We have just learned that the randomized clinical trial of proton beam radiation therapy (PBRT) vs. IMRT for men with localized prostate cancer (the so-called PARTIQoL trial) now has 10 active centers recruiting patients and another two centers that expect to start enrolling patients soon. A total of 173 patients have been enrolled to date.
The “New” Prostate Cancer InfoLink considers this to be a very important prostate cancer trial because — hopefully — it will be able to finally resolve the question of the value of PBRT vs. IMRT in the treatment of localized prostate cancer.
For those who are interested, you can:
- Get details about the trial protocol from the ClinicalTrials.gov web site of you click here.
- Read more about the trial in the first issue of the PARTIQoL trial’s newsletter.
The newsletter also contains useful information about low-residue/low-fiber diets for those who are being treated with radiation therapy for prostate cancer.
We encourage any patient who is thinking about having radiation therapy as first-line treatment for his prostate cancer to explore whether he is a good candidate to enroll in this trial. It will help to answer one of the important, outstanding questions related to the treatment of localized prostate cancer.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: IMRT, PARTIQoL, PBRT, proton, trial |
THE "NEW" PROSTATE CANCER INFOLINK 
I hope this study will be objective and unbiased and not another study to support predetermined conclusions.
Dear John:
I believe that this study is indeed objective and unbiased. And from that perspective it is interesting that the center at Loma Linda chose not to participate in the trial.
Thanks and Concerns About This Trial
As always, thanks for bringing us news about important developments, including this trial.
Mention of the diet advice in the newsletter, which is excellent, may help some radiation patients avoid the brief trouble I had. I was including too much fiber in my diet, and in the third week of IMRT treatment there was uncomfortable bloating. The radiation nurse helped me adjust my diet, and all was fine after that.
Having read the two links, here are six concerns/questions related to the trial description on clinicaltrials.gov. Perhaps this is just an issue of faulty transfer of information from the trialists to the web site, as sometimes happens. (Software sometimes did weird things to technical requirement statements when I was in Navy procurement. We caught errors when reviewing final documents prior to release even after producing perfect final drafts prior to electronic broadcasting.)
(1) The trial description lists the following eligibility criterion: “Gleason score ≤6 if PSA <20 or Gleason score 3 + 4 = 7 or 4 + 3 = 7 if PSA <20". I'm curious whether they really mean that, as, if so, it could be rewritten as: "Gleason score ≤7 and PSA <20." I'm thinking they might have meant to allow a higher Gleason of 7 if the PSA were lower, say 10, but that is not what the criterion states.
(2) It appears the trial is aiming at low- through high-risk patients as the criteria allow for patients at higher risk with a PSA of 10 to 19 and Gleason score of up to 4 + 3 = 7, a combination that would make them high risk. Yet the study says it is aimed at low- and intermediate-risk patients, not mentioning those at high-risk.
(3) Which brings us to the next issue. The exclusion criteria rule out androgen deprivation therapy (ADT), which is well accepted for intermediate- and high-risk patients because of known improvement in effectiveness (short-course ADT for intermediate risk and long-course ADT for high risk); here is the exclusion criterion: "Prior or planned androgen deprivation or bilateral orchiectomy." Neither of the study arms includes ADT. I am really puzzled as there are highly respected doctors and institutions involved in this trial, yet this basic advantageous tactic for intermediate- and high-risk patients is not included. (Moreover, pelvic radiation, which might be appropriate for the high-risk patients, is not addressed.) Perhaps there is something I am missing. At this point, because of this seeming important deficiency, I am not able, as a patient advocate/navigator, to recommend this trial to anyone who has been diagnosed with intermediate- or high-risk disease, but I hope this concern can be satisfactorily resolved.
(4) The third concern is that there is no statement that randomized patients will be stratified to each arm by risk level. It is very clear that risk level influences the rate of non-recurrence, which is an endpoint, along with the quality of life endpoints (as dose levels may be generally somewhat higher if risk is higher, and dose levels affect the kinds of endpoints being used in this study). Even though 400 patients may be enough to even out risk-level effects, I'm curious whether they have done a statistical analysis that supports the absence of stratification. Also, while about 120 patients have now been enrolled, there may be substantial under enrollment, as often happens, and stratification would likely bolster confidence in results if that occurred. At this point, I would prefer to see stratification of assignment to arms by risk so that endpoints are not confounded by differing risk levels.
(5) A parallel point is that there is no statement of dose levels, though the weeks of treatment are described as 8 to 9 weeks for both arms. That does allow considerable dose variation, even if delivery is 2 Gy per session, and variation in dosing might confound both effectiveness and quality of life results.
(6) The last concern is that the planned follow-up period for measuring the effectiveness (non-recurrence) endpoint is only 2 years (“Efficacy of PBT vs. IMRT [Time Frame: 2 years] [Designated as safety issue: No])”. Unless I have missed a research development about radiation, 2 years is too short a time frame to get a good handle on non-recurrence rates; 5 years seems to be a much more accepted time-frame.
Puzzled.
An additional concern came to mind: whether imaging during treatment will somehow be equalized.
My perspective after listening to the very influential Dr. Zietman talk in St. Louis — almost 10 years ago — is that he had irrevocably made up his mind. In any case, too little too late. SBRT will probably overtake both technologies if longer-term results are positive.
How many of these places are using “pencil beam” proton therapy?
Mark:
Sorry. I don’t know the answer to that question. You’d need to look at the web sites of each of the centers participating in the trial. Or contact the trial coordinators, who could probably tell you.
John:
Since MSKCC now has a proton beam radiation therapy unit, I don’t think Dr. Zeitman can have made up his mind “irrevocably”. On the other hand, I do think he is still skeptical about any great benefit from PBRT over modern IMRT (or SBRT either) in the treatment of localized prostate cancer. The other thing to bear in mind is that there is no good reason why PBRT could not be used in a highly hypofractionated manner that would equate to SBPT. It is even possible that one or two of the PBRT centers is experimenting with this. However, using PBRT in that manner would certainly affect the revenue models for PBRT centers in a less favorable manner.
Dear Jim:
I would advise you to be very cautious about over-analysis of detail in what is little more that a brief summary of the trial protocol. Without being able to read the entire trial protocol, it is impossible to know exactly what it states. However, I would make the following comments with respect to your comments:
Your comments no. (1) and no. (2): I suspect that the specificity was deliberate in order to emphasize the inclusion of patients who met Gleason score criteria of 3 + 3 = 6, 3 + 4 = 7 and 4 + 3 = 7 as well as the PSA levels. It is actually open to interpretation whether a man with a Gleason score of 4 + 3 = 7 and a PSA level as high as 19 is high risk or not. Many would still consider him to be unfavorable intermediate risk unless his PSA was also > 20 ng/ml.
Your comment no. (3): I suspect that the exclusion of ADT was very deliberate since the use of ADT among some or all patients in either or both arms would probably have “swamped” any differences in the relative effectiveness and the safety of the two different types of radiation therapy over the initial 2-year follow-up period.
Your comment no. (4): As indicated above, just because it doesn’t state explicitly there is stratification in this trial also doesn’t mean that there isn’t. You’d need to read the trial protocol (or you could contact the trial managers directly).
Your comment no. (5): It would be customary in a trial like this to give a maximum and minimum range for the dose level, to leave the actual dose delivered to the discretion of the different centers, and then to exclude from analysis patients who were treated at dose levels that fell outside the prespecified dose range. You also need to appreciate that there are differences between the precise way in which these centers deliver PBRT; for example, as already suggested by another commentator, some will be using pencil beam delivery but others may not — such differences in delivery would impact the actual dose considered to be necessary. Again, I expect that there would be a lot of detail on this topic in the full protocol.
Your comment no. (6): The initial 2-year follow-up period is the primary endpoint. The whole issue being addressed by this trial is really around whether PBRT is safer than IMRT. Few people would argue that it is likely to be meaningfully more effective. It should be possible to answer the safety question within 2 years without any real difficulty. Thus, if the two forms of radiation have similar efficacy at 2 years (which they almost certainly will), then the justification for widespread use of PBRT as opposed to IMRT in patients of this type would be a statistically significant difference in GI and GU side effects over that 2-year follow-up period (if there actually is one).
Thanks Sitemaster for Your Response to My Comment
One takeaway I have is that the clinical trial protocol as expressed at clinicaltrials.gov is likely much less detailed in key areas than what is in the full protocol. In this case in particular, that is reassuring. I am also assured by some of your other comments, with one main concern remaining and now an added concern.
The remaining concern relates to your reply: “Your comment no. (3): I suspect that the exclusion of ADT was very deliberate since the use of ADT among some or all patients in either or both arms would probably have “swamped” any differences in the relative effectiveness and the safety of the two different types of radiation therapy over the initial 2-year follow-up period.” That makes sense, but it strikes me as an unacceptable excuse for persuading lightly informed patients to accept substandard care. I’m assuming we agree that the care – without ADT for intermediate (or higher) risk patients – is substandard. On the one hand I have trouble believing that expert, caring radiation oncologists would do that, but on the other I have seen too many instances where “getting the scientific data” trumps the welfare of the patients, and I’m concerned that this trial may be one of those cases. You did not comment on that aspect, and I would be most interested in your view.
My added concern, I’ll call it (7), was mentioned by John in his comment of September 8, 2016 at 5:28 pm: the powerful emergence of SBRT is already pushing the kind of radiation in this trial, which extends over 8 or 9 weeks (the kind I got), into obsolescence.
Dear Jim:
I have no idea when the protocol for the PARTIQoL trial was initially “finalized”, but what I do know is that it was several years ago now (at least three and probably more like five). It took a long time to get this trial off the ground. At that point in time, the use of a short course of ADT prior to radiation therapy was not standard or widespread. I think we have to accept that this trial is not “perfect” and never had a chance to be perfect. Few trials like this do. That doesn’t make it a “bad” trial. It is simply the victim of circumstance and inertia.
One of the problems with all trials related to the treatment of early-stage prostate cancer is that they can take years to initiate and carry out. In the case of the PARTIQoL trial, we have the added problem that this was a trial that should have been initiated at Loma Linda in about 1996 as opposed to by people at Boston and Philadelphia in more like 2010. And with respect to SBRT, that’s just another “fact of life” related to all this.
Thanks very much!
Ah, another thought – the ethics issue.
How do trialists properly handle the ethical aspect in a trial situation where there is respected research data indicating that a different treatment approach (here, adding short-term ADT for intermediate risk patients) is likely superior to the study protocol (no ADT allowed)? A number of trials have indicated such superiority, such as the trial reported by Jones and colleagues in a 2011 issue of the NEJM.
Jim:
That would depend on the trial being done and the degree of compellingness of the “new” data. As I said before, in this case there is a high chance that allowing patients to have ADT would eliminate any chance of demonstrating a benefit for either form of radiation therapy (in terms of either efficacy or safety). Sometimes one can just alter the trial protocol, but I don’t think that would be possible in this case. I am not a medical ethicist, and in the past I have noticed that I found some decisions made by at least some medical ethicists to be open to considerable debate.
Looking Into Ethical Aspects
I am now trying to pursue the ethical aspect with the office one of the two principal investigators, Dr. Jason A. Efstathiou, MD, PhD, of Massachusetts General Hospital. I hope there is a good answer, as a lot of us would like to see this trial’s results after being carried out with proper concern for the well-being of patients. That concern must be paramount, and we advocates must accept no less!
I am especially sensitive to the patient welfare aspect based on my experience with research involving castrate resistant prostate cancer, and the remainder of this comment relates to that. I have found it most discouraging that many researchers in this area (CRPC) use an operational definition of castrate resistance as a testosterone level of < 50 with a rising PSA. (By "many" I mean "typical," based on reviewing studies/proposals and contact with numerous doctors/researchers on DoD CDMRP Prostate Cancer Research Program proposal review panels and specifically raising this issue, with discouraging responses!)
The doctors I have followed for many years as experts in ADT consider that level of 50 for testosterone for determining CRPC to be far too high, being convinced that the patient has not truly been determined to be castrate resistant unless testosterone is about 20 or lower with a rising PSA. If a patient has testosterone in the range 20 to 50, these doctors will first ensure that the ADT is being properly delivered and that the dosing interval is appropriate to the patient, shortening it if necessary for patients who clear the dose unusually rapidly. They will also increase the dose of the antiandrogen if needed, all in the context of monitoring DHT as well, and making sure that DHT too is adequately suppressed.
I am convinced that many patients dubbed castrate resistant simply have experienced inadequate ADT treatment, and I suspect that inadequacy is the standard of care for ADT, with a first and apparently common indication being failure by the doctor to monitor testosterone and DHT. Of course, dipping into a cynical view for the moment, it sure makes it easier to recruit patients for CRPC studies if that higher threshold of 50 for testosterone is used in the context of neglecting to use tactics to ensure adequate androgen suppression, but I would bet a large sum that many such patients are unwittingly losing their chances for years more of successful ADT.
The further we can get from the Tuskegee study approach and researcher culture, the better!
Just one more concern — adequately informed consent re active surveillance
While this trial was launched several years ago (first registry in clinicaltrials.gov on June 8, 2012), by that time there was convincing research that active surveillance was at least an equal and arguably a superior approach for men with low-risk prostate cancer.
I am interested in how the active surveillance option is being presented to men with low-risk disease considering enrollment in this trial. (I can understand not addressing the AS option for men with intermediate-risk disease who are considering enrollment, as the favorable research about AS for such patients with “favorable intermediate-risk disease”, while encouraging, is not yet compelling.)
Dear Jim:
(1) I suspect that by the time anyone gets referred to a center as a candidate for the PARTIQoL trial, they are already likely to have turned down active surveillance as a management option (whether that is a good idea or not).
(2) I think there are better places to focus your views on the definition of CRPC than on the investigators in the PARTIQoL trial. They are only interested in men with low- and intermediate-risk prostate cancer who have already determined that they want to have PBRT or IMRT. The rules for the definition of castration-resistance today are set by the Prostate Cancer Working Group and by the National Comprehensive Cancer Network. Unless you can change their minds, no one else is going to pay you much attention — however compelling your belief system and your story.
(3) A wise advocates picks battles to focus on that he thinks he might have a shot at winning — and then goes about implementing a strategy targeted at the people whose minds have to be changed. In the case of your last two comments, you are picking the wrong target audience for your frustration. I have already informed you about why.
I understand your well-taken point about wise advocacy.
That discussion about CRPC was not intended to relate to the PARTIQoL trialists but rather to convey the background of my concern for high ethical standards in clinical trials. I’m afraid the length of my explanation overrode the point I was trying to make, and I’ll plead guilty as charged to that.
NCCN Guidelines for Intermediate Risk Prostate Cancer and Radiation
I just checked the Guidelines and found that the NCCN is presenting a 4 to 6 month course of ADT in support of radiation as optional for intermediate-risk prostate cancer patients. I thought the research was more definitive than that, and the NCCN position gives the trialists a green light for omitting ADT. (I’m curious what the ASCO and ASTRO guidelines say — haven’t checked yet.)
However, based on the text in the patient guidelines, it seems to me the trialists should be advising prospective trial enrollees that “Research has shown that ADT can extend life” (from the NCCN patient guidelines as of today) and give them the option to forego the trial based on that information, with follow-up detail if the patient asks.
Jim:
I think that most of the men who are deciding not to enroll in the PARTIQoL trial have: (a) decided that active surveillance is not for them; (b) decided that they want to have PBRT because it is “safer” (even though there are absolutely no data to support that perception); (c) may have already decided that they want to have ADT anyway.
There is a reverse ethical problem that you seem to be ignoring, which is how much data should the PARTIQoL trialists be required to give to a patient when those data are not 100% certain but which may have a high likelihood of discouraging patients from participating in an important trial to which we really need an answer?
Conversation with Mass General on PARTIQoL Trial is Reassuring Regarding Informed Consent
This is a follow-up to previous discussion here whether patients participating in this trial were informed as part of the consent process about active surveillance and ADT in support of radiation.
I talked to a nurse practitioner involved in the trial this morning, and she assured me that men in this trial had and were being informed about active surveillance and ADT (for intermediate risk) but were electing treatment instead of active surveillance and, if classed as intermediate-risk patients, were choosing to forego ADT. At least at Mass General, patients later offered the trial were first counseled by a multidisciplinary team of doctors regarding their situation and options.
She also indicated that the intermediate-risk patients in the trial mainly had milder forms of intermediate-risk cases.
Although the trial has an endpoint for effectiveness against cancer, she added that the main objectives involved quality of life.
I was reassured by this. It is another instance where the information at clinicaltrials.gov, while excellent for fundamental facts about a trial, does not capture key information about the trial protocol.
Personally, while I would suggest to anyone interested in participating in this trial that they give active surveillance a serious look (if they had a low-risk case) and get a thorough understanding of a short course of ADT (for intermediate-risk patients), I feel I can now fully support this trial.
Dilemma Posed by Sitemaster Regarding Potential Discouragement of Trial Participation
Sitemaster posed this issue: “There is a reverse ethical problem that you seem to be ignoring, which is how much data should the PARTIQoL trialists be required to give to a patient when those data are not 100% certain but which may have a high likelihood of discouraging patients from participating in an important trial to which we really need an answer?”
I recognize that problem, but I come down firmly on the side of giving the patient informed consent. In the early days of a then life-threatening case back in early 2000, I recall at least two attempts to recruit me to clinical trials that would have required me to forego the robust ADT that gave me years for technology to improve and allow me to go for a cure in 2013. The early information I received about the ADT option was poor; that said, while much better information existed, it was not well distributed in the urology and oncology communities. While I did not opt for the trials, I did consider them; I’m certain I would have rejected them immediately if made aware at the time of the potential of well-done ADT for my situation. I believe that participating in a trial in 2000 would have enabled me to be a proud but long-dead data point.
How I wish that data were closer to 100% certainty when I have to choose a medical approach that has known side effects! I faced that when choosing ADT to remain on ADT in the early months after becoming aware of the “Lupron victims” website. I faced that again when choosing to add Proscar to Lupron and Casodex, at a time when Dr. Eric Small was making a reasonable argument that Proscar might lead to more rapid failure of ADT, a view that has been disproved, at least to some of us. (In 2016 I suspect there is a strong consensus.) Choosing low-dose thalidomide (with vitamin B6) was a riskier call, but I made the decision (and have some very mild side effects after three courses involving a little more than 2 years of the drug).
I take the position that patients have a right to know the key facts and make their own decisions; if they are discouraged from trial participation, thereby preventing certain valuable research, we need to accept that. If science comes to be perceived by patients as trumping patients’ right to be informed about strategies with likely better outcomes, is that perception not also going to discourage patients from participating in trials?
Being informed as a prospective trial participant should involve risks that are put in proper perspective, so that we patients can do our own risk/benefit calculation. Using just one side effect of a short course of ADT as an example related to the PARTIQoL trial, we need to know more than that a decrease in libido and potency is a likely side effect, we need to know that it is extremely likely that these side effects are reversible within months after a short course of ADT. On the other hand, we also need to learn from the trialists why our participation will be important in advancing knowledge. For some of us, that may outweigh all risks, but it should be our decision.
Thanks for raising this issue.