Diagnosing Extraprostatic Extension (EPE)

Extraprostatic Extension (EPE) or "Stage T3a" means the cancer has eaten through the edge of the prostate and is penetrating into the tissue outside. It can be difficult to diagnose before a prostatectomy. Sometimes, it can be felt using a digital rectal exam (DRE) as a bulge or irregular texture, but that is an exception rather than the rule. More often, it is seen on an mpMRI or ultrasound image.

It is important because its presence is a strong predictor of recurrence after treatment. It is one of three risk factors used in the NCCN definition of "high-risk" prostate cancer. That definition is based on the AJCC staging criteria (see this link), which means that it is strictly only based on DRE. DREs almost always fail to detect EPE. If the bulge is so big that one can feel it through the rectum, it adds significantly to the risk. But how much does it add to the predicted risk if it can only be seen on a powerful MRI?

Reisaeter et al. evaluated the Mehralivand EPE Grading System and found it was somewhat more sensitive in clinical practice as the commonly used Likert EPE scoring system. (The interested patient may also wish to read this editorial by Peter Choyke)

The Likert score looks at certain imaging abnormalities (tumor contact length with the prostate capsule, irregularity, bulging, gross extension, and loss of rectoprostatic angle) and summarizes them using five categories:

• 1 = criterion not present
• 2 = probably not present
• 3 = uncertain if present
• 4 = probably present
• 5 = definitely present.

The Mehralivand System uses three grades:

• Grade 1 refers to tumors with a contact length of 1.5 cm or greater or contour bulge or irregularity. 
• Grade 2 refers to tumors with a contact length of 1.5 cm or greater and contour bulge or irregularity, 
• Grade 3 refers to gross visible extension beyond the prostate.

Both systems require very well-trained radiologists - interobserver agreement is only fair.

Mehralivand compared the predictions of the EPE detection system to what was actually detected after the same patients had prostatectomies. Even when the Mehralivand System assigned Grade 3 to a suspected EPE, a third of them were false (positive predictive value (PPV) = 66%). False positives may be caused by inflammation, tumor scar tissue, or biopsy scar tissue. Contact with the capsule may be wholly inside, and a bulge may be wholly contained within the capsule. 

What's worse, the Mehralivand System incorrectly predicted there would be no EPE in 18% of cases where EPE was eventually found (negative predictive value (NPV) = 82%). False negatives are caused by tumors below the size where MRI can detect them. 

• The PPV was 41%, 48%, and 66% for Grade 1, 2, and 3, respectively
• The NPV was 90%, 88% and 82% for Grade 1, 2, and 3, respectively

Since DREs are so bad at detecting EPE, and MRIs are little better, what can be done to better predict EPE, and is better prediction necessary?

Is better prediction always necessary?

It has been found that focal EPE (extensions of less than 3 mm) and EPE comprising low Gleason score tumor tissue are not predictive of treatment failure. In this Johns Hopkins study, 10 year biochemical recurrence-free survival was 76% among men with focal EPE (post-prostatectomy) and 59% among those with more extensive EPE. A surgeon discovering a focal EPE may simply cut wider to get it all. GS 6 tumors have low metastatic potential (see this link). However, a patient who learns in advance that the surgeon will "cut wide" thereby increasing his risk of incontinence or impotence may opt instead for radiotherapy.

mpMRI-targeted transprostatic biopsy

It may be possible to detect clinically significant EPE by detecting suspicious sites using an mpMRI and following up with a real-time ultrasound fusion-targeted biopsy. Some pathologists have argued that needle-biopsy cores that show close proximity to the prostate margin, admixture with skeletal muscle at the apex, or admixture with adipose or other peri-prostatic soft tissue predict for EPE. This suggests that clinically significant EPE may be diagnosed with transprostatic needle-biopsy cores. This is an unusual procedure. Of course, as with any needle biopsy, it may miss the site, and several cores from the suspicious site should be taken. A periprostatic nerve block is required (which imho should be required on all needle biopsies) to prevent any additional pain. There is also some risk of extra bleeding if a blood vessel is nicked. It is worth discussing with the biopsy urologist. It is also important that the designated cores be evaluated by an experienced pathologist like Jonathan Epstein at Johns Hopkins.

(update June 2022) Moroianu et al. reported a "deep learning" algorithm that is better at detecting EPE from an mpMRI than a radiologist.

• Model sensitivity was 80% vs. 50% for radiologists (model predicted more true positives)
• Model specificity was 28% vs. 77% for radiologists (model predicted more false positives)

A combined computational/radiologist approach may be best.

Declining use of RT in treating clinical stage T3 patients and those with adverse pathology after surgery

Patients clinically diagnosed with prostate cancer outside of the prostate capsule (stage cT3), are increasingly treated with radical prostatectomy (RP) rather than with primary radiation therapy (RT). In addition, patients who have adverse pathological features after first-line surgery (stage pT3 and/or positive margins) are increasingly not receiving either adjuvant or early RT.

Nezolosky et al. looked at the SEER database records of 11,604 patients clinically diagnosed with stage T3 prostate cancer from 1998 to 2012. They found:

• ·      RP use increased from 12.5% to 44.4%.
• ·      RT use decreased from 55.8% to 38.4%
• ·      “No treatment” decreased from 31.7% to 17.2%
• ·      For extracapsular extension (stage T3a), RP use was 49.8% vs. 37.1% for RT in 2012.
• ·      For seminal vesicle invasion (stage T3b), RP use was 41.6% vs. 42.1% for RT in 2012.
• ·      RT use exceeded RP by 59% if the biopsy Gleason score was 8-10.
• ·      RT use exceeded RP by 3% among those with higher PSA, and by 7% among older patients.

This trend is troubling because RP for cT3 is often not curative. The following biochemical recurrence-free survival rates have been reported and are very consistent:

• ·      Mitchell et al. (Mayo Clinic): 41% after 20 years for cT3 patients.
• ·      Freedland et al. (Johns Hopkins): 49% at 15 years for cT3a patients.
• ·      Carver et al. (Memorial Sloan Kettering): 44% at 10 years for cT3 patients.
• ·      Hsu et al. (Leuven, Belgium): 51% at 10 years for cT3a patients.
• ·      Xylinas et al. (Paris, France): 45% at 5 years for cT3 patients.

The rates are similar among those diagnosed with stage T3 at pathology. Hruza et al. reported bRFS of 47% and 50% for those staged pT3a and pT3b respectively. Pagano et al. reported bRFS of 40% for those staged pT3b. Watkins et al. found that 40% of pT3 surgical patients had already biochemically relapsed after a median of 18 months.

There are other factors that affect recurrence prognosis after surgery. Age, a high pre-treatment PSA, high Gleason score, positive surgical margin (including its size and Gleason score at the margin), and the length of extraprostatic extension (EPE) are all risk factors (see Fossati et al., Djaladat et al., Ball et al., Jeong et al.). In the Watkins et al. study, patients with EPE and negative surgical margins biochemically relapsed at the rate of 0%, 28% and 63% for Gleason scores of 6, 7 and 8-10, respectively. However, if the surgical margins were also positive, the relapse rates were significantly worse: 33%, 50%, and 71% for Gleason scores of 6, 7 and 8-10, respectively. Briganti et al. found that the 5-year bRFS was 55.2% among surgical patients categorized as high risk, which includes stage T3, Gleason score 8-10 or PSA>20 ng/ml.

Can primary radiation alone do any better? I haven’t seen breakdowns for stage cT3 patients specifically, but we have long-term follow up in many clinical trials where high-risk patients were treated with radiation and ADT. Here are some bRFS results we discussed recently:

• ·      HDR brachy monotherapy: 77 – 93% (3-8 years)
• ·      HDR brachy boost + EBRT: 66 - 96% (5-10 years)
• ·      LDR brachy monotherapy: 68% (5 years)
• ·      LDR brachy boost + EBRT:  83% (9 years)
• ·      EBRT monotherapy: 71 - 88% (5 years)

While primary radiation typically does about 50-100% better than primary surgery at controlling the cancer, urologists often argue that adjuvant or salvage RT will bring the numbers into line. There is an ongoing randomized clinical trial (NCT02102477) among men diagnosed with stage T3 comparing initial radiation treatment to prostatectomy plus salvage radiation. While we wait for those results, we have to rely on retrospective studies. In many of the studies cited above, about a quarter of the patients received salvage/adjuvant RT following surgery. In the Mayo study, 72% were recurrence-free after 20 years, which does bring the combination close to what radiation alone often delivers. However, that comes at a cost. Adjuvant and salvage RT usually has worse quality-of-life outcomes than the patient would have suffered had he had radiation to begin with.

This brings us to the second alarming trend: adjuvant and early salvage RT rates have been declining among men with adverse pathology after prostatectomy. We discussed this previously (see this link). So not only are T3 patients receiving a therapy upfront that is less likely to control their cancer, they also may not be receiving the adjuvant or salvage RT that might control it if used early enough.

It is especially troubling that there has been no corresponding shift to later salvage RT. Sineshaw et al. conjecture as to the reasons for the trend:

“This pattern of declining use could be due to multiple factors, including patient preference, physician and referral bias, concern about toxicity, lack of a consistent survival benefit seen in the updated randomized trials, or a growing preference for salvage radiation at time of biochemical failure, rather than immediate adjuvant RT. With respect to the last point, our data did not show a rise in RT use after 6 mo and within the first 5 yr post-RP, suggesting that a shift to salvage RT does not likely entirely explain the declining use of immediate (within 6 mo) postoperative RT.” [emphasis added]

I’d like to believe that the decline in salvage radiation utilization is attributable to better selection of patients. Utilization was higher in those with positive surgical margins and those with Gleason scores 8-10. However, Dr. Sandler may very well be right in attributing the drop-off to urologists who don’t immediately refer patients with adverse pathology to radiation oncologists. In my experience, many patients making the primary therapy decision also never consult with a radiation oncologist. High-risk patients are especially needful of guidance from the first doctor they see – almost always a urologist – to seek second opinions. It would be unconscionable if they are not receiving that guidance.