Which Biopsy for Elevated PSA?

Employing MRI-targeted biopsy instead of systematic biopsy reduces overdiagnosis of low-grade prostate cancer by more than half, although diagnoses may be delayed among a small minority of patients with higher-risk disease, according to the authors of a new paper.

Considered alongside the reduced biopsy burden at a population level and the fact that very few patients in the higher-risk group had incurable cancer when they were diagnosed, these findings support the MRI-targeted approach, reported lead author Jonas Hugosson, MD, PhD, of the University of Gothenburg, Gothenburg, Sweden, and colleagues.

What Clinical Question Did This Study Address?

The above support for MRI-targeted biopsy over systematic biopsy addresses a long-standing debate about prostate cancer screening.

“Several large randomized trials of screening for prostate cancer have been published, but no consensus has emerged as to whether population-based screening should be recommended,” Hugosson and colleagues wrote in The New England Journal of Medicine. “The largest obstacle has been the high rate of overdiagnosis when prostate-specific antigen (PSA) is used as the identifying marker of risk.”

The central issue concerns overdiagnosis of patients with low-grade (International Society of Urological Pathology [ISUP] grade 1, also called Gleason grade group 1) disease, which must be balanced against underdiagnosis of grade 2 and higher disease.

In an accompanying editorial, Paul F. Pinsky, PhD, of the National Cancer Institute, Bethesda, Maryland, described how patients with ISUP grade 1 disease are typically advised to undergo active surveillance, as outcomes are no worse than with curative treatment.

While this path avoids treatment, it can still be a thorny one.

“Active surveillance has its own costs and harms, and a substantial proportion of patients eventually choose curative therapy as a result of psychological and family pressures, even in the absence of evidence of disease progression (which is relatively infrequent),” Pinsky wrote. “Furthermore, even for patients who continue to undergo active surveillance in the long term, important downsides include anxiety, healthcare system costs, and complications of the required periodic biopsies.”

The emerging consensus aims to avoid detection of ISUP grade 1 disease altogether, according to Pinsky, as this circumvents decisions about active surveillance. Ideally, patients would be diagnosed at ISUP grade 2, which is considered “clinically significant.”

How exactly to hit this sweet spot remains unclear, however, prompting the present study.

With MRI-targeted biopsy, “[w]ill the cancer progress and later become visible on MRI but still be at a curable stage, or will it be diagnosed too late for cure?” Hugosson and colleagues asked.

How Did This Study Compare Systematic and MRI-Targeted Biopsy?

The population-based trial, conducted in Sweden, invited men aged 50-60 years to undergo PSA screening. Those with a PSA level of at least 3 ng/mL underwent MRI. From there, participants were randomized into the MRI-targeted biopsy group or the systematic biopsy group.

In the systematic biopsy group, systematic biopsy was performed regardless of MRI findings, with MRI-targeted biopsy added if suspicious lesions were found. In the MRI-targeted biopsy group, only MRI-targeted biopsy was performed if suspicious lesions were found.

These two strategies were compared across a range of metrics, including detection of clinically significant vs insignificant cancer, need for biopsy, and adverse events.

Which Biopsy Strategy Was Superior?

The final dataset included 6575 men in the systematic biopsy group and 6578 men in the MRI-targeted biopsy group. After a median follow-up of 3.9 years, prostate cancer was detected in 4.5% of patients in the systematic biopsy group vs 2.8% in the MRI-targeted biopsy group.

The risk of detecting grade 1 prostate cancer in the MRI-targeted biopsy group was 57% lower than in the systematic biopsy group (relative risk [RR], 0.43; 95% CI, 0.32-0.57), and risk of undergoing biopsy was reduced by the same percentage (RR, 0.43; 95% CI, 0.37-0.50).

Severe adverse events were also less common with MRI-targeted biopsy than systematic biopsy, with just two occurring in the former group, and five occurring in the latter.

Still, not all findings favored MRI-targeted biopsy.

RR of detecting grades 2-5 prostate cancer was 16% lower in the MRI-targeted biopsy group, although this was not statistically significant (RR, 0.84; 95% CI 0.66-1.07). Similarly, MRI-targeted biopsy was 35% less likely to detect advanced or high-risk cancers; however, again, this was not statistically significant (RR, 0.65; 95% CI, 0.34-1.24).

“From a public health perspective, these results are best expressed in absolute terms,” Pinsky wrote. “[P]er 1000 enrolled men, the MRI-targeted biopsy approach led to 51 fewer men undergoing biopsy and 14 fewer men receiving a diagnosis of ISUP grade 1 disease, but it also led to a delay in the diagnosis of ISUP grade 2 or higher disease in three men. The meaning of this delay is not immediately clear, but such a delay could lead to worse outcomes in a fraction of those men.”

Should MRI-Targeted Biopsy Be Adopted Instead of Systematic Biopsy?

In their concluding remarks, Hugosson and colleagues emphasized the benefits of MRI-targeted biopsy.

“In this trial, omitting biopsy in patients with negative MRI results eliminated more than half of diagnoses of clinically insignificant prostate cancer, and the associated risk of having incurable cancer diagnosed at screening or as interval cancer was very low,” they wrote. “These results should encourage guideline committees to update recommendations around prostate cancer diagnosis and screening.”

After noting that an MRI-targeted approach may be more cost-effective than performing systematic biopsies, Pinsky maintained a neutral perspective, suggesting that more data may be needed before amending screening protocols.

“The way in which MRI is used in the context of PSA-based screening is evolving,” he wrote. “This trial gives additional evidence regarding the comparative effectiveness and resource utilization of MRI-based strategies designed to reduce biopsies and the diagnosis of clinically insignificant…disease. This information contributes to the ultimate goal of designing screening strategies that preserve most of the benefits of PSA-based screening while reducing harms and costs.”

The study was supported by Karin and Christer Johansson’s Foundation, the Swedish Cancer Society, the Swedish state under an agreement between the Swedish government and the county councils, and others. The investigators and editorialist disclosed no relevant conflicts of interest.