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.”
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.
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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.
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.
Trio of dolphins in Gulf of Mexico at Everglades National Park, Florida; BJ Gabrielsen photo.
Imagine God or Jesus Himself writing this to you. “Every time you affirm your trust in Me, you put a coin into my treasury. Thus you build up equity in preparation for days of trouble. I keep safely in My heart all trust invested in Me, with interest compounded continuously. The more you trust Me, the more I empower you to do so.
Practice trusting Me during quiet days when nothing much seems to be happening. Then when storms come, your trust balance will be sufficient to see you through. Store up for yourself treasure in heaven” (Matthew 6:20-1) “through placing your trust in Me. This practice will keep you in My Peace.”
Psalm 56:3-4: “When I am afraid, I will put my trust in Thee. In God, whose word I praise. In God I have put my trust; I shall not be afraid.”
The excerpt above was taken from January 10th, “Jesus Calling” by Sarah Young; Thomas Nelson publisher.
ODM-201 (also known as BAY-1841788) is a non-steroidal, oral anti-androgen (specifically a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer Healthcare for the treatment of advanced, hormone-resistant prostate cancer. [An antagonist is a drug (blocking agent) that binds to the cellular receptor for a hormone (e.g. testosterone) thus blocking the effect of the hormone without producing any physiologic effect itself.] Bayer HealthCare and Orion Corporation have begun to enroll patients in a Phase III trial with ODM-201. The study, called ARAMIS, evaluates ODM-201 in men with hormone-resistant prostate cancer (CRPC) who have rising Prostate-Specific Antigen (PSA) levels and no detectable metastases. The trial is designed to determine the effects of the treatment on metastasis-free survival (MFS). The trial is being conducted at 502 locations in the US. For enrollment and location information see the following clinicaltrials.gov link.
The ARAMIS trial is a randomized, Phase III, multicenter, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral ODM-201 in patients with non-metastatic CRPC who are at high risk for developing metastatic disease. About 1,500 patients are planned to be randomized in a 2:1 ratio to receive 600mg of ODM-201 twice a day or matching placebo. Randomization will be stratified by PSA doubling time (PSADT < 6 months vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. no). In men with progressive non-metastatic CRPC, a short PSA doubling time has been consistently associated with reduced time to first metastasis and death.
The primary endpoint of this study is metastasis-free survival (MFS), defined as time between randomization and evidence of metastasis or death from any cause. The secondary objectives of this study are overall survival (OS), time to first symptomatic skeletal event (SSE), time to initiation of first cytotoxic chemotherapy (such as taxotere), time to pain progression, and characterization of the safety and tolerability of ODM-201.
A Phase II clinical trial conducted in patients with progressive metastatic castration-resistant prostate cancer assessed the efficacy and safety of three dose levels of ODM-201 (100mg, 200mg and 700mg given twice a day) in 124 patients. The study included patients who were treated previously with abiraterone and/or chemotherapy as well as patients who were chemotherapy-naïve. The results showed that ODM-201 provided disease suppression and had a favorable safety profile. The results were presented at the international ECCO oncology congress at the end of September 2013 and published in June 2014 in The Lancet Oncology.
Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent non-steroidal antiandrogens, ODM-201 shows some advantages. ODM-201 appears to negligibly cross the blood-brain barrier. This is beneficial due to the reduced risk of seizures and other central side effects that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide.Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone levels in mice or humans, unlike other non-steroidal antiandrogens. Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation that produces resistance to enzalutamide and ARN-509. ODM-201 has been studied in phase I and II clinical trials and has thus far been found to be effective and well-tolerated with the most commonly reported side effects including fatigue, nausea and diarrhea. No seizures have been observed. As of July 2015, ODM-201 is in phase III trials for CRPC. For more specific information, see the following link.
A new study published in the Journal of Urology suggests that anxiety may prompt prostate cancer patients to opt for potentially unnecessary treatments.
The research included more than 1,500 men newly diagnosed with localized prostate cancer. They were more likely to choose surgery and radiation therapy than active surveillance. Active surveillance — also known as “watchful waiting” — is when the patient is monitored closely, but not treated.
“Men’s level of emotional distress shortly after diagnosis predicted greater likelihood of choosing surgery over active surveillance,” said the researchers from the University at Buffalo and Roswell Park Cancer Institute in Buffalo, N.Y.
“Importantly, this was true among men with low-risk disease, for whom active surveillance may be a clinically viable option and side effects of surgery might be avoided,” they noted.
Though the study found an association between anxiety and more aggressive treatment, it didn’t prove cause and effect.
“Emotional distress may motivate men with low-risk prostate cancer to choose more aggressive treatment,” said study author Heather Orom, an associate professor of community health and health behavior at the University at Buffalo.
“If distress early on is influencing treatment choice, then maybe we help men by providing clearer information about prognosis and strategies for dealing with anxiety. We hope this will help improve the treatment decision-making process and ultimately, the patient’s quality of life,” Orom said in a university news release.
Study co-author Dr. Willie Underwood III, an associate professor in Roswell Park’s department of urology, said that to help men and families through this difficult process, “it is helpful for physicians to better understand what is motivating men’s decisions and to address negative motivators such as emotional distress to prevent men from receiving a treatment that they don’t need or will later regret.” Overtreatment is a concern because surgery and radiation therapy can cause side effects such as erectile dysfunction and incontinence. These problems can be avoided in men with low-risk prostate cancer by choosing active surveillance, the researchers said.
