another set of safety questions regarding avastin

first it was bleeding when Avastin used to treat colon cancer

Now it is a rare but interesting problem involving breeching the blood-brain barrier when treating kidney cancer patients with high blood pressure:

Avastin May Cause Leukoencephalopathy Syndrome

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NEW YORK (Reuters Health) Mar 02 - Genentech is advising physicians to discontinue the use of Avastin (bevacizumab), a monoclonal antibody that inhibits vascular endothelial growth factor, in patients who develop reversible posterior leukoencephalogpathy syndrome (RPLS), a brain-capillary leak syndrome, according to a letter published in the March 2nd issue of The New England Journal of Medicine.

Dr. Hal Barron of Genentech responded to two letters, also published in NEJM, that describe the development of RPLS in two patients with metastatic renal cancer, who also had hypertension, after they were treated with bevacizumab.

The company is also updating package inserts in Avastin in the U.S. to include RPLS syndrome. Its corporate partner Roche is taking similar actions outside the United States, Dr. Barron said.

In one letter, Dr. Peter Glusker and colleagues at Sanford University Medical Center believe the syndrome was attributable to Avastin "Because of the increasing use of this agent, clinicians should be aware of this potential association," they point out.

The physicians describe a 59-year-old woman who received seven infusions of bevacizumab at 2-week intervals for metastatic renal cancer, during which time her blood pressure remained within her usual range at about 100/70 mm Hg. Eight days after the last infusion, she was admitted to an emergency room with severe lethargy. While the physical examination was essentially normal, her blood pressure was 168/88 mm Hg.

"Laboratory assessment was remarkable only for a white-cell count of 14,000 per cubic millimeter; urinalysis showed more than 100 white cells per high-power field and a moderate number of bacteria." Neurologic examination on the first hospital day revealed cortical blindness and extensor plantar responses.

Magnetic resonance imaging (MRI) of the brain showed nonenhancing extensive leukoencaphalopathy in the subcortical (distal vasculature) distribution. The women had a normal brain MRI less than 2 months earlier.

The patient made a rapid recovery, despite having a small, hemorrhagic stroke.

Dr. Glusker's group said they were aware of at least 82 reports in the literature of RPLS in association with chemotherapy and immunosuppressive treatments.

Reported adverse effects of bevacizumab include hemorrhagic stroke, arterial thrombotic events, hypertension and the nephrotic syndrome.

"Since bevacizumab has a 20-day half-life, we believe this patient's reversible posterior leukoencephalopathy is attributable to bevacizumab," they added. "We speculate that this may have resulted from effects of this VEGF inhibitor on the blood-brain barrier. Because of the increasing use of this agent, clinicians should be aware of this potential association."

In the second letter, Dr. Cevher Ozcan and associates from the Medical College of Wisconsin report the case of a 52-year-old woman with hypertension and metastatic rectal adenocarcinoma who had three cycles of chemotherapy with fluorouracil, leucovorin and oxaliplatin.

She presented with acute bilateral loss of vision, headache and confusion 16 hours after her first dose of bevacizumab, which was administered with the fourth cycle of the chemotherapy regimen.

Her clinical presentation and imaging findings "were characteristic of RPLS," the physicians said. "Bevacizumab-based combination chemotherapy is associated with a risk of grade 3 hypertension in up to 16% of patients, possibly secondary to vasospasm," they write. "We speculate that bevacizumab may have induced vasospasm, which coupled with hypertension in our patient, led to RPLS.

"We suggest that RPLS is an important consideration in patients with poorly controlled hypertension who are treated with VEGF inhibitors," Dr. Ozcan's group continues.

"Clinicians should be aware of this potential complication and control blood pressure strictly during and after the bevacizumab infusion. Controlling hypertension and discontinuing the offending agent appear to help reverse the complication."

"The letters from Dr. Glusker and colleagues and Dr. Ozcan and colleagues provide valuable information about a very rare syndrome," Dr. Barron writes.

"We agree that the two patients reported meet the clinical criteria for RPLS. At this time we are reviewing the global safety database to look for cases with clinical signs and symptoms associated with RPLS and are investigating one additional case."

N Engl J Med 2006;354:980-

Roche to Brief Regulators on Avastin Brain Link

ZURICH (Reuters) Mar 02 - Swiss drug maker Roche Holding AG said on Thursday it would brief healthcare regulators on rare cases of a brain condition seen in some patients taking its blockbuster cancer drug Avastin.

According to correspondence in this week's New England Journal of Medicine, two women developed reversible posterior leukoencephalopathy syndrome, or RPLS, while on Avastin. Both patients later recovered from the condition, which can lead to blindness and other complications.

A third possible case is being investigated.

"This is a very rare syndrome and it is reversible as well," said Roche spokesman Alexander Klauser.

"We will be updating regulators with these findings so prescribers can change treatment as required. We are not aware of any additional cases."

Roche certificates were trading 0.6 percent lower at 195.50 Swiss francs at 0935 GMT, weighed down modestly by the journal report. Analysts at brokerage Julius Baer said the cases appeared to be limited and there should not be a significant impact on demand for Avastin.

"RPLS is a rare condition and the use of Avastin is not actually in danger," they wrote in a note.

Avastin was co-developed with Roche's U.S. biotech partner Genentech Inc.

...will help get Herceptin in to the brain to avoid the brain metastases occuring in patients on Herceptin...

[StephN]

Lani -
For those of us with the disease, this seems like a good idea.
We need a small molecule drug to pass the BBB, if they do not rework Herceptin.

However, I can see the insurance companies balking at the expense of two such drugs given together. Especially for any length of time, unless the patient is already known to have some mets to the brain.

Will be interesting to see if the other reasons for the RPLS will shed any new light on this rare side effect.

I do not see how Herceptin can be reworked to cross the blood-brain barrier
as it is such a large molecule that it cannot get through. However, other means mechanical, electro-magnetic, chemical, immunological may be found to "open" the BBB (ie, make it more permeable) so that Herceptin and other large molecules can get through.

A young woman with ALL I met recently had a terrible case of meningitis brought on when a team of doctors gave her chemo when they were unaware that she was on a monoclonal antibody usually used for rheumatoid arthritis (as it is directed against nKB alpha, a marker which happend to be found on her leukemic cells). As it turned out the monoclonal antibody made her BBB permeable and the chemo got in in very high concentrations, when it normally wouldn't have been able to pass through at all.

She had no known sxs or involvement of the CNS, so this unexpected "treatment" was entirely unwelcome.

These monoclonal antibodies will be used by many more patients in the future, and hopefully their price will decrease, therefore. So let's be hopeful...

Food for thought!

[al from Canada]

Apprarently, WBR will blow holes (or make permiable) in the BBB so certain amounts of herceptin will pass. I don't know if the same is true with cyber / gamma knife proceedures.

Al

[StephN]

The fact that the BBB can be made more permeable by certain other treatments which would then allow some so-called seepage of Herceptin, Taxol or other drug into the brain is only applicable to a few of us who DO have those other treatments (such as radiation).
(I did have this conversation with my rad onc brain specialist last month and he feels that my Gamma Knife procedure has allowed some Herceptin to get past my BBB.)
The group of women as a whole who are on ADJUVENT Herceptin would not get that benefit. Therefore their brains remain unprotected.
What can be done about this problem??
The occasional brain MRI is not a very good method of dealing with the threat of possible brain mets.
And I would LOVE to see the cost of some drugs go down!