News reports (and apparently a media release) have been suggesting that ‘A prostate cancer treatment using permanently implanted radioactive “seeds” doubles rates of 5-year tumor-free survival compared with conventional high-dose radiotherapy.’ Unfortunately, these reports are somewhat — or perhaps very — misleading.
The trial in question is a randomized clinical trial known as the ASCENDE-RT study. ASCENDE-RT stands for “Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy”. And it is absolutely true that this is the first randomized clinical trial of any use of brachytherapy compared to any use of external beam radiation therapy. However, it is very important to understand some key aspects of this trial.
First, the trial was limited to patients who have histologically-documented prostate cancer of clinical stage T1cN0Mo to T3aNoMo (i.e., no sign of seminal vesicle invasion or extension of the cancer into adjacent pelvic organs/structures such as the bladder, let alone metastasis). If the patients are thought to have clinically organ-confined disease, it must be of intermediate risk according to the Canadian consensus definition (i.e., clinical stage T2b or Gleason 7 or PSA between 10 and 20). The patient can have had no prior surgery or radiation or other significant interventional treatment. And the patient’s pre-treatment PSA has to have been ≤ 40 ng/ml.
Second, it needs to be appreciated that the patients weren’t just being randomized to brachytherapy or external beam radiation therapy. The two actual treatment arms of the trial were as follows:
- Arm 1 (the “standard therapy” arm): This comprised a total of 12 months of continuous androgen deprivation therapy (ADT) and, starting 8 months after initiation of the ADT, 4.2 to 5 weeks of external beam radiation (46 Gy in 23 equal fractions) followed by an external beam radiation boost lasting 3.2 to 4 weeks (32 Gy in 16 equal fractions).
- Arm 2 (the “experimental” arm): This comprised a total of 12 months of continuous ADT and, starting 8 months after initiation of the ADT, 4.2 to 5 weeks of external beam radiation (46 Gy in 23 equal fractions) followed by low-dose iodine-125 brachytherapy using permanently implanted seeds of iodine-125 carried out 14 to 25 days after the last external beam treatment.
In other words, this trial only compared two differing types of “boost” radiation after all patients had received a standard combination of ADT + 46 Gy of external beam radiation.
The early results of this study, with 5-year follow-up, were presented at the 3rd European Society for Radiotherapy and Oncology forum, ongoing in Barcelona, Spain.
Here are the core facts as we know them:
- The trial enrolled 398 patients.
- 200 were randomized to Arm 1.
- 198 were randomized to Arm 2.
- After the initial 8 months of ADT, all patients received 46 Gy of external beam radiotherapy to the prostate and the regional lymph nodes.
- At 5 years of follow-up (according to the principal investigator) there was “a large advantage in progression-free survival” in patients in Arm 2 of the trial.
- 8 percent of patients in Arm 2 of the trial experienced severe, late, urinary side effects compared to just 2 percent of patients in Arm 1, but
- “Many of these severe adverse effects were temporary and reversible, or could be ameliorated by procedures.”
- > 80 percent of patients in Arm 2 had few or no long-term urinary side effects.
The study’s principal investigator is also quoted as stating that
Although, to date, overall survival and prostate cancer-specific survival do not appear to differ between the two groups, existing trends favour [the patients in Arm 2] and an overall survival advantage is likely to emerge with longer follow-up.
At best this statement is optimistic. At worst it is very misleading.
When you compare these actual data to the media headlines (see here and here, as examples), you will see that, as yet, there are actually no data at all to suggest that brachytherapy is “better” than external beam radiation therapy. What we have here are some preliminary data suggesting that, in a highly-defined subset of patients who all initially received ADT and 46 Gy of external beam radiation therapy, the patients in Arm 2, who were given a brachytherapy boost using low-dose, permanent seeds (as opposed to a boost of an additional 32 Gy of external beam radiation therapy), had
- A higher (but unspecified) frequency of short-term, progression-free survival
- A significantly greater risk for severe urinary side effects
Whether these results will actually demonstrate an improvement in prostate cancer-specific or overall survival at 10 or 15 years of follow-up is completely unknown at this time. Maybe they will and maybe they won’t. It is impossible to tell. The combination of neoadjuvant ADT, initial external beam radiation therapy with continuing adjuvant ADT, and then a brachytherapy boost may well be a highly appropriate form of treatment for carefully selected patients with high-risk, localized prostate cancer — but it certainly isn’t the only option. Furthermore, as is well understood, high-quality brachytherapy requires considerable skill and experience on the part of practitioners if patients are to minimize risk for serious side effects of treatment.
Filed under: Diagnosis, Management, Risk, Treatment | Tagged: ASCENDE-RT, boost, brachytherapy, external beam, low-dose, radiation |
THE "NEW" PROSTATE CANCER INFOLINK 
Puzzling aspects of study from an RT/ADT veteran’s perspective (high risk case)
The sponsoring institution is the University of British Columbia in Canada, where there is impressive expertise treating prostate cancer, reflected in many publications over the years. From my layman survivor’s viewpoint, I’m thinking they should know what they are doing, clearly having contact with experts in ADT, and likely being strong in radiation therapy (RT) as well. But I’m quite puzzled by a few aspects of their protocol.
First, based on eligibility criteria, it appears the whole trial population may have a lot of low-risk patients. A fair amount of research suggests that while ADT is helpful to high-risk patients to support RT and perhaps to some intermediate-risk patients for RT, it is not helpful to low-risk patients for RT. Yet the low-risk patients in this trial would have been given a year of ADT. Why would they do that?
Second, a related sub-issue is why they would have used a year of ADT for all, instead of a shorter course for intermediate-risk patients (say, 4 months, and maybe none for low-risk as addressed in the first point), and a substantially longer period, such as at least 18 months, for high-risk patients, the “at least” being supported by research.
Third, again considering the low-risk patients, radiation to the pelvic nodes, in the absence of any imaging suggesting the presence of prostate cancer in some of the nodes, is not standard of care, per my impression; such pelvic radiation, I believe, is not supported by research for low-risk patients as far as I know. So again, why would they do that? To a lesser degree the issue applies to intermediate risk patients.
These issues would probably impact side effects to some degree, likely increasing, arguably unnecessarily and without benefit, side effects particularly in low-risk patients.
Fourth, an issue that might affect survival, the protocol gives no indication that patients are stratified into the two arms by risk level, yet the trial allows low-, intermediate-, and even high-risk (Gleason 8) patients to participate. Therefore, it seems somewhat likely that overall risk will be somewhat unequal in the two arms, which could make interpretation of results more difficult as risk level has a significant effect on results of RT. I don’t understand why there is no stratification.
I do not suppose we will learn how the research team would have addressed these concerns, but perhaps one of us can sort some of this out.
Dear Jim:
You appear to have completely misread this trial protocol. It is made extremely clear that any patient who is thought to have organ-confined disease must have at least intermediate-risk disease (and any patient who does not have organ-confined disease is, by definition, at least intermediate risk anyway). Thus, this trial shouldn’t have included any patients with low-risk disease, but is entirely limited to men with intermediate- and high-risk disease.
Jim,
Other than your misunderstanding of the risk groups here, which the Sitemaster addressed, I think I can explain why they did 8 months of ADT before treatment. They were trying to shrink the prostates so they would be amenable to brachytherapy (BT). Because it was a clinical trial of a BT boost vs. EBRT only, they had to keep all other variables as constant as possible (although there was pelvic lymph node treatment in some), so everyone had to have the same ADT treatment. Whether the intermediate-risk men would have done fine with a shorter course or none at all, and the high-risk men with a longer course remains a question for future trials. I do wish that they had treated the favorable intermediate-risk patients as a separate group (perhaps they will in the full text), and that they had included patients with stage T3b.
There was one terminology issue I had with their write-up: they described the second round of EBRT treatments as a “boost.” While they may have had different planned target volume and clinical target volume, I have never seen it described as a “boost” in any other study when EBRT is used throughout. The EBRT total dose was 78 Gy, which is very typical in the dose-escalation era. So this was a clinical trial comparing combo therapy (EBRT + BT boost) to an EBRT monotherapy.
The gains in recurrence-free survival were pretty impressive. At 5 years, it was 89 percent vs. 77 percent, and at 9 years, it was 83 percent vs. 63 percent for the combo vs the monotherapy, respectively. If anyone wants to read the unpublished abstract, they can at this link.
Allen,
Questions then would come up whether the EBRT data would have been different if the total 78 Gy dosage would have been applied within the initial 5 weeks.
Wolfram:
Allen will correct me if I am wrong, I am sure, but as far as I am aware one can’t give 78 Gy to any patient over just 5 weeks. That dose level would be too toxic. It is customary to give a total dose of 78 Gy over more like 7 or 8 weeks.
I agree with the Sitemaster. If EBRT were to be delivered in 5 weeks (called hypofractionation) the total dose would probably be no greater than about 68 Gy to avoid excess toxicity. Hypofractionation was not the subject of this study. In a previous post I described several trials of SBRT for treating high-risk patients. It would be great to see a randomized comparison of brachy combo therapy vs. SBRT for high-risk patients, but to my knowledge there is currently no such trial. I am aware of an experimental protocol at MSKCC of SBRT with an LDR brachy boost. I don’t really understand what advantage that might have over SBRT monotherapy, although it significantly reduces the treatment time compared to traditional combo therapy.
Mike,
You are absolutely correct. What I overlooked is the fact that the fractional dosages during the first 5 weeks are exactly identical to the dosages delivered during the “boost” phase afterwards and that is why Allen refers to it, quite correctly, as EBRT monotherapy, in line with current protocol.
There is a trend to shorten the treatment for radiation by using higher dosages, as pointed out recently again after FDA approval (based on data from a Phase II trial) of a device (the SpaceOAR system) that can deliver an injectable gel that achieved a significant reduction in rectal radiation dose and late rectal toxicity.
This trial looks encouraging now that I’ve changed my viewpoint.
Thanks Sitemaster and Allen for clarifying the point I had missed about the exclusion of low-risk patients from the trial. Your comments reassured me about the research team and eliminated my confusion regarding how a presumably good team could miss such a fundamental issue, as did the abstract which stated that patients were stratified by risk to the two arms of the study. I really did review the issue low-risk issue several times before posting but still could not avoid looking at it the wrong way. Thanks especially Allen for the added link.
Use of ADT: I’m also viewing other issues from a favorable viewpoint. First, I had been puzzled why the researchers used a year of ADT for all, instead of a shorter course for intermediate-risk patients (say, 4 months), and a substantially longer period, such as at least 18 months, for high-risk patients, the “at least” being supported by research. I’m now thinking the answer is that back when the protocol was being established, studies about the length of ADT for intermediate- and high-risk patients were in process but not yet published. The accrual period for this study was December 2002 through September 2011, so the protocol was likely finalized in 2002. While the “extra” radiation used in this study for the intermediate-risk patients may have increased side-effects somewhat, still, at only 1 year of one ADT drug, that extra dosage would have been unlikely to have increased health risks significantly. The 12-month course for high-risk patients is now seen as likely sub-par, but research on the survival impact of 12 months versus a longer period is not definitive at this time.
Pelvic radiation: Second, radiation to the pelvic nodes, in the absence of any imaging suggesting the presence of prostate cancer in some of the nodes, is not standard of care, per my impression, for intermediate-risk patients; such pelvic radiation, I believe, is not supported by research at this time per my recollection, but that also was not known when the protocol for this study was set.
Aggressive dose for the time: On a very positive note, the researchers chose a fairly aggressive dose of radiation for the EBRT/ADT only group, 78 Gy, which was probably a bit bold back in 2002 based on research at the time, though supported by a major study or two (though I believe using IMRT rather than 3D-conformal EBRT as in the protocol for this study). My impression is that doses in the lower 70s were the norm at that time. It is now recognized, I believe, that the dose of 78 Gy chosen is within the range of about 78 to 81 Gy that seems optimal.
Impressive success: As Allen noted, “The gains in recurrence-free survival were pretty impressive. At 5 years, it was 89 percent vs. 77 percent, and at 9 years, it was 83 percent vs. 63 percent for the combo vs the monotherapy, respectively.” (!) In thinking about these results, it is important for us to recognize two important points about the EBRT radiation technology employed in the study. First, it was 3D-conformal EBRT that was used, not the IMRT that is now favored. Second, this radiation would very likely have been delivered for many patients in the study without “image guided” radiation therapy (IGRT) that we now believe is having a favorable impact. (From the results section of the abstract: “Median follow up (FU) is 6.5 years; 65 men have >9 years FU.” IGRT was emerging about 5 years ago*, or 2010, shortly before the end of accrual for this study in 2011, so few patients would have benefited from such advances in imaging. “BAT” technology has been discredited.) As someone whose treatment was fairly close to that in the straight EBRT group, but with several hopefully important advances, I’m hoping that IMRT, image guidance, etc. will improve the success rate of such an approach, bringing it close to the brachy/EBRT group (with pelvic dose and ADT).
Comparison with impressive, earlier, long-term Dattoli study: It is worth noting that results for the combined arm for this study are in the neighborhood of results from a similar series (EBRT + brachy supported by ADT) reported by Dr. Michael Dattoli in 2010 for intermediate- and high-risk patients with very long follow-up (PMID: 20847945, with the complete paper available free online): “Results. Overall actuarial freedom from biochemical progression at 16 years was 82% (89% intermediate, 74% high-risk) with failure predictors: Gleason score (P = .01) and PSA (P = .03). Hormonal therapy did not affect failure rates (P = .14).” Success was about 85% for the total Dattoli group at 5 years. Patients were treated between January 1992 and February 1997, obviously prior to some of the advances that would have been available in the Canadian study and well before advances now in practice. While there are obvious differences between the Canadian and Dattoli studies, both show impressive results for radiation in treating intermediate- and high-risk patients.
* Re emergence of IGRT, Dr. Michael Zelefsky, the well-known radiation oncologist and researcher from Memorial Sloan Kettering Cancer Center in New York, provided this information on the emergence of IGRT in the current (May) issue of the “Prostate Forum” newsletter. In 2006 another well-known radiation oncologist and researcher, formerly from MSKCC, Dr. Michael Dattoli described the emergence of DART – Dynamic Adaptive Radiation Therapy, which provided verification of dose delivery both between and within radiation sessions; he was clearly an early adapter at that time. Early use of BAT imaging was discredited by a study led by Dr. Mack Roach, MD, a well-known radiation oncologist at UCSF.
Recently diagnosed as an intermediate PC victim with Gleason of 7 (4 + 3), my radiation oncologist has cited the Ascende RT study. Following CT and bone scans at the University of California, San Diego, doctor is requesting a 3-T mpMRI plus a consult with a medical oncologist. The radiation oncologist is (preliminary basis until MRI and consult are completed) proposing 6 months of ADT, then IMRT or pencil beam proton radiation therapy (PBRT) starting after 2 months, followed by low-dose permanant seed implant brachytherapy.
While a little different from the study, this seems appropriate relative to the follow-up comments above regarding the trial study. I don’t know the total greys proposed for IMRT or PBRT, but the radiation therapist described the total greys for the IMRT and brachytherapy as being 132 (I believe) or a thereabouts. I think I will need to pin that down. In any event, it appears he is making adjustments for the grade of my cancer at T2b, Gleason 7, and that only 5/12 cores were biopsied with cancer.
Hope I am interpreting all this correctly and that I am on the way to selecting an acceptable treatment plan.