Is ADT still needed for high-risk patients receiving brachy boost therapy?


Brachy boost therapy (external beam plus a brachytherapy boost to the prostate) is arguably the gold standard treatment for high-risk patients, reporting the best oncological outcomes of any therapy. While long-term adjuvant ADT has proven to be beneficial in prolonging survival in high-risk patients when used in conjunction with dose-escalated external beam radiation therapy (DART 01/05 GICOR), there has never been a randomized trial to determine if there is any benefit to ADT when used with brachy boost therapy .

All we have to go by are several single- or multi-institutional studies and one large database analysis. Almost all of the studies so far show no effect to short-term adjuvant ADT (i.e., 4 months of ADT, starting 2 months prior and running concurrent with the radiation therapy)

Two of the studies used a boost of low-dose-rate brachytherapy, predominantly using Pd-103 seeds. Dattoli et al.  found there was no significant difference in 16-year PSA progression-free survival (PSA-PFS) whether 4 months of ADT were added or not. D’Amico et al. also found no significant difference in 8-year prostate cancer-specific mortality (PCSM) with the addition of ADT. However, they felt that it was “approaching significance” (p = 0.08) and might become statistically significant with longer follow-up. In contrast to the Dattoli study, the D’Amico study did not treat the pelvic lymph nodes.

A recent analysis of the large National Cancer Database by Yang et al. did not detect any benefit to adding ADT on 8-year overall survival (OS). However, the database lacks specific information about type of brachytherapy, radiation doses, duration of ADT, and whole-pelvic treatment,

Several studies that used high-dose-rate brachytherapy as a boost also looked at this issue retrospectively. Demanes et al. was the earliest of those studies. They found no difference in 10-year PSA-PFS in their 113 high-risk patients treated between 1991 and 1998. Several subsequent studies confirmed those findings. Galalae et al. concatenated the databases from three institutions: Kiel University, the University of Washington in Seattle, and William Beaumont Hospital. Short-term adjuvant ADT failed to demonstrate improved 10-year PSA-PFS in the 359 high-risk patients treated between 1986 and 2000. And the lack of effect was demonstrated at all three institutions. Kotecha et al. also failed to find any differential improvement in 5-year PSA-PFS among 61 high-risk patients treated with HDR brachy boost at Memorial Sloan-Kettering Cancer Center between 1998 and 2009.

There has been one “outlier” study. Schiffmann et al. reported on 211 consecutive high-risk patients treated at the University Medical Center Hamburg-Eppendorf from 1999 to 2009. After 10 years, the biochemical recurrence-free survival rate was 50 percent with the adjuvant ADT but only 39 percent without it — a very statistically significant difference. However, even the “improved” outcome seems low compared to the ASCENDE-RT trial, in which everyone got early neoadjuvant and adjuvant ADT. In that trial, the 9-year PSA-PFS for high-risk patients receiving the trimodality therapy was 83 percent. Another multi-institutional study of HDR-brachy boost therapy reported 10-year PSA-PFS of 85 percent with ADT and 81 percent without ADT in high-risk patients. It is plausible that the patients in the Hamburg study had more advanced disease and had more undetected micrometastases compared to the other studies.

The following table summarizes the treatments given in the aforementioned studies, and whether there was a statistically significant improvement (p < 0.05).

Short-term vs. long-term adjuvant ADT

ADT is believed to have two effects when used in conjunction with radiation. Used before radiation begins (neoadjuvant use) and during radiation treatments (concurrent use), it radio-sensitizes the cancer. Laboratory findings suggest that it interferes with cancer cell repair of the induced DNA double-strand breaks. After radiation (adjuvant use), ADT is believed to “clean up” any remaining local micrometastases that survived. The death of cancer cells from both the radiation and the ADT dumps antigens into the serum that may activate T-cells. Those T-cells may hunt out and destroy small amounts of cancer cells nearby (the bystander effect) or systemically (the abscopal effect).

The bulk of the above retrospective studies suggest that the radio-sensitizing effect is unnecessary with the very high radiation doses given with brachy boost therapy. However, what remains to be shown is whether long-term ADT might confer any additional benefit. The DART 01/05 GICOR trial proved that there was a significant benefit to 28 months of ADT compared to 4 months in high-risk patients treated with dose-escalated EBRT. It is possible that while short-term ADT may have no benefit, long-term ADT might. On the other hand, the very high rates of cancer control (around 80 to 85 percent) using brachy boost therapy may be as high as we can reasonably hope for, given that there will always be some patients with undetected,occult micrometastases.

Better patient selection

High-risk patients are usually given a bone scan and CT to help rule out distant metastases. Bone scans are non-specific to prostate cancer and are not very sensitive when the PSA is below 20 ng/ml. CT scans detect metastases larger than about 1.2 cm, but most metastases are smaller than that. The newly-approved Axumin PET scan, and the experimental PSMA-based PET scans now in clinical trials may be able to detect those distant metastases earlier in recurrent patients. However, there are currently no PET scans approved for high-risk patients outside of clinical trials. (They are only approved for recurrent and advanced cancer patients.) In the future, those high-risk men in whom metastases have been detected via PET scans may be better candidates for systemic therapies, while those in whom no metastases have been detected may be better candidates for brachy boost therapy. It may be economically justifiable to use PET scans for this purpose. Perhaps we will see another 5 to 10 percent increase in cancer control rates, even without ADT, with better patient selection.

Dose escalation

At the high biologically effective doses (BEDs) used in all the brachy boost studies, there does not seem to be a significant interaction between dose used and whether ADT was effective. The Dattoli study had the lowest BED, but no benefit to added ADT, while the Galalae study had the highest BED, but also no benefit to added ADT. The Hamburg study had high BED but did demonstrate a benefit to added ADT. All of the brachy boost studies seem to have adequate radiation doses.

Whole pelvic radiation

It is possible that pelvic lymph nodes are best treated with a combination of radiation and ADT.  Bittner et al. looked at 186 high-risk patients treated with the brachy boost therapy. The 10-year PSA-PFS was:

  • 94 percent if they received both whole pelvic radiation and ADT
  • 82 percent if the received whole pelvic radiation without ADT
  • 90 percent if they received ADT without whole pelvic radiation
  • 75 percent if they received neither ADT nor whole pelvic radiation

ADT seemed to have a bigger effect than whole pelvic radiation. This may be because the whole pelvic radiation dose is inadequate. The doses given to the pelvic lymph nodes are quite a bit lower (about 50 Gy in 28 fractions) than the dose to the prostate. If Dr. King is right that prostate cancer is inherently radio-resistant and requires a higher lethal dose (about 79.2 Gy/44 fx) to be effective, even when the cancer is only in the prostate bed (see this link), it is possible that pelvic lymph nodes require a higher dose as well. Because of the potential bowel toxicity of escalated pelvic doses, adjuvant ADT may be necessary to achieve effective cell kill rates without dose-limiting toxicity. We saw in a recent analysis that, in the salvage situation among patients with Gleason scores of 8 to 10, whole pelvic radiation and ADT both had significant benefits. Whether whole pelvic radiation is effective in high-risk patients treated with brachy boost therapy and ADT is the subject of a major ongoing randomized clinical trial (RTOG 0934).

Retrospective vs prospective trials

All of the published studies so far have been retrospective, and are therefore subject to selection bias: those who received the ADT had more progressed disease than those who received the brachy boost without ADT. Therefore, it will always be impossible to convincingly resolve this issue without a prospective, randomized clinical trial.

Patient decisions

Until we have definitive results from randomized clinical trials, the decision over whether to add ADT to brachy boost therapy will be challenging. Many patients are persuaded by the extra insurance ADT provides, and that only a short course seems to be necessary. Others are so ADT-averse that even a short course is unthinkable, especially with no concrete evidence of efficacy.

The decision over whether to include the whole pelvic area in the external beam radiation field may be an easier decision. High-risk patients have a significant probability that there are small metastases harbored in pelvic lymph nodes. Recent studies have shown the treatment field must be wider than was previously thought. For some patients with anatomical abnormalities, low visceral fat, and a history of bowel disease, this too may present a challenging decision.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

11 Responses

  1. Allen:

    Another fabulous analysis on your part! I’m feeling more and more comfortable with my decision in 2015 to have whole pelvic IMRT at 75 Gy in 50 fractions along with 13 months of ADT3 from Dr Dattoli. I believe this is the SOP for high-risk patients for his practice.

    Bob

  2. Great treatise. As a patient, I recall studying the ASCENDE trial along with STAMPEDE and CHARRTED — 2015 trial results. I think the higher doses (grays) possible with proton v. photon radiation therapy may obviate the need for brachytherapy by building the “boost” into the proton radiation therapy regimen which, when administered with ADT and adjuvant chemotherapy, may well yield outcomes quite similar to ASCENDE trial results. Food for thought? Great article — perhaps the best I have read dealing with high-risk prostate cancer. Keep up the wonderful work.

  3. Skip:

    The photon and proton absorbed radiation maximum is exactly the same – no higher than 82 Gy (or 82 GyE for protons). See here.

    Sometimes they deliver pelvic IMRT (photon) with a proton boost to the prostate, but that 82 Gy limit can’t be exceeded without undue toxicity. They are experimenting with hypofractionated proton therapy, which may be able to raise the biologically effective dose.

    The other experimental therapy is using SBRT to boost the prostate dose as high as can be achieved with brachytherapy. It can be used as a monotherapy (all done in 5 sessions) for both the whole pelvis and the prostate. Some are also trying IMRT for the whole pelvis with an SBRT boost to the prostate. Early results indicate low rates of toxicity for the monotherapy.

  4. I add my accolades as always, Allen. This particular time your piece is right on the money for me…

    Dx T3a by Shinohara at UCSF in 2007, I did the trifecta — 45 Gy of IMRT to the pelvic girdle that was Mack Roach’s signature treatment; around 90 to 100 Gy (I forget) of I-125 brachytherapy to the prostate (including seeds placed outside in the bed); and, 28+ months of ADT.

    My anecdotal experience has been totally positive. While it did take over 12 months post-ADT for my PSA to drop to < 0.1, it has remained there since 2011.

    I also fit into the low visceral fat with a history of bowel disease. That has left me with a few ongoing side effects like radiation proctitis and bleeding — but to my mind that's an inconvenience compared to the alternative!

    I have absolutely no regrets over my treatment decisions.

    Onward & upwards!

  5. Thank you. This article is probably the clearest I have read here on the exact treatment I got in Uppsala but which I could not have gotten in Amsterdam, even if I had known about trimodals in December 2008. Given that these results are not conclusive I’m glad I went through the 36 months of ADT, plus the concurrent ADT and the neoadjuvant ADT with Casodex. The doctors’ reasoning concerned micrometastases, exactly as written up here.

    This has gotten me curious. A few years ago I asked for all data on me held in the Swedish national centre in Uppsala. I have it and will study it carefully when I have time. A quick look showed me that several areas of cancer invasion were found before treatment that were missed in Amsterdam. (Not hard, as I had gotten no scans at all there, despite repeated requests from my partner and I. After I left she got a call from the Dutch hospital, with a date. She laughingly told them I had gotten it in Uppsala. What a joke.) As I understand it the locations of the brachytherapy catheters were designed to cover these areas and to hit a wide “margin”, to try to zap anything right outside the main volume. Lucky I decided to leave. The trimodal is available in one Dutch clinic since last February. But as I remarked to a person there, how many lives did this needless waste of time cost? Needless except to the Dutch private insurers, who saved money.

  6. This is a good article! However, my understanding is that the cancer cells need to repair the induced DNA double-strand breaks after the radiation and therefore adjuvant ADT will interfere with that.

    With SBRT you can achieve higher rates of cancer control than the mentioned 80 to 85 percent with brachy boost therapy. I was treated with 230 BED. Therefore adjuvant ADT may not be required with SBRT.

  7. I have not seen any long-term reports, other than from Alan Katz, on SBRT for high-risk prostate cancer. And he reported 9-year freedom from biochemical failure of 66%. SBRT for high-risk disease is the subject of several clinical trials, as we have reported. Where were you treated?

  8. Allen:

    Assuming you’re asking me, I was treated in June 2017 with SBRT in three fractions by Dr John Pablo at Lewis Cancer Center in Savannah. He used IMRT (rather than CyberKnife, which he also has) due — he said –to better imaging.

    Bob

  9. With SBRT you can achieve very good local control of metastases. Piet Ost and colleagues have reported that:

    “A lower radiotherapy dose predicted for a higher local recurrence rate with a 3-yr local progression-free survival of 79% for patients treated with a BED #100 Gy versus 99% for patients treated with >100 Gy (p = 0.01).”

    I did not take part in a study. My lymph node metastases were detected with a PSMA PET/MRT. To have them radiated I went to a CyberKnife center, presented the Decaestecker study, and asked to be treated as reported in the study. No side effects yet; PSA value reduced by 50%.

    Cannot report anything regarding overall survival but you sure feel better with fewer metastases.

  10. No, Bob. I was asking George. You did not have SBRT for high-risk disease, you had it for a met.

  11. And apparently, neither did he.

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