Predicting Prostate Cancer’s Future Behavior

BY MARK SCHOLZ, MD


Developing an accurate prognosis, i.e., predicting how a man’s cancer is likely to behave in the future, is the first and most important step toward optimal care. Future predictions are often looked at with some suspicion. With prostate cancer, however, our power to anticipate future cancer behavior is quite accurate unless there is a lack of thoroughness in gathering information.

The Size of the Tumor
Tumor size is a universally important prognostic sign for almost all types of cancer including prostate cancer. The method for incorporating tumor size into the Anthony D’Amico’s staging system relies on the degree of PSA elevation, the tumor grade and on how the prostate "feels" with the finger of a trained practitioner. These indicators are useful but don’t incorporate information from modern imaging. Imaging provides accurate information about tumor size and the presence or absence of extracapsular extension. These are very powerful prognostic predictors and it would be foolish to disregard their importance. As things stand presently these indicators are often used to divide the low, intermediate and high risk categories into "favorable" and "unfavorable" subcategories, each with a different spectrum of recommended treatment options.


Knowing Past Treatments Tells Something about Future Prognosis
Historically, since the total number of available treatments is relatively limited, practitioners have used a sequential "trial and error" treatment methodology that administers the standard treatment options in a fairly predictable sequence. For example, it is not uncommon for men to start with surgery or radiation. When a relapse occurs, standard hormone therapy (Lupron) is often started and given intermittently or continuously. Hormone therapy usually controls the disease for an average of 10 years. When Lupron stops working, immunotherapy with Provenge is usually follows. After Provenge, more potent hormone therapy with Xtandi or Zytiga is started. If these two agents prove ineffective, chemotherapy with Taxotere or radiation with Xofigo would be considered next.

The whole point of presenting the treatment sequence described in the previous paragraph is to convey the idea that the number of previous treatments communicates important information about that patients’ future prognosis. Having "failed" Lupron, for example, bespeaks of a much more worrisome prognosis compared to the situation where Lupron continues to be effective.


Response to Lupron, The Mother of All Metrics
The quality of the "response" to Lupron is actually one of the most powerful prognostic metrics available. The degree of PSA decline after Lupron is incredibly important. How low the PSA drops after starting Lupron is called the "PSA nadir." The specific PSA threshold used to determine a "good response" is less than 0.1. Believe it or not, there is a huge difference in prognosis between a man on Lupron for six months who has a PSA of 0.1 versus a man whose PSA levels off at 1.0.

An Established History is also a Prognostic Indicator
Another somewhat obvious prognostic indicator that is often overlooked and almost never discussed in textbooks has to do with the prognosis of men who have been diagnosed years ago -- over time it is apparent that things are turning out much better than what might have been expected based on their initial indicators. For example, take the case of a man who started off with a panoply of bad indicators—tumor is in the lymph nodes and Gleason 10—but after aggressive treatment remains in remission for 5 years. The fact that things have gone well for five years counts bigtime in his favor going forward. Remember, the original prognostic predictors of a Gleason 10 were just that, predictors. No predictor is 100% accurate. Five years of established history is a stronger predictor than the original Gleason score. The fact that things have gone well for five years, strongly indicates that the future is for that individual is bright. Such individuals have "beaten the odds."

The Location of the Tumor in the Body
Another extremely important indicator of prognosis, something that even laypeople anticipate by simple common sense, is the location of the cancer in the body. Location says volumes about how things are likely to progress in the future. For example, consider the following sequence of progressively more serious cancer sites:

•Contained within the prostate
•Extended into the seminal vesicle
•Spread to the lymph nodes
•Bone metastases
•Liver metastasis

Each of these locations is very important for determining prognosis.

This short blog is just an introduction to some of the "profiling" methods utilized in generating an accurate prognosis. Space limitations preclude discussion here about other known prognostic factors such as the size of the prostate gland (discussed in a previous blog), genetic tests and PSA doubling time. The D’Amico risk categories constitute the backbone of useful prognostic information. However, the additional prognostic information beyond the D’Amico risk categories that are discussed in this blog, provide additional useful information necessary for determining an accurate prognosis. An accurate prognosis is the starting point for accurate selection of treatment.

Androgen Deprivation Therapy for Prostate Cancer Causes Alzheimer’s Disease?

BY MARK SCHOLZ, MD


Dr.Kevin Nead authored an article published in the Journal of Clinical Oncology this month.  It created a media sensation and generated multiple calls to the PCRI Helpline.  Last week, three separate articles about this topic were posted on the Yahoo home page at the same time.


It’s no surprise that an article on this topic generates wide-spread interest. About 500,000 thousand men in the United States are undergoing prostate cancer treatment with androgen deprivation therapy (ADT). This treatment works by blocking the male hormone levels delivering notable anticancer efficacy and also proven to prolong life in men with prostate cancer. Despite it’s known effectiveness, a variety of side effects can occur, including memory problems.  The previously reported studies evaluating this phenomenon seem to indicate that when memory deficits occur, they usually reverse after ADT is stopped.
The research published in the Journal of Clinical Oncology, relied on a new method of searching through patient’s medical charts with computers.  No human review of these medical charts were performed. The computer software searched the medical records in an attempt to determine if men on ADT had a higher incidence of Alzheimer’s. The authors report that this new computer searching methodology in detecting a specific medical diagnosis is 74% accurate.


Review of all the charts at Stanford and Mount Sinai hospital unearthed 16,888 prostate cancer patients of which 2,397 were treated with ADT.  After the fancy computer analysis, designed to compensate for multiple factors such as patient age and underlying heart disease (both of which lead to Alzheimer’s more frequently), the conclusion was that the ADT-treated men were twice as likely to have developed Alzheimer’s. A total of about 9 cases would have been expected from normal causes, but 18 were actually detected.  If these conclusions are accepted as gospel truth, an additional 9 out of 2,397 men treated with ADT would equate to an increased risk of less than half of 1%.


The conclusion that there is tiny increase risk of Alzheimer’s with ADT, needs to be put in context based on what we already know about prostate cancer. First, is it possible that these men have reversible memory problems while still taking ADT? There was no attempt in the study made to determine if the “Alzheimer’s” patients were still on ADT when the diagnosis of Alzheimer’s was made. Second, men treated with ADT are substantially sicker than men who don’t need ADT.  There is no way for the computer analysis to compensate for how this may have impacted mental performance. Third, patients getting ADT receive closer medical surveillance and visit physicians more frequently than men who are not receiving ADT.  As such, memory problems are more likely to come to medical attention and be diagnosed when men are on ADT.  Fourth, general anesthesia (from surgery) is known to cause long-term memory problems.  This study did not perform any analysis to determine if surgery was performed with equal frequency in both groups.


In summary, it is not clear from this JCO article whether the men labeled having Alzheimer’s disease had memory problems while still receiving ADT or whether they had true Alzheimer’s, i.e., long-term irreversible memory problems continuing after the ADT was stopped. There is one thing, however, this study does show: At worst, memory problems serious enough to be labeled as “Alzheimer’s” occur in in less than one out of every 200 men treated with ADT.

Sir Spheres for Liver Metastases from Prostate Cancer

BY MARK SCHOLZ, MD

Cancer that spreads outside the prostate gland is what makes prostate cancer dangerous. Metastatic prostate cancer cells cause malfunction by impeding normal function. Some organs, like lymph nodes for example, continue to function quite nicely, even if the degree of cancer spread is extensive.  Lymph node spread, therefore, is the least dangerous form of prostate cancer metastases.  At the other end of the spectrum is the liver, which is far less tolerant.  The seriousness of bone metastases, the most common site of prostate cancer spread, lies about half way between that of node metastases and liver metastases.


The earliest stages of metastases are microscopic and therefore invisible even with the best available technology. To be detected with the best available PET scan technology, small tumors must measure more than 1/8 of an inch across. For detection with standard CT scans and MRI scans, more than a half-inch sized tumor is necessary. Since the presence of metastases is such a defining issue when describing a cancer’s character, men who are newly-diagnosed are labeled as low, intermediate or high-risk depending on their estimated likelihood of micro-metastatic disease. Liver metastases are extremely rare at the time of initial diagnosis of prostate cancer. When they occur it is usually after many years of ongoing treatment for known metastatic disease in the bone.


Prophylactic treatment with hormone therapy, chemotherapy or radiation to treat the possibility of micro-metastases is common for high-risk prostate cancer and occurs maybe half the time in intermediate-risk prostate cancer. The goal is to cure the micro-metastases at an early stage when they are most susceptible to eradication, thus preventing the future development of detectable metastases which is what makes cancer life threatening.


When talking about prostate cancer, even though this is a blog about metastases, it should always be remembered that many common types of prostate cancer never spread. These low grade “cancers” are genetically distinct and represent a totally different category of disease.  However, when discussing the type of prostate cancer that is capable of metastasis, the following factors impact how dangerous it is:

1. The site of spread.
2. The extent of spread
3. The tumor cell growth rate
4. The efficacy of available treatment

As noted above, the liver is far less tolerant to metastatic invasion than bone or lymph nodes.  In addition, because liver metastases tend to occur in men with advanced disease, tumor growth rates tend to be brisk. Also, the most commonly administered treatments, hormone therapies and chemotherapy, have often already been tried before liver metastases first develop. The advent of liver metastases, therefore, usually represents a very serious and life threatening issue.


Liver metastases may first be suspected when standard blood tests such as ALT, AST or ALP which are components of a hepatic panel blood test, register outside the normal range. Investigation into their cause often leads to doing a CT scan or MRI scan of the abdomen and pelvis to confirm the presence of disease in the liver. Alternatively, a scan may detect abnormal spots in the liver during routine periodic scanning that is being performed as regular surveillance.


Hormone therapy with Lupron, Zytiga and Xtandi, or chemotherapy with Taxotere, Jevtana and Carboplatin, is the standard approach to treatment for liver metastasis.  However, these treatments may have already been tried or may no longer be effective.  Since liver failure is tantamount to death, prostate cancer growth in the liver needs to be stopped immediately, regardless of how the disease is faring in the bones or nodes.


Much that has been learned about the treatment of liver metastases comes from reviewing common methods for managing metastatic colon cancer. The liver is the cancer’s preferred site of metastatic spread for colon cancer.  Treatments that have been employed include surgery, radiation and blockage of the blood supply to the liver by embolization of the arteries, all with variable success.  More recently, radioactive microspheres injected directly into the tumor, called SIR-Spheres, have shown notable efficacy with very tolerable side effects.


Prostate cancer and colon cancer are similar in that they are both adenocarcinomas which means they are derived from glands. Therefore, they are likely to have similar susceptibility to radiation.  As such, we have been administering SIR-Spheres to a limited number of prostate cancer patients with liver metastases.  Results have been encouraging with a notable improvement of survival compared to our historical experience treatment patients with liver metastases without SIR-Spheres.  Our preliminary results using SIR-Spheres in six patients is being presented at the 2016 Genitourinary Cancers Symposium - San Francisco in January 2016.