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.