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 nost 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 percent had pre-surgery ADT or chemotherapy.
  • 55 percent had adjuvant or salvage radiation therapy (68 Gy).
    • 39 percent of them had adjuvant ADT with radiation for a median of 22 months if adjuvant radiation, 12 months if salvage radiation.
  • 85 percent with biochemical recurrence and no detected distant metastases had salvage radiation.
  • 21 percent had a lower Gleason score (7 or 8) on final pathology, but 91 percent had any Gleason pattern 5 on final pathology.
  • 78 percent were stage T3 or T4 on final pathology (vs. 12 percent clinically).
  • 41 percent had positive surgical margins.
  • 16 percent had positive lymph nodes
    • Among those, 64 percent received no immediate treatment because of patient preference.

For the EBRT patients:

  • Median dose of radiation was 76.4 Gy.
  • 94 percent had ADT starting before EBRT.
    • The median duration of ADT was 24 months.
  • 76 percent 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 percent had ADT starting before radiation.
    • The median duration of ADT was 8 months.
  • 78 percent 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 percent for RP
    • 40 percent for EBRT
    • 30 percent 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 percent for RP
    • 21 percent for EBRT
    • 16 percent 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 percent for RP
    • 33 percent for EBRT
    • 10 percent 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 percent for RP
    • 20 percent for EBRT
    • 12 percent for EBRT + BT
    • None of the differences were statistically significant.
  • The 10-year rates of overall survival were
    • 75 percent for RP
    • 65 percent for EBRT
    • 59 percent 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.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel. We thank Drs. King and Kishan for allowing us to see the full text of this analysis, and responding to questions.

12 Responses

  1. More good stuff from my point of view. I was Gleason 4 + 4 at start of treatment in February 2009. PSA 31, stage T2cN0M0. I first got neoadjuvant ADT for several months, then EBRT + HDR-BT and then 3 years ADT. So far no cancer issue. I regret nothing except not suing the Dutch doctor who wished to under-treat me. He offered me either RP or EBRT but explicitly ruled out BT. His reason was “because your prostate is too large.” He did not tell me that neoadjuvant ADT could reduce my prostate volume to a value suited to HDR-BT. Doctors in Uppsala knew this and offered me the trimodal therapy. I did not hesitate to accept. As for legal matters I can argue that this failure to give me adequate information about neoadjuvant ADT was dangerously unethical. There is more, but this is all that is relevant now.

  2. Allen,

    Would you please explain how the median follow up was 4.6 years, but the study reported 10-year rates of BCR, metastasis, etc? If the median follow up was 4.6 years, how many of the participants made it to 10 years prostate cancer-specific survival (and does that explain why those results are not statistically significant, even though risk of death was about 50% less for EBRT + BT compared to RP)?

    Thank you.

    Richard

  3. Allen, I’m curious to see the expanded analysis with toxicity data because I had a phone consult with Dr. Chris King about 5 months ago and he recommended that, being a G9, I should go with 86 gy IMRT because he felt IMRT plus BT boost was more toxic to the urinary system.

  4. Richard,

    Remember that this is a retrospective study across a wide time period (2000 to 2013), so many men are lost to follow-up or die. (In a prospective clinical trial, a minimum follow-up can be set as a requirement.) It looks like 70 of the baseline 487 men were included in the 10-year Kaplan-Meier survival curve at 10 years. Yes, this study was under-powered to detect a statistically significant difference at that level, and with increasing prostate cancer survival, it will take increasingly longer follow-up to detect a statistically significant difference. As I said, the survival curves between EBRT + BT and the other therapies are steadily diverging, so it is likely that with the increased statistical power of adding patients from other institutions, we will see statistical significance.

  5. Len,

    It’s true that we’ve seen an increase in urinary toxicity with the BT boost, and that can be particularly concerning to those with a history of urinary retention. Most of the patients who received BT in this study had high-dose-rate (HDR) BT, but the follow-up study will include many who had a low-dose-rate (LDR) BT boost as well. I hope they will have a large enough sample size to break those out separately.

  6. Very interesting data. It leads me to ask: Under what circumstances would one ever recommend RP to a Gleason 9 patient? I guess RP could be justified in case of urinary retention or very large prostate. How large would a prostate have to be for a patient to not be a good candidate for EBRT + BT?

  7. Dear Tom:

    Since we don’t know what the complication rates are for EBRT + BT (potentially in combination with ADT), I don’t believe your first question is answerable. All this really means is that (as usual) patients have to make their own risk/benefit assessments in association with their physicians.

    Your second question is equally unanswerable because some really very large prostates (of > 100 cm3) can be shrunk down to a much smaller size through the use of ADT — and then some can’t.

    You also need to understand that some patients are as averse to radiation therapy (because of the risks associated with secondary cancers) as others are to surgery (because of the risks for erectile dysfunction and urinary incontinence). In the end, all such decisions are just personal ones. And many men who have surgery as first-line therapy for a high-risk prostate cancer will need to have adjuvant or salvage radiation therapy too.

  8. Tom,

    I talked to a high-risk patient recently who had a large transition zone tumor with nothing in the peripheral zone — I thought he was an excellent candidate for RP. I also talked to a man who had two prior TURPs and BT was ruled out for him (although experimental SBRT monotherapy or boost therapy may still be an option for him). There is a rare genetic disease that causes supersensitivity to radiation, but that’s hard to know in advance.

    The kind of BT in this study was primarily HDR brachytherapy. There are no size limits for that (although outcomes are better if the prostate is not huge). For seeds, they don’t like to treat prostates bigger than about 50 cm3. In this case, because they are using ADT anyway from 2 months prior to treatment, they can shrink it. They will pick up more patients treated with LDR brachytherapy (seed) boost from Cleveland Clinic and MSKCC when they do the expanded study.

    Sitemaster,

    While they didn’t report toxicity in this study, they did in the randomized clinical trials of brachy boost vs EBRT (links in the article). Toxicity is certainly worse for the boost vs the monotherapy. All we can do for RP ± adjuvant/salvage RT ± adjuvant ADT is look at historical data. I guess we have a pretty good handle on that by now — a negative synergy of all three therapies.

  9. Allen,

    According to a friend of mine who is a cancer genetics researcher, the germline BRCA2 mutation predisposes those patients to hypersensitivity to the effects of radiation and, as we now know from your recent coverage of the NEJM article, the incidence of germline BRCA2 is 5.3%. I would not characterize that percentage as rare and it could easily be determined in advance for anyone considering RT.

    Len

  10. Len,

    The operative word is “predisposes.” Fortunately, we have many redundant systems for gene repair following radiation. In fact, for many of those genes, one would have to have inherited mutations from both parents to have a problem with gene repair after radiation therapy because they are autosomal recessive, and that’s before the redundant systems that may override the defect. Actually, it’s not BRCA2 so much as ATM and ATR — again from both parents (ATM is recessive) that is worrisome with radiation therapy. Such people have a hypersensitivity to sunburn, often have spider veins in their skin and eyes, and suffer from poor motor coordination. (ATM stands for ataxia telangiectasia mutated — the genetic disorder it causes.)

    According to Pritchard et al. (see this link), the incidence of BRCA2 in the population is only 3 in a thousand, and about the same in the non-metastatic prostate cancer population. It is 5.3% only among men with metastases, who would ordinarily not be candidates for radiation therapy anyway. As for ATM and ATR, the population incidence is also about 3 in a thousand (1.9% among men with metastases), but the incidence of inherited ATM defects from both parents is estimated to be about 3 per million. I would characterize it as rare.

    As for “easily determined,” I think the cost of getting a BRCA/FOX analysis is over $3,000. It is a lot more difficult than you may know, because it is not at all clear which and how many SNPs are needed to create genes in which the defect is clinically meaningful.

  11. Could I request you provide a print command at the start of each new presentation. Would save us time highlighting the full page. We can then paste and edit as we wishl

    Thanks

  12. Bruce:

    Sorry. Unfortunately, I can’t add such a print command. I am using free software to manage this site that does not include that option.

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