Should perineural invasion influence active surveillance and radiation treatment options?

Perineural invasion (PNI) is a risk factor detected on a biopsy in 15%-38% of men with a prostate cancer diagnosis. It means that the pathologist saw nerves infiltrated with cancer cells. As they grow, tumors cause nerves to innervate them. The cancer infiltrates in and around small nerves that connect to nerve bundles (ganglia) outside the prostate, becoming a route of metastatic spread (see this link).  The data on whether it is independently prognostic for T3 stage after surgery are equivocal, although PNI is often the mechanism for extracapsular extension.  After considering Gleason score, PSA, stage, and tumor volume, PNI does not seem to add much to the risk of recurrence after surgery. PNI is not associated with higher surgical margin rates, and it is not considered sufficient to preclude nerve-sparing surgery. An open question is whether it raises risk enough to warrant more aggressive radiation options, like brachy-boost therapy, whole-pelvic radiation and long-term adjuvant ADT.

Peng et al. retrospectively examined the records of 888 men who were treated with external beam radiation at Johns Hopkins from 1993 to 2007. 21% of them had biopsy-detected PNI. Compared to men with no PNI, those with PNI had:

• lower 10-year biochemical failure-free survival (40% vs 58%)
• lower 10-year metastasis-free survival (80% vs 89%)
• lower 10-year prostate cancer-specific survival (91% vs 96%)
• similar 10-year overall survival (68% vs 78%)

It isn't surprising that PNI is associated with higher risk, but does it add any new information not already captured by Gleason score, stage, and PSA (i.e., the NCCN criteria for risk stratification)? After correcting for those other risk factors, PNI was still found to be associated with lower rates of biochemical failure-free survival, but not of metastasis-free survival, prostate cancer specific survival or overall survival.

PNI independently predicted for lower biochemical failure-free survival in low-risk and high-risk patients, but not for intermediate-risk patients.  Although it is a relatively rare finding among low-risk patients, when found, PNI also predicted for lower prostate cancer-specific survival. Biochemical failure in low-risk men with PNI differed according to whether they received adjuvant ADT or not:

• 33% in men not treated with ADT
• 8% in men treated with ADT

An earlier analysis of 651 men treated at the University of Michigan similarly found an association between PNI and biochemical failure-free survival, freedom from metastases, prostate cancer-specific survival, but not overall survival at 7 years after radiation treatment. They also found a more marked effect among high-risk patients. A meta-analysis of 5 studies among men who received EBRT found that PNI increased the risk of biochemical recurrence by 70%.

Although PNI may increase the risk associated with an unfavorable intermediate-risk or high-risk diagnosis markedly, brachy boost therapy is the best treatment for any such patient regardless of PNI, according to our best retrospective study and prospective studies like ASCENDE-RT. This study suggests that adding ADT may be beneficial for these patients. Low and intermediate-risk patients with PNI who opt for conventional IMRT may also benefit from the addition of short-term ADT.

(update 4/2020) In a ten-year follow-up of the TROG 03.04 RADAR  randomized trial, Delahunt et al. found that PNI detected at biopsy was independently associated (after adjusting for other risk factors) with later appearance of bone metastases.

Biopsy-detected PNI may have implications for active surveillance. Cohn et al. detected PNI in only 8.5% of 165 men selected for active surveillance. Within 6 months, they were given a confirmatory biopsy. AS was excluded at the confirmatory biopsy due to higher Gleason grade in 57% of men with PNI vs. 13% of men without PNI. PNI should not automatically exclude active surveillance, but it should be recognized as a risk factor in the decision. It would be interesting to know if there is an association between PNI and genomic risk (based on Oncotype Dx, Prolaris, or Decipher tests). It has yet to be determined whether PNI is still a significant risk factor after NCCN risk category, % core involvement, and genomic risk have been accounted for.

It is worth noting that PNI is not always reported on biopsy cores by pathologists, and there is no uniform method for quantifying it. Whether nerve infiltration is small or large, or outside or inside the nerve sheath, it is just reported as PNI, if it is reported at all. It will be difficult to include PNI as part of any risk stratification system until its reporting has been standardized.

Note: Thanks to Daniel Song for allowing me to see the full text of the study.