Showing posts with label very high risk. Show all posts
Showing posts with label very high risk. Show all posts

Thursday, March 8, 2018

Brachy boost therapy and surgery extend survival about the same in high risk patients, but brachy boost does more

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 - 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 radical prostatectomy (RP).
  • 734 were treated with EBRT only.
  • 436 were treated with BBT (BT was either low dose rate in 62% or high dose rate in 38%).
  • All patients were Gleason 9 or 10 on biopsy.
  • Pelvic LN involvement was discovered in 17% of RP patients ; 40% 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% clinical stage T1/T2) compared to EBRT (70% clinical stage T1/T2 ) or BBT patients (79% clinical stage T1/T2)
  • RP patients had lower pre-therapy PSA (7 ng/ml) compared to EBRT or BBT patients (10 ng/ml)
  • RP patients had lower percentage of Gleason score 10 (4%) compared to EBRT (6%) or BBT patients (9%)
Treatment specs
  • Among the RP patients, 43% had adjuvant or salvage radiation therapy (68 Gy).
  • Among radiation patients, about 90% had adjuvant ADT
  • Median dose of EBRT was 74 Gy.
    • adjuvant ADT continued for 22 months, median.
  • 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% for RP 
    • 44% for EBRT
    • 13% for BBT
    • Differences between BBT and the two others were statistically significant.

  • The 10-year rates of prostate cancer-specific mortality (PCSM) were
    • 23% for RP
    • 26% for EBRT
    • 13% for EBRT + BT
    • Differences between BBT and the two others were statistically significant.

  • The 10-year rates of all-cause mortality (ACM) were
    • 32% for RP
    • 39% for EBRT
    • 31% 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 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%) 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:
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 PC from 2004 to 2013. The database covers about 70% 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 8-10, 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% clinical stage T1/T2) compared to EBRT (84% clinical stage T1/T2 ) or BBT patients (85% 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 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 percent of RP patients had adjuvant or salvage radiation.
  • There was no data available on post-reatment metastases or prostate cancer-specific survival
Because surgery is sometimes aborted when pelvic LN cancer is discovered, 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 percent who had positive nodes was 10% of RP patients, 34% of EBRT patients, and 23% 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 (i.e., 53% 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:
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 death 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% 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%-35% 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 two years of adjuvant ADT.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% 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.

- with thanks to Amar Kishan for allowing me to see the full text.

Wednesday, August 24, 2016

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only

A retrospective analysis of oncological outcomes among modern-era patients with a Gleason score of 9 or 10 demonstrates a clear advantage to a combination of external beam radiation therapy (EBRT) with a brachytherapy (BT) boost to the prostate and short–term androgen deprivation therapy (ADT).

Kishan et al. reported on 487 patients with biopsy Gleason scores of 9 or 10 who were consecutively treated between 2000 and 2013 at the University of California Los Angeles and Fox Chase Cancer Center. The patient characteristics were as follows:
  • 170 were treated with radical prostatectomy (RP).
  • 230 were treated with EBRT only.
  • 87 were treated with EBRT + BT, and most of the BT was high dose rate.
  • All patients were Gleason 9 or 10 on biopsy.
  • RP patients were younger (median 62 years of age) compared to all radiation patients (median 70 years of age).
  • RP patients had more favorable disease characteristics: lower initial PSA, and lower clinical stage.
The patient characteristics by treatment category are listed below.
For the RP patients:
  • 11% had pre-surgery ADT or chemotherapy.
  • 55% had adjuvant or salvage radiation therapy (68 Gy).
    • 39% of them had adjuvant ADT with radiation for a median of 22 months if adjuvant radiation, 12 months if salvage radiation.
  • 85% with biochemical recurrence and no detected distant metastases had salvage radiation.
  • 21% had a lower Gleason score (7 or 8) on final pathology, but 91 percent had any Gleason pattern 5 on final pathology.
  • 78% were stage T3 or T4 on final pathology (vs. 12 percent clinically).
  • 41% had positive surgical margins.
  • 16% had positive lymph nodes
    • Among those, 64% received no immediate treatment because of patient preference.
For the EBRT patients:
  • Median dose of radiation was 76.4 Gy.
  • 94% had ADT starting before EBRT.
    • The median duration of ADT was 24 months.
  • 76% had pelvic lymph nodes treated.
  • 2 patients received salvage cryotherapy.
For the EBRT + BT patients:
  • The median equivalent dose of radiation was 88.7 Gy
  • 86% had ADT starting before radiation.
    • The median duration of ADT was 8 months.
  • 78% had pelvic lymph nodes treated.
  • 1 patient received salvage cryotherapy.
After a median follow-up of 4.6 years, the oncological outcomes were as follows:
  • The 10-year biochemical recurrence rates (BCRs) were
    • 84% for RP
    • 40% for EBRT
    • 30% for EBRT + BT
    • Differences between RP and EBRT and between RP and EBRT + BT were statistically significant.
  • Percentages of patients who began lifelong ADT after therapy failure were
    • 31% for RP
    • 21% for EBRT
    • 16% for EBRT + BT
    • Differences between RP and EBRT and between RP and EBRT + BT were statistically significant.
  • The 10-year rates of distant metastases were
    • 39% for RP
    • 33% for EBRT
    • 10% for EBRT + BT
    • Differences between EBRT + BT and the two others were statistically significant, while the differences between RP and EBRT were not.
  • The 10-year rates of prostate cancer-specific mortality were
    • 22% for RP
    • 20% for EBRT
    • 12% for EBRT + BT
    • None of the differences were statistically significant.
  • The 10-year rates of overall survival were
    • 75% for RP (they were younger and healthier)
    • 65% for EBRT
    • 59% for EBRT + BT
    • None of the differences were statistically significant.
The authors conclude:
These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9–10 prostate cancer.
It will come as no surprise to readers that EBRT + BT boost has better outcomes than EBRT alone (see this link and this one). Dose escalation has been found to improve outcomes, and the use of ADT to radiosensitize the cancer, and to systemically clear up micrometastasis, seems to improve outcomes still further. However, ADT for as long as 2 years could not compensate for the lower radiation dose of EBRT used by itself. Longer duration of ADT was not associated with improved outcomes after accounting for the dose effect.
Those who were treated with EBRT + BT were at a considerable disadvantage in this study: they were older, had worse disease characteristics, and were given less local salvage, yet they performed much better. When controlling for those disparities, the total radiation dose emerged as the single most important variable, affecting biochemical recurrence, metastases-free survival, and prostate cancer-specific survival. No other variable – neither duration of ADT nor adjuvant/salvage radiation – was statistically significant.
Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While the combination therapy did not make a statistically significant difference in prostate cancer-specific survival, the study was probably under-powered to detect that with statistical significance. The survival curves between EBRT + BT and the other two therapies did consistently diverge throughout the follow-up period, so the difference might well be statistically significant on a larger sample size or longer follow-up.
Not everyone in this study received optimal therapy. The EBRT-only dose was sometimes low by today’s standards, salvage radiation was under-utilized, use of concurrent ADT with adjuvant/salvage radiation was low (see this link) and of too-short duration.  However, most were treated according to the standards of care. The authors looked at the subset of patients who were treated optimally and found no difference in conclusions. The conclusions were robust even excluding those who were lymph-node positive.
What is new here is the comparison of the three potentially curative treatments for very high-risk prostate cancer in the 21st Century. There have been several long-term database analyses that compared surgery to radiation therapy as offered in the 1990s, when radiation doses were often inadequate to achieve cures. We recently saw a comparative benefit to radiation over surgery in the modern era among high-risk patients at the University of Alabama Birmingham (see this link). Ideally, we would like to see a randomized comparative trial between surgery and radiation, but that is unlikely to occur. Meanwhile, this kind of analysis is about the best we have to inform our treatment decisions.
We understand that a future, expanded analysis will include data from other institutions, including Harvard, the Cleveland Clinic, and Memorial Sloan-Kettering Cancer Center. That analysis will also include toxicity data. We will certainly report on that when it is published.
note: Thanks to Drs. King and Kishan for allowing me to see the full text of this analysis, and responding to questions.