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Conversations With Prostate Cancer Experts


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Dr. Charles Drake On A Memorable Patient

DRAKE charlesDr. Charles G. Drake is the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/Columbia University Medical Center.

Dr. Drake discusses a patient whose case intrigued him.

Have you had a particular patient who changed how you approach your work?

Dr. Charles Drake: Absolutely. I had a gentleman who had metastatic, castrate-resistant prostate cancer. He had been treated with hormonal therapy. He was about to go on chemotherapy. He had progression in his bone lesions, but he developed hematuria.

On CT scan, there was a fairly clear lesion in his bladder. We couldn’t tell what it was just by the scans, and his PSA was doubling quickly, it had reached 30 or so in less than a couple of months. We sent him to Dr. Ronald Rodriguez, who was at Johns Hopkins at the time, and he thought it looked like this was probably metastatic prostate cancer invading the gentleman’s bladder. Dr. Rodriguez did a transurethral fulguration, meaning he burned all of the tumor he could find in the bladder. After the procedure, he told me that there was a fair amount of prostate cancer left behind. While the procedure went well, and he got most of the tumor, he didn’t get all of it.

What happened next was fascinating. The patient’s PSA dropped. His PSA went from 30 to 20 to 10. It eventually nadired, or reached its lowest point, at less than 1 ng/ ml and he remained in remission for nearly two years. Although clearly anecdotal, in my mind, there is almost no question that this was one of those anecdotal abscopal responses, which makes you believe that it can happen. Almost certainly that was what happened for this patient. I’ll never forget it, frankly.

Interesting. An unexpected systemic response from local treatment, right?

Dr. Drake: Yes. It was brilliant. Just by treating the local disease in the bladder, this gentleman did well for over two years before it apparently progressed again, and he wound up getting chemotherapy. He also did very well with the chemo, so in my hopeful view, that suggests that maybe this fulguration procedure sparked a systemic immune response.

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Dr. Robert Bristow On Genomics, Radiation Therapy + Prostate Cancer

Dr. Robert B. Bristow talks with Prostatepedia about the intersection of genomics and radiation therapy for prostate cancer.

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Let’s talk about genomics. Do we have a way of predicting who will respond to radiation? And who will have severe side effects?

Dr. Robert B. Bristow: The short answer is no. My work with my colleagues in Canada involved a huge effort to sequence the entire genome, or the entire DNA network within prostate cancer in patients in the localized setting. What we know in localized disease is that there are a number of patients that under the microscope look like they have the same Gleason score. When we do whole genome sequencing, we see that about a quarter of these actually have a number of genetic rearrangements and mutations within their tumor.

It’s quite clear that the patients who have more aggressive mutations and increased number of mutations actually do worse. The way that they do worse is that they actually fail radiotherapy quite quickly after treatment. We therefore think that genetic instability, or the increased burden of mutation, is associated with hidden metastases as opposed to information about responding to surgery versus radiotherapy.

We’ve looked very hard in the Canadian study for a predictor of who would respond to radiotherapy versus who would respond to surgery. Although some early leads suggested one gene or another, I’m not confident right now that we actually have a marker so that when a patient comes into the clinic, we could do a quick test to say whether his disease was more or less sensitive to radiotherapy. We hope that will change, of course, with further data. But we don’t have it yet.

The other aspect that you pointed out is whether or not radiation side effects are associated with germline or blood DNA. Some data suggests there are specific gene mutations associated with cell growth, the way the cells contact each other, or DNA repair that might put patients at risk for erectile dysfunction or rectal bleeding. A lot of validation studies still need to be completed. It is also not ready for prime time.

Something that has come up in the last two to three years is that patients can have defects in genes associated with DNA repair. Your readers will have heard about the BRCA1 and BRCA2 genes normally associated with ovarian and breast cancer. We now know if you are a male BRCA2 carrier you have an increased risk for prostate cancer and an increased risk of aggressive prostate cancer.

One Canadian study suggested that some of these localized cancers in BRCA carriers already had acquired resistance patterns to hormone therapy and other types of therapy even though they had never seen the therapy. They are almost primed for resistance.

We also know that maybe up to 15% of patients with metastatic castrate-resistance prostate cancer have DNA repair defects. This is important because it speaks to mechanisms of resistance and aggressiveness based on genes in your bloodline. The other important thing we’ve learned in the last five years is that prostate cancer patients with BRCA1 and BRCA2 DNA repair defects respond to PARP inhibitors.

This is a very exciting area of precision oncology using genomics to predict those patients that might respond to a molecular-targeted therapy in this case.

One can only assume that there might be other stories like the DNA repair defect story that would give us more information about different types of tumors.

Dr. Bristow: This comes back to what we were talking about before: carefully designing clinical trials to compare one treatment versus another in large numbers of patients in which there is high content information about the immune landscape, genetics of the tumor, genetics of their bloodline, and functional imaging of the tumors. This will allow us to start to put this information together to come up with a more precise way of treating our patients.

Cancer is complex. The complexities of cancer are for us to discover, but also for us to develop a number of tests that give us a sense of that complexity so that we can use the right treatment for the right patient at the right time.

The promise of genomics in the last decade is now leading to novel treatment for patients. There are still situations for which we don’t know the best treatments. In those cases, patients need to demand from their healthcare givers information about which clinical trials are available to them so that we can solve these questions together. The reality is that we do require clinical trials to answer them.

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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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Anthony D’Amico Comments On Prostatepedia’s Radiation Therapy Issue

Photo by Sam Ogden. Anthony D'Amico, M.D., Ph.D.

Dr. Anthony D’Amico is Professor of Radiation Oncology at Harvard Medical School and Chief of the Division of Genitourinary Radiation Oncology at Brigham and Women’s Hospital and Dana- Farber Cancer Institute in Boston, Massachusetts. He frames this month’s conversations for us.

Join us to read our July issue on radiation therapy.

Dr. Charles Drake and others have done an outstanding job of describing all of the knowledge that has been assembled to date about the potential role of radiation in the immune-oncology setting.

We know that immune therapy works by removing immunologic breaks. That is, they remove the body’s inability to fight against the cancer because the cancer itself has put a break on the immune system. That is what drugs like Keytruda (pembrolizumab) and others do. These drugs activate a T cell response against specific antigens that exist on the surface of cancer cells.

Everyone knows now that tumors are heterogeneous. They don’t have only one antigen on their surface, so if you made only one antibody against it, it won’t kill every tumor cell. Tumors can have many hundreds of different antigens that the immune system has to find, bind to, and connect with to kill. Radiation has the opportunity to make this happen if you irradiate the primary prostate cancer tumor. You ignite the immune T cell response against the antigens that live in the primary tumor as many people have discussed doing.

But that may not be sufficient. If a tumor has, say, a hundred antigens, but there are already cells in circulation that have escaped, then sometimes we can’t detect them with imaging because they’re below the level of resolution of our scans. Those cells developed different antigens (or mutations) that give them the ability to get away from the primary tumor, and they’re continuing to mutate and develop new antigens. If all of that occurs, then those cells can go on eventually to metastasize. The immune system won’t recognize them because the antigen(s) on their surface are different from the antigen(s) that are in the primary tumor.

To circumvent this issue, people are now combining radiation with immunotherapy. They irradiate the primary tumor in select men who have a couple of metastases—the so-called oligometastatic state—and then they irradiate those as well. By doing so, you potentially capture the antigens on the cells that have escaped the primary tumor and metastasized. This increases the probability of capturing all of the antigens and eliciting an immune response with T cells being activated against all the possible antigens that this tumor might carry.

Therefore, radiation therapy may have its biggest impact in the immune oncology setting in a patient with oligometastatic disease. For diffuse metastatic disease, it may be too overwhelming to radiate all sites safely. In summary, I’m concerned that if we just treat local, regional disease, the tumor volume that you’re radiating may not be expressing all of the mutations or all of the antigens that the T cells need to be directed towards. There could be cells already in circulation that have new mutations and new antigens that the primary just doesn’t have.

I’d like to make a point about Zytiga, (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide), which are mentioned in several conversations in this issue of Prostatepedia.

When a man is diagnosed with high-risk prostate cancer, the usual treatment is radiation followed by 18 months to 3 years of hormonal therapy.

After radiation therapy, and after about six months of hormonal treatment, the nadir value of the PSA is a very important value. It can predict the future. Many studies show that, at that point, a PSA value over 0.5 ng/ml portends a bad prognosis. Many of those men will die of prostate cancer. If that nadir value of PSA is above 0.1, they won’t do as badly, but they still do more poorly than those whose PSA becomes undetectable.

It is thought that this is because people who still have a persistently elevated PSA after being on standard hormonal therapy like Lupron (leuprolide) and Casodex (bicalutamide) already have evidence of castrate-resistant disease. Even though it may not be visible on staging scans, it appears to be refractory to the hormonal therapy they’re receiving. The novel thought is that using drugs like Zytiga (abiraterone), Xtandi (enzaludamide), and Erleada (apalutamide) at an earlier time will improve outcomes.

Specifically, if we intervene earlier, i.e. before the person is declared a PSA failure—PSA failure is defined as his nadir, or lowest, PSA plus 2 points—we have a chance to do better. Currently, if the nadir value is 0.2, you’d be called a PSA failure at a PSA level of 2.2 or higher. That could take months or years to happen after the nadir. So, if we know someone is destined to do poorly based on their nadir value, we can intervene earlier.

To that end, we have created a randomized trial in which men with high risk prostate cancer, who are on track to receive at least 18 months of hormonal therapy, are entered at the time of PSA nadir. This is usually six to eight months into the radiation and hormonal treatment plan, while their remaining hormonal therapy is still ongoing. We then randomize them to either standard of care, which is continuing the standard hormonal therapy for their intended 18-month to 3-year course, or to the rest of their hormonal therapy (supplemented by both Zytiga (abiraterone) and Erleada (apalutamide)).

This concept was recently approved. The trial will launch in 2019 as an international, randomized study. This trial is quite exciting because, while the doctors in this issue of Prostatepedia discuss the current and future use of these drugs, nobody has studied them in this particular setting. This unique setting captures people who have a poor prognosis and are very likely to die of the disease.

This concept is also novel because we catch them at a time when intervention with these novel agents may have a higher likelihood of success. We’re not waiting months and years for that formal definition of PSA failure to happen before we intervene.

Finally, I’d like to add that it’s an absolute privilege to work clinically and do research in the field of prostate cancer in this day and age. I’ve never seen so many opportunities and new discoveries in such a short period of time. I believe that, given all the ongoing research, it will continue.

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Frontiers In Radiation Therapy

When you’re diagnosed with prostate cancer, you’re usually offered three options: monitor the cancer to see if it progresses, elect to have your prostate surgically removed, or elect to have the cancer treated with radiation therapy. Radiation is also used after surgery or in the event that the cancer comes back after that initial treatment.

Most of you are familiar with radiation therapy for prostate cancer—how it works, potential side effects, and special considerations. Even if you have not had radiation, chances are you’ve got a friend of relative who has.

This month, however, we’re delving into less often discussed aspects of radiation therapy: the role genomics will play in radiation therapy, why we might consider combining radiation with immunotherapy, the impact imaging has on radiation therapy, and the role radiopharmaceuticals play.

Dr. Robert Bristow of the University of Manchester gives us a sweeping overview of precision radiation therapy—from functional imaging to genomics—as well as a run-down of molecularly-targeted agents.

Dr. Charles Drake of the New York- Presbyterian/Columbia University Medical Center discusses radiation therapy and the elusive but intriguing abscopal effect.

Dr. William Hall of the Medical College of Wisconsin talks to us about the precision radiotherapy movement and how it will revolutionize patient care.

Dr. Daniel Spratt of the University of Michigan Health System talks abouta clinical trial he’s working on with Dr. Felix Feng from the University of California, San Francisco (UCSF) that uses genomics to determine which patients will receive a combination of radiation therapy and Erleada (apalutamide) and which will get a placebo.

From Dr. Ralph Weischelbaum of the University of Chicago we hear about the thinking behind combining radiation therapy with immunotherapeutic agents—with a cautionary note.

Dr. Johannes Czernin from the University of California, Los Angeles (UCLA) talks about a clinical trial he’s running on a radiopharmaceuticalagent—a PSMA targeted lutetium-177. He is looking for patients to join, so if you think you might be a fit, please reach out to him at the email address included at the end of his conversation.

Ms. Merel Nissenberg offers the National Alliance of State Prostate Cancer Coalition’s stance on hypofractionated radiation therapy.

Finally, Ron B. tells us about his experiences with stereotactic body radiation therapy. He has some advice for those of you in a similar situation to the one in which he found himself.

We suggest you read through this month’s conversations and then send the issue to your health care team so that you can discuss the contents with them.

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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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