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PET/CT Imaging + Radiation?

 

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Dr. Michael Zelefsky, a radiation oncologist, is Professor of Radiation Oncology, Chief of the Brachytherapy Service, and Co-Leader of the Genitourinary Disease Management Team at Memorial Sloan Kettering Cancer Center in New York City.

Prostatepedia recently spoke with him about how advances in imaging have impacted radiation therapy. Subscribe to read the entire conversation.

Do you think molecular imaging will be incorporated soon?

Dr. Zelefsky: There’s a lot of excitement with PET/CT imaging. PET imaging fused with MRI is also emerging now. This has been used effectively for various disease sites, not only prostate cancer. For prostate cancers specifically, newer PET tracers such as PET C-11 Choline and exciting developments in PSMA tracers will be used. These provide us unique opportunities to see where micrometastatic disease could be lodged. That information is critical for the radiation oncologist to pinpoint the disease. There are also exciting developments using some of these tracers as a form of therapy. Tracers such as PSMA are linked to lutetium-177 and tracers can be integrated with radiation planning as well. We are on the verge of seeing these new developments; these changes will soon be integrated with radiation.

Is there anything else you think patients should know about imaging’s role in radiation therapy?

Dr. Zelefsky: With new advances in imaging and by working in close collaboration with diagnostic radiology, we are getting much more accurate information concerning where microscopic disease is located and the critical zones within the prostate where tumors are lodged. We use imaging to consider re-biopsying patients where there may be a discrepancy between what looks like earlier states of disease, but the MRI shows there is greater volume of disease than what was anticipated. We need to know this information in order to plan the radiation well. We need to consider opportunities to intensify the dose to the DIL in the prostate and whether there is nodal disease and where exactly the nodal disease could be within the pelvis. Imaging plays a huge role in our follow-up with patients, allowing us to detect recurrences earlier than ever before. This is vital information for patients because earlier detection of recurrences allow for salvage therapies much sooner and treating such patients at earlier time points is often associated with more successful outcomes.

In the future, imaging will help us consider focal ablative therapies where the paradigm is shifting in earlier cancer s. Simply put, we could just focus on the DIL and spare the rest of the prostate if we can be sure that there is no significant disease in other parts of the gland. There have been a number of efforts to use focal therapy with advanced imaging to small subunits of the prostate. So new imaging possibilities are opening up new directions and opportunities in the treatment of prostate cancer.

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Imaging + Radiation Therapy

Dr. Michael Zelefsky, a radiation oncologist, is Professor of Radiation Oncology, Chief of the Brachytherapy Service, and Co-Leader of the Genitourinary Disease Management Team at Memorial Sloan Kettering Cancer Center in New York City.

Prostatepedia recently spoke with him about how advances in imaging have impacted radiation therapy. Subscribe to read the entire conversation.

What role does imaging now play in radiation therapy?

Dr. Zelefsky: Radiation therapy has been linked to imaging for many years. In the late 1970s and early 1980s with the advent of the CAT scan, those images were used in the treatment planning process to provide greater accuracy for targeting the radiation. Over the ensuing 20-30 years, there have been significant advances in imaging, from CAT scanning to MRI, and from multiparametric MRI to molecular imaging. These advances in diagnostic imaging continue to be linked to radiation treatment. We use multiparametric MRI imaging to target radiation to the prostate with exquisite precision. Just as importantly, we use these technologies to understand the geometry and anatomy of the surrounding normal tissues. For the prostate, that could mean the bladder, rectum, bowels, and even specific anatomic regions like the bladder neck and the neurovascular bundles that control erectile function.

Advances in imaging have allowed us to visualize these normal tissue structures, and this information is incorporated into treatment planning, giving us a way to deliver the radiation with a precision we’ve never had before.

What sorts of changes do you think are on the horizon as we develop better imaging techniques?

Dr. Zelefsky: We have successfully moved from CT-based imaging to MR-based imaging. Now, we commonly use MRI and fuse those images with the CAT scan. At Memorial Sloan Kettering, we have moved to the next step, which is pure MRI-based planning. This means we don’t need the intermediary step of a CT scan anymore. We can plan directly off the MRI, and we map everything out from these sets of specific We’ve also moved beyond MRI to what we call multiparametric MRI. We look at different sequences and formats of the MRI, including dynamic contrast enhanced imaging, and diffusion-weighted imaging to give us further information about the location of the disease within the prostate, which is called the dominant intraprostatic lesion (DIL). This dominant intraprostatic lesion is an important area to target because recurrences after radiation stem from regrowth of disease from that initial site of disease in the prostate.

Radiation oncologists are recognizing that there may be opportunities to intensify the focus of the radiation to the DIL to improve the tumor control rates with radiation. We have moved from CT-based to MR-based radiation therapy to pure MRI-based planning, and now we incorporate important information from multiparametric imaging. In the future, we’ll also incorporate molecular imaging, which comes from advanced nuclear medicine studies.

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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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Advances In Imaging

In October, we’re discussing advances in imaging that could dramatically improve how we treat prostate cancer. (Issue to be released to subscribers on Wednesday October 4.) In our Guest Commentary, Dr. Neal Shore does an excellent job summarizing these advances from a urological perspective, expanding on the interviews by Drs. Matthew Cooperberg and Raoul Concepcion. Dr. Michael Zelefsky discusses the impact these new imaging approaches, especially MRI, have in prostate cancer treatment planning.

Several common themes emerge. One is that the American healthcare system renders the best imaging technologies so expensive that rapid implementation at the community level is limited. The situation in Europe is markedly different; costs are 70-80% lower. As a result, Europe is leading both the development of better imaging technologies and the delivery of these technologies at a community level.

Another common theme is that advanced training and experience are required to use these imaging technologies well. Dr. Cooperberg does an excellent job of outlining this problem in prostate multiparameter MRI. The message for you is just because a nearby medical facility has purchased state-of-the-art imaging equipment does not mean they know how to use that equipment well. For now, travel to centers with a documented track record in using a new imaging technology.

Perhaps the most important point is that before a new imaging technology becomes standard treatment, extensive clinical trials need to validate the technique. How do you know when an imaging technique has passed such scrutiny? One landmark is whether or not the imaging technology has been FDA approved. For example, the C-11 Choline and Axumin imaging scans are FDA approved and covered by Medicare to detect metastatic prostate cancer. The Gallium-68 PSMA PET/CT scan is very promising, but not yet FDA approved.

In several of this month’s conversations, we mention the role of imaging in the management of oligometastatic disease. In oligometastatic disease treatment, we use radiation or surgery to eliminate metastases, potentially delaying cancer’s progression for a clinically useful time. By now, it is clear that there are patients who benefit from this treatment.

What is not clear is how effective we are at identifying who those patients are. This will only be resolved by well-designed randomized clinical trials. Fortunately, such trials are in progress and additional trials planned.

Charles E. Myers, Jr., MD

 

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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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