Merry Christmas!

Merry Christmas to you! Please check out these sites for prostate cancer info.

www.prostateoncology.com
http://pcribc.org/forum.php

 We are excited about 2013 and we'll see you in the new year.

Urologist and Radiation Therapist Attitudes toward Active Surveillance

BY MARK SCHOLZ, MD

In May of every year over 10,000 medical oncologists from around the world attend a 5-day meeting sponsored by the American Society of Clinical Oncology (ASCO) where preliminary results of the latest cancer research are presented.  Thousands of research projects are summarized and published in short 300-word abstracts.  What follows is a long quote of almost the entire abstract published in 2012 by Dr. Simon Kim from the Mayo Clinic:

“While active surveillance is well recognized as an acceptable treatment strategy for low-risk prostate cancer, the extent to which radiation oncologists and urologists perceive active surveillance as effective and routinely recommend it to patients is unknown. Therefore, we sought to assess the attitudes and treatment recommendations for low-risk prostate cancer from a national survey of prostate cancer specialists.

Methods: A mail survey was sent to a population-based sample of 1,439 physicians in the U.S. from late 2011 and early 2012. Physicians were queried about their attitudes regarding active surveillance and treatment recommendations for patients diagnosed with low-risk prostate cancer (PSA<10 ng/dl; Stage = T1c; Gleason 6 in one of twelve cores).

Results: Overall, 321 radiation oncologists and 322 urologists completed the survey for a 45% response rate. Most physicians reported that active surveillance is effective for low-risk prostate cancer (71%) and stated that they were comfortable routinely recommending active surveillance (67%). Urologists were more likely to agree that active surveillance is effective (77% vs. 67%; p=0.005) and were comfortable recommending active surveillance (74% vs. 61%; p=0.001) compared with radiation oncologists. Most physicians recommended radical prostatectomy (47%) or radiation therapy (32%), but fewer endorsed active surveillance (21%) for low-risk disease. After adjusting for physician covariates, radiation oncologists were more than eleven-times more likely to recommend radiation therapy, while urologists were 4.7-times more likely to recommend surgery and 2.1 times more likely to recommend active surveillance for low-risk prostate cancer.

Conclusions: Although active surveillance is widely viewed as effective by radiation oncologists and urologists, most urologists continue to recommend surgery, while most radiation oncologists recommend radiation therapy. Our results may explain in part the relatively low contemporary use of active surveillance in the U.S.”

My Comment: This study clearly documents that urologists and radiation therapists, while acknowledging that active surveillance is acceptable, overwhelmingly recommend surgery and radiation. Not surprisingly, the urologists recommend surgery and the radiation therapists recommend radiation. The study findings are remarkable because they were not generated by a third party. This report depicts urologist and radiation therapist behavior though a self-description survey. Clearly, broader acceptance of active surveillance will be impeded until the day when urologists and radiation therapist physicians are willing to act on what they know to be true about active surveillance rather than simply giving it lip service.   

 

 

 

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!

 

The Science Behind Active Surveillance

BY MARK SCHOLZ, MD

Active Surveillance versus the “Gold Standard”         
Ten years ago surgery was called the “Gold Standard,” the treatment to which every other kind of treatment should be compared.  Now you rarely encounter the Gold Standard argument to bolster surgery as the preferred treatment approach.  What scientific studies led to this change in perspective and why has it taken so long for this change to come about?
 
Finally, a Clear Answer
The final nail in the “Gold Standard” argument occurred in 2012, when the New England Journal of Medicine published a study by Dr. Timothy Wilt comparing the long-term outcome of surgery versus observation.¹ Between 1994 and 2002, seven hundred and thirty-one men volunteered to undergo either surgery or observation based on a coin flip. 

No Benefit for “Good” Cancer, Modest Benefits for “Bad” Cancer

The average age for the whole group of men was 67. The median PSA was 7.8. The study ultimately concluded that here was no difference in prostate cancer mortality with either approach. Mortality was within the expected range of statistical variation (5.8% died in the surgery group and 8.4% died in the observation group).  A small survival benefit for surgery was seen in men with a PSA over 10.  (Mortality was 12.8% in the observation group and 5.5% in the surgery group.) Dr. Wilt also reported the side effects of surgery.
     
Even before Dr. Wilt’s report was published, Active Surveillance had been gaining mainstream acceptance in the medical community. Multiple, independently-published studies consistently reach the same conclusion that Active Surveillance is safe.  Some of these studies are briefly summarized in the next few paragraphs. The full abstracts are posted on our website at www.keepmyprostate.com. 

Do All Men Have Prostate Cancer?

One of the most compelling arguments for forgoing radical treatment is based on the fact that prostate cancer is simply too common in the general population to represent an imminent threat to life. Studies of prostate glands removed from men dying of unrelated causes show that by the time they die, most men harbor prostate cancer.¹ That prostate cancer is incredibly common in the normal male population is also supported in another report from the New England Journal of Medicine where 4,692 healthy men over age 50 with a normal PSA (average 2.7) volunteered to undergo a simple six-core prostate biopsy.  The resulting biopsies showed that one-fourth of the men had cancer.²

Many Studies, Same Conclusion

Additional research has looked into comparing Active Surveillance with surgery. For example, a study from Johns Hopkins reported that life expectancy is only extended an average of 1.8 months by having immediate surgery.³  Another study in the Journal of Urology confirms that the grade of the tumor is an excellent method for determining which type of cancer is safe to monitor because prostate cancer mortality was almost nonexistent in 12,000 men with Gleason score of six or less  who were monitored for 12 years after surgery.⁴

Additional studies reporting the long-term outcome of Active Surveillance have been published: In a ten-year study of 1,000 men undergoing observation at Johns Hopkins Hospital, not a single man has died of prostate cancer or developed metastases.⁵ In another study of 450 men undergoing observation in Toronto that included some men with grade 7 disease, five out of 450 men died of prostate cancer.⁶

The Dark Side of Treatment

The idea of living with cancer may not seem at all attractive, but once the side effects of surgery are factored in, Active Surveillance starts to look really good. Unfortunately, the side effects of radical treatments like surgery are universally underemphasized by doctors and patients alike. Doctors downplay the effects of surgery because their years of working in the field accustom them to impotence and incontinence in their patients. The patients who have had treatment and are lucky enough to have had a good outcome, sing the praises of treatment because they took a radical step to remove their cancer and were fortunate to avoid bad consequences. The patients with bad outcomes are frequently too embarrassed to talk about their diapers and sexual incapacity.  They minimize the bad effects of the treatment and emphasize their gratefulness about “having been saved from cancer.”

The fact is that surgery and radiation cause permanent side effects with astounding frequency.  In a study of 475 men, four years after having surgery or radiation, less than 20% of men described their sexual function as returning to normal.⁷ In another study of 785 men, three years after surgery or seed implantation, less than 20% of men who had surgery and less than 50% of the men who had seeds described their sexual function as returning to normal.⁸ Unfortunately, to many people, all these statistics are an abstraction. Nevertheless, the tragedy of unnecessarily destroying even one man’s sexual identity cannot be calculated.

At First, New Thinking Always Seems Radical  

Let me close with an acknowledgement that Active Surveillance involves a totally new way of thinking. The very first conference to review the science of Active Surveillance was convened in San Francisco in 2007. At that time two hundred prostate cancer experts laid down the basic guidelines for Active Surveillance.  Doctors around the world are still being introduced to the idea of Active Surveillance. Believe it or not, some doctors have not even heard about it.  Inevitably, it takes time for people to change. Even so, that’s no reason for you to be trapped by outdated thinking.