for those with (or worried about) brain mets Avastin seems to cross the bbb

[Lani]

Blood brain barrier) and is effective in prolonging survival and function when combined with chemo in primary brain tumor (glioma). The fact that it crosses the blood brain barrier in these tumors (hope same will be the case for breast ca brain mets) and has been shown to be syngergistic with herceptin in a relatively small group of metastatic breast patients studied by Dr. Mark Pegram, is reason to hope (especially as it is already FDA approved for other purposes):

Cancer Drug Can Extend Survival in Patients with Deadly Brain Tumors [DukeMedNews]
DURHAM, N.C. — Avastin, a relatively new type of drug that shrinks cancerous tumors by cutting off their blood supply, can slow the growth of the most common and deadly form of brain cancer, a pilot study conducted at Duke University Medical Center has found.

The study marks the first time that Avastin has been tested against brain tumors, the researchers said. The drug, whose chemical name is bevacizumab, currently is used to treat lung and colorectal cancers.

The researchers tested the effectiveness of Avastin in conjunction with a standard chemotherapy agent in patients with recurrent cancerous brain tumors called gliomas. They found that the two drugs together halted tumor growth up to twice as long as comparative therapies. Though gliomas remain incurable in nearly all cases, the combined drug therapy may buy precious time and preserve physical and mental function longer for patients facing this grim diagnosis, the researchers said.

"These results are exciting because of the possible implications for a patient population that currently has the poorest possible prognosis going into treatment, those with malignant brain tumors that have recurred after initial treatment," said James Vredenburgh, M.D., a brain cancer specialist at Duke's Preston Robert Tisch Brain Tumor Center and lead researcher on the study.

The findings will appear in the Feb. 20, 2007, issue of the journal Clinical Cancer Research. The study was funded by the National Institutes of Health, the Preston Robert Tisch Brain Tumor Research Fund, the Bryan Cless Research Fund and Genentech, the maker of Avastin.



ABSTRACT: Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma [Clinical Cancer Research]
Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma.

Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m2, whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m2. Toxicity and response were assessed.

Results: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke.

Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.

[AlaskaAngel]

Lani,

In demonstrating what does cross the BBB and what doesn't.... I'm puzzled... a drug could have a higher success rate without crossing the BBB if it acts upon something else in a way that then leads to a higher success rate.

I know it is a little gruesome to ask this common sense question... but what I don't understand is why proof of various drugs crossing the BBB isn't available by autopsy down the road?

A.A.

[heblaj01]

I am a bit surprised that the trial used Irinotocan (which has relatively high toxicity) instead of Temodar to partner with Avastin.

I found this link to a patient whose onc prescribed this combo off label:
http://64.233.167.104/search?q=cache...n&ct=clnk&cd=5
I noticed among several trials using Irinotocan in combination with an other drug for brain cancer one trial of irinotocan +Temodar ,for children,taking place at Duke university.

[Lani]

As I understand it--sometimes the drug crosses the blood brain barrier when it is intact eg. if the size of the molecule is small enough for it to get through. It is not just the size of the molecule of the drug as given, but many drugs circulate bound to proteins, which makes the size the blood brain barrier (which is like a sieve) "sees" just that much bigger.

Yes it seems that sometimes a drug can have an effect outside the Central Nervous System which produces a substance, immune effect or alters some pathway which produces different metabolites which do/does cross the blood brain barrier.

Also, sometimes the disease itself (or the treatment given for it eg radiation) can make the blood brain barrier more permeable (eg. think of making the pores of the seive bigger which lets more in)

So I would think there are many ways to outwit the Blood brain barrier. As we discover more about it, hopefully more will be found.

By the way, the rate of autopsy is AMAZINGLY low. People don't agree to it as often, doctors don't ask for it as often and institutions are not willing to "ruin their bottom line" by performing the studies needed to learn from those who have died--as it is not reimbursed by insurance companies.