Two retrospective studies were published in the last week, and they had some similar findings, but some dissimilar things to say about which treatment is best for high-risk prostate cancer. The three therapies they looked at were the combination of brachytherapy and external beam radiation (brachy boost therapy or BBT), external beam therapy alone (EBRT), and surgery (RP).
Kishan et al. reported on 1,809 men with Gleason score of 9 or 10 who were treated between 2000 and 2013 at 12 tertiary cancer care institutions (UCLA, Los Angeles VA, California Endocurie Therapy Center, Fox Chase, Mt. Sinai, Cleveland Clinic, Wheeling Jesuit University, University of Michigan, Johns Hopkins, Oslo University, William Beaumont Hospital, and Dana-Farber).
Patient characteristics:
- 639 were treated with RP.
- 734 were treated with EBRT only.
- 436 were treated with BBT (BT was either low-dose-rate in 62 percent or high-dose-rate in 38 percent).
- All patients were Gleason 9 or 10 on biopsy.
- Pelvic lymph node involvement was discovered in 17 percent of RP patients; 40 percent had positive surgical margins.
- RP patients were younger (61 years of age) compared to EBRT or BBT patients (68 years of age).
- RP patients were lower stage (87 percent clinical stage T1/T2) compared to EBRT (70 percent clinical stage T1/T2 ) or BBT patients (79 percent clinical stage T1/T2).
- RP patients had lower pre-therapy PSA levels (7 ng/ml) compared to EBRT or BBT patients (10 ng/ml).
- RP patients had a lower percentage of Gleason score 10 (4 percent) compared to EBRT (6 percent) or BBT patients (9 percent)
Treatment specs
- Among the RP patients, 43 percent had adjuvant or salvage radiation therapy (68 Gy).
- Among radiation patients, about 90 percent had adjuvant ADT
- Median dose of EBRT was 74 Gy.
- Adjuvant ADT continued for an average (median) of 22 months.
- Median equivalent dose of EBRT + BT was 92 Gy
- Adjuvant ADT continued for 12 months.
Oncological outcomes
After a median follow-up of 4.2, 5.1, and 6.3 years for RP, EBRT, and BBT, respectively, the oncological outcomes (adjusted for age and disease characteristics) were as follows:
- The 10-year rates of distant metastases were
- 46 percent for RP
- 44 percent for EBRT
- 13 percent for BBT
- Differences between BBT and the two others were statistically significant.
- The 10-year rates of prostate cancer-specific mortality (PCSM) were
- 23 percent for RP
- 26 percent for EBRT
- 13 percent for EBRT + BT
- Differences between BBT and the two others were statistically significant.
- The 10-year rates of all-cause mortality (ACM) were
- 32 percent for RP
- 39 percent for EBRT
- 31 percent for BBT
- None of the differences were statistically significant.
- There was a difference at 7.5 years in favor of BBT that vanished by 10 years.
In additional analyses, the authors looked at outcomes by duration of androgen deprivation therapy (ADT) for those receiving any kind of radiation. They found that ADT duration made no significant difference in detected metastases or PCSM within EBRT or BBT, and did not account for the difference between them. They also looked at radiation doses. EBRT patients who received < 70 Gy had PCSM significantly worse than those who received ≥ 78 Gy. The rates of metastases did not differ. Notably, very few (11 percent) of the EBRT patients had both ≥ 78 Gy and ≥ 2 years of ADT, a combination that is now considered standard of care. Those that did had superior outcomes compared to RP. The use of LDR-BT or HDR-BT as part of BBT made no difference.
The authors conclude that:
Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.
In an analysis of the National Cancer Database, Ennis et al. reported on the overall survival of patients who were treated with RP, EBRT, and BBT for high-risk prostate cancer from 2004 to 2013. The database covers about 70 percent of all new prostate cancer patients treated in the US. The patient profile was:
- 24,688 patients treated with RP, at least at first
- 15,435 patients treated with EBRT
- 2,642 patients treated with BBT
- All EBRT patients also had adjuvant ADT
- BBT patients may or may not have had ADT
- All were high risk by the NCCN definition: either Gleason score 8 to 10, stage T3/4, or PSA ≥ 20 ng/ml
- RP patients were younger (62 years of age) compared to EBRT (70 years of age) or BBT patients (67 years of age)
- RP patients were lower stage (89 percent clinical stage T1/T2) compared to EBRT (84 percent clinical stage T1/T2 ) or BBT patients (85 percent clinical stage T1/T2)
- RP patients had lower pre-therapy mean PSA (19 ng/ml) compared to EBRT (23 ng/ml) but the same as BBT patients (19 ng/ml)
- RP patients had a lower percentage of Gleason score 8-10 (70%) compared to EBRT (78%) or BBT patients (73%)
- Comorbidities were similar among groups.
- The above risk factors as well as socioeconomic factors and year of diagnosis were used to adjust the raw data.
- It is unknown what percentage of RP patients had adjuvant or salvage radiation.
- There was no data available on post-treatment metastases or prostate cancer-specific survival
Because surgery is sometimes aborted when cancer is discovered in the pelvic lymph nodes, they estimated the probability that patients had positive nodes, and included it as a risk factor. This would seem to double count those risk factors, but the authors say it had little effect. Based on their model, they estimated that the percentage who had positive nodes was 10 percent of RP patients, 34 percent of EBRT patients, and 23 percent of BBT patients.
After a median follow-up of 36 months, the relative oncological outcomes (adjusted for age and other patient and disease characteristics), expressed as hazard ratios were as follows:
- RP: 1.0
- EBRT: 1.53 (53 percent worse survival vs. RP)
- EBRT with < 79.2 Gy: 1.68
- EBRT with ≥ 79.2 Gy: 1.33
- BBT: 1.17 (not significantly different from RP)
- Not different if ADT included
- No interaction between comorbidities and treatment effects
The authors conclude that:
This analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival.
In an accompanying editorial, Ronald Chen discusses the problem of drawing conclusions about comparative effectiveness from this kind of registry data in the absence of clinical trial data. He points out that patient selection criteria are not completely reflected in comorbidity data. He believes that those who are selected for EBRT are just less healthy than those who can undergo anesthesia for surgery or brachytherapy. Other unmeasured confounders include burden of disease, and patient and physician preferences.
The two studies had similar conclusions, but tell us different things. They both found no effect of treatment on overall survival. Lest one walk away thinking it then doesn’t matter, the experience of living with painful, crippling metastases and the experience of dying from prostate cancer are horrific in themselves. In the Kishan study, among top institutions, there is greater confidence than in many studies that deaths due to prostate cancer could be distinguished from deaths from other causes. Still, overall survival is impaired in patients with cancer, even if the cancer itself isn’t the ultimate cause of death.
Although several randomized clinical trials (RCTs) have demonstrated significant improvements in progression-free survival from BBT compared to EBRT, none have yet demonstrated improvements in overall survival. We saw this recently in the 2005 Sathya RCT. But the prostate cancer-specific mortality advantage of BBT has been confirmed in another study. In a recent analysis of the SEER database, PCSM was 40 percent higher among patients who had EBRT compared to those who had BBT.
Other than the lack of metastasis data and PCSM in the NCDB, there were other important differences between the two studies. In the Ennis study, only 25 to 35 percent of patients were Gleason 9 or 10, whereas all were in the Kishan study. Other differences included the lack of comorbidity data in the Kishan study, and the lack of adjuvant/salvage radiation data in the Ennis study.
Prostate cancer-specific mortality rates were cut in half by BBT, and metastases were only a fraction compared to the other treatments. While this does not prove causality (only a randomized clinical trial can do that), it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high-risk patients may have to forgo brachy boost therapy in favor of high-dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy will probably be the best choice. Patients who are treated with EBRT only should receive a radiation dose of at least 79.2 Gy and 2 years of adjuvant ADT.
Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high-risk patients declined precipitously from 28 percent in 2004 to 11 percent in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.
Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink. Allen thanks Dr. Amar Kishan of the Department of Radiation Oncology, University of California, Los Angeles for allowing him to see the full text of his paper.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: "high risk", BBT, brachy boost, EBRT, external beam, outcome, radiation, surgery |
THE "NEW" PROSTATE CANCER INFOLINK 
If I were diagnosed today with Gleason 9 and a PSA of 15 I would use brachy boost (with HD brachy) and forego surgery with radiation following, as I did.
Dear Sitemaster:
Why the dearth of brachytherapists in the US? How does this compare with the ÙK and/or other parts of the EU?
Dear George:
One of the problems with brachytherapy is that it requires a surgeon and a radiation oncologist to work together as a team to carry out treatment. Thus the cost of executing the treatment in terms of people’s time is relatively high for a relatively short period of time and coordination of everyone’s time is complex. The only way this really works well is at dedicated brachytherapy units, but not a lot of radiation oncologists or surgeons are willing to limit what they do in that way.
I have no idea whether it is any easier or more difficult to get high-quality brachytherapy in EU countries or elsewhere than it is in the USA or Canada.
In the US, it’s also not compensated well by insurance or Medicare. If an RO specializes in brachytherapy, he is not likely to make as much money as if he gives every patient who walks in the door 44 EBRT treatments. Only a specialized high volume center will find it worthwhile to offer it.
I see. Sure, there was a top radiation oncologist and a top urological surgeon at work when I got it. And a few specialised nurses. The entire thing took 4.5 hours. The actual insertions of the small iridium rod was robotic, its motions computed beforehand. I did not mind it, I listened to classical music the whole time, on Sweden’s excellent public service classical station P2.
A few months ago I looked at my complete record from the National Prostate Cancer Registry. I saw a stylised diagram of the catheter insertion points through my perineum. About 15. Two points were pretty far off the volume that would have been irradiated had I stayed in Amsterdam. Of course HDR brachy had no problem zapping me there. Just two more points. For safety there was a wider margin than usual. I like to think that these new points and margin helped save my life … so far.
Allen:
What if, instead of 43% of RP patients receiving adjuvant or salvage radiation therapy, all of them received it. Would it be safe to figure that the RP percentages would be better, making this combined treatment more competitive with BBT, or in some ways even favorable?
You are assuming that RP + EBRT would have been more curative than RP for those who only got RP, whereas those who got adjuvant/salvage EBRT were the ones identified by their doctors who needed the additional therapy the most. Radiation on top of cut tissues always carries greater risk of side effects. This was an observational study. I think that ethically they might have a hard time doing a clinical trial where high-risk patients are randomized to RP alone or RP + EBRT, whether there were indications for it or not.
I should add Kishan’s response to the same question (see here): He did look at the group who received RP + EBRT and reports that:
“The results are consistent with the previously reported outcomes comparing the overall radical prostatectomy cohort vs the EBRT + BT cohort. We acknowledge that these subset analyses are likely to reflect selection biases [which was the point I made above], which is why we did not previously report them.”