Prostatepedia

Conversations With Prostate Cancer Experts


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Imaging + Salvage Focal Therapy

Dr. R. Jeffrey Karnes is an Associate Professor and Vice Chair of the Urology Department at the Mayo Clinic in Rochester, Minnesota.

Prostatepedia spoke with him about how imaging impacts salvage focal therapy.

Subscribe to read our November issue on focal therapy.

How does newer imaging like gallium-68 PSMA PET/CT impact salvage focal therapy?

Dr. Karnes: PET imaging has been good at detecting metastases, but in terms of imaging the primary tumor, the resolution hasn’t been the best. Now, we and others are moving into a PET/MRI scan.

That is a fusion scan?

Dr. Karnes: A fusion scan with MRI rather than the PET/CT. Obviously, an MRI provides more resolution of the prostate. To me, MRI is obviously the gold standard when it comes to imaging the primary prostate. We’re certainly using the technology. Others are using it. We don’t really know what the exact accuracy is of the MRI/PET fusion scan in those who have had radiation failure.

And, as I mentioned, I don’t think we have really much in the way of a clue regarding the biology of this index lesion in radiation-recurrent cancer in the prostate. I think that in the glands of men who recur after radiation, there is probably higher tumor burden compared to the newly diagnosed patient.

A third problem we have when it comes to focal salvage therapy is that I don’t think we even have a great definition of what constitutes a potential local recurrence after primary radiation. The Phoenix definition used by the American Society for Radiation Oncology is the nadir (or lowest) PSA plus 2. This definition predicts recurrence, but what it really predicts is progression, not necessarily local recurrent disease.

In this country, for many men who fail radiation, the next treatment is hormonal therapy. Hormonal therapy really has only a palliative intent and won’t cure anyone of localized radiation-recurrent disease.

We need to do a better job of appropriately diagnosing radiation failure patients in the first place. What that better job would be, I don’t know. I don’t think routine biopsies, which have been looked at in the past, are the answer. But perhaps imaging sooner rather than waiting for the Phoenix definition makes sense. Maybe, as you mentioned appropriately, with the newer PET/MRI fusion scans, we can image men sooner to try to detect a local recurrent disease earlier.

That being said, I do a lot of salvage radical prostatectomies, almost one a week. This is unpublished, but I have not seen a big stage migration (less extraprostatic extension and/or nodal metastasis) in the last decade. I still see a lot of patients with radiation failure; they come to their salvage prostatectomy with seminal vesicle invasion and nodal disease. Up to a third of patients will have seminal vesicle invasion and I see nodal involvement in up to 20% at salvage surgery.

Why is that relevant to salvage focal therapy?

Dr. Karnes: A lot of the seminal vesicle invasion is not always evident on MRI. And a lot of these patients don’t get routine biopsies of their seminal vesicles. If they undergo a salvage focal therapy, their doctors are obviously going to be missing a significant component of their disease because salvage focal therapy, in my opinion, doesn’t work to ablate the seminal vesicles. Obviously, salvage focal therapy can do a job in the gland itself, but in the appendages, such as seminal vesicles, it is hard to get an appropriate ablation of the entire seminal vesicles because of the risk to adjacent structures— the bladder, the ureters, and so forth.

Another thought I have about salvage focal therapy is when we look at other forms of ablation technologies like cryotherapy or HIFU, we’ve morphed them from whole-gland to focal and now to focal salvage therapies. But I don’t think we even know who the ideal candidate is for whole-gland HIFU or whole-gland cryotherapy let alone the focal form of the therapies in a treatment-naïve patient. Obviously, these are alternatives or options for patients who are newly diagnosed, but more troubling for me is this: I don’t think we know exactly what constitutes a success. How do we monitor whole-gland cryotherapy or whole-gland HIFU? We’ve used PSA failure as a definition, but are we really using the right tool to monitor?

Subscribe to read the rest of Dr. Karnes’ comments on salvage focal therapy.


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Using Genomics To Guide Treatment

In March, Prostatepedia is talking about how we’re using (or not using) genomics to guide prostate cancer treatment.

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Dr. Snuffy Myers says in his introduction to the issue:

This month, we’re talking about our understanding of the genetic and molecular mechanisms driving prostate cancer. If we can understand how cancer differs from your body’s normal tissues, we can selectively kill cancer while minimizing damage to normal tissue. As it turns out, this type of research is very difficult.

How can genetic changes cause cancer? How do they determine the biology of the resulting cancer?

Genetic information is stored in DNA. The DNA molecule is like a library filled with instructions for a cell to accomplish various tasks. At any one point, only a small set of the instructions are activated and followed.

In normal biology, the instructions activated are appropriate to the task at hand: liver cells activate instructions for liver structure and function; muscle cells activate instructions for muscle structure and function.

shutterstock_520680199Normally, these cells’ growth and spread are tightly controlled. If you remove half a liver, the liver regrows to its normal size and then stops. Cancers cells’ growth and spread are no longer controlled. Liver cancer cells grow and spread beyond the liver and, if untreated, kill the patient.

How does your body read those DNA instructions?

Your body first creates a RNA molecule that is a copy of the instruction. You use this RNA molecule to produce a protein that makes cells change their structure or behavior. Cancer behavior comes from a set of proteins that promotes inappropriate growth and spread. Several mechanisms cause the production of these protein sets.

The DNA instruction set itself can change, or mutate. We can detect these mutations in DNA instruction sets through DNA sequencing.

shutterstock_440437171.jpgDNA sequencing technology has advanced rapidly and costs less then $1,000/sample. If you can get a sufficiently large biopsy of your cancer, we can sequence the DNA. Foundation Medicine is the largest commercial firm offering this service today.

Unfortunately, mechanisms not involved in DNA mutation, and therefore not detectable by DNA sequencing, can change that RNA copy. Adding the methyl group to DNA commonly alters RNA copy production and plays an important role in prostate cancer. One approach measures RNA copy production of genes important to prostate cancer biology. Tests like Prolaris and Decipher used in early, organ-confined prostate cancer use this approach.

Another approach measures proteins that control prostate cancer behavior or response to treatment. Caris Life Sciences measures the presence or absence of proteins that determine responsiveness to two major prostate cancer chemotherapy drugs called Taxotere (docetaxel) and Paraplatin (carboplatin).

All of these tests require a biopsy. It is often difficult to biopsy prostate cancer and especially bone metastases.

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In advanced prostate cancer, we find cancer DNA in the blood. We can isolate and sequence these cancer DNA fragments to identify mutations in a liquid biopsy.

Guardant Health is the most established company in this area. At my clinic, we’ve used the Guardant360 liquid biopsy extensively to identify hormone-resistance mutations, as well as DNA repair mutations that predict for PARP inhibitor response.

We are only beginning to apply molecular biology to prostate cancer treatment, but the approach has great promise.

Subscribe to read Prostatepedia March 2017: Using Genomics To Guide Treatment.


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If Your Cancer Comes Back: Radiation

Dr. Michael Zelefsky of Memorial Sloan Kettering Cancer Center talks with Prostatepedia about using radiation therapy if a man’s prostate cancer comes back after treatment.  (Download Prostatepedia’s August issue to read the interview.)

 

After surgery, patients are generally followed. There is always a concern if we see

high-risk features after surgery that would put a patient at risk for the disease coming back. High-risk features could be positive margins or if the cancer breached the capsule or invaded the seminal vesicles.

We also ask if preventative radiation therapy, which is known as adjuvant radiation therapy, could be of benefit? Or would it be just as reasonable and logical to watch such patients? Should we treat a patient with radiation therapy if his PSA goes from zero to some level or he has a rising PSA level?

This is one of the most significant controversies in urologic oncology right now.
There are several important trials going on in the world that are trying address this very question. Is there a need for adjuvant radiation therapy? Or would early salvage radiation be acceptable? Can we delay the need to give these patients radiation? In general, when a patient’s PSA goes up after surgery, we consider radiation treatments to the prostate bed. That area could harbor microscopic cells. Frequently, patients who get radiation earlier, especially if they are at high risk for harboring microscopic cells in the prostate bed, can be successfully salvaged. Their PSAs could go down to zero once again. That is why close follow-up after surgery is necessary.
Of course there are many ongoing studies trying to figure out if hormonal therapy in the salvage radiotherapy setting could improve these results. Those studies are important. Hopefully, the results will become available in the near future. Radiation is also used in a recurrent setting when the disease comes back after radiation. The other option in that setting could be salvage prostatectomy, but many who do such salvage surgery procedures recognize that there is a risk of significant incontinence—from 25% to 50%.

More recently, we used seed implants to target the areas where the disease had come back based on careful imaging studies. For the last five years, we’ve been utilizing this so-called salvage brachytherapy in patients with what appears to be lower rates of incontinence. Results are comparable to what is achieved with salvage prostatectomy with lower risks of urinary incontinence.

 
Of course, there are other approaches such as salvage cryotherapy.
At Memorial Sloan Kettering, we are also treating patients in whom the disease has come back years later with salvage brachytherapy or salvage seeds. We tell patients that there is a risk of side effects when you add radiation on top of radiation. Fortunately, newer technologies to place seeds with image guidance and computer planning have significantly improved over the last number of years. This allows us to broaden radiation therapy options in the salvage setting.