6,7

This variation in lethality of prostate cancer subtypes highlights the importance of accurate prostate cancer diagnosis.

Currently, the transrectal, ultrasonographically guided, 12-core systematic biopsy is the most common method for the initial diagnosis and grading of prostate cancer.8 Whereas in most other cancers diagnostic biopsies target abnormalities detected on imaging or physical examination, systematic prostate biopsy provides a nontargeted, systematically spaced sampling of the prostate gland.

This systematic-biopsy method is associated with missed cancer diagnoses and substantial grade misclassification at the time of biopsy. In addition, further upgrading or downgrading of the cancer diagnosis at the time of radical prostatectomy is common.9-12 One consequence of this diagnostic inaccuracy is overtreatment of patients with low-grade disease because of concern that a high-grade cancer may have been missed.

These uncertainties contribute to findings that 43% of prostatectomies are performed in men who are subsequently confirmed to have indolent disease on histopathological analysis and that 60% of men who receive radical therapy (i.e., radiation or radical prostatectomy) are found to have grade group 1 cancers on preoperative biopsy.13 Conversely, when aggressive disease is missed on biopsy, patients risk undertreatment.

Advances in prostate multiparametric magnetic resonance imaging (MRI) have allowed for MRI-targeted biopsies of suspicious imaging findings.14-16 Studies have shown that MRI-targeted biopsies result in a higher rate of detection of high-grade cancers than systematic biopsy.14,17-19

However, despite the improved detection of clinically significant cancers with MRI-targeted biopsies, debate persists about whether MRI-targeted biopsy should be used in place of systematic biopsy or in conjunction with it.18,20,21 Specifically, controversy exists regarding whether the systematic biopsy should still be performed and whether previous biopsy status should affect the type of biopsy method that is selected.22-24

The Trio Study was a substudy of a larger clinical trial, called Use of Tracking Devices to Locate Abnormalities During Invasive Procedures. In this substudy, we assessed the use of MRI-targeted, systematic, or combined prostate biopsy in an attempt to define the most effective method for prostate cancer diagnosis.

Discussion

The current approach to prostate cancer diagnosis is characterized by a considerable degree of diagnostic uncertainty. This uncertainty has contributed to both overtreatment and undertreatment and has left the medical community uncertain of the most effective method for diagnosing prostate cancer.

With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer.

In this study, we found that combined biopsy leads to an increase in the number of cancer diagnoses and improves the likelihood that the biopsy findings are predictive of the true pathologic nature of the patient’s disease. Patients who are found to have grade group 2 prostate cancer on combined biopsy have only a small chance of having clinically significant disease of grade group 3 or higher. This knowledge should reduce the risks of both overtreatment and undertreatment out of fear of misdiagnosis.

An alternative perspective may argue for the use of MRI-targeted biopsy alone, since it is responsible for the detection of a majority of clinically significant cancers, requires 12 fewer biopsy cores, and leads to 5% fewer diagnoses of clinically insignificant cancers.

However, we found that the omission of systematic biopsy would lead to missing 1.9% more grade group 3 cancers and 5.8% more grade group 2 cancers in our study population. More important, among the patients in whom prostate cancer is diagnosed, the use of MRI-targeted biopsy alone leads to high diagnostic uncertainty, since this method used in isolation is associated with a 30.9% rate of any upgrading of the cancer group and an 8.7% rate of upgrading the cancer to a clinically significant grade group on whole-mount histopathological analysis.

Therefore, although combined biopsy resulted in a small net increase in the diagnosis of indolent cancers, its high predictive value for a patient’s true pathological grade group reduces the likelihood of misdiagnosis and should translate into decreased diagnostic uncertainty. With decreased diagnostic uncertainty, both overtreatment and undertreatment should be reduced.

Several earlier studies have shown that MRI-targeted biopsy outperforms systematic biopsy in the diagnosis of clinically significant cancer.17,20,38 However, few of the previous trials have shown whether systematic biopsy can be entirely omitted17,39 and lacked a reference test against which to assess the various biopsy methods.

Rouvière et al.18 assessed combined biopsy as a possible improvement in diagnostic method; however, the investigators did not routinely use MRI-targeted biopsy software or 3.0-tesla MRI scanners, which led to some uncertainty regarding their conclusions. Controversy remains regarding whether the use of targeting software results in better cancer detection than cognitive fusion.18,40,41

In addition, Rouvière et al. also lacked a reference test, such as whole-mount histopathological analysis. Our data, which represent a substantially larger population, show improved cancer detection with combined biopsy and correlation with whole-mount histopathological analysis. Potentially, these data may usher in a new era of increased confidence in the selection of prostate cancer treatment on the basis of biopsy results. Future research may define prebiopsy measures under which selected patients may undergo MRI-targeted biopsy only.

Our study has several strengths, including the enrollment of patients who had undergone previous biopsy and those who had not, which allowed for comparisons between these two subgroups. By design, all the patients underwent all available diagnostic methods, which reduced the possibility of selection bias.

In addition, the definition of clinically significant cancer as grade group 3 or higher represents a liberal threshold. If grade group 2 or higher had been used as a threshold for clinically significant disease, combined biopsy would have resulted in the detection of even more clinically significant cancers (Table S2). Finally, this study assessed each diagnostic method against the standard of whole-mount histopathological analysis among the men who underwent radical prostatectomy.

However, our study also has several limitations. It was performed at an institution where many practitioners were experienced in performing and interpreting prostate MRI and prostate histopathological analysis. These results may not be reproducible at institutions with less experienced practitioners.42 In our study, if any MRI scans were incorrectly labeled as normal or abnormal, such errors could have led to bias.

Also, since MRI-targeted biopsies were performed before systematic biopsies, it is possible that MRI information, such as hemorrhage tracks, might have influenced the performance of systematic biopsies. Furthermore, the use of one physician to perform the systematic biopsy and another to perform the MRI-directed biopsy is not representative of actual practice patterns.

The study focused specifically on patients with MRI-visible lesions, so these findings are not applicable to patients with normal results on prostate MRI. In addition, radical prostatectomy was not performed in all the patients with a prostate cancer diagnosis, which created the possibility of selection bias in the prostatectomy cohort.

All our patients were referrals, and the referral patterns of our institution may not reflect the pattern of disease in the community. Finally, our study was conducted in a single institution, a factor that may limit its generalizability.

Among patients with MRI-visible prostate lesions, the addition of MRI-targeted biopsy to systematic biopsy increased the detection of clinically significant cancers (grade group ≥3) and led to a net decrease in the detection of clinically insignificant cancers.

Although many of these benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers. Furthermore, among the patients who underwent subsequent radical prostatectomy, combined biopsy was associated with the lowest rate of upgrading of the cancer grade group between biopsy and whole-mount histopathological analysis.

Collectively, these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.

reference link :https://www.nejm.org/doi/10.1056/NEJMoa1910038


More information: Martin Eklund et al, MRI-Targeted or Standard Biopsy in Prostate Cancer Screening, New England Journal of Medicine (2021). DOI: 10.1056/NEJMoa2100852

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