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Patients Speak: Getting The Gallium-68 PSMA Scan

Mr. Michael Dietrich had the gallium-68 PSMA scan as part of a clinical trial when his PSA starting rising three years after the completion of radiation therapy. He spoke to Prostatepedia about the scan and how the results altered his treatment path.

How did you find out you had prostate cancer?

Mr. Michael Dietrich: I had a bad case of prostatitis in 2006. A PSA test done at that time read a value of 6 ng/ml. My urologist was concerned and I had a six-core biopsy performed. All six cores came back negative. I was treated with antibiotics for the prostatitis, which alleviated my symptoms. The urologist thought my elevated PSA was related to the infection and did not stress close monitoring of my PSA. I didn’t know any better and I put it out of my mind. I had another bout of prostatitis in 2011. A PSA test then revealed a high value of 65 ng/ml. A 12-core biopsy (a newly established standard) was performed and revealed 80% involvement, 4+3=7 Gleason score, and seminal vesicle involvement. I don’t know if there is a relationship between my prostatitis and my cancer, but the synchronicity is odd. Either way, the prostatitis led me to my urologist and, weirdly enough, I have to say I’m grateful for it. Gratitude for prostatitis. Weird, huh? I also was diagnosed with osteoporosis at that time. I was 50 years old.

Young.

Mr. Dietrich: Yes, pretty young. Though undetected, I probably had prostate cancer at 45 years old when I had that original PSA test and biopsy done. If I had had a 12-core at the time rather than a six-core biopsy, they very well may have found it then. Needless to say, I’m a fan of 12-core biopsies.

What treatments were suggested to you and which did you choose?

Mr. Dietrich: After the tumor board at Hollings Cancer Center here in Charleston, South Carolina, discussed my case and I was presented all my options, I opted for aggressive radiation and hormone therapy. As I had seminal vesicle involvement, I believed I would need radiation anyway, as I understood typical surgical outcomes involving seminal vesicles were often not so great.

What type of radiation did you get?

Mr. Dietrich: I had both intensity modulated radiation therapy (IMRT) and brachytherapy. For about six months before treatment, I had androgen deprivation therapy (ADT). I chose to have it a little longer than normal in hopes that it would further shrink the tumors to narrow the target for radiation and further sensitize the cancer to radiation toxicity. I don’t know if the wait really helped, but in my mind it made sense. After radiation treatment was finished, I received 18 months of ADT3: Lupron (leuprolide), Casodex (bicalutamide), and Avodart (dutasteride). I’ve really been very happy with all the treatments I’ve received.

What kinds of side effects did you have from the radiation and ADT?

Mr. Dietrich: During radiation treatment, I got tired and a little achy. It also constipated me, which surprised me because a more common symptom is diarrhea. I asked for a peristaltic drug as I felt GI motility was an issue, so I was on Reglan (metoclopramide) at the end of treatment and it did help. Currently, I have the extended side effect of having to urinate a couple times a night, but it’s tolerable. I have moderate, not severe, erectile dysfunction (ED). I use Viagra (sildenafil) if necessary.

My very fine radiologist is an advocate for the use of rectal balloons during radiation treatment to help protect the colon from unwanted exposure. They were used during every treatment. Having a rectal balloon inserted in your colon (20 plus times) in conjunction with maintaining a full bladder during treatment to minimize organ movement is not a comfortable combination, but yes, it’s absolutely worth the beads of sweat you may develop on your brow it if helps with outcome and your future health.

The hormone therapy had its challenges for sure (like hot flashes, mood swings, and tender nipples), but like any other experience that a life can be presented with, be it negative or positive, I found it a learning experience.

As I was going through hormone therapy, my wife was going through menopause at the same time. We would trade the ceiling fan remote back and forth all night long dealing with our hot flashes. It was a bonding experience and it was interesting to be a guy understanding menopause.

I tried an experiment: from the day I started my hormone injections, I never shaved. I wondered how a lack of testosterone would impact beard growth and, interestingly enough, I had a 5-inch beard after my two year castrate period. Much of my body hair receded, though.

I lived in a beach town while I was on hormone therapy. If you fully want to understand how testosterone rules an adult male’s perception, remove sex hormones from your body, go to the beach, and monitor your perception and interest. An attractive, half-naked body can be as interesting as a sea gull or a dead horseshoe crab. Interesting, yes. Desirable, not so much.

I was surprised to find, at times, a certain beauty in neutrality and in being in a state of unsexually biased perception. Like the lifting of an obscuring fog to some degree. I was happy when my hormone therapy was over and I got my energy and sexual interest back, but the window of perception was interesting.

I found myself often viewing the world more like when I was a 10-year-old boy. I often experienced lightheartedness and unbiased acceptance of everybody. It was a perception benefit that I’ll never forget for the rest of my life. To this day, because of that insight, I am very aware of how hormones currently skew my perception. Aggression, arousal, competitiveness. It’s all there, but now subject to more acknowledged objectivity than before I attended eunuch university.

I’ve not heard that before.

Mr. Dietrich: Really? I am 50. I went to a liberal arts college in the 1970s where there was quite a bit of experimentation with mind-altering substances, myself included. Controversial, I know, but maybe that early use of hallucinatory drugs in my formative years did set a template for accepting/embracing shifts in perception. Maybe, maybe not. Regardless, I would encourage anybody entering hormone therapy to not be overly wary of it and realize that as your testosterone levels fall, so falls your caring about the fact that your testosterone is going away. Testosterone tends to be very possessive of itself. Be flexible with its passing. Speaking of mind-altering drugs, I was on a low dose of the antidepressant Effexor (venlafaxine) for hot flashes. It cut back hot flashes by 50% and did impact mood as well. It no doubt helped my attitude.

Getting off the Effexor (venlafaxine) definitely requires gradual weaning. I missed a dose or two by accident and felt quite nuts. It requires quite a structured commitment, a commitment not to be deviated from.

What did all this do for the cancer control? Did the radiation and ADT keep your prostate cancer in check?

Mr. Dietrich: My hormone therapy ended in 2013. My testosterone came back to my normal (between

700 and 900) and my PSA stabilized between 0.2 and 0.4. Normal readings for a patient who had received radiation, that is. After three years of stability, my PSA started rising mid-2016.

My mother passed away in January of 2016. Right afterward, my PSA started rising. My father passed on as well in December. My parents lived next door to us and we grew incredibly close. Perhaps it was coincidental, but I can’t help but wonder if the extreme grief and stress I experienced exacerbated my recurrence and contributed to my short three-month doubling time.

Progressively, my PSA rose beyond 2 plus my nadir of 0.15, signaling likely recurrence in a radiated patient. I had a skeletal CAT scan and an MRI. The bone scan was negative. The MRI was largely negative, but it revealed one—and I can quote—area of enhancement involving the right apex and the right posterolateral midgland to base, which could possibly represent residual recurrent disease, and no lymphadenectomy or other metastatic disease to the pelvis. My oncologist here in Hollings, South Carolina, mentioned the gallium-68 PSMA scan. We found a clinical trial at the University of California, San Francisco (UCSF), which I went ahead and joined.

You traveled so far to get the scan?

Mr. Dietrich: Yes. I had options somewhere on the East Coast and in Texas, but I chose UCSF because I have friends and family out there.

What was it like to get the scan?

Mr. Dietrich: I had to wait for about a month for a space to become available on the clinical trial. The scan generally costs $4,000, but my insurance covered it.

It wasn’t much different than an MRI. Very benign. I was worried about side effects, but I can’t say it was any more than with the MRI I had done with a tracer involved. I guess the only thing that really comes to mind is that there was a fairly ominous stainless steel-encased device that shielded the syringe from radiation leakage. I didn’t have any side effects from the solution or the scan. Within days, I communicated with the team performing the scan and they sent me an image and reading. There was one active 3mm node on my right side and a vague, nondescript one on the left, indeterminate but suspicious. No uptake shown on the prostate gland or anywhere else.

What was the plan after imaging?

Mr. Dietrich: That was a process to navigate. Treating oligometastatic disease is controversial with many people feeling that there is no long-term survival benefit in local treatment of local lesions and the correct treatment path is to go on systemic therapy. I was presented with chemotherapy (docetaxel) in conjunction with ADT3. I wasn’t ready for that and my gut instinct (or an extreme sense of denial) kept me looking for an alternative.

Having already had radiation to my pelvis, I was wary of further exposure so I looked into lymph node surgery.

I discovered Dr. Jeffrey Karnes at the Mayo Clinic, who regularly performs lymph node dissections on oligometastatic patients.

He performed a biopsy of my prostate and seminal vesicles, which luckily turned out negative on all cores.

On July 12, 2017, I had the lymph node dissection. Twenty-seven lymph nodes were removed. The pathology revealed two active nodes, the very same two nodes that the gallium-68 PSMA scan revealed. I’m in recovery right now from that surgery.

If you compare the gallium-68 PSMA scan to my MRI, the MRI suggested possible local disease in the prostate and nothing in my lymph nodes. The gallium-68 PSMA scan didn’t show anything in the prostate but did show active lymph glands, which was accurate. It was clear. Very clear.

Had I not had that gallium-68 PSMA scan done, it wouldn’t have been clear to me what to do. The clarity of the scan and the biopsy made me comfortable with the option of lymph node dissection, which in my situation may offer an up to a 20% chance of durable remission/cure or, if nothing else, may extend my time till I have to consider systemic treatment. A gamble perhaps, but one worth taking I feel, especially as I currently have no gross negative side effects.

How is the recovery going?

Mr. Dietrich: So far, I just have regular incision tenderness and soreness. No infection or anything else. The gastrointestinal recovery is a slow process. They have to really move your guts around quite a bit and anesthetize your intestines in order to work. Motility and digestive activity take a while to return even if you’re not feeling pain. I should probably have waited a couple more days for the flight back home, as it was just a week after surgery.

Do you have any advice for men who are considering getting this scan?

Mr. Dietrich: I wouldn’t hesitate. When I compare the results of what my MRI read compared to the clarity of the gallium-68 PSMA scan, it’s a no-brainer.

Do you have any thoughts about participating in a clinical trial?

Mr. Dietrich: Well, the gallium trial was just an investigational scan, not a comparative trial involving placebos or a control group. It just felt like any other scan.

As far as my thoughts of seeking treatment options, it can be a frustrating process as you can be presented contradictory beliefs on what’s your best path. Keeping focused on current data and talking to several educated oncologists is essential.

Collect data from everywhere, remain objective, and don’t stop. Web health message boards can be extremely good sources of both knowledge and support. There are other patients present on boards who are fighting for their lives as well and are very aggressive hounds on collecting and sharing current clinical trial, evidence-based data.

I own a company that services pathology instruments here in the Southeast. I’m always telling my technicians to practice distant objectivity and try to revoke preconceived notions when diagnosing a complicated, failed instrument. Preconceived beliefs can block our subconscious mind from connecting abstract dots into a correct forward path of figuring out a complicated problem.

Beginner’s mind?

Mr. Dietrich: Yes, beginner’s mind. That’s a good way to put it. Be confident. As a patient, you are in a position where you might be more open-minded, motivated, and educated on current data than even some physicians. You are fighting for your life and if you remain open-minded and if you don’t have a preconceived belief or a professional position to defend, you can think your way clearly.

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How Has Imaging Impacted Treatment?

Shore_001Dr. Neal Shore comments on this month’s discussion of the ways imaging has impacted prostate cancer treatment.

Imaging is important for newly diagnosed prostate cancer patients who may or may not have localized disease, and it’s especially important for advanced prostate cancer patients, whether they continue to be androgen sensitive or have developed some level of androgen resistance. For earlier stages of disease, there has been a lot of interest regarding multiparametric MRI. Nonetheless, the efficacy of multiparametric MRI is limited by the expertise of the interpreting radiologist. The fusion technology software championed by several of the academic centers has been rolled out without consistency within the community. For some practices, it was adopted due to marketplace competition and the device developers’ promotions. Companies that develop multiparametric fusion technology have not made a significant contribution to the advancement of urologic and radiologic educational needs. That said, some groups incorporated dedicated specialists within their practice to train for high-quality multiparametric fusion-based biopsies. Purchasing the newest promising technology without ensuring a framework to optimize clinical results will lead to poor implementation. In the United States, MRI is still mostly recommended for patients who have had a negative prostate biopsy, but due to age, PSA kinetics, or rectal examination, there is still a concern of possible malignant disease that was missed on the first biopsy. MRI is most uniformly accepted for additional information when evaluating patients for the need for a second biopsy. MRI will no doubt have an ongoing role in the active surveillance population. MRI will no doubt have an eventual role in decision making for possible first biopsies.

 

There has been a lot of very good, evidence-based literature coming from European countries that suggests that whole-body MRI, with the right software protocol, is exceptionally helpful in evaluating metastatic disease. Unfortunately, in the United States, this protocol takes 45 to 60 minutes to accomplish, and unfortunately, translates to a challenging economic utility model for the MRI efficiency from an administrator perspective. There are many interesting and promising blood-, tissue, and urine-based markers, genomic assays, and additional imaging techniques, which require ongoing trials to determine how best to use them for the most efficient value-based care model. No single test—MRI or any other blood-, tissue-, or urine-based marker—is perfect. Eventually, we will hopefully develop a cost-effective algorithm that combines a panel of all the different biomarkers. MRI is part of that discussion, but we don’t have that sorted out currently. There have been multiple PET scan technologies developed in the last several years that have been assessed for improved potential sensitivity and specificity, and ultimately, to improve the accuracy of the data that shows cancer spread and its location. MRI and Axumin PET scanshave been approved for advanced prostate cancer patients. There have been other PET scans such as FDG, C-11 Acetate, C-11 Choline, sodium fluoride, which have not received widespread reimbursement approvals nor widespread accessibility. There is also no consensus recommendation for these technologies.


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Living With Erectile Dysfunction After Prostate Cancer

Tim M. had a Gleason 9 prostate cancer removed by his urologist. He spoke with Prostatepedia about his struggles with ED posttreatment.

How did you find out you had prostate cancer?

Tim M: I had the typical issues that people talk about: urination and a PSA that was increasing a little bit. I had a phenomenal general practitioner, a doctor who really cared. He wanted me to do a biopsy. I was resistant. I said, “Oh, come on, Doc. This must be an infection or something.” Unfortunately, I resisted for about six or seven months, maybe even longer.

Finally, he said, “No, you’ve got to go for the biopsy.” So I went to a top doctor in my area. He did a check and said, “I don’t really think there’s going to be a problem, but let’s do the biopsy.” So I did it. He called and said he was surprised to say that I had aggressive cancer.

What kinds of treatment did you have?

Tim M: I really didn’t have much of a choice. My doctor said I needed surgery right away. He was a leading surgeon with a phenomenal reputation. I had the surgery two years ago.

Did the urologist talk to you before surgery about the potential for erectile dysfunction (ED) after treatment?

Tim M: Not really. He did not really touch on it. We asked him about it at one of the interviews. If we hadn’t asked him, I don’t think he would have really talked about it. I’ll never forget his answer. He said it was 50/50 whether or not I’d get ED.

What happened after the surgery?

Tim M: The surgeon completely removed the prostate. The cancer had gotten out of the capsule, but he thought he got it all because my margins were clean. I was very lucky. He was comfortable that we had it all. I didn’t have any problems with urination. The catheter clogged up one time, which was actually one of my biggest fears, believe it or not.

The catheter?

Tim M: When I was about 17, I went to see a friend who was in the hospital. He had a catheter and he explained to me what they had done to him. It left a burning impression in my mind. There’s a tube where? That kind of stuck with me. That was one of my concerns. I did have some issues with the catheter, but after that, everything was fine except for the erectile dysfunction.

Can you talk a bit about that?

Tim M: Nothing seems to really work anymore.

Have you been able to talk to your urologist about it?

Tim M: He gave me some pills—Cialis (tadalafil) and the other pills. It didn’t help. Then he said to try the injections, which seemed to help a little bit, but not really. He wanted me to increase the dose, but I really didn’t want to do that because of all the warnings: if something goes wrong, get to a hospital right away. The whole deal with the needle and the possibilities of side effects put a damper on things.

Did you talk to him about any other options?

Tim M: He went through all the options with me, including the vacuum and an implant and none of them seemed too attractive to me.

How do you feel about all that?

Tim M: Pretty bad. But you know, as you get older, you begin to accept things a little bit more. I guess you have to. I wasn’t happy about the cancer to begin with. All I can do is do what I can do.

I just turned 70 this month. I also have some cardiovascular issues. I go to the gym. I try to do what I have to do to keep conditions under control as best I can.

My doctor called me at 8:30 the night of my diagnosis and said, “I have to tell you you’ve got an aggressive cancer. It has to come out right away.” There was no light discussion. It’s not like I had a choice. If I had let it go, I would have died.

He was so focused on your cancer that he wasn’t really even thinking about potential ED?

Tim M: Yes, I believe so. That was the priority.

Did you have any problems with incontinence after the surgery?

Tim M: A little bit. I still wear pads, but I barely need them. I just got used to them.

He had suggested that I do Kegel exercises. But it’s weird. Because of my cardio situation, I wind up going to the gym and working like a fool for hours a week, but I just couldn’t get into those exercises. The pads were just too convenient, but that’s pretty much dried up at this point. The only time I have a problem is with stress if I’m exercising or something like that.

Do you have any advice for other men about to have prostate cancer treatment?

Tim M: You have to do what you have to do and deal with what you have to deal with. What you have to deal with might not be too good. There is nothing good about it in my view. My advice is to consider that ED is going to be an issue.

Do you think that more men are suffering from ED than surgeons think?

Tim M: Yes. I do absolutely think that. I’ll tell you something else. It’s a little bit sensitive to talk about, but I’ll just come out and say it. How do you define erectile dysfunction? You know what I’m saying? There are different levels of an erection. Obviously, when you are younger, it’s one way. My question is, where is the threshold? What if you end up with a three-quarter situation? My doctor told me 50% of men have ED, but of the other 50% what in the hell was the quality of what they had left?

Was the erection like what they had before or was it just enough so that they could use it?

Tim M: Yeah, just enough to use. I mean if you’re not going to be able to perform to some degree of quality, why bother?

Also, there’s a secondary problem, which is a psychological issue. When you ejaculate, there’s nothing there.

That must be a bit demoralizing.

Tim M: That was very demoralizing. Some people say, “What’s the difference?” There is a difference. It’s a mental thing. To tell you the truth, my first thought was: “Have I become like a woman? Is this an orgasm that a woman would have?” The physical aspect is not the big thing. It’s how you’re interpreting it and what’s going on inside your mind that’s the major thing.

It changes the whole experience.

Tim M: Thank God this didn’t happen when I was in my forties.

It might be worth going to see an expert in ED.

Tim M: Well, I know all the possibilities. It’s the shots. It’s the vacuum. It’s the operations.

From age 15 to 68, it was all just a natural happening. And now, you’re talking about mechanisms and devices and shots and operations and you have to push a button?

It sort of takes you out of the moment.

Tim M: It puts a whole different perspective on the deal. Men should definitely be prepared for what’s going to happen. I do think more information needs to be out there.

The more men know about what may happen the better they can prepare themselves?

Tim M: Yes. I think where doctors make a mistake, at least in everything I’ve seen and read and everything that the doctor has said to me, is that this is not a binary A or B thing. Do you have ED or don’t you? It’s not like that. It’s more like: do you have no dysfunction or do you have some? Is it the same as before or not? That’s important. My guess is that the vast majority of guys are going to say no.


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Your Number One Fan Is Looking for Love

 

AG.headshotWellness speaker Angela Gaffney teaches simple and effective strategies to help people achieve health, increase productivity, and live stress-free while reaching their personal and professional goals.

She offers her tips for nurturing your Number One Fan.

Picture your number one fan, the one who supports you most in life. The one who shows up no matter your mood, how tired you may be feeling, or how much pain you may be experiencing. Whatever the situation, your number one fan is there for you. I’m sure many of you pictured your spouse, partner, or maybe a parent or best friend. While these people are all great supporters in your life, your number one fan is much, much more! Your number one fan is your body.

We hurry through life at such a fast pace that we often forget to support the one that supports us most! Sometimes it takes a diagnosis or health crisis before we realize that our body may need more from us than what we’ve been willing to give. It was true for me, and it was true for many of you. Caring for your body goes far beyond just eating well and exercising. It takes commitment and conscious effort to ensure you’re giving your body all it needs to heal and achieve optimal health.

We all need to practice these four principles to care for our bodies through diagnosis, treatment, and in lifelong health.

Build Awareness

Daily habits are so second nature that it’s easy to underestimate the impact they have on our health. Start tapping into your daily habits and assess whether they’re offering you the supportive environment your body needs to heal and be well. If change is needed, take it one step at a time.

Consciously Choose

We often make decisions, big and small, out of convenience, haste, or emotions we’re feeling. It’s time to pause and choose differently. Before every decision you make, stop and ask yourself: “What will this provide me?” Just answering this one question will help you make a conscious choice and to move forward in a healthy direction.

Create a Supportive Environment

It’s hard to avoid sugar if there are cookies and cake in the kitchen. Building a supportive environment is of greatest importance if your goal is lifelong health. Replace processed foods with whole, fresh foods that nourish the body. Say no to unnecessary obligations to give yourself space and time to heal. Share your needs with your friends and family so they too can support you in this journey. Everything in our environment— the food we eat, the toxins we’re exposed to, and the stress we feel from everyday life—impacts our health. Do your best to create a healthy, supportive environment for you and your family.

Above All Else, Be Kind

You are on a health journey, which means some days will be easier than others. Use positive affirmations and encouraging words to support yourself in healing and lifelong health. If you veer off track, assess what you’d like to do differently next time and move forward. You have a choice in every matter, and you get to decide how you’d like to participate. Above all else, be kind to yourself in the process.

You are your best advocate! Take care of your number one fan by assessing your current habits, making conscious choices that serve you well, creating a supportive environment, and above all else, being kind to yourself through the process.

To hire Angela to speak at your next event, discuss a wellness program for your corporation, or take advantage of complimentary health tools, please visit http://www.AngelaGaffney.com.


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Join A Clinical Trial On Neuroendocrine Prostate Cancer

GEORGE.DAN.002Dr. Daniel James George is a Professor of Medicine and Professor in Surgery at Duke University.

Prostatepedia spoke with him recently about a clinical trial he is running for men with neuroendocrine prostate cancer.

What is neuroendocrine prostate cancer?

Dr. George: For a long time, people have known about neuroendocrine prostate cancer, which is a different biology of prostate cancer. The testosterone pathway drives most prostate cancers, as well as the androgen receptor or the testosterone receptor. That biology accounts for probably over 90% of initially presenting prostate cancers. A downstream protein that’s coded for and turned on from the androgen receptor is prostate-specific antigen (PSA). We have a blood test for PSA that measures this biology to some extent.

Also, for a long time, we’ve known about the activity of the androgen receptor in prostate cancer through the PSA and its kinetics—its ups, downs, and whatnot. We have thought of neuroendocrine prostate cancer as a rare form of prostate cancer that— instead of growing out of the basal cell of the prostate and into a luminal cell, which secretes PSA—grows out of a cell in the prostate environment called a neuroendocrine cell. It’s called that because it’s derived embryologically from the same types of cells derived from our endocrine system into neurons.

The neuroendocrine cell has characteristics very different from other prostate cancers. It doesn’t have the androgen receptor, it can secrete different types of proteins like CEA or chromogranin, and it grows irrespective of our effects on testosterone. It can spread to soft tissues like the liver, lung, and other areas in a pattern that differs from the spread in more common prostate cancers. It’s got an aggressive clinical course. It spreads quickly and can kill people in a matter of months.

More recently, we have come to understand that prostate cancer evolves in patients over time to have more and more neuroendocrine features. Some of our more novel ways of blocking the testosterone pathway with drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) have stressed this system so much that we’re seeing a greater percentage of patients evolve into or select for a neuroendocrine phenotype. This is becoming a more prevalent problem as patients live longer and as we use more of these hormone therapies.

How is the trial designed? What will you do and what should patients expect?

Dr. George: This project started when we were looking at how to block the testosterone receptor downstream.

Drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) are fantastic at blocking the androgen receptor by binding to a certain part of the receptor called the ligand-binding domain. Over time, this can get overexpressed to such a level that these drugs can inhibit it or result in a splice variant. A splice variant means that the DNA gets expressed only partially so that a shortened or truncated form of the receptor is made that doesn’t have the ligand binding domain and is therefore completely resistant to those drug therapies. That’s becoming more and more prevalent.

We looked to see if we could block some biology downstream. We found that when the androgen receptor is activated in these hormone resistant models, the copper transporter and other genes involved in copper metabolism were highly expressed. So, we tested drugs that would bind up copper, but it didn’t work well. It only worked at very toxic levels.

Then we decided to turn this around. Instead of blocking copper, we fed the cancer copper. We allowed the cancer cells to accumulate a bunch of copper, and then we screened for drugs that would kill the copper-laden cells particularly in this setting. We found several drugs in the dicarbamate family. First and foremost is a drug called disulfiram, also commonly known as Antabuse. This is a drug that is used to block alcohol dehydrogenase, making alcohol toxic in alcoholics. However, in tumors, we found that when disulfiram binds copper, it becomes lethal to cancers.

We’ve taken this to clinic, and under an investigational new drug authorization from the FDA, we’re going to load tumors with intravenous copper, image with a copper PET scan, and then treat patients with oral CX-02 (disulfiram) and additional oral copper. This strategy gets interesting for neuroendocrine tumors is because the copper transporter is also essential for platinum transport. Copper and platinum are both cations (positively charged ions), and platinum chemotherapies like carboplatin and cisplatin are very effective in neuroendocrine tumors for a period of time. For those cells to be sensitive to platinum, the platinum must get inside the cells, so we know they must also express the copper transporter.

We think targeting this copper transport mechanism may represent a second and novel way to target neuroendocrine prostate cancer.

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Small cell? Or neuroendocrine cancer?

AparicioDr. Ana Aparicio is an Associate Professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Prostatepedia spoke with her about rare but highly aggressive forms of prostate cancer.

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How did you become involved in such a specialized subset of prostate cancer research?

Dr. Aparicio: I was very frustrated by the fact that we treat homogeneously a disease that we perceive in the clinic to be heterogeneous. It drives me crazy that different people walk into the clinic with different diseases and yet we do the same thing to each and every one of them. This ends up meaning that many large Phase III trials are an enormous resource expense. It’s difficult to advance the field. I had remarkable responses for patients with Yervoy (ipilimumab) and yet the Phase III trial was negative. I felt like that was wrong. We should be smarter about what we’re doing. We need to understand the heterogeneity of prostate cancer and incorporate that understanding into clinical trials. Otherwise, it’s going to take us 200 years to make a difference in this disease.

I think of it in the following way. I take all of the prostate cancers and peel away the most aggressive ones. I then look to see how that relates to the rest of the disease. If we peel back in that way, we will start to understand the disease.

So then the work you’re doing can potentially change not only how we treat patients, but also how we design clinical trials?

Dr. Aparicio: Yes.

What is neuroendocrine prostate cancer?

Dr. Aparicio: Neuroendocrine prostate cancer is a histological definition of a prostate cancer variant. The prostate is composed of glandular tissue. When a pathologist looks at your garden-variety prostate cancer under the microscope, she sees it is composed of groups of glands. That is why it’s called adenocarcinoma: adeno meaning of or relating to the glands, carcinoma referring to the cancer arising from epithelial tissue. It’s cancer and not normal prostate tissue, but you can still recognize the glandular structures. Prostate adenocarcinomas respond very well to hormonal therapies.

On the other hand, small-cell prostate cancers basically look like sheets of cancer cells under the microscope. There is no glandular formation of any sort. These are small, round cells that have small amounts of cytoplasm (the gel-like material surrounding the nucleus) so their nuclei look very prominent. Small-cell cancers often express neuroendocrine markers, which are a type of protein expressed by a number of different tissue types and in a number of different cancers. Neuroendocrine markers are in no way specific to small-cell prostate cancers, but because the small-cell prostate cancers express them frequently, the other name that is given for small-cell prostate cancers is ‘poorly differentiated neuroendocrine prostate carcinoma.’ Many garden-variety prostate adenocarcinomas (those composed of groups of glands) also express these neuroendocrine markers. Again, the word neuroendocrine is not specific to small-cell cancers. Small cell refers to sheets of cells that are small with little amounts of cytoplasm.

The presence of small-cell cancer morphology on a surgical specimen or a biopsy is often associated with atypical clinical features for prostate cancer and a poor response to hormone therapies.

Garden-variety prostate adenocarcinomas most often spread to the bone and make round sclerotic (hardening) or osteoblastic bone metastases that show on a CT scan like a white patch.

In contrast, small-cell prostate carcinomas are often associated with what we call lytic (relating to disintegration) bone metastases, which show on a CT scan like a dark, punched-out hole. And that’s when the carcinomas go to the bone because they often don’t even show up in the bone. Men with small-cell cancer morphology can have exclusive visceral metastases, meaning their cancer has only gone to the liver, lymph nodes, or lung. They might also have bulky tumor masses, including bulky and symptomatic primary prostate tumors or bulky liver or lymph node masses. While they don’t respond well to hormonal therapies, small-cell prostate cancers often respond to chemotherapy.

A problem we ran into was that we would often find these atypical clinical features that I just described, but under the microscope where we expected to find small-cell prostate carcinoma morphology to justify chemotherapy, we didn’t. What happens when we see those atypical clinical features, but the biopsy doesn’t show small-cell morphology? Our experience shows that those people don’t do well with hormone therapies. In other words, when we do a biopsy and we find small-cell carcinoma morphology, we know that those cancers need to have chemotherapy sooner rather than later, as opposed to treatment with hormonal therapy. They need early chemotherapy as well; so we coined the term aggressive variant prostate cancers, which are tumors that share clinical features with small-cell cancers but may have different morphologies under the microscope. When we do a biopsy, they might look like adenocarcinoma, but they behave like small-cell cancer.

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Diagnosing Neuroendocrine Prostate Cancer

Prostatepedia spoke with Dr. Himisha Beltran, an Assistant Professor of Medicine at Weill Cornell Medical College in New York City, about diagnosing neuroendocrine prostate cancer.

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How is small-cell or neuroendocrine prostate cancer diagnosed? Biopsy? Imaging?

Dr. Himisha Beltran: Small-cell or neuroendocrine prostate cancer is diagnosed by tumor biopsy. The pathologist typically makes the diagnosis by looking at the morphologic features of the cancer under a microscope and may perform additional testing to look at expression of neuroendocrine markers or classical prostate markers to support the diagnosis.

One of the reasons why neuroendocrine prostate cancer was thought to be so rare was that doing metastatic biopsies on patients already diagnosed with prostate cancer was just not done in the clinic. It is only recently that we are recommending biopsies to look for neuroendocrine prostate cancer in select patients with aggressive clinical features and low PSA levels. Biopsies are also being considered to look for other emerging molecular targets. There are now several prostate cancer clinical trials targeting different mutations and alterations.

An obvious next step is to try to diagnose neuroendocrine prostate cancer noninvasively. Imaging is a noninvasive way to detect different cancers, but there hasn’t been any sort of imaging tool yet that can really identify these patients. We’re starting to see clues that there may be some molecular markers that are expressed that might help future research in this area. Another noninvasive approach we have been investigating is the use of liquid biopsies that include circulating tumor cells as well as circulating tumor DNA to see if there are clues that can help us identify these patients without a biopsy. This is still in research development.

 

 

 

 

 

Read the rest of Dr. Beltran’s comments on neuroendocrine prostate cancer.