Conversations With Prostate Cancer Experts

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Dr. Robert Bristow On Precision Radiation Therapy

Robert Bristow portraitDr. Robert G. Bristow is the Director of the Manchester Cancer Research Centre (MCRC) at the University of Manchester in the United Kingdom.

Prostatepedia spoke with him about precision radiation therapy.

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What is meant by precision radiotherapy?

Dr. Robert Bristow: There are at least two aspects to precision radiotherapy. The first is the “physical precision” of radiotherapy; the actual targeting of the radiation beams or radioactive compounds to the specific tumor tissues that you want to treat, with maximum protection to the normal tissues that surround that particular tumor. For example, external precision radiotherapy uses intensity modulated radiotherapy or proton therapy where you then deliver the radiation in very precise defined volumes.

The other type of physical precision in radiotherapy uses brachytherapy, actually placing seeds or catheters with radioactivity directly in the prostate and being able to conform the dose tightly to the prostate gland, with that dose falling off rapidly around the surrounding normal tissues that could acquire side effects (e.g. the bladder or rectum). The concept of physical precision has allowed us to increase the total dose to the prostate cancer and yet maximally spare the normal tissues from side effects.

Another aspect of precision radiotherapy is “biological precision” whereby we think about the entire treatment using radiotherapy based on the innate characteristics of a particular patient’s tumor.

This includes information about the genetics and microenvironment of the tumor cells within the cancer that make it uniquely suited to be cured by radiotherapy alone, or in combination with drugs that modify biology or the immune system.

This can have the effect of increasing the chance that the cancer is cured locally and also attack cancer throughout the entire body to kill what we call occult, or hidden, metastases.

Precision radiation therapy therefore now means both an understanding of the biology of the tumor in a specific patient as well as physics to optimally deliver that radiotherapy.

What role does functional imaging play?

Dr. Bristow: Imaging is a cornerstone for staging cancer and understanding its biology. It is absolutely required for staging patients to understand the anatomy of their cancer—not only where the local tumor is, but also the spread to the pelvic lymph nodes and beyond that to the bone, for example.

Anatomic imaging therefore gives us the geography of where those tumors are in the body. Functional imaging adds further components to start to understand the biology of those tumors. For example, by using functional imaging with MRI, we can look at differences in tumor blood flow, oxygen levels, or metabolically active versus metabolically inactive tumors.

For PET scanning, we can use specific radioactive tracers that will tell us about the glucose in the tumor, the amount of the tumor that has low oxygen status (called hypoxia), and the relative growth rate of tumors.

So imaging can now give us both anatomy and biology.

Totally different world, right?

Dr. Bristow: It is. If you understand the biology from the imaging and where things are, you can certainly target specifically those areas with precision radiotherapy using novel biological agents, which we call molecular targeted agents.

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Dr. Robert Bristow: On Becoming A Physician-Scientist

RobertBristowDr. Robert G. Bristow is the Director of the Manchester Cancer Research Centre (MCRC) at the University of Manchester in the United Kingdom.

Prostatepedia spoke with him about how and why he became a physician-scientist.

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Why did you become a doctor?

Dr. Bristow: I was very interested in doing a PhD to understand how cancer cells actually divided. As part of my graduate studies, one of my mentors, a clinician-scientist, invited me to the clinic so that I would understand the implications of my research with respect to real patients undergoing real therapy. This was when I was in Toronto training at the University of Toronto.

From that experience, I realized three things. One is that the models that I’m using to try to understand how patient tumors respond to radiation and chemotherapy can be quite limited. Finding new ways to study cancer directly in patients would be profound.

The second is the reality that every patient is different and has a different story to tell; therefore, the impact of the cancer, as well as the impact of the cancer treatment on the patient can be very different, even if the biology might be exactly the same. That was a really important lesson to learn.

As I attended more and more of the clinics with my mentor, I saw that there really was a satisfaction in a career as a clinician-scientist; having the benefits of both worlds for basic and clinical research. You can ask clinical questions in collaboration with patients, but at the same time you can interrogate tumor resistance or side effects back in the lab and bring the information into the clinic. That is the real truth. I started off as a scientist, and I became a physician after meeting patients in real clinics with real clinical problems.

You’re saying that your role as a physician and your role as a scientist have a push-and-pull: each informs the other?

Dr. Bristow: That’s exactly right. Most days are terrific as they both feed off each other. But sometimes the laboratory studies do not go as well as planned as your experimental hypotheses are proven incorrect or the funding for studies is not optimal. Even with those setbacks, the reality is that when you go into the clinical realm, it’s just so rewarding and challenging.

The second part, of course, is that your favorite patients may, despite all of the best treatments that you try, not do well. In fact, some will even die of their disease. That really is an upsetting moment. The first time you’re a physician and that happens even though you think you’ve done everything right for that patient, just as you did the same for others, suggests that we don’t have all of the precise answers for an individual patient.

You’ve got to go back into the lab and work harder. It absolutely is a push/pull, but also it’s so rewarding to go back and forth. There’s a real challenge in terms of getting it right: to feed each area with the best ideas that will maximally impact on patients.

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Ms. Merel Nissenberg: Hypofractionated Radiotherapy

IMG_3119Ms. Merel Nissenberg is the President of the National Alliance of State Prostate Cancer Coalitions, a nation-wide organization comprised of state prostate cancer coalitions dedicated to saving men’s lives and enhancing the quality of life of prostate cancer patients and their families through awareness, education, and the development of a public policy network.

She offers two views of hypofractionated radiotherapy for prostate cancer.

NASPCC supports the use of new treatments and therapies that good evidence shows help prostate cancer patients, but only those that do not have more risks than benefits as compared to conventional care. Consider radiation therapy in prostate cancer. As radiation therapists and medical oncologists consider future trends in radiation therapy for prostate cancer, there are two settings in which the idea of hypofractionated radiotherapy is being explored. It may not yet be ready for prime time.

The first setting is either the postoperative adjuvant period for prostate cancer patients with aggressive pathological features following radical prostatectomy or as salvage therapy for patients with biochemical recurrence after prostatectomy. Although there is now evidence from Phase III trials supporting the use of hypofractionation in terms of good biochemical control and favorable short-term toxicity, the role of such radiotherapy in these patients is still considered investigational due to conflicting results with long-term genitourinary late toxicity.

The second setting involves men with localized prostate cancer who are often treated with external beam radiation therapy (EBRT) as their primary treatment, with treatments given over the course of 8-9 weeks. For these types of localized prostate cancer patients, trials are now being conducted to ascertain the noninferiority of hypofractionation.

That is, can larger doses of radiation per treatment over a shorter time be just as effective as standard EBRT and with no increased toxicity?

In one such trial reported in Journal of Clinical Oncology in 2017 (V35, no. 17, 1884-1890), intermediate risk patients were randomized to either conventional radiotherapy of 78 Gy in 39 fractions over 8 weeks (598 patients) or to hypofractionated radiotherapy of 60 Gy in 20 fractions over 4 weeks (608 patients). No androgen deprivation was allowed during the trial.

The primary outcome was “biochemical-clinical failure” (BCF), defined as the first occurrence of any one of 4 outcomes: PSA failure, hormonal intervention, clinical evidence of local or distant failure, or death as a result of prostate cancer. Median follow-up was 6 years.

The five-year BCF disease-free survival was 85% in both arms of the trial, and there were no significant differences between the two arms in terms of grade 3 or worse late GU and GI toxicity. There were twelve deaths as a result of prostate cancer in the standard RT arm, and ten deaths as a result of prostate cancer in the hypofractionated arm.

The trial investigators concluded there is evidence to support the use of moderate hypofractionated RT in patients with intermediate-risk prostate cancer but not in high-risk disease.

For hypofractionated radiotherapy to be adopted as standard practice for patients with intermediate-risk disease, it must be shown to be equivalent or superior to conventional radiotherapy in terms of excessive toxicity, especially late radiation genitourinary and gastrointestinal toxicity. More studies are therefore needed, particularly because there has been conflicting evidence in terms of such toxicity.

While some reports from last year conclude that moderate hypofractionation is safe and effective for localized prostate cancer and further suggest it should be standard of care, it cannot be over-emphasized that caution is strongly urged.

Longer-term toxicities are not yet known from the increased dosage of radiation with the new modalities. NASPCC strongly supports more clinical trials and longer-term follow-up to answer the question of long-term toxicity with the use of hypofractionation.

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