Can the PACE study resolve key questions about treatment of localized prostate cancer?


According to a media release from Accuray, Inc., the company has initiated a multi-center, multinational clinical trial in Europe to compare the outcomes of patients with localized prostate cancer treated with CyberKnife stereotactic body radiation therapy (SBRT), da Vinci robot-assisted laparoscopic surgery (RALP),  manual laparoscopic surgery (LRP), and conventionally fractionated intensity modulated radiation therapy (IMRT). Details of this trial are available on the ClinicalTrials.gov web site. The formal study name is the Prostate Advances in Comparative Evidence (PACE) study.

The “New” Prostate Cancer InfoLink is not surprised to see this trial being done in Europe — with no participation from centers in the USA. It would probably have proved difficult to get cooperation between the surgical and the radiation oncology communities in the USA … and even if such cooperation had been achieved, persuading patients to be randomized to surgery or to SBRT would likely have been just as difficult.

If this clinical trial can really be completed to appropriate standards over time, it may finally resolve the question of whether there really is a “gold standard” for the treatment of localized prostate cancer — but the Devil will very definitely be in the details.

According to the trial protocol on the ClinicalTrials.gov web site, eligible patients must meet the following criteria:

  • PSA < 20 ng/ml
  • Gleason score ≤ 3 + 4 = 7
  • Clinical stage T1c -T2c, N0-X, M0-X

These criteria correspond to low- and intermediate-risk disease as defined by the National Comprehensive Cancer Network.

Treatment of eligible patients will be carried out as follows:

  • Men who are eligible for and wish to consider surgery will be randomized to treatment by laparoscopic prostatectomy (LRP or RALP) or SBRT.
  • Men who are not eligible for or do not wish to consider surgery will be randomized to treatment by IMRT or SBRT.

The estimated number of patients to be enrolled in this trial is 1,036 and patients will be followed until 2025, although initial data are expected as early as 2020. The first patients are already being enrolled at The Royal Marsden Hospital in England.

The key questions that will need to be resolved by this study will have to include both the oncologic efficacy of the various types of treatment (i.e., is any one of them actually better than any other in the elimination of cancer) and also the long-term follow-up related to quality of life.

3 Responses

  1. BRAVO, & QUESTIONS AND CONCERNS ABOUT STUDY DESIGN

    This ambitious study has potential to advance our knowledge considerably. It is wonderful that the researchers and sponsor are taking on this large trial. I do have several concerns after viewing the description at the clinical trials site.

    Low- and intermediate-risk categories are apparently being intermingled without stratification into low and intermediate risk groups. I’m concerned that some of the treatment groups may have disproportionate risk distributions, which could cloud interpretation. Perhaps the trial is large enough to avoid that. If I were designing the study, I think I would opt for risk stratification. Perhaps they considered that but decided against it in order to have larger groups.

    Also, I’m concerned about conventional bias in medical practice affecting informal and formal advice on treatments to patients, specifically whether bias could lead to disproportionate assignment of higher-risk cases to the radiation treatments, as has been common in the US in the past and is still somewhat prevalent. The second arm of the study includes “non-surgical candidates” (as well as men refusing surgery), who by definition would have some higher-risk features. While that second arm compares two kinds of radiation, I’m thinking a comparison with the surgery results for the first arm would probably be an apples-to-oranges comparison from a risk standpoint. Perhaps no such comparison is planned by the researchers, but the media tend to overlook such niceties.

    I’m really puzzled by the absence of active surveillance (AS) as an option for low-risk patients, especially with involvement of the Erasmus Medical Center where Dr. Schroder and team have reported on their AS series. I’m wondering whether AS will be presented as a prominent option for low-risk patients eligible for AS. That is not clear from the description of the trial at the trials website.

    Eligibility criteria exclude patients with prior ADT, which is reasonable, but I trust that does not rule out post-randomization neoadjuvant (and continuing adjuvant) ADT for radiation, particularly for the intermediate risk patients, as research has indicated that approach is beneficial. Neoadjuvant and adjuvant ADT would introduce another variable; stratification might be enhance interpretation, but no such stratification for ADT is described in the overview of the trial.

    I’m also concerned that the sponsor, Accuray, clearly hopes the study results will help promote CyberKnife SBRT as the “gold standard” for localized prostate cancer. I’m wondering how the researchers are insulated from influence by the sponsor.

    To me, one of the daunting aspects of trials of moderate to long duration, like this one, is the emergence of new technology during the trial that affects (or could, or should affect) the patients in the trial. The most likely prospect to me is the emergence of new imaging techniques to reliably determine the presence of small metastases for patients thought to have localized prostate cancer. At the moment three technologies come to mind, all now existing, but not widespread, and likely not now cost-effective at least for localized disease, at least for patients with other low-risk disease features. The three technologies are the Na 18F PET/CT scan for bone mets, the Feraheme USPIO high resolution MRI/CT scan for lymph nodes, and the C11 choline scan for lymph nodes. Gene testing is another technology area with potential to affect treatement decisions in the near future. I’m wondering if the trial protocol provides flexibility for adjusting to emergence of technology.

  2. Jim:

    (1) The trial protocol doesn’t say that patients aren’t being stratified by risk group. It simply doesn’t address the issue. It is pefectly possible that they are. The trial results can be given for the entire set of patients receiving a specific form of treatment and also broken down by risk groups. Whether they will be statistically signifciant when broken down by risk group is a different question.

    (2) I don’t think you can give the option of neoadjuvant or adjuvant ADT in this trial. The patient numbers aren’t large enough. If you were going to do this, you’d probably need to double the number of patients.

    (3) If this trial is going to work, the researchers are going to need to recruit all 1,036 patients within 24 months or less (which ought to be possible), so I am not too worried about the esoteric imaging methodologies which, to a large extent, are not widely available in Europe anyway.

    (4) My assumption is that appropriate low-risk patients who are good candidates for active surveillance would only be given the option of entering this trial if they had already turned active surveillance down.

    All large trials like this come with problems. I would hope, for example, that there is a standard explanation form being used for all the patients so that they are all given the same base information about their options once they agree to enter the trial. Data from the ProtecT trial has already demonstrated that recruitment to a trial like this is actually best done by nursing personnel working with a specific explanation process who have no personal interest in the type of treatment given to a specific patient … but only in making sure that the patients understand their options. I have to assume that the trial managers are already well aware of those data.

    Is this going to be a “perfect” trial? No. Of course it isn’t. My guess is that it will not be able to differentiate between the long-term survival benefits of the various treatments (which are probably small anyway). However, it may well be able to differentiate between quality of life issues over time. If I was Accuray, I would be betting that if it showed that SBRT was as effective as surgery in the surgical patients and as effective as IMRT in the radiation patients and it had better quality of life than surgery and similar quality of life to IMRT, then they would have hit a home run. But of course all trials like this are faced with the problem that what they prove may be outdated by the time it is proven. From Accuray’s point of view, that is probably the single biggest risk involved in this trial.

    Finally, all commercially supported trials come with risks for bias. However, the major academic centers involved in this trial ought, by now, to be pretty good at managing such risks. And the commercial companies have also become pretty good at avoiding them too. … The consequences of getting caught trying to influence trials like this are now far too large.

  3. Sitemaster:

    Thanks for your thoughtful and reassuring comments in response #2. It is helpful to get the benefit of your experience.

    I’m hoping that Accuray does hit that home run. But even if it does, some other radiation approaches might still be in contention for top honors. rachytherapy studies have posted some impressive success marks, particularly for low-risk patients. Combos of brachy and IMRT have looked excellent. Radiation with adjuvant ADT has looked effective. The proton folks will probably hang in there. All that said, the few sessions needed for SBRT will make it very attractive if Accuray does get that home run.

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