Taxotere (docetaxel®) and taxol are plant alkaloids derived from the European yew tree, Taxus Baccata. Taxotere is synthetically obtained by chemically converting a precursor extracted from the needles of the yew plant. Administered intravenously, both are used to treat several malignancies including breast, stomach, lung, ovarian and prostate cancers. Clinical trials completed in 2004 demonstrated that taxotere increased survival in hormone-resistant (refractory) prostate cancer patients. An excellent, updated review of taxotere in prostate cancer was recently published in the August, 2014 issue of the Prostate Cancer Research Institute (PCRI) Insights. The review article discussed taxotere’s mechanism of action, dosages and protocols of administration and significant side effects. Importantly however, it cited a recent study of 800 men with hormone-sensitive prostate cancer. The study concluded that taxotere’s beneficial effects may be even further enhanced by administering it at an earlier stage in men with newly-diagnosed, high-risk disease or men with hormone-sensitive, metastatic disease. Significant side effects include peripheral neuropathy, anemia, fatigue, hair loss, lowered white blood cell (neutorpenia) and platelet counts. Therefore the maximum benefit of using taxotere may be achieved by using it at the right time and in the right combination. Since there are several alternative therapies now approved and available for men with metastatic, hormone-resistant or -sensitive prostate cancers, consultation with an expert prostate cancer physician is absolutely critical. For additional information, see a 2007 article from Dr. Richard Lam, published in the PCRI Insights.
Xtandi (Enzalutamide) Now Approved for Metastatic, Hormone-Refractory Prostate Cancer Before Chemotherapy.bjgabrielsen : September 15, 2014 3:01 am : 2014
The following is an important blog in three sections. It describes another approved therapeutic agent for men with metastatic, hormone-refractory prostate cancer. Also included are important discussions regarding the need for future clinical studies to maximize cancer remissions and overall survival.
In 2012, the Food and Drug Administration approved Xtandi® (enzalutamide) for men with metastatic, hormone-refractory prostate cancer who previously had undergone chemotherapy with taxotere (docetaxel®). This month, however, the FDA approved Xtandi® for use in the same patients before they had been treated with chemotherapy, thus creating one more option for men. Xtandi® is a second line hormonal therapy administered orally once daily which can suppress testosterone at three different sources giving many men an additional cancer response after initially failing hormone therapy. The November 2012 issue of the Prostate Cancer Research Institute (PCRI) Insights contains a very informative article by Dr. Neal Shore summarizing the use and mechanism of action of Xtandi®. The reader is advised to see the 2012 link at this point.
The second article by Dr. Mark Scholz is a blog from the February 2014 meeting of genitourinary section of American Society of Clinical Oncology (ASCO). Dr. Scholz mentions that Xtandi® (also formerly known as MDV3100 during its developmental stage) has been shown to extend life in both cohorts of prostate cancer patients discussed above. For specific details of the PREVAIL study, see the linked blog. Xtandi® now joins Zytiga® (abiraterone acetate) and Provenge® as therapeutic options for men before administering chemotherapy with taxotere. The question is now raised as to the optimal way to sequence administration of these agents. Dr. Scholz makes an argument that Provenge® which works by stimulating the immune system, should be administered first. After Provenge®, it is specially noted that the anticancer effects of Xtandi® is reduced when administered after Zytiga® and vice versa. This progressively increasing cancer resistance is not surprising. No data is currently available on the effect of sequencing these therapies on overall survival. Comparative studies and studies involving combination therapies are in order.
The third portion of this post are two very informative videos from Dr. Charles “Snuffy” Myers wherein he discusses the PREVAIL study results and prostate cancer remissions in general. In the first video, Dr. Myers notes the significant delay in radiological progression (e.g. bone, lymph node metastases) demonstrated by Xtandi® (11.2 months vs. 2.8 months for placebo). This will enable Xtandi® to be recognized as a first choice option for therapy. However, in the PREVAIL study, the overall survival result was less dramatic; only 2.2 additional months for Xtandi®. Dr. Myers poses the question of how a therapeutic agent can delay metastases yet minimally affect survival time. He notes it may take a long time to observe the effects of a drug if one is basing the effects on following PSA changes alone. The PSA can increase while the whole cancer is responding. Hence, one should not overly depend on PSA. Instead he proposes using alkaline phosphatase and the circulating tumor assay (CTC) as better markers. Insurance coverage is also discussed. One needs to have a complete remission in order to see significant survival effects. It is rare to observe remissions from a single agent. Studies involving combination therapies are needed. Dr. Myers suggests that studies involving sequential single agents may not be the best, but combination studies are needed to witness overall survival benefits. The second video mainly discusses the mechanism of action of Xtandi®, its safety profile and potential side effects. Dr. Myers notes that under 20% of patients receiving Xtandi® in the PREVAIL study went into complete remission. It is more safe and effective than casodex (liver damage). The major side effect is fatigue. Four-six weeks are needed to reach a therapeutic drug level and 2-3 months are required to see a clinical benefit. The unique mechanism of action of Xtandi® may also require changes in other drugs being taken by a patient.
The Alliance for Clinical Trials in Oncology is conducting a Phase III clinical trial of enzalutamide (Xtandi®) with or without abiraterone acetate (Zytiga®) and prednisone in men with hormone-refractory, metastatic prostate cancer with the hope of improving overall survival. Details of this trial can be found at the U.S. National Institutes of Health (NIH) clinical trials website, ClinicalTrials.gov. Enzalutamide works by disrupting a tumor cells’ ability to use testosterone by blocking the cell’s testosterone receptors and prevents the production of androgens within the cell itself. Zytiga® inhibits two distinct steps in the production of testosterone from cholesterol even in tumor cells by blocking a cell membrane enzyme called CYP17A1. Both drugs have been approved by the Food and Drug Administration for treatment of men with metastatic, hormone-refractory prostate cancer. For further information on these two agents, see the January 3rd, 2012 website blog.
Affinity: A Phase III Trial Using Custirsen and Jevtana® for Men with Metastatic Hormone-Resistant Prostate Cancer.bjgabrielsen : August 26, 2014 2:35 am : 2014
The goal of the Phase III Affinity Trial is to test whether adding an experimental drug called custirsen to Jevtana® (cabazitaxel) chemotherapy can help treat men with hormone-resistant prostate cancer. In the latter case, chemotherapy with taxotere (docetaxel®) or Jevtana® (cabazitaxel) are often the first lines of chemotherapy adminstered. However, they are often accompanied by undesirable side effects and patients may eventually become resistant to the treatments. The current trial will examine whether adding the drug custirsen to the treatment with Jevtana® can help slow the progression of the prostate cancer. Custirsen is an experimental drug designed to block the production of a protein (clusterin) associated with treatment resistance in many cancers. Phase 2 trials suggest that custirsen may improve overall survival for patients with prostate cancer. While Jevtana® has been approved by the Food and Drug Administration, custirsen has not yet been approved. For additional details, see the following link to the Affinity trial as well as the January 3rd, 2012 website blog describing various prostate therapies in differing stages of clinical development.
An article published in the January 4th, 2014 issue of the journal European Urology reported the outcome of a Swiss trial involving men with hormone-resistant (refractory) prostate cancer (defined as a testosterone level of less than 50 ng/dL with progressive disease) who were given the anti-diabetic drug metformin. For the trial, 44 non-diabetic men who had not been treated with chemotherapy for progressive, metastatic hormone-resistant prostate cancer causing few or no symptoms were given 1,000 mg (one gram) of metformin twice a day until disease progression. Assessment of disease status- included computer tomography of the abdomen, pelvis and chest, bone scanning and serum prostate cancer-specific antigen (PSA) level measurement- was conducted every 12 weeks. After initiation of metformin therapy, 36% of the group was progression-free at 12 weeks and 9% were still progression-free at 24 weeks. PSA doubling time, a measure of disease progression, was beneficially prolonged in 52% of patients after the initiation of metformin. It should be noted that metformin is also associated with improved insulin sensitivity. It should be administered only under a physician’s approval, care and control.
PROSPECT: A Phase III Clinical Trial of the Immunotherapy Vaccine Prostvac in Asymptomatic Hormone-Resistant Prostate Cancer Patients.bjgabrielsen : August 5, 2014 5:47 pm : 2014
The goal of the Prospect Trial is to enhance a man’s immune system to fight prostate cancer. It is a Phase III trial for metastatic, hormone-resistant prostate cancer patients who are either asymptomatic or minimally symptomatic. The trial utilizes the investigational immunotherapy, Prostvac, a therapeutic pox virus cancer vaccine directed at PSA-producing cells. It is administered with or without GM-CSF (granulocyte macrophage colony-stimulating factor). GM-CSF is a protein secreted by immune system cells that functions as a white blood cell growth factor. Prostvac is delivered via a series of injections over five months. The end point of the trial is to improve overall survival. Prostvac was developed at the National Cancer Institute (NCI), the largest of the institutes of the National Institutes of Health (NIH), Bethesda, Maryland. There is considerable interest in administering this vaccine to men in earlier stages of their disease. For more information such as concerning qualification and locations of the trial, see the following link. One can also find information at the National Cancer Institute’s clinical trial website, http://www.cancer.gov/clinicaltrials or call the NCI’s help line at 1-800-4-CANCER. Prostvac was also discussed in earlier blogs posted on this website on Sept. 20th, 2011, January 3rd, 2012, and the Bavarian Nordic website, who are co-developers of Prostvac. For a fact sheet on Prostvac and its results in previous trials, see the following link.
As the purveyor of this website, I occasionally hear from other men who relate their experiences with prostate cancer. I’d like to recount the testimonial of one such person whom I know well. He has asymptomatic but metastatic prostate cancer and had been receiving intermittent hormonal therapy for eight years. His PSA had a rapid doubling time which worried his physicians to some degree but his on-going therapy seemed to be starving the prostate cells of the testosterone needed for their growth. His PSA would be reduced to nearly undetectable levels, then would rise again when therapy was discontinued. His hope was that God would enable the on-going intermittent therapy to be effective for many years to come. On a recent visit, his oncologist noticed that the reductions in PSA levels upon receiving therapy were not reaching as low a value (around 0.1 ng/mL) as they had previously and that the times “off” from therapy were getting shorter. These conditions could indicate that he was becoming resistant (refractory) to the therapy. If this were to be the case, then additional therapeutic agents would be needed such as taxotere (with its undesirable side effects), Zytiga or Enzalutamide. The eventual result would be the unrestrained growth of prostate cells which did not require external testosterone for their survival. My friend was initially devastated. His hopes and faith that God would maintain his “chronic” condition indefinitely were being severely challenged. He would see himself running out of therapeutic options and facing a painful death quicker than he had anticipated. After spending a restless night of sporadic sleep, the next morning he decided to read his Bible and related devotionals to seek some answers, if any, from the Lord.
First, he read from Isaiah 61:1-3 where God is speaking through the prophet Isaiah saying the following. “The Spirit of the Lord God is upon me, because the Lord has appointed me (Isaiah) to bring good news to the afflicted. He has sent me to bind up the broken-hearted,……giving them the mantle of praise instead of a spirit of fainting, so they will be called oaks of righteousness, the planting of the Lord that He may be glorified.” The accompanying devotional had a quote from 16th century John Calvin’s sermons from Job which stated “…..if God sends us such great afflictions that we are as it were swallowed up, let it not cause us to despair….but let us resist it, knowing that God still reserves mercy ready for us at the proper time. And if we languish more than we would wish, let us know that God will let the illness ripen in order to heal it better.” My friend went on to recount that when we pray for a specific issue, we must come to the throne of God in submission, trust and gratitude if we are to hear the truth from our caring Father. Thus, when we realign our personal wills with God’s perfect will, then perfect peace is a resulting by-product. God will then give us the desires of our heart according to Psalm 37:4, “delight yourself in the Lord and He will give you the desires of your heart.” Additionally, my friend had been challenged by the question, “do you feel chained to difficult circumstances?” The answer was that only God can provide contentment. Lasting satisfaction can be found only with Him, for in His “presence is fulness of joy; at His right hand are pleasures forevermore” (Psalm 16:11). Our view of changing circumstances and contentment is a personal choice. The way we view our circumstances is more important than the circumstances themselves. The Apostle Paul writes in Philippians 4:11, “I have learned in whatever state to be content.” Paul drew his ultimate satisfaction from His personal knowledge of a God who never changes. “Let us hold fast the confession of our hope without wavering, for He who promised is faithful,” according to Hebrews 10:23. When all we have is God, we have all we need. Finally, it will be interesting to see the next chapter in my friend’s on-going saga. He left me quoting Jeremiah 17:7-8. “Blessed is the man who trusts in the Lord and whose trust is the Lord. For he will be like a tree planted by the water, that extends its roots by a stream and will not fear when the heat comes; but its leaves will be green and it will not be anxious in a year of drought nor cease to yield fruit.”
In an online April 18th, 2014 publication in the journal Cancer Epidemiology, Biomarkers and Prevention, Johns Hopkins researchers reveal a link between chronic inflammation and a greater risk of high-grade prostate cancer. The study included 191 men with prostate cancer and 209 controls without the disease who received a placebo in the Prostate Cancer Prevention Trial, which evaluated the effect of the drug finasteride on prostate cancer prevention. Biopsies conducted at the end of the study provided information on the presence of inflammation in benign prostate tissue. Among men who had inflammation in one or more of the biopsy cores, there was a 78% higher risk of having prostate cancer and more than twice the risk of aggressive disease in comparison with men who had no cores indicating inflammation. This observational study reveals an association between prostate inflammation and prostate cancer, although it is not proof that inflammation is the cause of prostate cancer.
A recent study published in Clinical Cancer Research, (May 1, 2014; 20; 2289-99) indicated that men at risk of prostate cancer are more likely to develop an aggressive form of the disease if they are deficient in vitamin D. University of Illinois – Chicago and Northwestern University researchers examined data from 667 men aged 40 to 79 who had elevated PSA levels or other prostate cancer risks. The men were screened for vitamin D levels. In general, normal blood levels of 25-hydroxyvitamin D range from 30-80 ng/mL. Typical values for men in the study were under 20 ng/mL. About 44% of men with positive biopsies had low vitamin D levels. Among the men who had a positive cancer biopsy, those with very low vitamin D levels (under 12 ng/mL) had greater odds of more advanced and aggressive cancers than those with normal levels. The lower the vitamin D level, the greater the risk. It should be noted that while 25-hydroxyvitamin D is known to impact growth of both benign and malignant prostate cells, this is the first study to link vitamin D deficiency and biopsy outcomes in high-risk men. The authors note that “vitamin D deficiency could be a biomarker of advanced prostate tumor progression in large segments of the general population”, however, more research is needed. But it would be wise for men to be screened for vitamin D deficiency using the 25-hydroxyvitamin blood test and treated if needed.