Yervoy Fails to Shut Down Prostate Cancer But Could Be Used in Combination Therapy

A recent article from Prostate Cancer News Today (April 4th) stated that Yervoy (ipilimumab) showed little benefit when administered to 16 patients awaiting surgery with locally advanced prostate cancer at the University of Texas M.D. Anderson Cancer Center. The study was published in Nature Medicine.

Ipilimumab (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. It is currently undergoing clinical trials in metastatic, hormone-refractory prostate cancer among other cancers. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. Specifically, it targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), preventing the antigen from interacting with its ligands and thereby activating the patient’s own immune system by causing these T-cells to potentially combat tumor cells. More simply, Yervoy blocks a switch that turns off an anti-tumor cellular response. Therefore, Yervoy is an agent that “blocks a blocker” thereby aiding the immune system to fight the tumor. The bad news however is that prostate cancer responds to Yervoy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a “don’t-eat-me signal” to immune cells. That reaction is why Yervoy, by itself, offers little patient benefit.

Yervoy increased the numbers of T-cells in tumors, as well as another kind of immune cell, macrophages. But researchers also discovered that the tumor cell tissue had two proteins on their surfaces, PD-L1 and VISTA, that were not there before treatment. These proteins are called immune checkpoints because they can stop the chain of events that lead to an immune reaction. Basically they signal the shutdown of T-cells in the tumor environment. These results are prime examples of the dynamic state of the immune system; when a change is made in one specific area, it may manifest itself in other areas simultaneously. It is like trying to alter one card while not changing other cards comprising a house of cards.

“Observing immune response at one point in time doesn’t reflect what’s going on because the immune system is so dynamic,” said Dr. Padmanee Sharma, a professor of genitourinary medical oncology and immunology at the University of Texas MD Anderson Cancer Center. You can change the immune response with Yervoy, but what else changes becomes incredibly important.

Compressing Eight Weeks of Radiation Into Four Weeks Is Just As Effective in Treating Localized Prostate Cancer

I received the following article by e mail from a recent issue of Prostate Cancer News Today. I am posting it however I urge the reader to discuss the findings cited herein with a radiation oncologist if it may apply to your treatment.

According to an article published in the April 1st, 2017 edition of the Journal of Clinical Oncology, four weeks of radiation therapy at larger doses has the same effect as conventional radiation therapy administered to prostate cancer patients over eight weeks, according to results from a Phase 3 randomized clinical trial of 1,206 men in Australia, Canada and France. The findings provide a new standard of care for men at intermediate risk of prostate cancer. The PROFIT Phase 3 trial (NCT00304759) followed participants for a median of six years.

“External beam radiation, a treatment option for localized prostate cancer, is commonly used alone for men with intermediate-risk disease. The treatment is typically delivered in 37 to 42 sessions, given five days a week over the course of 7.5 to 8.5 weeks. Studies have suggested that hypofractioned radiation therapy, given over a shorter time with larger doses per fraction, is also an option, but some experts raised concerns about increased toxicity and reduced tumor control. Even so, modern radiation therapy techniques are highly specific and can deliver hypofractioned radiation therapy without increased toxicity by avoiding radiosensitive normal tissues. Researchers hypothesized that hypofractioned radiation therapy given in 20 fractions over four weeks would be similar in efficacy — and without increased toxicity — to standard radiation therapy, delivered in 39 fractions over eight weeks.”

Co-principal investigator Charles Catton, a radiation oncologist at Toronto’s Princess Margaret Cancer Centre, stated that “using modern radiation therapy techniques that are very precise, we determined there was no noticeable difference between eight- and four-week treatment regimens in terms of cancer control or side effects of treatment. In fact, for some men, the shorter regimen meant slightly fewer side effects (particularly regarding bowel function) and therefore improved quality of life. The compressed course of treatment is of great benefit to patients and also to the system in terms of being able to treat more patients in less time.”

Men in Their 20’s and 30’s With a Specific Early Balding Pattern May Be at Higher Risk of Aggressive Prostate Cancer

When I come across a newsworthy article of interest, I usually summarize it on this post and link the reader to the entire article for more information. This is an exception as the original article from the Prostate Cancer Foundation (March 30th, 2017) contains specific visual and verbal information; hence I refer you to the following link.

Finding Useful Prostate Cancer Clinical Trials

Clinical trials are on-going at many institutions across the United States. Many men think about enrolling in a clinical trial only when there are no further treatment options for them. But trials are not just for advanced stages of disease. They can also include men recently diagnosed and treated. The trials cover areas such as screening, diagnosis, imaging and scans, quality of life, as well as surgery, radiation and other specific treatments and combinations. At some time, you might want to go to the clinicaltrials.gov site, and enter your pertinent areas of interest under “Search for Studies”. Hundreds may appear but they can be filtered under categories such as “recruiting”, “active not recruiting”, “completed”, “terminated” etc. You can also search them by location as well. You might want to ask your physician to demonstrate the site by incorporating your specific health status and generating a shorter list of pertinent recruiting trials.  An excellent review of clinical trials (see the link) was recently published online by the Prostate Cancer News Today. It is concise and informative but will not be summarized here. The article also leads the reader to a Bayer Oncology Clinical Trial Finder wherein you can enter specific data and a listing of available trials can be sent to you. There is a wealth of information here and the reader is urged to spend some time perusing these sites. They also provide a picture of the current cutting-edge areas of research.

When God Does Not Heal

Baby robins bathing on way north in late February, 2017; Photo: BJGabrielsen

“Trust in the Lord with all your heart and do not lean on your own understanding. In all your ways, acknowledge Him and He will make your paths straight.” (Proverbs 3:5-6).

If God is all-powerful, why do we witness so few miraculous healings? There are many reasons for this. Sometimes we do not ask Him. Other times, we might ask but with wrong motives or a lack of faith. And then there is the reason that we do not like to hear: God may choose not to heal.

Beware of theology that promises healing to anyone who asks. This is not biblical. The problem is not inability; God is able to heal anyone and anything. And be careful if someone claims the lingering illness is the result of sin. This may be true, but often our heavenly Father, in His great love and unfathomable wisdom, allows our ailments to persist.

Consider Paul, who asked the Lord three times to remove his “thorn.” (See 2 Corinthians 12:7-8.) Yet it remained. We can learn from his response—he did not question God’s authority, nor did he complain. Instead, recognizing that divine strength would show through his weakness, Paul trusted God.

We, too, can believe that God will work all things for good in His children’s lives (Romans 8:28). In fact, character growth usually occurs in times of suffering, loss, or hurt. While adversity is uncomfortable, we can feel hope and joy in what our Father is accomplishing through painful times.

Ultimately, God brings glory to Himself and good to His children. There are instances when this involves miraculous healing, but He often refines us by allowing the hardship. As with silver and gold, impurities are usually removed from hearts in the fiery furnace of life’s struggles. Trust God’s plan and rest in His love.

From Dr. Charles Stanley, In Touch Daily Devotional, January 13th, 2017.

Help For Our Healing

God cares about our physical well-being. After all, He made our bodies as a temple for His Spirit. And while He is able to heal sickness, His original intention was not for His perfect creation to experience disease.

But in this sinful world, ungodly choices at times lead to illness. So when we’re afflicted, it’s wise to ask God to search our heart and reveal anything He wants us to address (Psalm 139:23-24). Since sin can act like a blockage to prayer (Psalm 66:18), confessing any known wrongdoing is also a good idea.

Most of the time, though, health problems are just part of our human condition—a symptom of mankind’s fallen state rather than evidence of personal sin. The truth is, disease affects just about everyone at some point. So how does God want us to respond?

Certain situations, of course, require prompt medical attention, but even in a crisis, our Father wants us to be aware of His presence and to stay in communication with Him (“pray without ceasing”, 1 Thess. 5:17). Developing a pattern of prayerfulness before an emergency occurs is the best way to prepare for the unexpected.

The Bible’s instructions also include praying for one another and calling the elders of the church to come and pray, anointing the afflicted person with oil in Jesus’ name. (See James 5:14).

Our Father is able to heal even the most deadly disease, but He sometimes chooses to allow the condition to remain. When requesting restored health, we should ask with faith and trust—faith in God’s ability but trust in His perfect will, whether that means healing or suffering-induced growth.

See James 5:13-20. This devotional by Dr. Charles Stanley was published on January 12th, 2017 in the In Touch Devotional Magazine.

Hormone Therapy (Androgen Deprivation) Not Found to Increase the Risk of Dementia, Alzheimers.

Recent studies summarized on this website on December 30th, 2015 and November 7th, 2016 concluded that hormonal therapy of prostate cancer was linked to an increase in dementia and Alzheimer’s disease. Now a recent study published in the Journal of Clinical Oncology and summarized in the February 6th, 2017 e mail issue of Prostate Cancer News Today has concluded the opposite, namely that prostate cancer patients receiving androgen deprivation therapy (ADT) are not at increased risk of dementia or Alzheimer’s disease.

Cognitive impairment is a known side effect of declining testosterone, in general, so it is naturally of concern with ADT. However the study authors noted that “there is a significant difference between cognitive limitations and the biological mechanisms associated with dementia.” Because ADT is so often given to older men, very careful statistical analysis is required to assert a causal relationship.

Using data from the United Kingdom’s Clinical Practice Research Datalink (CPRD), researchers analyzed the medical records of 30,903 patients diagnosed with nonmetastatic prostate cancer over 27 years. During a mean follow-up of 4.3 years, 799 patients were diagnosed with dementia. Researchers did not find a link between ADT and the condition. Secondary analyses — assessing whether the risk varied with the type of ADT or length of use — also failed to show a connection. There are side effects to every medication. The authors note that “if patients believed that ADT doubled their risk of Alzheimer disease they may be reluctant to take it for their cancer. Thus, our analysis should be welcome news for men whose prostate cancer is being controlled with ADT.”

Please Consider Subscribing to and Commenting On This Website

Inter-coastal waterway and banyan tree landscape; Boca Grande, Florida; Photo: BJ Gabrielsen

This post was originally sent on Feb 21st. Another post (about Decipher) was sent the same day which generated some confusion. Hence I am trying to separate them the sake of clarity. Please forgive the confusion as both posts are important.

Godandprostate.net contains posts that deal with both medical (prostate cancer) and spiritual issues. Every blog may not be applicable to your personal situation or interest but hopefully, occasionally one might be very useful. Therefore, please consider subscribing to the blogs by e mail as they are posted. If a specific subject title does not apply, just delete it. Simply go to the home page and write your e mail address in the area on the right side of the page under “get blog posts by e mail.” Your personal comments to a specific post are always welcome and often published.

Predicting Prostate Cancer Metastasis and Mortality Using Decipher Genomic Score

The Decipher prostate cancer gene-expression classifier can predict patients’ risk of metastasis and prostate cancer-specific mortality (PCSM) using biopsy specimens prior to radical prostatectomy or radiotherapy plus androgen (hormonal) deprivation, according to a mixed-cohort study presented at the 2017 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held February 16–18 in Orlando, Florida.

Decipher is a 22-gene metastasis risk-predicting RNA gene expression signature designed for use after radical prostatectomy, using surgical specimens, to provide adjuvant or salvage treatment decision making. Decipher is one of several commercially-available genomic tissue tests (including Prolaris and Oncotype DX) used to help determine prostate cancer aggressiveness.

The Decipher signature includes gene markers for cell cycle proliferation, adhesion and motility, immune modulation, and androgen signaling pathways. Previous studies have evaluated the use of Decipher after radical prostatectomy. The authors of the new study sought to assess the Decipher classifier’s prognostic utility when used earlier, with biopsy specimens, in order to inform initial treatment decisions.

The team studied mortality and metastasis among 175 patients treated with radical prostatectomy at the Cleveland Clinic or Johns Hopkins or radiation plus androgen deprivation therapy (ADT) at Dana-Farber in Boston. Just over half of the patients’ cancers were deemed to be intermediate-risk, 33.7% were high-risk. Only 13% of cohort patients had low-risk prostate cancer. At a follow-up of 6 years, 32 patients had developed metastatic disease and 11 had died of prostate cancer.

The classifier scores did correlate with the risk of metastasis. According to Dr. Paul Nguyen, the lead investigator from Dana-Farber, “the 5-year distant metastasis risk by Decipher score showed that the high-risk patients had a 23.4% risk of 5-year metastasis, the intermediate-risk patients had a 9.3% risk of metastasis, and the low-risk patients had a 5% risk of metastasis at 5 years.” There was no difference in outcomes between patients treated with radical prostatectomy and those treated with radiotherapy and androgen inhibition. For low and intermediate risk patients, the Decipher score also stratifies the risk of distant metastasis and “in fact, identifies a very high-risk group for distant metastasis that developed a 33.1% risk of metastasis at 5 years,” Nguyen said.

The Decipher test has prognostic value, but more work is needed to demonstrate its predictive value. That will require randomized clinical trials comparing different treatments. The full article appeared in the February 17th e mail issue of cancernetwork, home of the journal Oncology.

For further information on Decipher, see the following link.

Identifying Suitable Candidates for Active Surveillance in Prostate Cancer

This review is designed for physicians and patients who have access to multiparametric MRI technology available in several major health research institutions.

A recent article by Drs. Peter Choyke and Stacy Loeb  (from the National Cancer Institute, NIH) in the journal Oncology and e mailed through the CancerNetwork provided a important summary of active surveillance, a safe, appealing approach that spares radical treatment and does not increase disease-specific mortality. However, the authors conclude that current methods of identifying low-risk patients are flawed and cannot always accurately predict candidates for active surveillance. In the article, the authors focus on the role of active surveillance for patients with low-risk disease and how multiparametric MRI (mpMRI) can impact decision making for entering and monitoring patients on active surveillance. The article is written mainly for physicians and should be discussed with them if you are considering active surveillance as an option.

The active surveillance decision-making process begins with a prostate biopsy, for which there are two main triggers: elevated PSA and/or a palpable lesion on digital rectal examination. The current standard of care is to obtain a 12-core biopsy under transrectal ultrasound (TRUS) guidance, in which two samples are obtained from the apex, the middle, and the base of the prostate on two sides (six samples per side). Each sample is interpreted by a pathologist using the Gleason scoring system ranging from 3+3 to 5+5. Patients who harbor low-volume 3+3 tumors or 3+4 tumors with only a small percentage of grade 4 are eligible for active surveillance. The use of active surveillance in the United States has increased in recent years, with over 40% of low-risk tumors managed in this manner, and even higher rates for men over 75 years of age. Active surveillance is different from watchful waiting, which is usually reserved for elderly men with reduced life expectancy. In watchful waiting, the physician will not perform serial tests such as biopsies because there is no curative intent, so treatment is only given for symptomatic progression. In contrast, active surveillance infers that the patient is followed with a schedule of serial PSA tests and biopsies, with the latter meant to detect patients who convert from a low-grade to an intermediate- or high-grade tumor over time.

Implementing active surveillance varies with the medical  institution and presents its own problems. At this point, for this discussion, I would refer you the reader to the linked section entitled “Implementing Active Surveillance”.

The next section discussed the role of mpMRI in identifying active surveillance candidates. mpMRI can identify lesions missed by the standard TRUS biopsy or can more properly characterize cancers detected at TRUS biopsy. “Because a standard TRUS-guided biopsy predominantly samples the posterior peripheral zone, the rest of the gland is undersampled. Moreover, since TRUS-guided biopsies are really blind samples of the prostate, tumors in the posterior peripheral zone may be incompletely sampled or their size greatly underestimated. Therefore, before placing a patient on active surveillance, we perform an MRI to identify any lesions that were potentially missed or undersampled. In the case of active surveillance candidates, approximately 20% to 30% of patients who were initially considered good candidates for active surveillance are directed toward active treatments such as surgery or radiation as a consequence of finding additional lesions or resampling known lesions with MRI guidance. For patients in whom the MRI is negative or reveals nothing more than was discovered by TRUS biopsy, active surveillance is an excellent choice. Thus, an initial MRI followed by MRI-TRUS–guided biopsy has become routine in our institutions to identify patients who are ideal candidates for active surveillance. This provides greater assurance to the clinician and patient that the proper management has been selected.”

“It would seem logical that MRI could also be used in place of repeat biopsies to monitor patients who are on active surveillance. Although this is a very attractive possibility for patients due to the risk and burden associated with multiple biopsies over time, good long-term data are not yet available to support this policy. In our own institutions, MRI is commonly performed on a routine basis (annually in the case of the National Cancer Institute), and changes in the appearance of the MRI can trigger a repeat targeted biopsy.” …..” In our own experience, the vast majority of active surveillance patients who have an initial qualifying MRI and MRI-TRUS biopsy exhibit minimal or no change in their MRI over many years, making this approach quite promising.”

A variety of other commercially available serum, urine, and tissue biomarkers have been introduced to help clinicians decide whether to initiate and maintain a patient on active surveillance. Their value relative to MRI has not been tested adequately to draw conclusions as to whether these can be used in place of MRI or as an adjunct to MRI. One of these serum markers is the Prostate Health Index, which combines total, free, and proPSA using a mathematical formula. This test was previously shown to predict changes on biopsy in men on active surveillance, and in the future might be used to monitor patients in conjunction with mpMRI.  Several genomic tissue tests including Prolaris, Oncotype DX, and Decipher are also commercially available to help determine aggressiveness beyond the information provided by Gleason score. These may be used to help assess eligibility for active surveillance in borderline cases such as high-volume Gleason 6 or low-volume Gleason 3+4; however, there are no published data on their utility for monitoring during surveillance, and they require tissue from a biopsy.”

The authors conclude that “active surveillance is an excellent alternative to surgery or radiation in patients with low-risk cancers. However, the current methods of ascertaining whether a patient harbors a low-risk cancer are flawed, and data obtained by PSA or traditional TRUS biopsy do not accurately predict good candidates for active surveillance. MRI- and MRI-TRUS–guided biopsies of the prostate appear to assist in the decision to place a patient on active surveillance by detecting lesions outside the normal biopsy template or by providing more information about a lesion within the potentially undersampled template. Less certain is the role of MRI in delaying or eliminating subsequent biopsies, although it is increasingly being used in this manner, since repeat prostate biopsies are a source of patient noncompliance. The role of other new biomarkers in the decision-making process and their utility compared with MRI remains to be determined. What is most encouraging is that more men can now safely and confidently delay or avoid unnecessary radical surgery for low-risk prostate cancers and retain a high quality of life even with a prostate cancer diagnosis.” The full article can be accessed in this link.