Advanced Prostate Cancer

As my regular readers probably have noted from prior posts, I am a strong advocate for research and the development of a prostate cancer vaccine. A cancer vaccine is different from the more “common” types of vaccines that are familiar to us. The “common” vaccines (i.e. tetanus or polio) are administered prior to having an illness. They are designed to expose a person to either dead or living antibodies to encourage an individual’s own body to make its own antibodies. These antibodies will then fight off the disease if there is an exposure in the future. A cancer vaccine is given after the cancer has developed, and is designed to “teach” the immune system how to recognize cancer cells as foreign bodies and then fight them.

Sadly, today, cell Genesys, Inc. (CEGE) announced that it has terminated VITAL-2, the second of two Phase 3 clinical trials of GVAX immunotherapy for prostate cancer. This trial compared GVAX immunotherapy combined with Taxotere (docetaxel) to Taxotere plus prednisone in survivors with advanced-stage prostate cancer.

The Independent Data Monitoring Committee (IDMC) recommended that the trial be terminated. The committee’s recommendation stemmed from its observation of an imbalance in deaths between the two arms of the study.

Out of the 408 enrolled survivors, the IDMC noted 114 deaths had occurred of which 67 occurred in the GVAX plus Taxotere combination treatment arm (experimental arm) and 47 deaths occurred in the Taxotere control arm. Neither the IDMC nor Cell Genesys have been able to account for imbalance in deaths.

Cell Genesys has said that it plans to analyze the clinical data to attempt to understand the cause of the higher death rate in the experimental arm.

Cell Genesys has requested that the IDMC perform a previously unscheduled futility analysis of VITAL-1, the other Phase 3 clinical trial of GVAX immunotherapy. It is hoped that the results of the VITAL-1 analysis will become available in one month.

GVAX immunotherapy for prostate cancer is comprised of two prostate tumor cell lines that have been modified to secrete GM-CSF (granulocyte-macrophage colony-stimulating factor), an immune stimulatory cytokine that plays a key role in stimulating the body’s immune response, and then irradiated for safety. GVAX is designed to be administered through intradermal injections on an outpatient basis.

These results are an unfortunate loss for our community.

Joel T Nowak MA, MSW

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According to Ohio State University researchers processing the red tomato boosts the absorption of the all important antioxidant lycopene when consumed. We usually think of processed food not being healthy, but in this case processing is better.

Lycopene belongs to a family of antioxidants named carotenoids. Carotenoids’ antioxidant properties have long been associated with protecting cells and regulating cell growth and death, all of which play a role in multiple disease processes, including protecting against prostate cancer.

When lycopene molecules in tomatoes are combined with fat and subjected to intense heat during the processing procedure, the molecules are restructured in a way that appears to ease their movement into the bloodstream and tissue.

Normally, lycopene molecules in human blood are configured in a bent shape. In the natural, unprocessed red tomato the lycopene molecule are in a linear configuration, a structure that hinders the molecule’s absorption through the intestinal walls and into the blood stream.

In order to gain the benefits of the lycopene the body somehow transforms lycopene molecules through reactions that have yet to be identified so that the lycopene are able to be absorbed into the blood and transported to tissue, or they must be bent prior to ingestion.

Heating red tomatoes and adding oils during processing has the potential of creating a sauce that contains the bent molecular forms of lycopene.

Steven Schwartz, an investigator in Ohio State’s Comprehensive Cancer Center and a professor of food science and technology at Ohio State conducted a small clinical trial in collaboration with Steven Clinton, a medical oncologist and physician scientist in Ohio State’s Comprehensive Cancer Center. The trial demonstrated that people had more lycopene in their blood after eating the specially processed sauce than they did after eating regular red tomato sauce. The trial was described at the August 20 at the American Chemical Society meeting in Philadelphia.

“What we have found is we can take the red tomato molecular form of lycopene and by processing it and heating it in combination with added oil, we can change the shape of the molecule so it is configured in this bent form,” Schwartz said.

Schwartz hypothesize that lycopene in its linear form will be absorbed into the bloodstream, but not easily. The bent forms of lycopene are able to more easily absorbed during digestion, and increasing amounts of the antioxidant in that form are more likely to be transported to the blood along with the fats.

The researchers processed two sauces: a sauce rich in cis-lycopene, the bent configuration, and a sauce containing mostly all-trans-lycopene, the linear form. Both sauces were flavored similarly and initially heated using the same methods. Corn oil was added to both sauces as well. But the sauce designed to produce lycopene in the bent molecular forms was subjected to a second round of heating at 260 degrees Fahrenheit for 40 minutes. The resulting sauce contained nine times more cis-isomers (bent form) than the regularly processed sauce.

The study only included twelve people; all ate both kinds of sauce over the course of the study. After completing each meal, blood samples were taken seven times during the following 9 1/2 hours to measure lycopene levels. The scientists used a special testing method to analyze lycopene levels in the blood associated only with the tomato sauce meal, avoiding any other possible sources of those compounds in the bloodstream.

After eating the specially processed sauce when compared to eating the regular sauce the lycopene blood levels were 55 percent higher. This finding reinforced the expectation that the bent forms of lycopene are more easily absorbed into human blood, Schwartz said.

Details of this study were first published in the British Journal of Nutrition in 2007. Additional clinical trials are ongoing.

Most currently available commercial products don’t contain the bent forms of lycopene molecules. However, some home cooking practices might be able to produce the same results as the special processing method.

“Some people like to cook tomato sauce for prolonged periods, sometimes reheating it day after day, because it tastes better on the second and third day. They add fat by using oil or meat, and that’s going to start to induce cis-isomers of lycopene if fat is present and the cooking continues,” Schwartz said. “So it’s possible people could induce this process and increase lycopene absorption by routine food preparation procedures, as well.”

So, cook and re-cook your tomato sauce. Also, don’t forget to enjoy it.

Joel Nowak MA, MSW

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On August 9, Skip Ciccarelli, a 60-year-old prostate cancer survivor arrived at New York City’s Manhattan Kayak Company, located at Pier 66. He was greeted by almost nobody and without any representatives of the press to cover the end of his journey!

Ciccarelli arrival at Pier 66 having completed his Olympian type marathon. His arrival completed a 1,700 mile, 54-day kayak trek to raise awareness for prostate cancer and to mark the seventh anniversary of his prostatectomy. This past Fathers’ Day weekend he set off from Lake Michigan in Chicago and headed for New York City.

In 2002 he was diagnosed with aggressive prostate cancer and was told by his doctors that he had two months time before the cancer spread to other parts of his body. After consultation with a team of doctors in Boston, he decided on a course of treatment that included surgery. He is now cancer-free, or so we hope.

“At the time I realized, that like most men, I was clueless about prostate cancer and at how little men know about their own bodies,” said Ciccarelli. “I later realized that I could use my own abilities to help raise awareness. By drawing attention to prostate cancer, I’m hoping more men will get prostate checkups and PSA screenings, and that more research will focus on this disease. When was the last time you heard someone talk about prostate cancer?”

(My comment- The last time I heard an outsider talk about prostate cancer was to attack the need for PSA testing and to recommend that men over 75 years old not be given PSA tests.)

Ciccarelli’s marathon paddle took him through Lakes Michigan, Huron, St. Claire and Erie, the Detroit River and the Erie Canal before he started down the Hudson River.

While resting in Albany he said that “It has been a gratifying experience. I was one man, but the support, generosity and personal stories of so many wonderful people who traveled with me in my heart lifted my kayak. Along the way I met hundreds of men of all ages and their families, many of who have been touched directly by prostate cancer. For others it was the first time they really thought about this disease. If I reached just a dozen men who are now committed to annual prostate screening and early detection, it has been worth the effort.”

You can read more about Skip and his journey at http://www.paddle4prostate.org.

So, where was the press? They were not there nor did they make any mention about his accomplishments or prostate cancer. I guess that their failure to greet him should not surprise me. We all know that prostate cancer is a disease of old men and nobody dies from it, just with it.

Joel T Nowak MA, MSW

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At the last ASCO Annual Meeting Saad et al. presented a report about a Phase II trial of custirsen (OGX-011) + docetaxel + prednisone vs. custirsen + mitoxantrone + prednisone in metastatic hormone-refractory prostate cancer. The subjects in the study had experienced relapses of cancer progression within 6 months of treatment with first-line docetaxel therapy.

Both the control and the experimental drug combinations were well tolerated at a median follow-up of >15 months. The combination of custirsen + docetaxel + prednisone (experimental treatment) had a higher level of efficacy and a superior safety profile compared to the combination of custirsen + mitoxantrone + prednisone.

OncoGenex Pharmaceuticals announced that OGX-011 has received a Fast Track designation from the U.S. Food & Drug Administration in combination with docetaxel for potential treatment of progressive metastatic prostate cancer.
The actions of OGX-011 are to inhibit the production of the protein, clusterin, which has been associated with treatment resistance in chemotherapy treatment.

I anticipate that this trial will start in the near future. Once the trial commences and you experience chemotherapy failure you might consider talking with your oncologist about entering into the trial. Chemotherapy resistance is one of the many problems that plague advanced prostate cancer treatment.

Joel T Nowak MA, MSW

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Hair on a man’s head offers clues about versatility of a molecule central to Advanced Prostate Cancer.

Once again, those of us fighting advanced and recurrent prostate cancer are confronted with contradictory and confusing information. The usual first line treatment for advanced prostate cancer is hormone therapy (ADT). We all know that ADT is short lived in effectiveness as our cancer will become androgen independent and continue to progress, despite the therapy. According to the literature, ADT will be generally be effective for only two years before becoming androgen independent. Of course, there are individual differences, some men never gain any control of their cancer with ADT while others are able to experience successful control for many years.

It was recently discovered that sometimes the ADT drugs will actually spur some of the prostate cancers to grow, not what we really want! This shocking information was published online this week in The Findings of the Proceedings of the National Academy of Sciences. These information might help explain why ADT eventually becomes hormone independent.

Chawnshang Chang, Ph.D., director of the George Whipple Laboratory for Cancer Research at the University of Rochester Medical Center, explained the process by showing that the androgen receptor, through which male hormones like testosterone attach to the prostate cancer cells, is very versatile. Sometimes, the molecule spurs prostate cell growth, while other times the molecule halts the prostate cancer cell growth. He explained that this phenomenon was similar to the situation when the same molecule has different effects in hair growth depending upon the location of the molecule on a man’s head.

This frightening new findings raises the concern that under some conditions, some treatments (ADT) designed to treat prostate cancer could instead be removing one of the body’s natural brakes on the spread of the disease in the body and promote cancer growth. The researchers stressed that these results are based only on laboratory studies and on findings in mice. It is yet too soon to know if these findings apply directly to prostate cancer in men.

Chang’s team found that blocking the androgen receptor does prevent some cells in the prostate from continueing to grow. The big surprise was they also discovered that blocking the receptor in some situations actually encourages other prostate cancer cells to grow.

Chang said “The androgen receptor acts differently in different cells in prostate tissue. It’s always been assumed that blocking the androgen receptor will stop all prostate cells from growing, but we have found that that’s not the case. Since current treatment acts non-specifically on all the cells having androgen receptors in the prostate, blocking the androgen receptor will give mixed results.” Or, encourage the cancer to become androgen independent.

The unexpected discovery was that the androgen receptors in prostate cells known as stromal cells actually stimulates growth of cells, including cancer cells, in the prostate. In the converse they also found that the receptor actually acts as a tumor suppressor in epithelial cells known as basal cells in the prostate.

They then knocked out the androgen receptor in specific sets of prostate cells and studied the results. As expected, when the molecule is turned off in stromal cells, growth of cancer cells in the prostate slows. But when the molecule is turned off in the epithelial cells, it removes one of the body’s natural inhibitors that prevents prostate cancer cells from spreading, making cells more likely to invade other tissues.

The conclusion is that the androgen receptor both can drive prostate cancer and it also appears that the receptor inhibits the spread of cancer cells depending on the type of cell to which they are attached. Androgen receptors seems to have a dual and sometimes conflicting role.

Chang stated that the molecule’s versatility in the prostate should not come as a surprise, since the molecule’s function elsewhere depends on its location. “The effects of the androgen receptor on hair growth in men vary dramatically depending on where in the body the receptor is working,” said Chang. “When the receptor is very active in the mustache area, more hair grows. When it’s very active on the top of the skull, toward the front, hair falls out and men become bald. And the hair on the back of the head is insensitive to the receptor. The effects of hormones depend on the location.
“We found that the same is true within the cells of the prostate itself,” said Chang.

He concluded that androgen receptors work differently in different types of cells. Depending upon the role of the cell the androgen receptor will also performs different tasks. Bearing this in mind, to be effective ADT treatments need to be able to target the androgen receptors differently in different cell types. Ultimately, the goal would be to turn off the receptors in some cells while keeping it on in others. A new research challenge.

Chang’s team included researchers Yuanjie Niu; Saleh Altuwaijri; Kuo-Pao Lai; Chun-Te Wu; William A. Ricke, Ph.D., assistant professor of Urology; Jorge Yao; Shuyuan Yeh, Ph.D., associate professor of Urology; Shengqiang Yu; Kuang-Hsiang Chuang; Shu-Pin Huang; and Edward Messing, M.D., professor and chair of Urology. Henry Lardy of the University of Wisconsin is an author on one of the papers.

Joel T Nowak MA, MSW

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We all know, or at have heard, that drinking grapefruit juice can increase the absorption of certain oral drugs. The result of the increased levels of absorption is the possibility that normal doses of drugs become toxic overdoses. At the 236th National Meeting of the American Chemical Society there was a presentation that provided new evidence that grapefruit and other common fruit juices, including orange and apple, can have the opposite effect. It seems that these juices can substantially decrease the absorption of other drugs, potentially wiping out their beneficial effects.

We now have a reason to avoid drinking grapefruit juice as well as these other juices when taking certain drugs. The drugs that are affected are the drugs prescribed for heart disease, cancer, organ-transplant rejection, and infection. These findings come from a controlled human study conducted by David G. Bailey, Ph.D., a professor of clinical pharmacology with the University of Western Ontario in London, Ontario, which was designed to evaluate the drug-juice interaction.

Dr. Bailey said, “Recently, we discovered that grapefruit and these other fruit juices substantially decrease the oral absorption of certain drugs undergoing intestinal uptake transport. The concern is loss of benefit of medications essential for the treatment of serious medical conditions.”

Bailey’s original research, almost 20 years ago, demonstrated that grapefruit juice could dramatically boost the body’s absorption levels of the high-blood-pressure drug felodipine, causing blood toxicity issues. Other researchers, in the intervening time, have identified around 50 additional medications that also carry the risk of grapefruit-induced drug-overdose interactions. This “Grapefruit Juice Effect,” now causes some prescription drugs to carry warning labels against taking grapefruit juice or fresh grapefruit during their consumption.

In the most recent research, volunteers were given fexofenadine, an antihistamine used to fight allergies. The subjects consumed the drug with either a single glass of grapefruit juice, water containing only naringin (substance in grapefruit juice that gives the juice its bitter taste), or water. When fexofenadine was taken with grapefruit juice, only half of the drug was absorbed compared to taking the drug with water alone, Bailey says. Loosing half of the amount of drugs taken into the body can be critical for the performance certain drugs, he points out.

Additionally, the naringin blocked a key drug uptake transporter, called OATP1A2. OATP1A2 moves the drug from the small intestine to the bloodstream, blocking it reduces drug absorption and neutralizes their potential benefits. By contrast, those drugs whose levels are boosted in the presence of grapefruit juice appear to block a metabolizing enzyme, called CYP3A4 that normally breaks down drugs.

“This is just the tip of the iceberg,” Bailey says. “I’m sure we’ll find more and more drugs that are affected this way.”

Our important take home message is to consult your doctor or pharmacist before taking any medications with grapefruit juice or any other fruits and juices. Dr. Bailey recommends that unless it is known to be a problem, he recommend taking most medications only with water to avoid either under or over absorption of your treatment drugs.

Joel T Nowak MA, MSW

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Today’s New York Times had an article written by Jane Brody that discusses the painful issues surrounding the decision to stop treatment, and its negative side effects, and let a cancer survivor live their last weeks in relative peace. This is always a difficult decision as many of us wish to hold on to life, even if it just for a few days or weeks. However, receiving aggressive treatment close to the end usually does not extend live.

What is unusual about this article, besides its being a very important and relevant topic for those of us dealing with advanced prostate cancer, is that it opens with a story about a man names Forbes Hill who was diagnosed with prostate cancer at age 50 years.

Mr. Forbes elected Watchful Waiting and for 12 years his prostate cancer remained under control. Then in 1990 the cancer progressed. He elected to receive radiation which provided some additional control, eventually starting hormone deprivation.

When his PSA again went through the roof he was found to have metastatic disease in his bones and liver. His doctor informed him that “90 percent of patients die within five years no matter what the doctors do, and about 10 percent survive six or more years” when in his situation.

He did agree to have some radiation to the brain to relieve some of the effects of the tumors and also “I’ll try chemo for six months, but if it gets too uncomfortable and inconvenient… ,” he said, trailing off. “Having lived 80 years, I’ve done a lot. I don’t have reason to think I’ve been badly treated by life.”

Mr. Hill has made the decision that many people are unable to make, to limit treatment and instead allow the end of his life to be filled with preparation for the unavoidable, ones own death. This time is better spent preparing a will, resolving interpersonal issues left unresolved. Saying goodbye and locking down ones legacy.

Ms. Brody’s excellent article may be read on line at: In Cancer Therapy, There Is a Time to Treat and a Time to Let Go

Joel T Nowak MA, MSW

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Last April HealthDay News ran an article about chemotherapy and patients fear about starting it. Most cancer survivors involved in a recent survey reported that they had been fearful of undergoing chemotherapy. The good news is that most also said the treatments were much less difficult than they had expected.

The truly startling fact is that 94 percent said they would advise others to undergo chemotherapy if their doctor recommended it.

Linda Ellerbee, 63, an award-winning broadcast journalist and author, who underwent a double mastectomy and chemotherapy after being diagnosed with breast cancer 16 years ago reported at a news conference, “Like most people, I was filled with fears about chemotherapy, particularly about the possible side effects.
It wasn’t fun — no one will tell you that chemotherapy is fun. But it wasn’t as bad as I expected, either.”

The survey polled 326 U.S. adults who had undergone cancer chemotherapy within the past five years. The survey was sponsored by the nonprofit National Coalition for Cancer Survivorship (NCCS) and drug maker Sanofi-Aventis,

Some of the survey’s findings:

* Around eight out of 10 cancer survivors said they had been fearful prior to starting chemotherapy, with most (76 percent) worried primarily about side effects such as hair loss, nausea and fatigue.
* Looking back, almost two-thirds (62 percent) said those fears were unjustified. Just 14 percent described their side effects as “very difficult,” and about a third (32 percent) had a “somewhat easy” or “very easy” experience with treatment.
* Almost all (87 percent) of survivors said that new supportive care products made the side effects that they did experience much more manageable than they had expected.
* Eighty-seven percent of survivors who had experienced side effects said that chemotherapy was worth going through, and 90 percent said the treatments had given them real hope for survival.

Too often, survivors do not express their fears about chemotherapy and the side effects that they do experience. If you are considering chemotherapy and have any fears talk to your doctor. Tell them how you are feeling and what concerns you have about the potential side effects. Most importantly, ask them what they can do to help you.

I strongly advise that you ask for a written “Treatment Plan” from your doctor before you begin chemotherapy. The plan should outline interventions you will receive, potential side effects, and ways to manage those side effects.

I have over the years met many men with prostate cancer who have taken chemotherapy. Some do report very significant side effects, but to my surprise, many more report that the side effects are very manageable. Additionally, most report along with their PSA declines that they feel better and can resume some of their activities that they had been forced to end.

Give it a try, work closely with your doctor and feel better.

Joel T Nowak MA, MSW

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A recent Finnish study released interim results comparing intermittent androgen deprivation (IAD) to continuous androgen deprivation (CAD) in 856 men. All the men had locally advanced or metastatic prostate cancer and they all were treated at 27 clinics in Finland.

The period of study was between 1997 and 2003 and all men were required to have a life expectancy of at least 12 months to be includer. All men received a 24 week cycle of continuous LHRH agonist therapy. The men were then randomized to IAD or CAD.

Mean age was 72 years and mean PSA at entry was 383ng/ml. The men had either stage T3 tumors (61%) and stage T4 tumors (29%). A total of 564 men completed the initial cycle of therapy and 279 were randomized to IAD and 285 to CAD.

PSA, alkaline phosphatase, proportion of T4 tumors, poorly differentiated tumors, metastatic disease, and skeletal hot spots among men with M1 disease were significantly higher in the IAD group. Baseline testosterone was not significantly different.

A significant proportion of men with the most aggressive and advanced CaP did not respond to the original cycle of androgen deprivation therapy. Men with advanced CaP, with a high PSA, alkaline phosphatase and metastatic disease, with more than 5 skeletal hot spots, did not show adequate biochemical response to ADT and should be considered for alternate treatments.

The investigators concluded that IAD appears feasible for patients with locally advanced, hormone sensitive CaP. A low limit of testosterone at baseline did not select for IAD or CAD.

This research is consistent with prior findings from other studies already conducted. If you are on hormone therapy and responding, talk with your doctor and evaluate if you are a candidate for intermittent treatment.

Salonen AJ, Viitanen J, Lundstedt S, Ala-Opas M, Taari K, Tammela TL
J Urol. 2008 Jul 15. Epub ahead of print.

Joel T Nowak MA, MSW

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Memorial Sloan Kettering Hospital publishes, on the web, a prostate cancer calculator that among other things can calculate PSA doubling time and PSA velocity. It will now take values generated by the ultra sensitive PSA tests.

The calculator can be used by going to:
http://www.mskcc.org/mskcc/applications/nomograms/PSADoublingTime.aspx

For example, if you use my current PSA numbers which are:
02/10/2008 PSA .04
03/10/2008 PSA .06
04/10/2008 PSA .05
05/10/2008 PSA .09
06/10/2008 PSA .11

The calculator will tell you that my doubling time is now 4.24 months (0.35 years) with a velocity of 0.01 ng/mL/mo (0.14 ng/ml/yr).

To learn more about PSADT and PSAV read my posts of February 3, 2008
“PSA Levels & PSA Velocity (Doubling Time) Is Predictive of Your Survival Time” and June 6, 2007 “Biochemical Failure, PSADT and Morbidity Rates.”

Joel T Nowak MA, MSW

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