Advanced Prostate Cancer

If the thought of eating servings of broccoli and cabbage every day does not appeal to you, then you should read this post to learn why you should grin and bear it.

Multiple recent studies continue to document diindolylmethane (DIM) as one of the most effective phytonutrients in the prevention and treatment of breast, prostate, colon and pancreatic cancers. DIM is the compound found in cruciferous vegetables that regulates hormone balance and cell behavior.

“In a study published in the May 1, 2008 Biochemical Pharmacology Journal, researchers report having previously shown that DIM is able to stop tumors from establishing their own blood supply (angiogenesis) in cultured endothelial cells in rodents. In this study, they demonstrated that DIM reduces the level of hypoxia-inducible factor (HIF)-1alpha in hypoxic tumor cell lines, as well as HIF-1 transcriptional activity. Moreover, the level of oxygen in tumor cells was increased. This study is the first to show that DIM can decrease the accumulation and activity of the key angiogenesis regulatory factor, HIF-1alpha, in hypoxic tumor cells.

The April 22, 2008 Pharmaceutical Research reports that prostrate apoptosis response-4 (Par-4) is a unique pro-apoptotic protein that selectively induces apoptosis in prostate cancer cells. Apoptosis is the planned appropriate death of cells without which cells may exhibit excess proliferation. Researchers sought to identify the functional significance of Par-4 in pancreatic cancer. Results revealed that low doses of the B-DIM (the most bioavailable formulation of DIM) induced Par-4 in pancreatic cancer cells. DIM reduced cancer cell viability and caused cell growth inhibition and apoptosis.

The Cancer Letter, March 28, 2008 reports that the interaction between the chemokine receptor and its unique ligand is known to mediate the progression and metastasis of breast, prostate and other cancers. Organs to which these cancers metastasize secrete the particular ligand which binds to the chemokine receptor on the surface of primary cancer cells. This process subsequently stimulates the invasive properties of the cancer cells and attracts them to the preferred organ sites of metastases. The researchers found that DIM down-regulates both the ligand and the receptor in breast cancer cells as well as in ovarian cancer cells at the transcriptional level and in an estrogen-independent manner. They demonstrated that the potential of cells for chemotaxis and invasion is inhibited by DIM. Furthermore, they showed that DIM down-regulates the chemokine receptor under hypoxia and the ligand under estradiol-inducing conditions. The data suggest that one mechanism whereby DIM protects against breast, ovarian, and possibly other cancers is through the repression of this mechanism, thereby lowering the invasive and metastatic potential of these cells.

From the March 15, 2008 Cancer Research comes a study reporting that platelet-derived growth factor-D (PDGF-D) is a newly recognized growth factor known to regulate many cellular processes, including cell proliferation, transformation, invasion, and angiogenesis. Recent studies have shown that PDGF-D and its receptor are expressed in prostate tumor tissues, suggesting that PDGF-D plays an important role in the development and progression of prostate cancer. Researchers found that PDGF-D was significantly inhibited by B-DIM. This correlated with decreased cell proliferation and invasion. B-DIM also inhibited the tube formation of human umbilical vein endothelial cells. They concluded that B-DIM could serve as an efficient preventative and/or therapeutic agent in prostate cancer.

Molecular Cancer Therapeutics February, 2008, reports a study of human breast cancer cell lines to understand the mechanisms of DIM. In vitro experiments were done with breast cancer cell lines. Researchers found that DIM inhibited the growth of all four breast cancer cell lines. Because two of the cell lines over expressed Her-2 and two of the lines lacked estrogen receptors, these were studied further. In both cell lines, DIM appeared to induce expression of p27 protein before the loss of cell viability and apoptosis. DIM induced p27 transcript expression within 6 hours. DIM also induced nuclear localization of p27 in both cell lines. In one of the cell lines, DIM induced a decrease in phosphorylation. Researchers concluded that DIM modulates p27 through transcription, prolongation of protein half-life, and nuclear localization. These effects appear to be independent of Her-2, or estrogen receptor status.

The January, 2008 Journal of Nutrition finds that because recurrent or chronic inflammation has been implicated in the development of a variety of human cancers, researchers examined the anti-inflammatory effects of DIM and the underlying mechanisms using lipopolysaccharides (LPS) stimulated macrophages. DIM significantly decreased the release of nitric oxide, prostaglandin E2, tumor necrosis factor alpha, interleukin-6 and IL-1beta cells treated with LPS. DIM inhibited LPS induced increases in protein levels of inducible NO synthase. The messenger RNA levels of phospholipase A2 decreased, whereas neither COX 2 protein nor transcript was altered. Researchers concluded that DIM inhibits LPS induced release of pro-inflammatory mediators in macrophages.”

It is possible to purchase DIM supplements, but I am not aware of any good research that demonstrates that you get the same positive effects as you would if you ate the actual vegetable.

DIM is nature’s hormone modulator and you need to consume it. So, go ahead and enjoy your broccoli.

Joel T Nowak MA, MSW

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Many of us take all sorts of dietary supplements with the goal of slowing down and controlling our prostate cancer’s progression. Rarely do we think about the fact that there is no governmental or nongovernmental agency charged with the task of evaluating either the safety or efficacy of the supplements we consume.

Within months after beginning to take a hormonal supplement two men experienced an unusual course of clinically aggressive prostate cancer. Researchers at the University of Texas Southwestern Medical Center in Dallas investigated this rather unusual occurrence.

The researchers evaluated serum levels of total testosterone, luteinizing hormone, and follicle-stimulating hormone in both men and examined biopsy and metastatic specimens for expression of androgen receptor protein and mutations. After analyzing the supplement’s effect on human prostate cancer cell lines, they discovered that the two men had low hormone levels.

When they looked at the label on the supplement they discovered that (1) the listed ingredients that were not present, (2) misrepresented the concentrations of the ingredients that were present, and (3) did not list all steroid hormones contained in the product. A hormone analysis revealed that the supplement contained testosterone and estradiol, a female sex hormone. The supplement was actually a more potent stimulator of cancer cell growth than testosterone. The researchers tried in vain to stop the prostate cancer cell growth by giving the men increasing the concentrations of bicalutamide (Casodex®).

After filing an adverse events report with the Food and Drug Administration, the FDA issued a warning letter and the manufacture removed the supplement from the market.

The important message is that we must inform our doctors about any herbal or hormonal dietary supplements we are taking or are considering taking. Our doctors must ask us about all prescription and over-the-counter drugs they are routinely using, and this discussion should become part of routine health assessments.

(Source: Clinical Cancer Research, 2008; 14:607-611.)

Joel T Nowak MA, MSW

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I had written, about a month ago, about my feelings of distress because it appears that after my greatly loved ‘vacation’ from ADT might be entering the its final stage. Well, it is true. Yesterday, I received the latest PSA results and it has continued to escalate. I am now at 0.11.

Yes, the number is still minimal, but it is increasing. This is its third PSA increase
(01/08 = <.04; 03/08 =0.06; 06/08 =0.09 & 08/08 = 0.11). I now declare that the cancer has decided to reestablish itself and remind me that it forever lurks in my body.

The doubling time is also a concern. The current doubling time from June to August is now 4.2 months; it is aggressive just like when I had the recurrence.

To add to my concern is a test called GFR Estimation. This is a blood test that measures kidney function, or its ability to filter my blood plasma. Normal range is >60, but in June it fell to 57 and now in August it is at 52. I do not know the significance of these individual numbers, but the trend is very clear.

At the same time, I had the prostate cancer recurrence I was diagnosed with renal (kidney) cancer and had my left kidney removed. It is not a problem functioning on one kidney, many people do fine with only one, but I need it to function. I have just sent the blood work to my kidney doc and will have a conversation with in short order.

As to the PSA rise, I am scheduled for my regular prostate cancer oncologist appointment on Thursday. We will discuss it, but I am going to delay restarting ADT. The complicating factor is the doubling time, it is shorter than I would have liked.

I am feeling unhappy about the situation. Both of these complications were very predictable, but I still feel sad.

Joel T Nowak MA, MSW

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As new treatments, drugs and medical devices come to market the FDA is charged with making sure that they are both safe and perform as represented. Products that come under review include items such as human and animal drugs, blood and other biological products, medical devices, and foods.

The process of evaluating these products has become increasingly more complex as technology advances. Often, the evaluative process requires many areas of expertise. The FDA turns to outside experts for advice in their process of reviewing these drugs, treatments and medical devices. To access this expertise the FDA often uses advisory committees in their approval process. These committees are composed of groups of experts from outside the agency.

The advisory committees are specifically designed to provide independent, professional expertise related to specific questions posed by the FDA. The advisory committee meets with members of the FDA as well as the sponsor (applicant for approval or manufacturer of the product) to review and explore the pertinent data submitted by the applicant. The committees usually hear a presentation from the sponsor after which they have the opportunity to ask questions and follow up on concerns about the data submitted, pertaining to the questions asked by the FDA.

The FDA poses specific questions to an advisory committee that they wish answered to better allow a thoughtful and comprehensive decision. The committee’s specific job is to provide informed answers to these questions. The advisory committee will discuss the FDA’s questions after reviewing all submitted briefing materials that contain background information such as available studies on the product as well as information provided in the sponsor’s presentation.

Somewhere in the process, usually after the sponsor has finished their presentation, the committee chair will call on individuals from the community to make public comment about the treatment being reviewed. At this time consumer advocates can share the communities concerns about the product.

Once the sponsor’s presentation has been completed and the community has used its allotted time, the FDA’s representatives will ask additional questions of the sponsor to elucidate any unclear issues. The advisory committee will then vote on the questions posed by the FDA (i.e. Has this product demonstrated its efficacy?). The committee’s vote serves only as a recommendation to FDA as the agency makes all of the final decisions. (In the Provenge issue the committee voted and recommended that the FDA approve the treatment, however, the FDA reserved their right to make a different decision and sent the sponsor back to develop additional information).

FDA currently has 48 technical and scientific advisory standing committees. A committee generally includes a chairperson, several scientists and health professionals, an industry representative, a consumer representative, and sometimes a patient representative. As required the exact composition of an individual committee can be modified to modify the available expertise.

The consumer representative is usually a health professional with links to consumer advocacy groups or community-based organizations. FDA may also invite a patient representative to participate in a committee. A patient representative has knowledgeable about, or may even have, the disease or condition under discussion by the committee. While contributing to the scientific discussion, consumer and patient representatives bring to the committees an awareness of concerns of patients and family members directly affected by a serious disease.

The two most recent advisory committee meetings evaluating drugs or treatments specific for prostate cancer were the Provenge and Satraplatin hearings.

Joel T Nowak MA, MSW

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Hollis-Eden Pharmaceuticals, Inc. (NASDAQ:HEPH) has announced a new phase I/II clinical trial of Apoptone (HE3235) for late stage prostate cancer. Howard Scher, M.D., Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center said “The preclinical data generated to date suggest that Apoptone may offer a unique therapeutic approach to late-stage prostate cancer where traditional therapies have failed.”

To qualify for this trial with the oral drug candidate Apoptone™ (HE3235) one must have late-stage prostate cancer, failed hormone therapy and at least one round of chemotherapy treatment.

The trial is a dose ranging study that will evaluate the safety, tolerance, pharmacokinetics and potential activity of Aoptone when administered twice daily for 28 days in up to 44 late-stage prostate cancer patients. The primary endpoints will be measured by prostate-specific antigen (PSA) tests and effect on well-established markers of progression free survival (PFS).

The trial will also evaluate circulating tumor cell (CTC) enumeration as a marker for effectiveness for tumor treatment. Previous studies have shown that metastatic prostate cancer patients with less than 5 CTCs per 7.5 ml of blood have statistically better survival than patients with greater than 5 CTCs.

To date, Apoptone has been tested in a number of preclinical cancer models and has demonstrated that it is active in controlling the incidence, growth and development of new tumors. The manufacturer, Hollis-Eden believes that Apoptone may also induce apoptosis, or cell death.

Trial sites are located in New York, Seattle and San Francisco.

To learn more about Apoptone and this clinical trial go to the government’s clinical trial web page. In the upper right corner search for apoptone. Then click on “A Phase I/II Study of HE3235 in Patients With Prostate Cancer. “

Joel T Nowak MA, MSW

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Life is tough enough with all of its twists and turns. We all experience hardships on our path, but we all also experience many pleasures and euphoric moments. Those of us who are under the influence of advanced prostate cancer still experience many moments of great pleasure and contentment. As a matter of fact, I believe, based on my own personal experience, that the positive moments far out number the negative.

We need to step back and take a deep breath. Putting the positive and negative in proper prospective will help us to see that our lives remain rich, even with the hardships that prostate cancer create.

Joel T Nowak MA, MSW

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Amgen just completed, with positive results, a three-year Phase 3 placebo-controlled trial which evaluated denosumab for the treatment of bone loss (reduction of bone mineral density –BMD) in men undergoing androgen deprivation therapy (ADT) for non-metastatic prostate cancer.

One of the more common and significant side effects of ADT is loss of BMD. This loss is responsible for significant numbers falls and bone fractures. The effects of the ADT compound the natural BMD loss resulting from aging.

In this study of more than 1,400 men, were treated with denosumab. The treatment produced statistically significantly greater increases in bone mineral density (BMD) at the lumbar spine (primary endpoint) and non-vertebral sites compared with placebo at multiple time points. These improvements, as experienced by the men taking denosumab, were consistent with those seen in other denosumab studies evaluating BMD in women with breast cancer receiving aromatase inhibitor therapy (which also produces BMD loss), and in post-menopausal women with low bone mass.

The actual results were rather dramatic. At the completion of the evaluation period, which lasted for 36 months, men who received denosumab experienced less than half the incidence of new vertebral fractures (a secondary endpoint) compared with those receiving placebo, a statistically significant finding. Additionally, the men in the denosumab arm had fewer non-vertebral fractures over the evaluation period.

The adverse negative side effects and incidences reported in the study were similar between the denosumab and placebo arms of the study. The adverse events across both treatment arms were arthralgia (joint pain), back pain, constipation, and pain in extremity. Serious adverse infectious events occurred in approximately 5 percent of men receiving placebo treatment as compared with approximately 6 percent of those receiving denosumab, not a significant difference.

“This pivotal study in men with prostate cancer demonstrated once again that denosumab increases BMD consistently at all sites measured. We are also excited by the reduction in vertebral fractures, which permits the conclusion that the increased BMD seen in patients receiving denosumab is associated with improved bone strength,” said Roger Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. “We are encouraged by the potential benefit this may represent to prostate cancer patients who are undergoing ADT for whom bone loss and fractures are serious and under-recognized complications of cancer treatment.”

This study did not compare denosumab against Zomata, the current standard of care for men on ADT who have experienced BMD loss.

On ADT, speak to your doctor about the possibility of adding denosumab to your regime.

Joel T Nowak, MA, MSW

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Have I been abandoned? I feel as if I have.

In today’s mail was a letter from my kidney oncologist (I also have renal cancer) telling me that he will no longer accept my insurance!

He said that he hoped that I would continue to use him as my physician, but if not he recommended a colleague who does take my insurance. The colleague he recommended is my urologist. He is a good urologist, but he is not a kidney oncologist and he certainly is not of the same caliber.

What feels like salt in the wound is that I had just worked a new arrangement with my kidney oncologist and my prostate cancer oncologist. I was seeing my prostate cancer doctor every three months and the kidney specialist every 6 months. The schedule worked out so that every six months I was seeing both of them, usually in the same week. They both are at the same hospital, just two floors apart. Since the kidney doctor also sees prostate cancer patients and I have grown to trust him and his opinions about both the prostate and the renal cancers. Therefore, I changed the arrangements so that I would see one of them every three months, alternating each cycle. Both agreed to work together and assist me in monitoring both cancers. It felt like a perfect resolution.

Now I get this letter and have to decide if I am able to continue seeing him. I do have “out of network” benefits, but they are extremely limited.

It just doesn’t feel right. The very same thing as happened with my rheumatologist. When he stopped accepting my insurance, I went on and saw two different doctors, but ended back with him and paying out of pocket to see him.

Now I will have to make this decision all over again, it does not feel right.

Joel T Nowak MA, MSW

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We hear it time and again, consuming fat is bad for you, especially if you have prostate cancer. There have been numerous studies that all conclude that your diet should have only limited quantities of saturated fat.

MD Anderson recently published an article that showed dietary fat is unhealthy and dangerous when quantities are not strictly controlled. Men who ate high levels of saturated fat experienced worse outcomes after prostate cancer surgery for localized disease than controls who limited their fat intake. “Obese men with a high saturated fat intake had the shortest survival time free of prostate cancer (19 months), while non-obese men with low intake survived the longest time free of the disease (46 months).”

The conclusion, to slow down prostate cancer you should lose weight and limit your consumption of dietary saturated fat. The best and easiest way to accomplish this is to stick to a Mediterranean type diet.

What is a Mediterranean diet? It is one rich in vegetables and low in red meat, with poultry and fish replacing beef and lamb. According to a NEJM reference : “The moderate-fat, restricted-calorie, Mediterranean diet is best when we restricted energy intake to 1500 kcal per day for women and 1800 kcal per day for men, with a goal of no more than 35% of calories from fat; the main sources of added fat were 30 to 45 g of olive oil and a handful of nuts (five to seven nuts, <20 g) per day. The diet is based on the recommendations of Willett and Skerrett.21″

It is worth a try.

Joel T Nowak MA, MSW

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According to a study published April 16, 2008, regular exercise is the best way to manage cancer-related fatigue!

Fatigue is a common problem for men with prostate cancer. It is also a common side effect of all the available prostate cancer treatments, both primary and secondary treatments. The most common advice we receive for coping with it is to rest when you feel tired. According to this study regular exercise, not regular naps, may be a more effective way to cope with prostate cancer-related fatigue,

The study was an analysis of 28 different studies investigating exercise and cancer-related fatigue. It included more than 2,000 patients suffering from different cancers (not just prostate).

The exercise programs spanned a time period between three weeks and eight weeks with most lasting three months. The most common exercise was walking or stationary bike riding, but the length, type and intensity of exercise varied across the studies.

The meta-analysis found that regular exercise managed fatigue better than the standard “rest when tired” advice. Although further studies are needed to identify the specific type of exercise and the frequency, oncologists should recommended at least a walk 30 minutes a day three to five times a week.

Joel T Nowak MA, MSW

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