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Conversations With Prostate Cancer Experts


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Dr. Snuffy Myers On ED After Treatment

In September, we’re talking about erectile dysfunction after prostate cancer treatment.

Dr. Charles Snuffy Myers frames this month’s conversations.

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Most men with prostate cancer have concerns about sexual function because diminished erectile dysfunction is a frequent side effect of the most widely used treatments. Additionally, as men get older they often have issues with erectile dysfunction even if they do not have prostate cancer. In fact, prostate cancer and its treatments are not the major cause of male sexual dysfunction. The two most common causes are diabetes and cardiovascular disease.

One of the more common mistakes physicians make is to attribute all medical problems to the cancer and its treatment. Men with prostate cancer often suffer from undiagnosed or under-treated diabetes or cardiovascular disease. For this reason, newly diagnosed prostate cancer patients should be evaluated for these two diseases. This is especially true if you are likely to need hormonal therapy, as this treatment can exacerbate both diseases.

Several drugs used to treat cardiovascular disease and diabetes may well have a favorable impact on the clinical course of prostate cancer, including the statins used to lower cholesterol, ARBs used to treat hypertension, and metformin used to treat diabetes. With this in mind, there should be no hesitation to treat diabetes and cardiovascular disease appropriately in men with prostate cancer.

Standard treatment of erectile function often centers on the use of Viagra (sildenafil), Levitra (vardenafil), Cialis (tadalafil), or related drugs. Erections are normally triggered by dilation of the arteries that supply the penis. This is caused by the release of nitric oxide, a powerful vasodilator. Viagra (sildenafil) and related drugs make the arteries to the penis more sensitive to the action of nitric oxide. However, this effect is not limited to arteries in the penis but also develop in arteries elsewhere. As a result, some patients experience symptoms of low blood pressure and facial flushing. Drugs that release nitric oxide, such as nitroglycerine, can cause severe hypotension when co-administered with Viagra (sildenafil) or related drugs.

These drugs can be administered in a single dose shortly before sex or at much lower doses chronically. There is some evidence that chronic low dose administration is more effective for penile rehabilitation after surgery or radiation. There is a biochemical rationale for this. Arterial health appears to be at least partially supported by chronic release of nitric oxide and these drugs may augment that effect.

There are men who do not adequately respond to oral drugs, the vacuum pump, or penile injections. In this situation, the penile implant offers a reasonable option. In skilled hands, this procedure is usually very effective. Unfortunately, too few patients select this path.

Treatment for erectile dysfunction has improved dramatically over the past two decades. Most men with erectile dysfunction after prostate cancer treatment can recover sufficient function to have a sex life, but treatment needs to be initiated in a timely fashion. It is also important to not ignore aggressive options like penile injection or penile implant.

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Dr. Daniel Spratt: On Becoming A Doctor

Dr. Daniel Spratt is a radiation oncologist and the Chair of the Genitourinary Division of Clinical Research at the University of Michigan Health System.

Dr. Spratt talks to Prostatepedia about why he became a doctor.

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Why did you become a doctor?

Dr. Daniel Spratt: There are no physicians or healthcare workers in my family. I took an unconventional path to becoming a doctor. I started working as a personal trainer when I turned 18. I was always involved in fitness and exercise. I took some time off from going to college and worked one-on-one with clients.

At that time, I noticed that I liked being able to help change people’s lives and have that unique interaction. But there are limitations to what a personal trainer can do for a person. That inspired me to go back to college, focus on the research, and go to medical school to become a radiation oncologist.

How did you make your way to radiation oncology versus urology?

Dr. Spratt: In medical school, we rotate through a bunch of different specialties. All along, I thought I was going to be a neurosurgeon; that was my focus and my research. But I started to realize that I love to connect, to have the time and flexibility to discuss how patients are doing. I care more than just about the technical treatment. I enjoy emotionally connecting with patients.

The radiation oncology industry is a unique specialty in that a machine delivers our treatments, and then we get to see the patient. I almost do two things at once. If a surgeon is operating all day, they can’t see anyone other than the one patient in front of them. I get to see and treat dozens of patients a day.

Are you still involved in the exercise world?

Dr. Spratt: Definitely. It is not as strong, but if you spoke to any of my patients, they’d tell you that I prescribe exercise to all of them. The side effect profile for my patients who are inactive versus the ones who are active is like night and day. It’s amazing how patients undergoing prostate cancer treatment, including radiation and especially hormone therapy, are improved by exercise. It doesn’t need to be joining a gym—just being active in some way.

The guys who are active have much fewer side effects during treatment. I jokingly prescribe exercise while

I prescribe radiation to them.

Maybe you shouldn’t joke and really do it!

Dr. Spratt: Exactly. I don’t think a pharmacy can fill that.

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Shop Around For A Radiation Therapist

Dr. William Hall of the Medical College of Wisconsin offers advise to patients looking for a radiation therapist.

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Dr. Hall says: Radiation therapy is an extremely technical specialty that is rapidly evolving. Many patients think that radiation therapy is the same, regardless of where they receive it.

That is not so.

Expertise, delivery methods, and the unique methods of radiation therapy administration can vary tremendously from hospital to hospital. That’s extremely valuable for patients to understand.

You should seek a radiation oncologist who specializes in your type of cancer, someone who focuses their research and clinical efforts on a few types of cancer. In larger academic centers, radiation oncologists tend to do that.

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Radiation Therapy + The Abscopal Effect

Dr. Charles G. Drake of New York Presbyterian/Columbia University Medical Center, discusses the rare but intriguing abscopal effect.

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Dr. Charles Drake says: There was an article in the New England Journal of Medicine showing an abscopal response with Yervoy (ipilimumab) anti-CTLA-4 in a patient with melanoma. It was a beautifully done paper with nice immunological correlates. After that got published, we found that radiation oncologists and medical oncologists were giving people a combination of immunotherapy and radiation and were telling patients they would get abscopal responses. But that’s a bit overly ambitious. In the clinic, it’s not that easy. It’s going to be a while before we understand what’s needed therapeutically to be able to induce abscopal responses in the majority of patients. It’s going to take a little more work before we can have that happen broadly. On the other hand, if we can make it work, it’ll be fantastic. Dr. Hammers’ trial combining anti- PD-1, anti-CTLA-4, and radiation in kidney cancer is perhaps a more clever approach. That may be what we need to do.

In other words, abscopal responses do happen, but we don’t exactly know why or how and can’t reproduce it?

Dr. Drake: Exactly. And it doesn’t happen nearly as often as we’d like.

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Why Combine RT + Immunotherapy?

Dr. Charles G. Drake, of New York-Presbyterian/Columbia University Medical Center, discusses the thinking behind combining radiation therapy with immunotherapy.

Not a member? Join us. We’re talking about radiation therapy and prostate cancer in July.

Dr. Drake says: “The basic idea is that radiation, and perhaps other local modalities like cryotherapy, leads to destruction of tumor cells. If they’re destroyed in a way that’s immunogenic or pro-immunogenic, then the dying cells are taken up by resident antigen-presenting cells. These antigen-presenting cells get activated; they traffic to the draining lymph node, if you’re lucky. If they traffic to the draining lymph nodes, and then activate a systemic immune response (T cells), then maybe you can turn a local therapy into a systemic therapy. When that happens, it’s called the abscopal effect. We can demonstrate this in mice fairly readily, but it’s quite hard to demonstrate in humans.

In the literature, it’s not that common. There’s a review paper that reports around 60 total cases in the world that are clearly documented. But if you talk to people who take care of patients, everybody has one or two that they can talk about.”

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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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