There was a flurry of news articles over the last few weeks about the Oncotype DX prostate test (and others) which is worth thinking about. These genomic tests which are well reviewed in a recent NYT article, are based (in general) on the observations that certain genes, or sets of genes can be turned on or off more frequently in some cancers than others. By evaluating large numbers of patients, for example, with Gleason 7 cancer (intermediate risk), finding out those who live for 10 years and have recurrence or not, one can then separate the “bad” from the “good” intermediate risk cancers. The next step is to evaluate a second group of patients where the outcome is not known to the investigators and see if the gene profiles obtained on some banked tissue allowed them to correctly predict what was going to happen. Different labs/companies have come up with different panels of genes using sophisticated algorithms that allow a large gene set to be reduced to a much smaller set of genes which can then be relatively economically tested. (note I said “relatively”…$3,820 may not be so economical if you are an insurance payor or Medicare and there is no evidence that the results of the test save money…)
For all of these tests, the question is what men and their doctors will do with the results. The report that comes back to the office is often in the form of a bar graph showing the percentage of men who progress, or who die with a certain “number” that is derived from all the gene expression profiling data. It has taken several years for any of these tests to outperform the Gleason scoring system, but now many of them really do add additional information. For example one man with a Gleason 7 cancer might have a score of “23″, look on a graph and find that his likelihood of having progressive disease is “34% at 5 years, 43% at 10 years” while another man would find a score of “62″ and find worse odds. If your odds are high of dying, do you then decide to do less aggressive therapy or more? If you have a Gleason 6 cancer and a low score, will it make you more likely to choose active surveillance or will the word “cancer” be enough that you want treatment regardless? And if you were going to want treatment regardless, then why did you get the test?
A more profound outcome that is already becoming reality for oncologists is the use of such testing not just for prognosticating, but for predicting responses to various therapies. Already, many of the newest “targeted drugs” are approved only in the setting where a mutation analysis or gene profile predicts that the drug will work in a given patient. In this case, the savings (both in toxicity and finances) can be huge. Why take an expensive drug for 4 months if there is a test that says it only has a 4% chance of working in you? Set against this paradigm is the remarkable heterogeneity of cancer in any one individual. Does a “negative test” really tell us about the whole cancer situation or only the situation about that small snippet of tumor removed for testing? The good news is we are making progress, and it is the exceptional research infrastructure supported by the NIH and organizations like PCF and Movember that allows it to happen.
For those of us who grew up in a certain era, the memory of “downwinders” will be etched in our cold war memories. The strontium -90 that found its way into bone was not good, but it did give rise to Sr-89 which has been used for more than a decade to treat bone metastases, especially for pain in patients who have one painful spot after another and this can replace going back and forth to an external beam facility.
Radium, the Nobel Prize winning isotope for Madame Curie, has several isotopes, one of which, Radium-223 has now been approved for treating prostate cancer. The main difference from Strontium or Samarium (another approved isotope) is that it is an alpha emitter. Alpha particles are in the category of “high LET” radioisotopes meaning they deliver enormous amounts of energy over short distances. Due to their mass, they also do not travel “through” most materials, but are stopped by the nucleus of most atoms. Thus a sheet of paper can significantly stop alpha particles, while beta particles, the main energy of Sr and Sm, travel farther, and deliver somewhat less energy.
The good news here, is that Radium 223, now dubbed “xofigo” (don’t ask me where the pharmas come up with these names except that all the ones starting with A-W must be taken…seriously…”xgeva”, “zytiga”…you must be kidding) has now been approved for treating prostate cancer bone metastases and is the first isotope to show prolongation of survival. Rather than rewriting a nice news report in Medscape, I will simply quote it here. You may be able to sign on to Medscape and read it there for yourself, but here is the quote:
A novel radiopharmaceutical agent has been approved by the US Food and Drug Administration (FDA) for use in the treatment of prostate cancer.
The product, radium-223 dichloride (formerly known as alpharadin), will be marketed as Xofigo by Bayer for use in men with symptomatic metastatic castration-resistant prostate cancer that has spread to the bone but not to other organs. It is intended for men whose cancer has spread after medical or surgical therapy to lower testosterone, according to the FDA.
The FDA reviewed the product under its priority program, which provides for an expedited review of drugs that appear to provide safe and effective therapy when no satisfactory alternative therapy exists or offer significant improvement over products on the market. It was approved more than 3 months ahead of schedule.
Radium-223 dichloride “binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research.
The product, administered once a month by intravenous injection, contains the heavy metal radium, which is taken up by osteoblasts and then emits alpha radiation. This causes double-strand DNA breaks that are lethal to the prostate cancer cell at the site of increased bone turnover induced by the cancer.
In a Medscape video commentary, Johann de Bono, MBChB, PhD, MSc, from the Royal Marsden NHS Foundation Trust in Sutton, United Kingdom, explained that radium-223 dichloride has minimal myelosuppression, is very well tolerated, and shows an impressive overall survival benefit.
The survival data come from the pivotal phase 3 ALSYMPCA trial, which involved 809 prostate cancer patients who were resistant to hormone treatment and had developed 2 or more bone metastases. All of the participants received standard treatment, but the men who also received radium-223 chloride lived significantly longer. An interim analysis revealed a median overall survival of 14.0 months, compared with 11.2 months (hazard ratio, 0.695; P = .00185), and the trial was stopped because of benefit.
An exploratory updated analysis confirmed the product’s ability to extend overall survival, according to the FDA.
The most common adverse effects of radium-233 dichloride seen during clinical trials were nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot.
Radium-223 dichloride is highly targeted for bone metastases, so it is possible that it could be used in many different cancers that have spread to the bone, regardless of primary site, said lead investigator Chris Parker, MD, consultant clinical oncologist at the Royal Marsden Hospital in London, United Kingdom. Prostate cancer patients were studied in the first instance because this cancer has a high tendency to metastasize to the bone, Dr. Parker explained. About 90% of patients with advanced prostate cancer will develop bone metastases and, in many cases, there will not be any detectable metastases elsewhere in the body, he said.
This brings to about 7, the number of new drugs we have for treating advanced prostate cancer in the past few years. Great news for our patients, especially if we can figure out a way to get the costs under control.
The incredible blowback from various urologists who didn’t share the USPSTF guideline on screening has now been answered by the urologists (or at least their professional organization) themselves. In their just released guidelines, there is a more nuanced approach, but a clear recognition of the risks involved with screening, and adoption of an age-gated approach. Here are the core statements from their website:
Guideline Statement 1: The Panel recommends against PSA screening in men under age 40 years. (Recommendation; Evidence Strength Grade C)
- In this age group there is a low prevalence of clinically detectable prostate cancer, no evidence demonstrating benefit of screening and likely the same harms of screening as in other age groups.
Guideline Statement 2: The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk. (Recommendation; Evidence Strength Grade C)
- For men younger than age 55 years at higher risk (e.g. positive family history or African American race), decisions regarding prostate cancer screening should be individualized.
Guideline Statement 3: For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves weighing the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a manâ€™s values and preferences. (Standard; Evidence Strength Grade B)
- The greatest benefit of screening appears to be in men ages 55 to 69 years.
Guideline Statement 4: To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision-making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce overdiagnosis and false positives. (Option; Evidence Strength Grade C)
- Additionally, intervals for rescreening can be individualized by a baseline PSA level.
Guideline Statement 5: The Panel does not recommend routine PSA screening in men over age 70 years or any man with less than a 10 to 15 year life expectancy. (Recommendation; Evidence Strength Grade C)
- Some men over age 70 years who are in excellent health may benefit from prostate cancer screening.
As I have stated elsewhere in this blog, screening is viewed differently by men who have already been found to have prostate cancer, for all kinds of reasons, not least because they wish they were in the happy group of men who are doing fine and may or may not need to be detected. (or they feel that screening saved their life or could have…)
The bottom line remains that the decision is individual, and that going through the pros and cons is not a short discussion in a family practice office, or even less in the line at the 9 Health Fair or similar. It will take you at least 15 minutes to read through the VERY thoughtful AUA statement, which is the best summary I have read in a long time.
Mark Rubin’s team is one of the premier molecular oncology groups in the world. A paper recently published in Cell, one of the most prestigious journals looked at the molecular events in prostate cancer. Since a picture is worth a thousand words, here it is:
I don’t have the time to go into this (never mind the intellect to do it well), but here is a quote on the paper from Urology Times:
A new closer look at genomes in prostate cancer has revealed that genetic mutations occur in abrupt, periodic bursts, causing complex, large-scale reshuffling of DNA driving the development of the disease.
Reporting their findings in Cell (2013; 3:666-7), study authors call this process “punctuated cancer evolution,” akin to the theory of human evolution that states changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, the authors named these periodic disruptions in cancer cells that lead to complex genome restructuring “chromoplexy.”
“We believe chromoplexy occurs in the majority of prostate cancers, and these DNA shuffling events appear to simultaneously inactivate genes that could help protect against cancer,” said co-lead investigator Mark Rubin, MD, of Weill Cornell Medical College and New York-Presbyterian Hospital/Weill Cornell Medical Center, New York.
“Knowing what actually happens over time to the genome in cancer may lead to more accurate diagnosis of disease and, hopefully, more effective treatment in the future,” said Dr. Rubin.
The discovery of “chromoplexy” came after the authors sequenced the entire genomes of 57 prostate tumors and compared those findings to sequences in matched normal tissue.
This study sequenced 57 prostate cancer genomes as well as the entire genomes of matched normal tissue. Researchers revealed a large number of genetic alterations in the prostate cancer cells—356,136 base-pair mutations and 5,596 rearrangements that were absent from normal DNA. Of those rearrangements, 113 were validated by re-sequencing and other methods.
“We saw wholesale rearrangements of chromosomes—the cutting up and retying of chromosomes—mutations we have never seen on that scale,” said co-author Levi Garraway, MD, PhD, of the Broad Institute, Cambridge, MA, and Dana-Farber Cancer Institute, Boston. “Our research teams then charted a path of oncogenic events that appeared to drive prostate cancer.”
Using advanced computer techniques that modeled the genomic rearrangements and copy number alterations, the authors inferred that the chromosomal disarray in a typical tumor might accumulate over a handful of discrete events during tumor development.
“The rearrangement of chromosomes can coordinately affect specific genes, which provides a selective advantage for cancer growth,” Dr. Garraway said.
So, your job is to let me know what the answer should be when I get the weekly question, “Doc, are we making any progress?” Or, “Is there anything new out there?” My current answer is “sure enough…but it ain’t simple!”
Since I actually grew a scraggly mustache and some of you contributed, I am dedicating this post to Movemeber. They just released a video you can watch here. I think the positive message is terrific, although I personally do not believe we will “put prostate cancer out of business” as Jonathan says. My reality is that cancer is a disease of aging and will always be with us. Prostate cancer is no exception. If we age, we accumulate DNA damage, although some studies suggest it is more the cellular response to DNA damage than the DNA damage itself that does us in. Our telomeres shorten, and our ability to whack the bad cells in us slowly gets weaker. 100 years ago, very few men lived long enough to get prostate cancer. Now, most men in developed countries will probably live long enough to do so as you can see from this table.
So, our goal is to leave the unimportant prostate cancers alone, and keep men who have the more aggressive ones alive and in good health for as long as possible. We have lots of new and developing tools to help us with this, and for the most part, I think prostate cancer is already a “chronic illness”, even though some of us, sure enough, will die from it. Fortunately, even now, that is only about 3/100 men. So keep exercising, don’t smoke, eat the right things, and die of something else if at all possible, and as late as your genes will let you.
Use of calcium supplementation is commonly discussed regarding the side effects of androgen deprivation therapy (ADT). ADT and menopause share the phenomenon of accelerated calcium loss from bones. Numerous studies demonstrate that men who are placed on ADT lose from 2-4% of the calcium in their spine during the first year of therapy. Because of this, and the general phenomenon of low vitamin D levels in all of us who use sunscreens more regularly, we recommend that men take vitamin D and calcium supplements when we start ADT.
The results of calcium loss are an increase in the risk of fracture. For example, in a study published in 2007 on 8577 men with prostate cancer who had similar fracture rates prior to treatment, the use of ADT increased the fracture rate from 14.6% to 18.7% over a 36 month observation period. Critiques of these kinds of studies abound. For example, the men who received ADT had more metastases and poorer health in general. Beyond that, in my patients, there is nothing close to 15% of men whom I follow for 3 years who have clinical fractures. How are these determined? Many times it is due to the increase in bone scans and x-rays which may pick up clinically insignificant fractures. Nevertheless, the fact that women in menopause and men after drug-induced andropause have increased calcium loss and fractures is well-established. It is also true that pharmaceutical companies have come up with effective drugs to combat this phenomenon – notably bisphosphonates (like zoledronic acid) and antibodies (like denosumab). An example in men on leuprolide can be found here. In all of these kinds of studies, the placebo/control groups were given calcium and vitamin D.
A mild controversy in this arena arose when publications pointed out an apparent increase in myocardial infarction in patients receiving calcium supplements. In one such study, evaluation of 5 trials in which calcium and vitamin D supplements were randomly assigned to >8000 patients, there were 143 patients with myocardial infarction among calcium users compared to 111 in those on placebo. This has given rise to the concerns expressed by some patients about the safety of calcium and vitamin D supplementation.
Although I am no expert in this area, there clearly are 100′s if not 1000′s of people who are (or who think they are). Ask them or read all of the literature (and DON’T miss clicking on that link…) you wish and reach your own conclusion. The recommendation for normal healthy adults is about 800IU/day of vitamin D as a supplement. You could start here if your concern is primarily about the heart attack risk. Or if you are most concerned about the fracture risk, start here. It is probably reasonable to know your 25-OH vitamin D level to be sure you aren’t deficient. 1000-2000 units of vitamin D/day seems like a reasonable supplement dose in patients who aren’t deficient. You should probably avoid calcium over-supplemntation if you have a history of kidney stones. Avoiding milk products may make sense (see this blog), so taking 1000-1500 mg calcium carbonate (chewable tums or equivalent) daily seems logical to me in patients on ADT who should probably avoid dairy products anyway.
There are lots of news releases coming out from the ASCO meeting. Click here to see an example. As is often the case, some of the novel findings make people nervous or excited, depending on the context. In this example, Howie Scher, who is the leader of the clinical prostate cancer program at MSKI, did a post-hoc analysis of corticosteroid use (prednisone, dexamethasone, etc) in patients on a study of enzalutamide (Xtandi). It appears the patients on steroids did worse than those who were not on steroids. The problem with these kinds of headlines is that the situation/biology/patients are more complicated than the headlines. Often patients who are on steroids have worse disease (more pain, spinal cord metastases, etc.) and are just plain “sicker”. There are volumes of articles/literature suggesting patients may actually respond favorably to steroid use in many situations. We used daily low dose dexamethasone along with low dose cyclophosphamide in a trial that showed excellent psa responses, and in the 1990′s trials with some agents were found to be “positive” largely due to the inclusion of corticosteroids. So the timing and the context of steroid use can be very important in determining outcomes for prostate cancer patients.
In any case, the meeting was very informative with lots of new material. For the true “junkies” wanting new information, you can see all the abstracts here. I would be happy to try and expand or explain any of the abstracts you might find interesting to the best of my ability. It was fun meeting with all of the “old guard” prostate cancer researchers this year and it is an exciting time with the many new drugs, new approaches and young investigators entering the field.