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.

Declining trend in the utilization of adjuvant radiation.

A recent report in European Urology found that in spite of three randomized clinical trials (RCTs) that proved the efficacy of immediate or adjuvant radiation following surgery with adverse pathology results compared to a wait-and-see approach, a lower%age of such patients are getting adjuvant treatment. Why should this be?

I refer readers to a recent discussion of the issues involved, which I won’t fully reiterate here. First, let’s look at the report by Sineshaw et al. The authors examined the records of 97,270 patients in the National Cancer Database where patients were found to have adverse pathological features (pT3/4 or positive surgical margins) in the period from 2005-2011. What they found is this:

·      Postoperative RT utilization declined from 9.1% to 7.3%.

·      Utilization declined with age: 8.5% in patients aged 18–59 to 6.8% in patients aged 70–79. 

·      Utilization was 14% at community cancer programs compared to 7% at teaching/research centers.

·      Among those with stage pT3/4, utilization was 17% if they had positive margins, but 7% if they had negative margins.

·      Utilization was 17% among those with pathology Gleason score of 8-10 compared to 4% among those with Gleason score  of 6 or less.

First, a note about the timeframe examined in their study: only one of the three RCTs  (Thompson et al. 2009) was published in that timeframe. The Bolla et al. study was not published until 2012, and the Wiegel et al. study was not presented until 2013. The AUA/ASTRO guidelines advocating adjuvant radiation were not issued until 2013. So in the timeframe examined in their study, we would not expect to see the full impact of those three studies and the new guidelines. This conflicts with the statement made in the publication:

“In a retrospective analysis of 97 270 patients with prostate cancer, we showed that use of postoperative radiotherapy for adverse pathologic features has declined over time after the publication of findings from major randomized clinical trials and consensus guidelines supporting consideration of such therapy.”

A report in Medscape included comments from some illustrious radiation oncologists that are worth noting:

·      Jeffrey Michalski  (Washington University, St. Louis) echoed the authors’ anachronistic lament that doctors were not following the evidence in the RCTs and guidelines.

·      Anthony D’Amico (Dana-Farber and Brigham and Women’s Hospital) pointed out that only one of the RCTs showed an advantage in metastasis-free and overall survival. He further explained that multiple risk factors may be a better indication for adjuvant radiation.

·      Michael Zelefsky (MSKCC) noted that we don’t yet know if waiting for rising PSA would have any worse outcomes.

·      Howard Sandler (Cedars-Sinai) blamed low utilization on urologists who don’t immediately refer adverse pathology patients to radiation oncologists. They are not given options or provided with expertise.

Until the results of ongoing clinical trials on the benefit of early salvage radiation become available, this remains a difficult decision. A patient with adverse pathology should immediately begin discussions with a radiation oncologist, preferably at a teaching/research hospital, so that he fully understands what the risks and benefits are of waiting.

Trends in the use of radiation for primary therapy

Two separate database analyses have now reported an increasing trend in adoption of SBRT, while brachytherapy use has been declining.

In an analysis of the National Cancer Data Base, Baker et al. reported that use of SBRT increased from <1% in 2004 (it was first used for prostate cancer in 2003) to 8.8% of low-risk patients treated at academic centers in 2012. Similarly, Halpern et al., in an analysis of the SEER/Medicare database,  found that SBRT was the fastest-growing of all radiation therapies between 2004 and 2011, but it only accounted for 1.6% of all men treated with radiation in that database. They also found that adoption was highest among low-risk patients: 54% of those using it had a Gleason score of 6. The median cost was $27,145.

Proton beam therapy use also increased. It accounted for 2.3% of all radiation therapy utilization. Half of those using it had a Gleason score of 6. It had the highest cost of all radiation therapies at $54,706.

Brachytherapy use, on the other hand, is on the decline. It accounted for 28% of all primary radiation therapies. Compared to other radiation therapies, a higher proportion of those utilizing it had a low Gleason score: 64.2% of those utilizing it had a Gleason score of 6. It was the lowest cost of all radiation therapies at a median cost of $17,183.

It is unclear how combination therapies of EBRT with a brachytherapy boost were counted in The SEER/Medicare database analysis. Orio et al. reported that in their analysis of the National Cancer Data Base, use of such combination therapy in intermediate and high-risk patients declined markedly between 2004 and 2012. They found that among intermediate and high-risk patients, 66% were treated with EBRT alone, 20% were treated with brachytherapy alone, and only 14% were treated with the combination. Use of combination therapy declined from 15% to 8% in academic centers, and from 19% to 11% in non-academic centers. We will have to see if the results of the ASCENDE-RT randomized clinical trial last year (discussed here) reverses this trend.

IMRT took the lion’s share of all radiation therapies at 68.1%. Relative to the other radiation therapies, it was most likely to be used by patients with higher Gleason scores: almost two-thirds of patients using it had Gleason scores of 7 or greater. I suspect that it continues to be the treatment of choice in older patients, who tend to have more progressed prostate cancer at the time of diagnosis. Next to proton therapy, it was most expensive, costing a median of $37,090. Hypofractionation may be able to cut the cost if it is widely adopted.

It should be noted that the high rate of utilization of brachytherapy, SBRT and proton therapy among low risk patients has historical roots. Those therapies were originally tried in low risk patients before we had results from Active Surveillance trials. While proton therapy and brachytherapy are given as boosts to IMRT, their use as monotherapies has not been established in intermediate and high-risk patients. SBRT, as both a boost and a monotherapy, is in trials for the higher risk categories, but many institutions still do not offer it for that purpose, and insurance may be reluctant to cover it.

It is sad to witness the decline in brachytherapy utilization, especially considering it is the lowest cost alternative. But that works to its detriment as well: new practitioners are not attracted to its relatively low profit potential. With the passing of Peter Grimm this year, it has lost one of its greatest proponents. The generation of brachytherapists who developed its modern techniques at the University of Washington Seattle have mostly dispersed and some have retired. It is a very specialized therapy, requiring years of practice to get superlative results. I expect we will continue to lose our best practitioners, and patients will find it increasingly difficult to find.