Clinical Trials From Hell
Companies Test Castration Implants For Prostate Cancer Without Protecting Men From Testosterone Flare
March 11, 2000. Alza Corp., which specializes in time-release drugs including the nicotine patch, has developed and tested a new drug. Announced this week, Viadur is a twelve month testosterone-blocking implant for men with advanced prostate cancer.
Inserted under the skin at the top of a man's inner arm, a match-stick sized titanium pump dispenses 1/100th of a drop a day of leuprolide acetate. Now that the U.S. Food and Drug Administration has approved the drug and the dispenser implant, Alza plans to start selling Viadur later this year or early next year. They have not yet announced a price.
Seizing on negative sexual impact of long-term castrating drugs, reports in the press pass over a problem within the trial itself - a problem at ground zero, where prostate cancer cells are fueled by testosterone.
Not that problems with the delivery system and the long-term effects of the drug aren't on the horizon. Instead of an injection, as for Lupron or Zoladex, the man must get a shallow incision and may develop a local irritation or infection. The man will no longer need to come in to the doctor's office every month or three months(as for injection). But he and his doctor may be concerned about whether the implant is actually doing the job. Regular testosterone checks will be in order to find out. Office visits may not be reduced - nor necessarily should they.
Add to this a potentially negative impact on any pursuit of intermittent hormonal therapy. Plus potential psychological impact of a longer-term commitment to chemical castration and sexual shut-down.
The type of drug used in this implant is not new. Like Lupron and Zoladex, Viadur contains an analog of LHRH (luteinizing hormone-releasing hormone). These drugs (called analogs because they are human-made) send out a signal to the pituitary in the brain telling it to send a hormonal message to the testicles to make more testosterone.
LHRH drugs send out a constant signal which, paradoxially, brings about chemical castration. The pituitary goes into overdrive. The body's production of testosterone jumps above the normal scale. Feedback goes back to tell the brain that no more male hormone is needed. Within a month, the level of testosterone in the blood drops dramatically and usually will stay down.
During the first week, though, that vastly increased outpouring of testosterone may cause cancer to flare. Which patients in this trial were exposed to.
Disease flare is wholly preventible if money is available to pay for additional antiandrogen drugs to control the cancer ahead of and during the first month or so of LHRH use. In 1987, Dr. Fernand Labrie at Laval University Medical School in Quebec, Canada reported in the journal Urology that Flutamide "eliminates the risk of disease flare in prostatic cancer
patients treated with a luteinizing hormone-releasing hormone
agonist." For more than a decade, no man started on Lupron, Zoladex or any LHRH drug needed to go unprotected against flare. But reportedly (as the annals of P2P show), a lot of men have been exposed to unnecessary flare. Flutamide and Casodex add considerable cost to an already costly therapy.
Alza researchers evidently know all about flare, although they never use that term. They were studying the effects of Viadur on 131 patients, who had stage C prostate cancer. One thing they watched for was evidence of flare. Alza's package insert tells the story of how they did nothing to prevent it. In fact they appear to expect doctors who use Viadur merely to treat flare symptoms if they occur. This may give rise to disaster if the drug is exported into medical settings which do not make provision for the extra cost of using drugs to prevent flare or where a doctor or nurse relies on package inserts and a drug manual to know how to proceed.
Under "Adverse Reactions" the package insert submitted to the FDA states: "Like
other LHRH agonists, Viadur™ caused a transient increase in serum testosterone concentrations
during the first 2 weeks of treatment. Therefore, potential exacerbations [worsening] of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria."
Without mentioning that this can easily be prevented, they state: "If these conditions are aggravated, it may lead to neurological problems such as weakness and or parasthesia of the lower limbs or worsening of urinary symptoms." In plain words, a man may end upwith spinal collapse, paralyzed in the legs; or with urinary backup or kidney failure and on a catheter or dialysis.
The worst-case scenarios apply to men who are given LHRH agonist drugs on coming to the doctor with already advanced, stage D1 or D2 prostate cancer. The 131 men enrolled in the Viadur trials had mid-stage (stage C ) disease. For those men too flare is dangerous. It may cause progression, driving the disease further before the LHRH drug shuts it down temporarily.
Apparently, the researchers simply watched to see how many patients in their trials developed worsening of the disease. And the FDA let them get away with it. In material submitted to FDA for final approval, Alza state: "In the above-described clinical trials, the transient increase in serum testosterone concentrations was associated with an exacerbation of disease symptoms, manifested by pain or bladder outlet obstructive symptoms (urinary retention or frequency) in 6 (4.6%) patients."
The assumption is planted that progression of cancer is merely a matterof symptoms, not of cell proliferation and alteration. Yet researchers know that LHRH drugs are palliative, that is, do not kill cancer cells. If and when the cancer progresses, some of those "extra" cells produced during the period of flare may kick in.
Alza is not alone in this archaic treatment of men with prostate cancer. In a study at Royal Free Hospital, London, UK, six-month depot hormonal-blockade avorlin was tested on men who got no protection against flare, which occured. "After the expected flare in serum testosterone," the researchers say, "... medical castration ... was achieved within 4 weeks of depot injection." If flare was expected why did they let it happen? No scientific reason for this - no need of any further proof that it does happen and no question that it can be avoided by using Casodex, Flutamide,or comparable drug.
Some other researchers are protecting against flare. In Israel, patients in trials of an implant that
releases histrelin were treated with flutamide or
cyproterone acetate "2 weeks before implant insertion and continued for up to 12 weeks."
Looking at Alza's record of side-effects one may wonder, is that exceedingly precise-looking number (4.6%) really accurate? They say, 6.9% of the men experienced breast enlargement; 2.3% experienced anemia and 2.3% experienced impotence. Most support groups offer evidence to make those statistics look ridiculous.
In one respect Alza is forward-looking. The package insert they submitted to the FDA warns that Viadur exposes men to risk of osteoporosis (bone loss). "Decreased bone density has been reported in the medical literature," they say, "in men who have had orchiectomy or who have been treated with an LH-RH agonist analog." They cite a clinical trial in which half of the men treated with leuprolide acetate for six months or more showed lower than average bone density scores.
This warning may help more men get through to their doctors about this problem. For years, many doctors turned a blind eye to this visible effect of hormonal blockade on men. Even star oncologists denied any link between Lupron or Zoladex and osteoporosis; some even objected to patients requests for bone density scans and bone density replacement therapies. In this respect, the patient can show the oncologist what a drug company says about its own product.
Words are not deeds, though. Alza Corp. could have offered these 131 patients (80 Caucasian, 23 Black, 3 Hispanic) base line bone density scans and follow ups. They could have provided available drugs known to prevent bone loss. Maybe next time.
Alza package insert submitted to FDA
(an Acrobat Reader .pdf file, 375 k (from our downloads page)
ALZA Announces Approval of Viadur For Once-Yearly
Palliative Treatment of Advanced Prostate Cancer
(press release, WiredBird)
J Urol 1987 Oct;138(4):804-6
Flutamide eliminates the risk of disease flare in prostatic
cancer patients treated with a luteinizing hormone-releasing
Labrie F, Dupont A, Belanger A, Lachance R
Department of Molecular Endocrinology, Laval University Medical Center, Quebec,
The J Urol 1999 Dec;162(6):2019-23
Pharmacodynamics of a long acting depot preparation of
avorelin in patients with prostate cancer. Avorelin Study Group.
Kaisary AV, Bowsher WG, Gillatt DA, Anderson JB, Malone PR, Imbimbo BP
Royal Free Hospital, London, United Kingdom
J Urol 2000 Mar;163(3):838-44
An implant releasing the gonadotropin hormone-releasing
hormone agonist histrelin maintains medical castration for
up to 30 months in metastatic prostate cancer. Chertin B, Spitz IM, Lindenberg T, Algur N, Zer T, Kuzma P, Young AJ, Catane R, Farkas A
Department of Urology, Shaare Zedek Medical Center and Zer Laboratories, Jerusalem, Israel.
Abbott acquires Alza
Alza terminates the agreement http://www.alza.com/pr/pr421.htm January 20, 2000
Information on Zoladex and Casodex is available from AstraZeneca http://www.prostateinfo.com/
What to expect from Lupron depot (TAP Pharmaceutical site)