Edited from February Insights 2014 Vol. 17 Iss. 1 | By Mark Scholz, MD | Prostate Oncology Specialists
Over the years, as the pace of scientific advancement accelerates, the new science being presented becomes even more hopeful and innovative. The best meeting each year is hosted in October by the Prostate Cancer Foundation (PCF). The meeting is put together by Howard Soule, the PCF director of research. This year was the PCF’s 20th annual meeting. It consisted of two full days of presentations, each averaging about fifteen minutes long. The sheer volume of new information is delightfully overwhelming.
A good number of presentations are at the basic science level and therefore have little relevance to the average reader of Insights. Research into basic science is designed to elucidate the fundamental biology and biochemistry of tumor cells. It is a laborious and expensive process designed to work out the “basic blueprints” of cancer function. The idea is to build a scientific foundation for the future discovery and rational design of new drugs. I’ll try to summarize the presentations that may be of greater interest to our readers.
A Retrospective on Surgery
Historically the PCF has focused on developing treatments for advanced disease. However, this year they hosted a 45-minute panel session of five famous prostate doctors to discuss the modern role of surgery. Dr. Holden, the medical director of the PCF moderated a discussion with Patrick Walsh, Phil Kantoff, Chris Logotheitis, and Eric Klein (three urologists and two medical oncologists). Howard Sandler, a radiation therapist was asked to chime in from the audience.
In light of the acknowledged fact that surgery is unnecessary for low-risk prostate cancer it was fascinating to hear Dr. Klein and Dr. Walsh (the two surgeons on the panel) talk about the great research benefits and wonderful pathologic information we have obtained from actual prostates, the same ones that have been surgically removed over the last 20 years. As if this somehow gave purpose and meaning to the millions of men who have been treated with radical surgery! Patients in the audience must have felt a chill run up their spines at the cold blooded disregard for all the unnecessary, surgically-induced human sufferin
During the panel discussion both Dr. Kantoff, a medical oncologist, and Dr. Sandler, a radiation oncologist, were unwilling to make any remarks that could be construed as disagreement with Dr. Walsh. Therefore I apparently risk repercussions by disagreeing with a sweeping statement made by Dr. Walsh, “Men with high-risk disease treated with surgery don’t need hormonal therapy.” To be fair, I agree with Dr. Walsh that some favorable types of high-risk disease can forgo hormonal therapy. However, there is a least one piece of compelling evidence that men in the high-risk category treated with adjuvant hormone therapy experience lower relapse rates according to a large prospective study published in the Journal of Clinical Oncology by Dr. Tanya Dorff from USC.
My favorite quote from the panel discussion was from Chris Logotheitis, the medical oncologist from MD Anderson. He said, “If surgery was a new drug under evaluation for approval by the FDA to treat low-risk prostate cancer—it would never be FDA approved.”
On another note, Dr. Klein, the urologist from the Cleveland Clinic expressed the optimistic belief that all the new genetic tests that help confirm that low-risk prostate cancer is really low-risk such as Prolaris and OncotypeDX, will lead doctors to restrain themselves from the overuse of surgery and radiation. Personally, I am not so optimistic that the ingrained systematic overtreatment of men with low-risk disease will be so easily revolutionized.
New Immune Therapy
I am particularly excited about new treatments with the potential for harnessing the immune system to fight cancer. The immune system is very complex with many moving parts. The T-cells are a component of the immune system that is utilized to attack cancer cells directly. However, cancers often “cloak” themselves from the immune system using mechanisms to “blind” the T-cells to their presence.
Some of the new immune-based therapies work by awakening the immune system to “see” the cancer cell and attack it. Provenge is one such example, a FDA approved treatment for prostate cancer that sensitizes the immune system to the PAP antigen. At the meeting, new research was presented describing a newly created antibody that focuses T-cells on a different target, the PSMA antigen, a protein located on the surface of cancer cells. This new therapy uses a uniquely designed cancer-specific antibody that has been chemically altered to guide activated T-cells directly to the surface of the cancer cell.
Improving the Identification of High-Risk Prostate Cancer
Another important area of development in cancer therapy is what I call the reconnaissance aspect of cancer treatment. In military terms, you can’t fight the enemy if you don’t know the strength of his forces and their specific location. New research presented at the meeting gave details about the discovery of a new gene product called SCHLAP-1 that helps predict the likelihood of future metastases. SCHLAP-1 appears to have predictive power on the same order as Gleason score or possibly, even better. Most of you are already familiar with cancer grading using Gleason and how it is critically important in distinguishing low-grade from high-grade disease. The availability of a new predictive factor of this stature would be a wonderful addition to our clinical armamentarium.
It has long been suspected that when the androgen receptor gets blocked, the cancer cell’s lack of access to testosterone stimulates a switch in the cancer cell to start using other hormones like progesterone or cortisol as a substitute to feed itself. Research presented at the meeting seems to confirm this. However, these findings are preliminary as the studies were laboratory based rather than clinical studies in humans. We will have to wait to find out if these new discoveries are clinically factual or just an artifact of an artificial lab environment.
Getting a Leg Up on The FDA for Approving New Drugs
One of the biggest factors slowing down the new-drug FDA approval process is the requirement that all new medications demonstrate a survival advantage in a clinical trial. Ironically, this immutable demand from the FDA becomes harder to fulfill as the number of effective drugs increases. Just in the last few years Provenge, Zytiga, Xtandi, Xofigo, and Jevtana have become available. Many experts believe that it is not ethical to study new, unproven drugs until all the proven drugs have been tried and found to be ineffective. So as more and more effective drugs get approved, fewer and fewer patients will be available for participation in clinical trials and the ones who are eligible to participate will have very advanced, treatment-resistant disease.
A percentage drop in PSA after treatment has been repeatedly proposed as a measure of treatment effectiveness rather than survival. PSA actually works well in some situations such as with chemotherapy or hormonal therapy. However, PSA can be notably inaccurate as has clearly been demonstrated with Provenge and Xofigo as neither causes a consistent decline in PSA though both have shown to improve survival.
At the meeting Dr. Howard Scher presented some hopeful information about ongoing studies that rely on measuring a decline in circulating tumor cells (CTC) in response to therapy as an accurate method for the early prediction of long term survival. The actual protocol proposed by Dr. Scher used CTC levels in combination with a measurement of an enzyme in the blood called lactate dehydrogenase (LDH). Using this proposed system, patients with advanced disease were divided into three risk categories. “Low-risk” patients had normal CTC and LDH levels. “High-risk” patients had a CTC count above five. “Intermediate-risk” patients had an elevated LDH with a normal CTC count. What’s exciting is that this system has already been tested and validated to predict survival. Dr. Sher is planning to propose this new system for evaluating new drugs to the FDA in the near future. If successful, substituting the measurement of CTC for the existing system of measuring survival could really speed up the new-drug approval process.
Finally, A Way to Detect Microscopic Metastases?
Victor Velculecu from Johns Hopkins presented his work which suggests that the presence or absence of microscopic residual disease can be detected with new genetic tests called genomic analysis. If this work is confirmed it could revolutionize the way we treat cancer. For example, right now many men are treated with long term hormonal therapy after radiation because of the possibility that microscopic metastases are present. If an accurate test were available that could confirm that a patient is totally free of metastases, that patient could safely be advised that long-term hormonal therapy is unnecessary!
Reducing the Side Effects of Xofigo?
Dr. Morris presented some fascinating information about the function of injectable Radium (Xofigo) which was recently approved by the FDA. Xofigo is generally well tolerated but the most common side effect, if a side effect occurs, is GI related. This appears to occur because after the Xofigo is injected into the blood stream it lands in the bone and attacks the cancer. However, some of the Xofigo is not taken up by the bone and gets excreted through the small intestine. Therefore, the excess radioactivity passes sequentially through both the small bowel and the large bowel. Apparently the dose of radiation is too small for most men to feel it. However, some men are more sensitive and experience nausea or diarrhea as a result. Men who have GI symptoms from Xofigo (since the side effects caused by radiation are related to both dosage and duration of exposure) might want to consider taking a laxative to accelerate the bowel transit time.
Botox for Prostate Cancer?
At the meeting some fascinating data showed the dependence prostate cancer cells have on growth factors secreted by the nerves in the prostate. One of the possible culprits is a hormone called vasointestinal peptide. A study was performed by injecting Botox into half of the prostate of men with known bilateral cancer. The other side of the prostate was injected with an inactive salt solution. A month later the men underwent radical prostatectomy. After surgery it was confirmed that the cancer regressed on the side of the prostate that was injected with Botox. The physician presenting went on to theorize that the development of neuroendocrine prostate cancer, a feature that is common in advanced hormone refractory prostate cancer, is really nothing more than cancer evolving its own “nerves” so it has plenty of nerve growth factors to feed on. A paraphrased quote from him would perhaps read as follows, “Under stress [of hormonal therapy] the cancer makes its own nerves.”
The little snippets of information I have shared with you in this short article do no justice whatsoever to the absolute deluge of quality science that was presented at the two-day meeting. The PCF is doing a wonderful job of raising money and distributing it wisely to the best researchers in the world. Howard Soule and his excellent team should be greatly commended for the wonderful work they are doing to encourage the development of effective new prostate cancer treatments. It’s hard to believe the PCF had called this meeting a “retreat.” The way things are going I would recommend renaming it an “advance.” Happily, the development of new treatments for prostate cancer is moving forward at a furious pace.