A Xofigo Update

BY MARK SCHOLZ, MD

Since Xofigo was FDA approved two years ago, the doctors at Prostate Oncology—Dr. Richard Lam, Dr. Jeffrey Turner and I—have been avid users.  So this seems to be a good time to provide an informal update of our experience with Xofigo to the present time.

The clinical trial that led to Xofigo’s approval by the FDA was a prospective, placebo-controlled study demonstrating improved survival in Xofigo-treated men compared to men treated with placebo alone.  The trial showed a very low incidence of side effects and good relief for men who were suffering from bone pain.

Xofigo is made out of radium, a radioactive element. After it is injected into the blood stream it concentrates near the cancer and delivers a potent dose of radiation.  So after Xofigo is injected into the patient, it travels through the blood stream and concentrates in the irritated areas of the bone and emits radiation where the cancer is most active.  Since prostate cancer spreads almost exclusively to bone, an injection of Xofigo ends up targeting most if not all of the cancer. Radiation consists of high energy, subatomic particles that blast cellular DNA. Once the DNA of the cancer cell has been hit, the cell is rendered incapable of reproduction.  If you stop cancer reproduction you basically stop the cancer.

To almost everyone, radiation conjures up horrible visions of toxicity. Fortunately, bone marrow toxicity is rare in men because Xofigo emits a different type of radiation, “alpha particles,” rather than the standard “photon type” of external beam radiation. Alpha particles dissipate their energy over a very short distance, only a couple of millimeters. External beam radiation therapy, the type of radiation that has traditionally been relied on to kill cancer cells in the bone, needs to be used very judiciously because the radiation is “beamed” through the body to hit the target in the bone. Typically it causes irreversible damage to the surrounding bone marrow.

Over the last two years at Prostate Oncology, we have treated over 50 patients with Xofigo.  The treatment has been very well tolerated.  Occasionally, we have seen a few patients with mild diarrhea or nausea that has been easily managed with common medications. Men experiencing pain from cancer usually see either partial improvement or total resolution of their pain after one to three of the monthly treatments.

As reported from the original study that led to FDA approval, even though pain relief occurs and alkaline phosphatase (ALP) levels in the blood decline, PSA may continue to rise.  This “disconnect” between PSA and other clinical parameters such as pain and ALP can be disconcerting to doctors and patients alike.  The reason that it occurs is unclear. A similar phenomenon has been observed with another FDA-approved cancer therapy called Provenge.

Experts hypothesize that the survival advantage from Xofigo and Provenge is due to a slowing of cancer progression rather than an actual regression of the cancer. This “slowing” is powerful enough to extend patients’ lives but insufficiently powerful to consistently induce a decline in PSA.  However, in our practice at Prostate Oncology notable declines in PSA have been observed in a few patients treated with Xofigo.  One patient dropped his PSA from 50 down to zero and his PSA still remains at undetectable levels.  Another recent patient has dropped his PSA from 150 down to 8.

For the patients on Xofigo who have rising PSA levels, it is logical to consider adding another effective anticancer agent such as Xtandi, Zytiga or Taxotere.  It is encouraging to know that several studies now show that Xofigo can be safely combined with these other effective therapies.

Xofigo has been a very welcome addition to our anticancer armamentarium.  The standard FDA approved protocol consists of a course of monthly treatments continued for a total of six months.  Further trials are in progress to study the potential advantages of continuing Xofigo for longer than six months.  Our experience to date suggests that longer therapy would indeed be advantageous in some instances.

The Lowdown On Testosterone Supplement and Low T

BY RALPH BLUM

Low testosterone or “low T,” also called hypogonadism, affects millions of aging men. Testosterone levels normally peak in a man’s 20s, then fall by 1% to 2% per year. Indisputably, low T is responsible for reduced sex drive and sense of vitality, erectile dysfunction, decreased energy, and diminished muscle mass and bone density.  As the poet T.S. Eliot reminded us, time the healer is also time the destroyer.

Men through the ages have tried outlandish cures for impotence, including chewing the roasted penis of a wolf! More recently they have plunged the family jewels into cold baths, choked down heaping spoonfuls of wheat germ, swallowed vitamins and most recently stockpiled Viagra.

When, in 1939, two scientists shared the Nobel Prize for Chemistry for their work in isolating and identifying testosterone, the mad rush for injected, implanted, inhaled or absorbed versions of the hormone began, promising, in the words of one product’s pitch, “power, performance, passion.”

In 2013, U.S. sales of testosterone reached $2.4 billion. According to Global Industry Analysts, the market is projected to swell to $3.8 billion by 2018. Moreover, in 2013, 7.5 million prescriptions for testosterone were written. And all this is happening without explicit FDA approval. There have been few, if any, large, randomized studies on the long-term risks or benefits of testosterone supplementation. Some maintain that we are undergoing a massive science experiment with unknown risks. But foggy science has not deterred Big Pharma from spending untold millions to encourage those of us who are wan, limp and flabby to climb onto the low T bandwagon.

Meanwhile, the most heated debate is centered on whether testosterone fuels prostate cancer. Not long ago, the consensus was that, as far as prostate cancer cells were concerned, testosterone was nature’s perfect food. It was like spinach to Popeye. Suppressing the hormone is still a standard part of treating the disease. But attitudes are changing.

The debate goes something like this:  If it’s true that testosterone fuels prostate cancer, why do most men develop the disease when they are older and their testosterone levels are dropping?  Others, however, point out that when men take hormone therapy that virtually stops the production of testosterone, tumors regress. So wouldn’t the opposite be true--adding testosterone should be expected to accelerate tumor growth? I personally believe that my episode of hormone treatment—monthly Lupron injections over a 15 months’ period—helped to delay the growth of my non-aggressive cancer for many years.

So far a few small studies of using testosterone in men with prostate cancer have shown fairly positive results. For example, men who had been treated for prostate cancer and who then received testosterone therapy did not appear to have an increased risk of recurrent disease. But it’s impossible to make broad, generalized statements based on these studies. Chances are the result will depend on a number of variables, not the least of which is the seriousness of the cancer. It seems likely that a man with low-risk of disease recurrence would also have low-risk of testosterone creating a problem. Therefore, it would seem ridiculous to deny that man testosterone when it would improve his quality of life.

There has been a major push for reconsidering testosterone therapy from the large population of men who have been treated for prostate cancer over the last 10-25 years. No surprise there. Which of us wouldn’t prefer to be firm and sharp rather than soft and dull? But remember, marketers are spending millions to raise our expectations, and testosterone is not a silver bullet.

In September, the FDA is gathering a group of experts for a T summit. But it’s doubtful if they will clarify a topic that has more guesses and theories than real answers based on reliable information. Bottom line it is our decision when the conditions are right to use testosterone, and when to refrain. As the old saying goes, “You pays your money and you takes your choice.”

Prostate Cancer Clinical Trials

MARK SCHOLZ, MD

Clinical studies are primarily performed on men with advanced prostate cancer (the Royal Shade of Blue). Why?  The FDA.   FDA only approves new drugs when survival is proven to be prolonged compared to similar men treated with a placebo. The FDA’s insistence on a survival endpoint forces pharmaceutical companies to limit their research to men with a short life expectancy. If survival has to be the endpoint and the study participants live a long time, the cost of performing the study goes up exponentially.

Undergoing experimental therapy with a new medication is reasonable consideration when standard treatment is either no longer working or is causing unacceptable side effects.  However, it’s rare for doctors to recommend an experimental medication before other FDA-approved drugs on the market have been tried.  The commercially available treatments already proven to extend survival are Lupron, Provenge, Xtandi, Zytiga, Xofigo, Taxotere and Jevtana.

Getting Involved in a Trial Can Be Challenging

Eligibility requirements for participation can be rigorous. Trials have carefully specified pretreatment and health status criteria: Eligibility may be denied if the patient is either too sick or not sick enough, if there is too much previous treatment or not enough previous treatment. Criteria are pre-specified so that the final results of the trial are not skewed by a lack of uniformity among patients.  Other requirements designed to achieve trial uniformity include stopping all other anti-cancer medications and the use of placebos, both of which at times may be at variance with a patient’s best interest.

An additional challenge is finding the right trial that matches a patient’s need. The clinical trials landscape changes quickly.  New trials are initiated with limited fanfare and close as soon as they have met their pre-specified number of participants. Trials available at one center may not be so at another.  Another difficulty patient’s face is how to determine the effectiveness of a prospective study drug. Is it likely to work or not?  Due to a study drug’s newness, its functional characteristics are often unclear to patients and doctors alike.

There are different types of study designs to consider each with different goals.  Phase I studies, for example, are primarily designed to learn more about a drug’s side effects. Phase I studies sequentially escalate medication dosages up to determine the point of dosage intolerability. Phase II studies treat a group of patients at a fixed dosage to get a preliminary sense of a drug’s response rates. Phase III studies are the final step that leads up to FDA approval.  Phase III trials are the placebo-controlled trials.

The Business of Clinical Trials

Patients contemplating participation in a clinical trial should be aware that the clinical trial world functions like a business.  It’s funded primarily by the pharmaceutical industry. As such, doctors working in academia are highly motivated to find participants in their research.  If trials are not completed in a timely fashion funding for new trials will be harder to come by in the future.

Participating in a clinical trial has become more attractive over the last ten years as the pharmaceutical industry has made significant strides toward understanding cancer.  Now that they have access to cancer “blueprints” it’s feasible for brilliant biochemists to design “software patches,” new drugs that are far more effective and far less toxic than what has been traditionally available.  However, patients need be careful they don’t mistake a “new” drug for being an “effective” drug.  Despite the tremendous advances in research, most phase I and II drugs still fail to meet minimum standards of clinical effectiveness and never even advance to phase III testing. Sadly, many of the potential prostate drugs that have been tested in Phase III studies over the last ten years have failed to meet the FDA minimum threshold of showing a survival advantage.

Dr. Scholz is the Principal Investigator at Prostate Oncology Specialists - a list of the active trials are found at http://www.prostateoncology.com/clinical_trials

Detoxing for Jocks

BY RALPH BLUM

Recently my friend Michael Crocker—who is 59, a serious athlete (He calls himself “an over-the-hill jock”) and, because of his family history, at risk for prostate cancer—decided that he was not paying half enough attention to the  his diet. He was exercising and getting regular PSA evaluations, but he was eating as he always had, gaining weight and feeling that something in his diet was causing him bloating  and discomfort. He decided he might be having an inflammation reaction from foods that, while not allergy based, created a food intolerance that might be irritating his gut, leaving him depressed—and adding undesirable calories/weight. He put himself on what the profession calls “a food restriction diet.”

Michael made a list of what he called possible “food triggers” and going one week at a time, began eliminating them from his diet—and watching for improvement like decline in acid reflux, better sleep, more energy.

Here is Michael’s list of foods removed from his detoxing diet. He began by subtracting soy, then moved on to wheat and dairy and shellfish, He severely limited his sugar intake, cut out artificial sweeteners entirely, allowing himself honey in small amounts.

After about eight weeks, Michael told me, “I’m eating lean and clean, and probably eating more vegetables and fruit than I ever have before in my life.”

He started reading labels, something he had never done before. (“Jocks don’t read labels. Or at least they didn’t use to.”) He discovered that the FDA had called for labeling of “food allergens” in any packaged food (most of his items) and that even if items like soy were not specifically branded, they must be labeled somewhere on the package.

By the end of three months, Michael was eating limited amounts of lean meats, concentrating more on vegetables and fruits, and adding a side order of brown rice or sweet potato when he craved carbs. He rarely felt hungry on this diet. He dealt with his craving for snacks by carrying a bag of “Trail Mix” in his briefcase.

Here is a menu he found from Dr. Amy Shah on “RiseEarth”. As Dr. Shah writes in mindbodygreen

 A typical day may look like this:

 •    When you wake up: 1 glass green juice

•    Breakfast: Chocolate Cherry (Green) Smoothie: spinach, raw cacao, frozen organic cherries, chia seeds, coconut milk

•    Snack: Herbal tea

•    Lunch: Large salad with avocado, olive oil, balsamic dressing, and tomato soup

•    Dinner: 3 to 5 Black bean burgers (no bun) with guacamole, and salsa. (Optional: sweet potatoes, veggies, and kale chips)

 

•    Dessert: 1 serving of dark chocolate (my favorite is Green and Black's 85% dark)

Michael found that he was never hungry on this type of diet, and that while he wasn’t sure exactly which of “the usual culprits” had been causing his discomfort, he was happy to live with the results (including significant weight loss) of what he calls “The Aging Jock’s Anti-Inflammatory Detox Diet.” Aka AJAIDD.

Xofigo—A Wonderful New Treatment for Men with Advanced Prostate Cancer

BY MARK SCHOLZ, MD

It’s a special event when the FDA approves a new treatment.  Xofigo, otherwise known as Radium 223 or Alpharadin, is now commercially available.  The FDA approved Xofigo based on the results of a large, prospective, placebo-controlled trial that demonstrated significantly greater survival in Xofigo-treated men compared to placebo-treated men.  The trial also shows a very low incidence of side effects and good relief of bone pain. The treatment is easy to administer, consisting of monthly intravenous injections.

How Xofigo Works
Cancer treatment falls into four major categories. Chemotherapy selectively targets fast growing cells. Unfortunately, since chemotherapy works as a nonspecific cell poison, it frequently causes prominent side effects. Hormonal and targeted agents work by blocking the internal mechanisms of the cancer cell, thus forestalling growth. These treatments tend to have fewer side effects than chemotherapy.  However, by nature cancers are genetically variable, so resistant clones eventually appear. Immunotherapy stimulates the patient’s immune system. New forms of immunotherapy are promising and development is progressing very rapidly but this area of study is still in its infancy. Lastly, there is radiation consists of high energy particles that blast cellular DNA. A cancer cell with disabled DNA can’t reproduce.

Radiation needs to be given in a dosage sufficiently large enough to be effective. However, it also has to be targeted accurately to spare the surrounding healthy tissue. Xofigo addresses both of these demands elegantly. In terms of power, just one of the alpha particles emitted by radium 223 can cause irreversible cell damage because alpha particles are large enough to sever double-stranded DNA (typical beam radiation with photons requires multiple hits on DNA because it only damages one of the two DNA strands).

Xofigo Targets the Bone Metastasis
When cancer invades the calcium matrix of the bone it stimulates the bone to accelerate its rate of calcium uptake.  Radium 223 has structural similarities to calcium so Xofigo is “mistakenly” taken up by the bone cells adjacent to the cancer in lieu of calcium. So after Xofigo is injected, it travels through the blood stream and concentrates in the irritated areas of the bone where the cancer is most active.

Xofigo would be effective against almost any type of cancer since most cancers that spread to the bone increase calcium turnover in the bone cells adjacent to the cancer. However, the manufacturers and distributors, Algeta and Bayer Pharmaceuticals, were wise to seek FDA approval for prostate cancer before pursuing development in other types of cancer. Prostate cancer has an extremely fastidious pattern of spread. Metastases occur almost exclusively in bone. The major organs like lung, liver, kidney or brain are almost always spared. Since prostate cancer spreads almost exclusively to bone, Xofigo targets most if not all of the disease.

Alpha Particles Only Travel a Few Micrometers
To most everyone, the thought of radiation easily conjures up horrible visions of toxicity. The concept of radiation by injection is not new. Strontium and samarium are two radioactive elements that also concentrate in areas of increased bone activity. However, they emit a different type of radiation, beta radiation, which acts over a much longer distance and induces collateral damage to the surrounding cells in the bone marrow, the cells of the all-important immune system. Fortunately, bone marrow toxicity appears to be rare in men treated with Xofigo because alpha particles characteristically dissipate over the distance of a couple of micrometers, restricting the radiation effect to the active area of the cancer where it is invading on the surface of the bone.

Potent, Highly-Targeted Therapy—Just What the Doctor Ordered
Advanced prostate cancer in the bones eventually becomes resistant to other treatments. Historically, external beam radiation therapy has been a potent method for killing cancer cells, particularly to control pain, when the effectiveness of other options seems to be failing. However, beam radiation must be used very judiciously because it also causes irreversible damage to the surrounding bone marrow. Xofigo is likely to rapidly gain widespread acceptance with both doctors and patients because it simultaneously targets multiple metastases yet spares the closely adjacent bone marrow.

The FDA and Its Firing Squad (Combidex Part 3)

BY RALPH BLUM

There are a number of things concerning Invasion of the Prostate Snatchers of which I am proud. Two in particular stand out.

First, that despite his full and demanding schedule, Mark Scholz and I were able to collaborate effectively to produce this book. I have received a whole heap of emails from men thanking us and pointing out that, as far as they know, it is the first time in the literature on prostate cancer where the voices of doctor and patient were heard speaking as peers, each presenting those aspects of the disease he considered of primary importance to the newly diagnosed.

Second, it was both surprising and gratifying to learn that Snatchers had been awarded the 2011 Nautilus Book Award Gold Medal for “Conscious Media and Investigative Reporting” as the result of our tracking down the FDA rejection of Combidex. Since many of you have not read our book, and I know of no other readily available report on that destructive process, I want to review it here as part of the Combidex story.

I was determined to find out why the FDA had rejected Combidex back in 2005. I started by tracking down Jerome Goldstein, the former CEO of Advanced Magnetics (Ad Mag), the Cambridge, Massachusetts company that had marketed Combidex. I found him through his golf club, the Country Club in Brookline.

         “So what do you want to know?” Goldstein asked.

         “What went wrong? Why did the FDA reject Combidex? And can I quote you?”

         “I’m retired now,” Goldstein said in a gruff voice. “so I suppose you can quote me.

Some of the blame was ours. Our application was too broad. We should have gone for disease specificity. But that’s only part of it. The FDA bureaucrats in ODAC were also to blame. ODAC—that’s the Oncologic Drugs Advisory Committee—has total control over the life and death of every new drug application. And because of ODAC’s decision, prostate cancer patients are dying and suffering needlessly.”

Ad Mag’s fatal error was that instead of specifying Combidex as a contrast agent for establishing lymph node involvement in one type of cancer—prostate cancer—they had tried to broaden its application to cover all cancers. They should have known better. Once it has FDA approval for a single “indication,” it is legal for doctors to use a drug “off label,” meaning, wherever, in their judgment, it is useful.

I asked Goldstein if it was possible to obtain a transcript of the ODAC meeting, and he told me that their meetings were a matter of public record. Then, in a low angry growl, he said, “Nobody should ever die from this disease. It’s a crime.” I was about to hang up, when he said, “You know I have prostate cancer. I was diagnosed two years ago. Gleason 6. My internist said I should do surgery or put seeds in.”

         “So what did you do?”

         “Nothing.”

         “Nothing?”

         “Well, not exactly nothing. I bought a new putter.”

 
Although the transcripts of FDA meetings are a matter of record, they are not that easy to find. What’s more, they are not indexed so you have to dig. When I finally read the minutes and watched a video of the March 3, 2005 ODAC meeting, it was painfully obvious that there was plenty of blame to go around. But the way Combidex—NDA Application 21-115—went down really pissed me off.

ODAC found lots to attack. One patient went into anaphylactic shock from the Combidex. They delivered CPR and epinephrine, but it was too late: the man died at the hospital thirty-five minutes later. The fact that this single death had occurred a decade earlier, and had resulted in an immediate shift in method of delivery—from injection, to dilution of the contrast agent in saline and use of slow infusion—did not reassure the FDA. When I went through the Combidex records, I learned that the man who had died was so eager to participate in the trials that he failed to disclose his allergic condition, or that he had gone into anaphylactic shock on other occasions. Ad Mag pointed out that the vast majority of test subjects had only very minor and transient adverse (mainly allergic) reactions and that only four out of 1,236 patients had experienced a more serious adverse reaction. There had been no further deaths and no serious side effects.

 
After interviewing several staff members at Ad Mag, I became very aware of the financial reality. Contrast agents are not economically viable. Subjected to all the same requirements as a drug, a contrast agent like Combidex can cost over $100 million to develop, and the likelihood of FDA approval is increased by having a narrow indication. But here’s the irony: the narrower the indication, the less chance the company will ever recoup its money.

And there is a fundamental problem with imaging substances in general. Contrast agents are regulated just like drugs: the same standards apply for a contrast agent as for an antibiotic used to treat a life-threatening infection. Apparently it takes an act of Congress to get contrast agents regulated differently from drugs, and so far that hasn’t happened. But it’s obvious that there need to be different rules for approving imaging agents. Just another disgrace. Add it to the list.

What a crock! A normal lymph node for somebody with breast cancer is no different than a normal lymph node for somebody with prostate cancer. Combidex is “taken up” only in normal tissue. If the tissue’s not normal, the contrast agent is not taken up, and you know there’s cancer.

So while it would appear that applying for a broad application not only made medical sense, it was the only hope Ad Mag had of getting their money back.

There’s a lot more to the death of Comidex. You’ll find it in two chapters of our book: Chapter 15, “Now Playing for a Limited Time Only: The Combidex Follies,” and more in Chapter 17, “Anatomy of an Assisted Suicide.”

I admit it. I’m pretty much obsessed with the fate of Combidex. But as some French person once said, Rien ne vaut un bon obsession . . . (“There’s nothing as valuable as a good obsession.”) And now I’ve found an ally (See prior Combidex blogs) in the courageous Prof. Jelle Barentsz

Combidex redux!

 

Xtandi

BY MARK SCHOLZ, MD

It’s here!  Only 3 months after submitting the data from their phase III randomized trial, Medivation’s new prostate cancer super drug was approved by the FDA. Why so quick?  The FDA usually moves like molasses on a chilly morning. It can’t be simply because Xtandi (aka enzalutamide, aka MDV-3100) prolongs survival in men with life-threatening prostate cancer. We have all seen how the FDA ruminates, disseminates and procrastinates. Has the FDA suddenly grown a heart?

No, I think the quick approval of Medivation’s pill can be credited to the nature of the pill itself. It has an amazingly benign side effect profile.  The FDA is charged with two responsibilities: Confirming that a pharmaceutical company’s claims of anti-cancer effectiveness are valid and, ensuring that new products placed on the market are safe. In the latter case Xtandi made the FDA’s job simple.  The results from the study data submitted to the FDA for review showed that men taking Xtandi had fewer side effects than men treated with placebo.

What? Less side effects than placebo?  That sounds impossible. How can an active pharmaceutical agent that is potent enough to block cancer have absolutely zero side effects?  Even aspirin (stomach ulcers) Tylenol (liver damage) and Benadryl (drowsiness, slow urination) have known toxicity.

Actually Xtandi does have a significant side effect profile.  However, the side effects were completely masked because all the men being tested in the study—the men taking placebo and the men taking Xtandi—were also taking Lupron to block their testosterone. So the typical side effects of blocking testosterone (low libido, hot flashes and fatigue) already preexisted in everyone in the study. Therefore Xtandi’s side effects were “cloaked” by the Lupron.

The above explanation can account for Xtandi having the same side effect profile as a  placebo. However, in the study, Xtandi had fewer side effects than placebo. This mystery can be unraveled by considering the generally advanced stages of cancer present in the men being studied.  Uncontrolled cancer can cause “side effects” that are indistinguishable from drug-related side effects.  Xtandi works. It controls cancer and reduces “side effects.”

Medivation deserves enthusiastic commendation for developing this lifesaving new medication. The company should also be recognized for its generous community spirit because while waiting for FDA approval they have been distributing Xtandi free of charge to hundreds of patients through a compassionate-use research protocol.

 

Technology to the Rescue

BY MARK SCHOLZ, MD

My dad always told me that good ideas are a dime a dozen. The trick is to put the good ideas into motion so that by perseverance and hard work they come to fruition.  This is true of the pharmaceutical industry. Massive investment in basic research has yielded a much better understanding of how cancer “works,” creating opportunities for biochemists to design specific pharmaceuticals that will inhibit cancer growth and spread. However, the fact remains that multi-million dollar clinical trials must be performed before a new medicine can be approved and released by the FDA.

One pharmaceutical company that is making fast progress is OncoGenex.  They have developed an elegant solution for blocking an overactive enzymatic pathway that cancer cells use to protect themselves from chemotherapy. For example, blocking the effectiveness of one popular type of chemotherapy commonly used to treat prostate cancer is called Taxotere. The specific overactive enzyme the scientists at OncoGenex have identified is called clusterin. Cancer cells over-produce clusterin to protect themselves from chemotherapy.

OncoGenex has designed a medicine that accurately targets clusterin.  This new medicine, called Custirsen, sharply reduces the amount of clusterin inside the cancer cells. A preliminary trial, using Custirsen was added to the regimen of 82 men with advanced metastatic prostate cancer being treated with Taxotere (a chemotherapy drug that is commonly used to treat prostate cancer), showed a 40% improvement in survival rate when Custirsen was added to Taxotere--compared to the survival in men receiving Taxotere alone.

Clinicaltrials.gov reports that 141 centers around the country are currently participating in a larger trial combining Custirsen and Taxotere.  This larger trial, involving hundreds of men with advanced prostate cancer, is aimed at proving the effectiveness of Custirsen and getting approval by the FDA for commercial availability. Custirsen is administered as a weekly intravenous infusion.      

Over the course of my 20 years as an oncologist many of the common cancer medicines have proven to be  major disappointments—not very effective and overly toxic.  These earlier agents were discovered and developed through a slow and cumbersome process of trial and error. In that era we had only a vague idea of how the new treatments actually worked.  Most of those agents were broad spectrum inhibitors of cellular growth that resulted in considerable collateral damage on the faster growing normal cells of our body like the hair follicles and the white blood cells.  

Research leading to the discovery and development of newer agents like Custirsen is completely different. These agents are rationally designed and targeted to attack and destroy a very specific part of the cancer cells. As a result, they are not only more effective, they also have fewer side effects.

At last, it appears to be technology to the rescue.

FDA Roulette

BY MARK SCHOLZ

The notoriously stingy and demanding FDA gave the go ahead for two new treatments for prostate cancer in 2010.  New approvals are rare because of the hundreds of millions of dollars required to undertake the type of studies that the FDA requires. The FDA wants studies that randomly allocate men into two comparison groups. One group gets the new medicine. The other group gets an ineffective fake called a placebo. FDA approval comes when men getting the new medicine live longer than those given the placebo.

Finding volunteers willing to participate in these types of studies is difficult. The men know there is a 50% chance they will get an ineffective placebo. Who wants to take the chance of getting a sugar pill as their treatment? Even so, some men are so desperate, they sign up, hoping to be among the lucky ones who receive the real McCoy.

These studies often run for years because the study ends when the study participants die from progressive cancer.  To find men willing to participate, the supervising companies that organize and run these studies need contractual relationships with a hundred or more study centers. Just keeping track of all these different patients, at so many different locations, over a period of several years, is in itself very costly.

Provenge is the first FDA approved treatment for prostate cancer that works by strengthening the immune system. Dendreon is the name of the company that has patented a process of harvesting immune cells out of the blood by means of a technique known as “plasmapharesis.” Plasmapharesis is a three hour process similar to dialysis that extracts immune cells from the blood. The harvested cells are then taken to a special laboratory and mixed with substances that enhance their aggressiveness against cancer.  The cells are then re-infused back into the same patient. 

Provenge’s primary appeal is the low incidence of side effects. The treatment, which does not rely on chemotherapy, is so revolutionary that at first the FDA was very skeptical. They dragged their feet for years, forcing the company to run their studies over and over.  Lo and behold, additional studies again demonstrated that Provenge-treated men were 30% more likely to be three years after their treatment with Provenge compared to the men who received a placebo. Dendreon should be commended for patiently persevering time after time when the FDA kept turning them down. Now men with prostate cancer have access to an effective treatment that has very few side effects.

The other new treatment recently approved by the FDA, Jevtana, falls into the more familiar category of chemotherapy.  Jevtana was approved in July 2010 based on a randomized survival study evaluating Jevtana compared to an older, ineffective type of chemotherapy called Mitoxantrone. 755 men were treated with either Jevtana or Mitoxantrone. The survival of men receiving Jevtana was 30% better then the men treated with Mitoxantrone.  

This remarkable achievement took some industry experts by surprise because the participants in the trial had all been treated previously and become resistant to another type of chemotherapy called Taxotere.  Historically, resistance to Taxotere has been a bad sign predicting resistance to all types of chemotherapy. Jevtana, unlike Provenge has the traditional side effects of chemotherapy such as tiredness, hair loss and increased risk for infection. Even so, reversing cancer in men with Taxotere-resistant disease is quite an accomplishment. 

The FDA finally agrees that both Jevtana and Provenge are proven to make men live longer. Studies are ongoing with these newly-approved medicines to see if combining them with other drugs can further enhance their effectiveness. In the meantime, men with prostate cancer need to be aware that these new and effective tools are available.        

Playing “Chicken:” Sometimes You Both Lose

BY MARK SCHOLZ

I have never seen a real game of chicken where two cars race head on toward each other to see who will swerve first, i.e., who is chicken. However, we are seeing an actual game of chicken being played out before our eyes on the national stage.

In one car in this are the pharmaceutical companies that are charging mind-boggling prices for their new cancer drugs. FDA approval of a new medicine is like hitting the lottery because the insurance companies are legally obligated to pay for the drug. Recouping the cost of developing a new drug is certainly justifiable. Even so, in my recent blog I cited the example of Zytiga (abiraterone), an effective new pill for prostate cancer that retails for $5,000.00 per month.

The other car in this game is the insurance companies, who, to control costs, have begun imposing artificial restrictions on coverage of Zytiga by insisting that chemotherapy be administered first, before Zytiga can be prescribed. By imposing this artificial restriction the insurance companies are getting involved in making decisions about treatment that historically have been left to the doctor. The insurance company’s rationale is that the studies of Zytiga that led to FDA approval were performed in men after chemotherapy, so in theory we don’t know if Zytiga will work before chemotherapy.  What a travesty!  Any cancer expert—for that matter, anyone with common sense—can tell you that starting treatment earlier works better than waiting until the disease is more advanced. 

I really don’t know how this scary game of chicken is going to end.  No insurance company has endless resources. Yet, thanks to effective research being performed by the pharmaceutical companies, many new (and expensive) drugs are coming on the market. Presently in my daily practice, people who meet the criteria—men who have had previous chemotherapy—and have adequate pharmaceutical insurance, are getting coverage for their Zytiga pills. Also, Johnson and Johnson, the manufacturer of Zytiga has a generous program for drug access for people who can’t afford the drug.  Even so, at some point the costs to society are going to become unsustainable. Just like the game of chicken, if both the parties wait too long to take corrective action, we can anticipate a crash.