Radiation Therapy for Prostate Cancer: Where Are We and Where Are We Going?

Radiation Therapy for Prostate Cancer: Where Are We and Where Are We Going?

I was asked to speak about radiation therapy, which specifically we’re going to be talking about external beam radiotherapy. My charge is to speak about where we are right now and where we’re going.

Clearly, technological enhancements have revolutionized the way external beam radiotherapy is now delivered throughout the world. The movement from conformal radiotherapy, 3D radiotherapy to IMRT to image-guided radiotherapy has without a question had a major impact on the way radiation therapy, external beam radiotherapy, is delivered throughout the world.

We now as a result of these highly conformal approaches can deliver higher radiation doses, which really has a great impact on intermediate and high risk disease in particular, and the use of IGRT or image-guided radiation with the placement of fiducial markers, which could be done with gold seeds or with Calypso, which are ferromagnetic markers, which allow us to monitor the motion of the prostate not only as the patient gets on the table, but actually during the 5-6 minute course of treatment to make the appropriate adjustments; again, to keep the accuracy to within a millimeter.

As a result with these markers in, we’re able to indicate where the movement is going on within the prostate, the target. If there is any movement beyond the threshold of let’s say 2 mm the beam stops and then the adjustment is made to again once enhance the accuracy.

We have seen that with the application of image-guided radiation there’s been a significant reduction in toxicity, again, associated with enhanced accuracy, less volume of the normal tissues exposed to the high radiation doses leading to a significant reduction, in particular shown here in urinary toxicity. We’ve even to our surprise have seen that in the high risk group an improvement in biochemical recurrence in this paper as well possibly associated with enhanced accuracy, better coverage of the target we’re aiming at, delivering the necessary radiation dose.

There’s been a tremendous hype about hypofractionated radiation or what’s known as stereotactic body radiosurgery. You see on all the billboards Cyberknife, which is excellent marketing. The question is: is it hype or is it something that we should be giving much more attention to? There’s no question and I’m sure your patients have asked you about this. The popularity of stereotactic body radiosurgery for prostate cancer is there. It certainly has reduced the burden of treatment on the patient. Conventional ways of delivering external radiotherapy almost amount to 50 treatments delivered in a period of 10 weeks. Now we can deliver these treatments in five sessions over a period of a week to a week and a half.

We also know that the accuracy of targeting the prostate has been enhanced, as I mentioned, with the availability of image-guided radiotherapy. As a result of the enhanced accuracy, we can deliver our target radiation with tighter margins, which translate as I mentioned, into reduced volume of normal tissues included into the high-dose region. Not only is it more convenient, not only is it more accurate, but potentially the higher radiation doses delivered in a shorter period of time can achieve a higher biologic equivalent dose, which may result as we’ve seen in the brachytherapy literature correlated with potentially increased tumor control among the patients we treat.

Here is a color-washed dose distribution of the highly conformal dose delivery for this stereotactic radiosurgery where the concentrated doses are here with greater sparing even of the normal tissue, such as the rectum and the bladder.

If you look at the published literature with body radiosurgery, it’s still relatively not that mature as we know for external beam radiotherapy. We see that for ultra-hypofractionated or what we would call SBRT, stereotactic body radiosurgery, in general the followup is about 4-5 years. The PSA control rates we have to therefore interpret with a grain of salt, but it’s about 90%. Again, these are patients who are treated with five fractions where the doses are about 7 to 7.25 grade times 5. We’ve actually completed a dose escalation study where we move from 6.5 grade times 5 all the way to 8 grade times 5 with our endpoint of 2-year biopsy outcome. That data is still maturing.

Also what is encouraging as well and probably related to the fact that this is so conformal and so tight in its dose delivery is that the long-term toxicity at least at 4-5 years encouraging that we’re not seeing any significant GU grade 3 or even grade 2 toxicity that is beyond what we would have seen with conventional external beam radiotherapy. Unfortunately, this needs to be studied carefully and ongoing studies will better look at what the role is of Cyberknife or stereotactic body radiosurgery.

In this PACE study, a multicenter international randomized control study, there’s a comparison of laparoscopic or robotic surgery versus stereotactic body radiosurgery for low and intermediate risk patients. In the Swedish study, a randomization for intermediate and high risk patients with conventional fractionation and SBRT as well. I think some of these studies will give us and provide us with important information about what I believe is going to emerge as a very important tool that would likely replace external beam radiotherapy not simply because of its convenience, but potentially because of the fact that this may be associated with actually greater tumor control, greater cell kill.

A lot of hype about proton radiotherapy and protons I’m sure your patients ask you what you would say about that. Certainly protons have been around for a long time. At MGH they’ve used this back in the 70s and 80s. There’s certainly a long history of proton radiotherapy, but it’s emerging and becoming more popular. It’s basically because of the biologic advantage of this Bragg Peak associated with the proton beam which delivers less radiation or exit radiation beyond the target.

The resurgence of interest in proton radiotherapy, really we have to scrutinize that as well. The question comes up: is it really worth the expense of building the unit, which is about 100 million when all is said and done, and the cost of the actual treatment as well? Does this Bragg Peak effect translate into a biologic advantage which would lead directly to improved outcomes? We really don’t know that yet. Of course these color wash dose distributions, generally the beams come in from the laterals, indicating that there is less exposure of the radiation beam to other areas, perhaps except for the anterior rectal wall. Again, you can see here the reduced dose distributions overall.

Interestingly, I just took two of the latest publications on protons and this one publication which was a retrospective comparison of patients treated with protons versus IMRT interestingly with a followup in four years overall in this group. No differences noted in acute or late toxicity.

Another publication from the University of Florida in a cohort of about 1,300 patients showed what I would consider somewhat worrisome rectal bleeding rates with relatively short followup. Grade 1 rectal bleeding 17%, grade 2 rectal bleeding another 15%. Typical IMRT rectal bleeding from our experience in our institution is about 3% to 4%.

More importantly, what’s still unknown about protons is will protons reduce the secondary cancer risk, which possibly is the real impetus for using protons, again, because of the reduced exposure that’s going on to the normal tissues. We don’t yet see that, but of course we need longer followup.

Will tumor control outcomes be improved? We have yet to see that. I think it’s very promising. There are randomized trials comparing conventional fractionation or IMRT to protons. Actually, an interesting phase III trial comparing within protons conventional fractionation to the hypofractionated or stereotactic radiosurgery using protons. I think this will end up being an interesting study. I would’ve used it in the intermediate risk. I’m not sure how important it is of course in the low risk patients. As we’ve talked about before, that may not require any therapy.

Then I’d like to talk about really two other issues, which are vexing issues and I think we need future studies, the role of hormonal therapy in conjunction with external beam radiotherapy. We certainly know the established randomized trials in the high risk group. It’s really the intermediate risk that is very important. I would say standard of care in the radiation oncology community, that for intermediate risk disease the use of short course, androgen deprivation therapy with treatment is the routine.

It’s based on these two randomized trials where the patients got radiation therapy alone compared to radiation therapy and short-course hormonal therapy. In both of these studies, survival benefits were demonstrated. One caveat. These two trials utilize patients with low dose radiation of 70 gray, which we would consider nowadays antiquated.

The real question comes up. What about if you use tumoricidal doses, the appropriate radiation dose levels? Would then short course hormonal therapy be necessary? That’s not well known. In fact, hopefully this study, the RTOG 0815, will try to answer this question for intermediate risk receiving dose escalated radiation with a randomization to short course hormonal therapy or high dose escalated radiation alone.

In high risk disease, while we know we need to deliver of course androgen deprivation therapy and in studies like the Bola [phonetic] studies which have demonstrated long-term hormonal therapies necessary. The question of course also is what about in the setting of our dose escalation era? Do we need those kinds of long courses of hormonal therapy which we all know impair patients’ quality of life?

In this interesting systematic review of ADT and radiotherapy for high-risk disease, we see something very interesting. This pans out really from all the studies you get this impression. Shorter courses of treatment of ADT with radiation achieves overall in this literature review a 21% reduction in the risk of mortality, but longer treatment durations provided benefits of even greater magnitude.

I would say the general impression in the urologic community, the radiation oncology community, would be that for high risk patients we need close to 2-3 years of hormonal therapy with even dose-escalated radiotherapy, although the trials were not testing dose-escalated radiotherapy.

I believe that the real improvements will come with better targeted agents, better systemic therapies as well. We see now the emerging studies which are coming out and being done for high risk patients incorporating second-generation anti-androgens with radiotherapy. The RTOG 0015 or known as the TAK 700 looking at standard hormonal therapy with radiation versus LHRH and TAK 700 for two years. The ENZARAD study from the MGH, same thing. LHRH plus RT versus enzalutamide plus LHRH and RT. A Duke study is looking at abiraterone and LHRH and RT versus standard LHRH and RT. We are about to conduct a study, but it’s a single-arm, phase II study combining abiraterone, ARN-509 and the LHRH, which we like to all androgen annihilation.

In addition, with SBRT–and I think this is going to be really the trends in the future to shorten the course of treatment and actually in these studies only using hormonal therapy for a period of six months and not two years.

Here are my personal perspectives on where EBRT is going in the next five years and perhaps longer. Image-guided radiotherapy we recognize as further revolutionizing the treatment delivery, improving accuracy, and reducing toxicity. While we don’t have randomized trials showing this, clearly the use of these enhanced conformal technologies is what has become a standard tool in the radiation oncologist armamentarium.

Short course SBRT I believe–and it’s just the prediction; we don’t have the randomized trials yet–I would say not so far off this would likely replace in the future conventionally fractionated regimens in the treatment of prostate cancer.

The role of protons will need to be better defined with prospective studies, which are ongoing fortunately, but right now it’s just unclear what the outcome benefit is if there’s a real benefit or not. Even in terms of toxicity I’m just not sure.
The role of short course hormones for intermediate risk disease in the dose escalation era is uncertain, but that’s what we’re doing now and I’d say the standard of care. We’ll be addressing the RTOG study.

Finally, I think the future will lie of course with better biomarkers, gene sequencing to be able to tailor the appropriate therapies with or without hormones or with better targeted agents for improved outcomes in the future.

D’Amico AV, Chen MH, Renshaw AA, et al. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008 Jan 23;299(3):289-95.
http://www.ncbi.nlm.nih.gov/pubmed/18212313

Fang P, Mick R, Deville C, et al. A case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer. Cancer. 2015 Apr 1;121(7):1118-27.
http://www.ncbi.nlm.nih.gov/pubmed/25423899

Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18.
http://www.ncbi.nlm.nih.gov/pubmed/21751904

Zelefsky MJ, Kollmeier M, Cox B, et al. Improved clinical outcomes with high-dose image guided radiotherapy compared with non-IGRT for the treatment of clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):125-9.
http://www.ncbi.nlm.nih.gov/pubmed/22330997