Radiosurgery for Prostate Cancer with the CyberKnife®

Radiosurgery for Prostate Cancer with the CyberKnife®

So I’m an Accuray clinical consultant. The standard treatment option for prostate cancer is intensity modulated radiation therapy, and it’s basically commonly five radiation dose fields to the prostate. You get a high dose to the prostate. Unfortunately, you get a moderate dose to the rectum. The advantages are relative rectal sparing, normal tissue sparing with fractionation—42 fractions over nine weeks, but this number increases every time I look at it. I think we’re up to 45 fractions over nine weeks and it’s non-invasive. So eight to nine weeks of daily treatment. Who wants to go for eight to nine weeks of daily treatment when they could be out doing other things. Acute toxicity—we all know urinary frequency, bowel frequency, and we also know about late toxicity. Rectal bleeding is annoying. Impotence is annoying.

Unfortunately, this is a little dirty secret that radiation oncologists keep. There are PSA failures following conventional radiation. It’s actually common. If you look at low risk patients, they’re relatively low, but for intermediate and high risk patients we have a lot of PSA failures. So how can we improve on that? So first of all, our radiation dose is inadequate when we give IMRT. When we do post-treatment biopsies two years after the radiation we see that 30 to 40% of them are positive. This is due to the fact that the dose is limited by surrounding structures such as the rectum and the bladder. Hopefully I can convince you today that the CyberKnife can allow for safer dose escalation.

Also, your prostate moves. You guys woke up probably about an hour ago. You had some coffee. All the men in your room your prostate is probably moving right now. So when we use standard radiation techniques we commonly miss the prostate. One of the biggest advantages actually of brachytherapy is that we’re probably not missing. Also, we know that for people with high risk prostate cancer they probably have meds before we start and our imaging isn’t good enough to see them.

So prostate motion—it’s due to bladder filling and rectal filling. Your prostate can move up and down, sideways, and it can actually even rotate. If you don’t take that into account, you can actually miss the target. So what happens if you don’t take motion into account? You actually are not doing what you think you’re doing. Most radiation oncologists think they’re doing this but they’re actually commonly doing this where they’re missing part of the prostate and over-treating the rectum.

So one of the few things that we’ve learned in radiation oncology over the last 2 years is that if you give higher dose of radiation you have a higher chance of curing somebody. This is the MD Anderson trial. If you give 78 gray versus 70 gray you have a higher chance of decreasing a PSA failure. But when you do conventional radiation techniques this was at the cost of having increased rectal complications.

So there’s this thing called the alpha/beta ratio where it’s an estimate of relative fraction size sensitivity, high dose reactions relative to low dose fractions. It’s one solution to the inadequate radiation dose is to take advantage of this unique radiobiology that prostate cancer is more sensitive to large radiation fraction sizes than small radiation fraction sizes. So low alpha/beta tumors are very sensitive to fraction size like prostate cancer or large fraction sizes work better. In a high alpha/beta ratio something like lung cancer says that high fraction sizes don’t work better. We used to think that the alpha/beta for prostate cancer was six to ten, but data about five years ago showed that it’s actually closer to 1.5. These highly fractionated regimens that we’ve been using for years are probably flawed.

So who do hypofractionation? Well, it might actually make us cure more patients, but more importantly if outcomes are similar you have improved patient convenience, five treatments versus 45 treatments. You have increased patient access. Not everybody lives near a radiation center. They might be able to move to one for five days, but they’re not going to be able to move for nine weeks. Healthcare cost savings—if you do fewer fractions in the long run it’s going to be cheaper than doing more fractions.

Okay, so there is experience with limited hypofractionation. Instead of 1.8 gray fractions if you give it in 2.5 or 3.5 gray fractions you could actually give the radiation safely. There have been large trials with a number of patients and they get acceptable PSA outcomes with low rates of grade III GI and GU toxicity. Actually, we’ve actually had experience with extreme hypofractionation with HDR brachytherapy. These are some of the most experienced centers. They use seven gray times six fractions or 9.5 gray times four fractions. They have adequate follow-up and high control rates with low toxicity. So doing large fraction size radiation actually can be done in a safe manner. The disadvantage is that it requires anesthesia. It requires being in the dorsal lithotomy position for extended periods of time, and not everyone is an ideal candidate. Is there a way that we can give the same treatment with HDR in a more patient friendly way?

An alternative solution to prostate motion is actually to use intraprostatic fiducials which can be used as surrogates for the prostate gland. This limits our treatment margins around the prostate, which allows us to give the radiation more quickly. You know, your prostate actually moves during a course of radiation. It’s usually a slow drift—up, down, left, right, inferior, superior. Maybe that isn’t such a big deal, but unfortunately 20 to 30% of these patients you set them up, you start the treatment, and then they have these big motions and you’re probably missing half the time.

So what is the CyberKnife? The CyberKnife is a linear accelerator or a radiation generator that’s on a robotic arm. By the way, it looks a lot prettier now. This is our CyberKnife from 12 years ago. We’re one of the most experienced CyberKnife centers in the world. We’ve had them at Georgetown since 2001. Also, a kilovolt detector, which localizes the prostate with gold markers. We use hundreds of independent beams, so we can spare normal tissues by using hundreds of beams to treat the prostate. What we do is actually as we’re treating we do real-time tracking of the prostate and we update the position of the beam every time we image. So during our standard treatment which takes about 35 minutes to do we might image 40 or 50 times and actually adjust our radiation beam to make sure that we’re on target. That’s probably not that important when you have slow drifts, but when you have these big excursions that are unpredictable it’s probably really important to do this imaging every minute or so.

So what is IMRT compared to CyberKnife? So IMRT is an expanded treatment volume with more radiation to normal structures like the bladder and the rectum. This limits the total dose of radiation you can give, and it limits the daily dose of radiation you give. The CyberKnife you can treat with smaller treatment margins. This requires continuous tracking to do but allows for a higher total dose of radiation and larger radiation fraction sizes.

So why do we do fractionation with radiation? We do fractionation because it allows opportunity for normal tissue repair. We had a great lecture yesterday about, you know, how some patients might be more sensitive to radiation. The CyberKnife system allows for reduced treatment margins. These reduced treatment margins allow for safer delivery of few fractions or hypofractionation, and it’s five fractions over one to two weeks, which might be radiobiologically superior than the fractionated approach. A standard IMRT is a 74 gray treatment. Now I think we’re up to 79 gray treatment. The CyberKnife is 7.25 gray times five fractions. This is 36.25 gray, which sounds really low, but if you think the alpha/beta ratio for prostate cancer is 1.5 then the equivalent tumor dose is about 90 gray and the equivalent dose acute toxicity of an alpha/beta ratio of ten is 52 gray. The equivalent dose for late toxicity would be similar to the IMRT arm of 74 gray. If you believe that the biological equivalent dose for the CyberKnife is 90 gray, we can move this biochemical disease-free control survival curve from here to over here. That’s hoping that we can prove that with time.

So the first guy who did this treatment was Christopher King at Stanford University. This data came out in roughly 2009, and he was the first guy to show proof of principle that you could actually treat people with these large fractions of radiation with the CyberKnife. He had high biochemical disease-free control. His acute toxicity was similar to IMRT, and he had a very acceptable rate of grade III complications. So since him after he did it some of us other guys said well if Christopher King can do it we can do it too. We got similar results with high rates of biochemical disease-free control with low rates of grade III toxicity. So it’s clear that the CyberKnife for prostate cancer is a safe treatment.

We did a multi-institutional trial. We collaborated. We used 7.5 gray times five fractions. We had a long medium follow-up. Our PSA nadir is great, 0.2. By the way, Tom Cole, one of the best radiation residents we ever had, has a poster outside about PSAs. He’d love to talk to you more about how the PSAs drop after the CyberKnife treatment. We also saw similar rates of acute toxicity with IMRT and acceptable late grade III toxicity.

So Patrick Kupelian at UCLA with Christopher King decided to put together a prostate SBRT registry. They got 1100 patients. We contributed to this study with UCLA, Harvard, and a bunch of other people. We used about 35 to 40 gray of radiation in four to five fractions. The medium follow-up was three years. We presented this at our major society meeting. We’ve now published the PSA data in radiotherapy and oncology, and we’ve published the quality of life data into International Journal of Radiation Oncology Biology Physics.

Joy Kim has a poster outside talking about our quality of life outcomes if you want to see how we’re doing at Georgetown, but basically this consortium showed that the biochemical disease-free survival at five years for low risk prostate cancer is very good with the CyberKnife. It’s very good with intermediate risk disease. It’s also pretty good with high risk disease. I think anybody would argue that an 81% five year biochemical disease-free survival is pretty good for high risk disease. We didn’t see any benefit from using hormonal therapy. I’m not sure if this is a selection bias issue, but people have previously shown with HDR brachytherapy that hormonal therapy did not add a lot of benefit because you’re doing ablative treatment. We also didn’t really see a strong dose response, so we think that 36.25 in five fractions is going to be the standard treatment for treating with the CyberKnife in the future.

Our PSA responses were beautiful. The PSA drops quickly at one year to one and then drops to about 0.5 at two years and about 0.3 at three years. Tom Cole in his poster talks about there are two slopes we see in the PSA, the rapid cancer dying slope and then the slower prostate dying slope. We think the SBRT for prostate cancer with the CyberKnife is an ablative technology, and we think that this PSA is going to continue to drop with longer years of follow-up. So can you use SBRT for intermediate and high risk patients? Most of the early data with SBRT was for low risk patients, but if you look at the dose of the CyberKnife treatment around the prostate it gives adequate margins in most places. The only place that it’s tight is right by the rectum. There is a fascia here that prevents spread of the cancer, so we think that this is an adequate treatment for intermediate and maybe even for high risk patients in the future.

Quality of life is really important when it comes to radiation. We take it really seriously at Georgetown. We make patients fill out Epic questionnaires, which have about 26 questions in them about urinary, bowel, and sexual function. What we find is that like other radiation treatments there is an early decline in urinary function, but it comes back to baseline in three months. Actually at three years after treatment it looks pretty good. So we’re pretty happy with our urinary function. Our bowel function is great. We do a really good job of sparing the rectum. There is this little dip, but we’re back to close to baseline at three years. So I think SBRT or CyberKnife for prostate cancer is a very good rectal sparing radiation approach.

Our patients are 70 years old, mean age of 70 years old. Their baseline sexual function is pretty poor, and it stays pretty poor with follow-up. Maybe in the future if we treat younger patients we’ll have a better idea of the impact of SBRT on young men’s sexual function. You know, this isn’t one of those treatment techniques that is—you know, if you have really bad obstruction symptoms you can’t do it. What actually Christopher King showed in his recent paper is that actually men with poor urinary function actually do better at three years after treatment. Having bad urinary function at baseline is not a contraindication to getting this treatment.

This is what I’m most proud of. ASTRO has actually come out with a new consensus statement about SBRT for prostate cancer. I put it up here because I think they actually say it really well. There are now many clinical studies that support the efficacy and safety of SBRT in the treatment of prostate cancer. At least one study shows excellent five year biochemical control rates. Numerous studies have demonstrated the safety of SBRT for prostate cancer at a follow-up interval long enough to see toxicity. Usually two to three years is an adequate length of time to see the majority of bowel and urinary toxicity. We have many studies out now showing that it is acceptable. It’s now ASTRO’s opinion that data supporting the use of SBRT for prostate cancer have matured to a point where SBRT can be considered an appropriate alternative for patients with low to intermediate risk prostate cancer. I’ve even happier recently because the NCCN guidelines added a line saying that SBRT for prostate cancer is now an option for men. That’s important because insurance companies won’t pay for it if the NCCN guidelines don’t say that it’s a treatment option. So I think that over the last five years a lot of work from a lot of different centers around the country have shown that CyberKnife is a new convenient treatment option for prostate cancer.

I have a question for everybody in the audience. I do want to bring up my first question. So what else do you guys think that I need to do to show that this is a standard treatment option for prostate cancer. Do you think we have enough evidence now? Do you think the answer is no, or do you think the answer is maybe? So I think this is much better this year than when I gave the talk two years ago. I’m pretty happy with the fact that 30% felt it was maybe. I think our next direction is to see really is this a safe treatment option for men with high risk prostate cancer. Can I have the next question?

So I think that my job for the next few years—and actually at UCLA Christopher King is opening a high risk study. So hopefully Dr. Crawford can invite me back in two or three more years, and hopefully I’ll have data in the high risk group for you guys. Thank you very much. I always enjoy attending this meeting. I think it’s the best meeting in prostate cancer.

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Demanes DJ1, Martinez AA, Ghilezan M, et al. High-dose-rate monotherapy: safe and effective brachytherapy for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1286-92. http://www.ncbi.nlm.nih.gov/pubmed/18313526

Fowler JF. The radiobiology of prostate cancer including new aspects of fractionated radiotherapy. Acta Oncol. 2005;44(3):265-76. http://www.ncbi.nlm.nih.gov/pubmed/16076699

Fuller CD, Schillerstrom JE, Jones WE 3rd, et al. Prospective evaluation of pretreatment executive cognitive impairment and depression in patients referred for radiotherapy. Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):529-33. http://www.ncbi.nlm.nih.gov/pubmed/18411001

King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother Oncol. 2013 Nov;109(2):217-21. http://www.ncbi.nlm.nih.gov/pubmed/24060175

King CR, Collins S, Fuller D, et al. Health-related quality of life after stereotactic body radiation therapy for localized prostate cancer: results from a multi-institutional consortium of prospective trials. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):939-45. http://www.ncbi.nlm.nih.gov/pubmed/24119836

Kupelian PA, Willoughby TR, Meeks SL, et al. Intraprostatic fiducials for localization of the prostate gland: monitoring intermarker distances during radiation therapy to test for marker stability. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1291-6. http://www.ncbi.nlm.nih.gov/pubmed/16029784

Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1424-30. http://www.ncbi.nlm.nih.gov/pubmed/17544601

Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1124-9. http://www.ncbi.nlm.nih.gov/pubmed/21310546

DR. CRAWFORD: Dr. Pinto, as he said, has to leave, but there are a couple of questions that are for him and I would just like him to answer before we go on the break. One is do you think that aptamers that the PSMA have a future for clinical imaging in the prostate.

DR. PETER A. PINTO: Sure. So I think the work that’s been done so far has been on the therapeutic side. So I know there are some groups at Rutgers who have looked at alpha particle aptamers and looked at that in liposomes. I forgot her name, but she’s done some good work in that field. There’s a group out of Iowa, for example, that has done similar work in this field. So I think, you know, PSMA was discovered in the early 90s. It took a while to figure out how it really functions and how it really works. I think we’ll see that either – conjugates or alpha/beta particles aptamers will be present. I think so.

DR. CRAWFORD: Great. There was one also about as far as you remember Martin Pomper showed his slides on urea-based PSMA still at first – in 2008. It’s the same slides as you demonstrate today. Now after six years nothing has been implemented clinically and remained promising. Understanding in any drug cycle development. Anyway, it’s really slow progress. Your comment?

DR. PINTO: So we’ve seen that also. It’s amazing when you’re trying to bring drugs and imaging agents in what we call the combined imaging agent and drug. It’s very challenging. I mean Marty Pomper in proximity to the NCI is about a 40 minute drive down 95, and yet we’ve even struggled to get some of the compounds that they can make at Hopkins into our institution. These delays are present, but I put my money behind that group in Baltimore. I think they’ll get it done eventually, but it is I agree.

DR. CRAWFORD: Thank you.

MALE VOICE: Just a quick question, I mean the fusion capabilities – I do a lot of process instill. It is a test that has evolved over the years. Which do you consider the best standard fusion? Is it with the CT? Because we have been moving more and more towards an MRI and doing it as quickly as we can. When we use both we’ve published a 95% surgical accuracy rate, admittedly a small study.

DR. PINTO: I agree. That’s the future. We actually just installed our first MR PET imaging machinery. I forgot which vendor provided that to the NCI, but it’s remarkable how well those images appear compared to what we had 20 years ago. I agree with that, yes.

DR. CRAWFORD: Alright, Dr. Keane, while we’re on this subject – I know you have to leave too—but why does your department still use ProstaScint for salvage – when nobody else does it-  being frustrated with this modality?

DR. KEANE: The reason we still do it is we have been doing it—we’ve done over two and a half thousand ProstaScint scans. Anybody who believed that you can walk in and teach – person to do a ProstaScint scan in six months just doesn’t know their business. We have probably two or three – two people who I think are the best in the world in ProstaScint scanning, but they’ve been there. They have 15 and 20 years experience. This is a very operator dependent type test. The read is crucial. You know, when you look at the new images we have when we see central abdominal uptake on a patient who is recurring and we take a look at it and we look at their PSA doubling time and we look at their original disease, that’s pretty accurate. Also with the lymph nodes I mean the anatomy – that person in Baylor who has documented nine different pathways for lymph node spread to occur out of the pelvis. So the idea that, you know, oh it’s – – standard, it’s not. In fact, if you think about it, the number of times you see disease up in the neck region is remarkable.

If you look at data from Cyto and its 1990 Journal of Cancer. Look up that. There are post-mortem studies, and it shows that the commonest area for lymph node involvement in patients who died of prostate cancer – advanced disease is not the pelvis. It was the periaortic area. The second one was the pelvis, and this region in the chest was the third. So we don’t really understand most of the lymph node spread that goes on in prostate cancer. That’s my opinion, but yeah I’m still using it because I have very good expertise in my center.