Urology Times® is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, Anthony Zietman, MD, discusses the development of radiation therapy for prostate cancer. Zietman is interim chief of Radiation Oncology at Massachusetts General Hospital in Boston and has recently retired as Editor-in-Chief of the International Journal of Radiation Oncology Biology Physics (The “Red Journal”).
Radiation has been used for the treatment of urologic cancers for over 100 years. It's been well established that radiation kills cancer cells; the big problem is that it also kills healthy cells. The last century of development in radiation oncology has been about targeting. It's about focusing the radiation beams such that they hit the target—the prostate—and don't hit the normal tissues all around. Over the years, there has been an evolution from therapies that were very superficial—they simply couldn't treat deep tumors like those in the prostate—to those that just about reached the prostate but gave an awful lot of radiation to all the tissues around it. I'm talking about cobalt therapy in the 1950s/1960s.
And then in the late 1970s, early 1980s, something came along called a linear accelerator, which was able to throw radiation into the center of the human body. For the past 40 years, the linear accelerator has been the workhorse of every radiation oncology department. But it's not just the machines themselves, it's the software that drives them and the imaging that accompanies them that are critically important. As regards imaging, 40 years ago, we didn't even have CT scans; we just had a cystogram, and rectal barium, and somewhere beneath the cystogram and somewhere in front of the rectal barium was the prostate. We had no idea what size or shape it was; we just fired into that general area. There was a lot of indiscriminate damage of surrounding tissues. Since CT scans in the 1980s, we've been able to view the prostate not only at the time of planning, but now every day during treatment, so that we can really sharpen our focus and shape the radiation beam. With advances in software, we've learned how to use multiple radiation beams from many different directions and different intensities, to really increasingly focus the radiation, not just on the prostate, but now we can focus within the prostate. We can give extra radiation within the prostate to, for example, an MR-visible nodule. The past 100 years, but particularly the past 20 years, have been a phenomenal evolution in terms of radiation technology, in terms of what we can give. For us, all these advances are our equivalent of robotic surgery. These are huge steps forward. It's not just expensive technology. You'll hear all about intensity-modulated radiation, 3D radiation, stereotactic radiation, proton beam radiation. They're all variants of the same thing. I don't want you to think that there's a vast difference between them because there isn't. It's like if you want to get from Boston to Washington DC, you could drive a Lexus, you could drive a Mercedes, you could drive an Audi. You'll be comfortable whichever way you go. That's how we see these. Some people have greater expertise using one technology rather than another, but you just go with local expertise.
The whole story of radiation therapy is a story of progressive technological innovation and, over the last couple of decades, our high-end technologies have improved at an exponential rate. In parallel with this our ability to see the prostate and target with millimeter precision has added enormously. It's more than just the high-tech imaging, there has been low-tech innovations too. Nowadays, we can put little gold markers into the prostate, which sounds like nothing; they only cost $40. You will not break the bank with these, but they do improve the daily imaging during treatment. We can put biodegradable gels between the rectum and the prostate to separate the two such that the rectum isn't caught in the crossfire. Again, it's not high tech, and it's not hugely expensive. But it actually makes a big difference. So, by adding up all these big technological delivery improvements, and all these little advances, we've come a long way. They're all innovations that have improved the targeting of the radiation.
My clinics, when I went into practice 35 years ago, were unbelievably miserable. Every patient I treated was having severe adverse events, and you had to cross your fingers and hope that things would get better in the weeks and months after treatment was done. Usually they did, but often they didn't. Every now and then we had catastrophic adverse events. I just don't see that these days. These are innovations that have undoubtedly improved the welfare of patients. But again, it's not just about the innovations in technology; it's how we use the technology. We have learned over the years to become incredibly selective. There are patients we treat, and patients we've learned not to treat. There are patients we treat with a little extra radiation, and patients on whom we back off. Much of this is based upon a clinical trials infrastructure that has developed in Europe—in Britain, in particular—and in North America over the last 30 years. It isn't necessarily present in urologic surgery, but it's certainly present in urologic radiation therapy. So we've done randomized trial after randomized trial after randomized trial, each one building on the shoulders of the one went before to learn not only how much radiation to give, but over what period of time, who needs to have their lymph nodes treated, who doesn't, who needs more radiation, who needs less, and who needs no radiation at all. I would say our greatest advance of the past 30 years is our clinical trials infrastructure, because we can now use our therapies with intelligence. I'll give you a couple of great examples. Because radiation used to be so inaccurate, we had to take it slow. Patients would come in 5 days a week for 8 to 9 weeks of treatment, which is really burdensome for them, especially if they live a long way from a radiation treatment center. But as treatments became more accurate, we hypothesized that, if you're treating this normal tissue, you can give the treatment in a more abbreviated fashion. So we've done clinical trials comparing 8 weeks with 5 and a half weeks; it, turns out 5 and a half weeks is just as good. We've done 8 weeks vs 4 weeks, and 4 weeks is just as good. That's my standard; I get the treatment done in half the time I used to 10 years ago. We're now looking at 2 weeks or even 1 week of treatment. Although I am now a US passport holder, I am originally from Britain and I'm very involved in in the British randomized trial scene. There are currently 3 randomized trials going on that look at 5 treatments, compared with 20 treatments for prostate cancer—low risk, intermediate risk and high risk. We're really learning a huge amount about how to best use radiation. The other thing we've learned is through a big British randomized trial called ProtecT [NCT02044172] that there are certainly situations where we don't need to use radiation at all, or surgery for that matter. The ProtecT trial will be publishing its final 15-year outcomes this coming year. We're all very excited to see what that shows. It has certainly showed already that radiation is very competitive with surgery when it comes to eradicating cancer in patients. That may surprise a lot of surgeons, although it doesn't surprise radiation oncologists, but we were certainly gratified to see the results of that trial. And we'll see how those findings hold up at 15 years.
There are 2 pieces to this question. The first is in treating localized prostate cancer, I think treatments are just getting more and more accurate, and we are going to be able to use the great MRI imaging that we now have to treat to higher doses within the prostate. We're also going to be able to use the great imaging that we have now with PSMA PET scanning to treat patients better after surgery. We 're going to be able to pick out those who need postoperative radiation and those who don't. For those who need it, we will know exactly which area to target. That should reduce the morbidity of postoperative treatment. That's 1 great way in which urologic surgeons and urologic radiation oncologists can team up to provide certainty for patients with higher risk disease [that they're getting] the best maximal treatment possible. We're learning through randomized trials the best way to integrate radiation with hormone therapy, and not just old-fashioned leuprolide but the modern forms of androgen deprivation—abiraterone [Zytiga], enzalutamide [Xtandi], etc, all of which are going to integrate with radiation differently in the years ahead.
The second area where I expect the landscape to change completely is in patients with early metastatic disease. This has been defined as a new disease state. We used to think there were patients with localized disease and patients with metastatic disease. When patients had metastases, you just didn't think in a curative sense; it was essentially palliative. Well, it turns out there is probably a group in between: patients who have localized disease and have a few metastases but don't yet have full-blown metastatic disease. It is possible—and I say this is as a hypothesis—these patients are actually curable with a combination of hormone therapy, some treatment to their prostate, and then some additional ablative treatment to their few metastases. We can use our very accurate radiation therapy nowadays to literally wipe out metastases. So if a patient has 2 lymph node metastases and 1 bone metastasis, we could wipe those 3 metastases out and then see what happens afterwards. Maybe, in some cases, full-blown metastatic disease is the result of secondary metastases from a few initial metastases. If so, some of those patients may be cured. Again, randomized trials are going on at the moment that are going to test this hypothesis. If I had to predict over the next couple of decades, I think the role of radiation is actually going to expand from localized disease into a central role for metastatic disease.