Blood Brain Barrier Program - Anyone have info?

[CourtneyL]

Hi Ladies,

I am still waiting to see if Tykerb is going to be enough to do the trick to eliminate the six small tumors in my brain as I am NED everywhere else. If Tykerb isn't effective enough, we are going forward with Gamma Knife to blast the suckers.

In doing research on these topics, my husband Jay came across a program at Oregon Health & Science University called the "Blood Brain Barrier Program" where they apparently have a technology that temporarily suspends the BBB's function to allow medication to reach the brain. I was wondering if anyone knows anything about this and whether or not this is a possible treatment option for those of us with brain mets. It seems that if we could just get some of these amazing drugs into our brains, perhaps we could fight and beat these brain mets more easily.

Thoughts? I am going to ask my doctor about this at my next meeting. I am also wondering why drugs such as Herceptin can't be injected into the cerebral fluid and thus given access to the brain that way. I am no medical expert but was just wondering if any of you had any insight.

The website for the Oregon program is : www.ohsu.edu/bbb/

Any info on your personal experiences in treating brain mets is greatly appreciated. I am feeling scared and need something to hope for.

[kcherub]

Courtney,

I saw your post over on YSC. I know someone will chime in for you! Good luck!!!

Take care,

[Joe]

"I am also wondering why drugs such as Herceptin can't be injected into the cerebral fluid and thus given access to the brain that way. I am no medical expert but was just wondering if any of you had any insight. "

There was a study several years ago in Germany of this procedure. I found the following article which describes that study: Intrathecal Herceptin

Data was also released at this years San Antonio meeting from a phase II study of a drug being developed by Wyeth - Neratinib which is a small molecule drug similar to Tykerb and also crosses the BBB.

Regards
Joe

[Becky]

Cancer Centers of America do inject chemo and other therapeutics (possibly Herceptin) into a CNS port. I know of someone doing this that goes to the Philadelphia location (but this woman is triple negative so Herceptin wouldn't be considered). Is there a Cancer Center of America close to you to consult with? They do cool and radical therapies there.

[CourtneyL]

Intrathecal Herceptin - hmmm, that sounds promising. Thank you Joe and Becky! I will keep my fingers crossed that Tykerb and Gamma do the trick for my brain mets but it is interesting to know that there are people doing alternative therapies.

If anyone here on the her2support site has had intrathecal herceptin injections, I would be interested in knowing how that worked out? Any major side effects? Was it effective? Herceptin has worked incredibly well for me and has allowed me to reach NED status in body. I am suspecting that it could do the same for my brain if only it could get there.

[Becky]

Hi

Even though I have no experience with what you are seeking, I do have a good memory of the board. We do have a member who posts every so often, Johanna Johanndotter (Iceland) who did have intracranial/CNS Herceptin injections that worked well. Look up her posts and perhaps privately contact her for more information. She is the only one who got someone to do this for her and it worked out well for her. If what you are doing now doesn't work out, I bet Cancer Center of America would try it since they do try chemo this way.

Good luck and please keep us posted.

[Lani]

the others being meningiomatous or leptomeningiomatous involvement rather than mets within the brain tissue proper

Will try to forward on to you 1. and 6.

Good luck!

[Lani]

Items 1 - 10 of 10
One page.
1:
Extended survival of a HER-2-positive metastatic breast cancer patient with brain metastases also treated with intrathecal trastuzumab.
Colozza M, Minenza E, Gori S, Fenocchio D, Paolucci C, Aristei C, Floridi P.
Cancer Chemother Pharmacol. 2008 Nov 6. [Epub ahead of print] No abstract available.
PMID: 18987856 [PubMed - as supplied by publisher]



2:
High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer.
Mir O, Ropert S, Alexandre J, Lemare F, Goldwasser F.
Ann Oncol. 2008 Nov;19(11):1978-80. Epub 2008 Oct 9. No abstract available.
PMID: 18845838 [PubMed - indexed for MEDLINE]



3:
Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report.
Stemmler HJ, Mengele K, Schmitt M, Harbeck N, Laessig D, Herrmann KA, Schaffer P, Heinemann V.
Anticancer Drugs. 2008 Sep;19(8):832-6.
PMID: 18690096 [PubMed - indexed for MEDLINE]


4:
[Two cases treated with trastuzumab as primary chemotherapy]
Murakami K, Sakata H, Miyazawa Y, Matsushita K, Akutsu Y, Nishimori T, Yoneyama Y, Usui A, Kano M, Matsubara H, Ochiai T.
Gan To Kagaku Ryoho. 2007 Oct;34(10):1683-7. Japanese.
PMID: 17940391 [PubMed - indexed for MEDLINE]



5:
CNS complications of breast cancer: current and emerging treatment options.
Kaal EC, Vecht CJ.
CNS Drugs. 2007;21(7):559-79. Review.
PMID: 17579499 [PubMed - indexed for MEDLINE]



6:
Care with intrathecal trastuzumab.
Siderov J.
Lancet Oncol. 2006 Nov;7(11):888. No abstract available.
PMID: 17081914 [PubMed - indexed for MEDLINE]



7:
Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab.
Platini C, Long J, Walter S.
Lancet Oncol. 2006 Sep;7(9):778-80. No abstract available.
PMID: 16945774 [PubMed - indexed for MEDLINE]



8:
Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.
Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lässig D, Schoenberg S, Heinemann V.
Oncol Rep. 2006 May;15(5):1373-7.
PMID: 16596213 [PubMed - indexed for MEDLINE]



9:
Intrathecal therapy with trastuzumab may be beneficial in cases of refractory schizophrenia.
Sastry PS, Sita Ratna W.
Med Hypotheses. 2004;62(4):542-5.
PMID: 15050103 [PubMed - indexed for MEDLINE]


10:
Use of intrathecal trastuzumab in a patient with carcinomatous meningitis.
Laufman LR, Forsthoefel KF.
Clin Breast Cancer. 2001 Oct;2(3):235. No abstract available.
PMID: 11899418 [PubMed - indexed for MEDLINE]

[CourtneyL]

The knowledge of the women and men on this website never ceases to amaze me. Thank you so much for the info Lani. I am going to bring some of these articles to my onc to see what he thinks. I am praying that the Tykerb will do the trick but I always like to be two steps ahead in anticipating what my next move will be if things fail. Blessings to you all!

[Believe51]

Courtney, how are you feeling with the Tykerb? I hope all is well. Keeping you in thoughts and prayers.>>Believe51

[CourtneyL]

No side effects to speak of - I was a little worried because I'd read that a lot of women do not tolerate it well and have indigestion issues. But so far it has been smooth sailing. Now I just have to hope that it is doing something. I go for a follow-up MRI in a few weeks to see if the brain mets have shrunk or (miracle of miracles) are gone completley. My onc has seen this happen before!

[Believe51]

I am praying for your same miracle. If I has a magic wand I would wave it over your head to speed things up! (smiling). I am so pleased to hear of your lack of the terrible side effects. This news makes my heart smile. Go get 'em Courtney, we are all routing for you!>>Believe51

[SoCalGal]

Hi Courtney-There is a girl in my UCLA group who gets intrathecal herceptin at UCLA. She has been fighting stage 4 for quite some time - she's VERY young - maybe 30ish and now has to use a wheel chair due to multiple mets in her CNS. I know she's had gamma as well. Send me a pm with your email info and I'll forward it to her.
Flori

[Joan M]

Courtney,

I'll see whether I can get some information about Herceptin and intrathecal catheter from a neuro-oncologist that I'm scheduled to meet with in early February. He's at a major cancer research hospital.

In October I had a bc met removed from my left frontal lobe which was followed by stereotatic radiotherapy that ended on Dec. 12, and I'm supposed to follow up with a neuro-oncologist.

I'll let you know.

Joan

[CourtneyL]

Lani - Thank you so much for these abstracts and the ones you sent to my personal email. I am hopeful that there are going to be many options available for treating these brain mets if the Tykerb doesn't do the job. Thank you again!

[CourtneyL]

Thank you, Joan. Keep me posted. You will be in my thoughts and prayers as you wait for your follow-up.

[Lani]

Anticancer Drugs. 2007 Jan;18(1):23-8. Links
Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.

Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V.
Medical Department III, Ludwig-Maximilians University of Munich, Clinic Grosshadern, Munich, Germany. Joachim.Stemmler@med.uni-muenchen.de
Patients receiving trastuzumab for HER2-overexpressing metastatic breast cancer seem to suffer from an increased risk of brain metastases, even in cases with responsive disease. To evaluate whether trastuzumab is able to penetrate the blood-brain barrier, we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. At different time points, trastuzumab levels in the serum and cerebrospinal fluid were measured using a newly developed immunoenzymatic test for trastuzumab. Six out of eight patients were evaluable for determination of trastuzumab level in the serum and cerebrospinal fluid. Before radiotherapy, median trastuzumab level in the serum was 52 054 ng/ml compared with 124 ng/ml in cerebrospinal fluid (ratio 420 : 1). After completion of radiotherapy, median trastuzumab level was 20 185 ng/ml in the serum and 226 ng/ml in cerebrospinal fluid, respectively (ratio 76 : 1). With concomitant meningeal carcinomatosis, trastuzumab level in the serum after radiotherapy was 17 431 and 356 ng/ml in cerebrospinal fluid (ratio 49 : 1). For the first time, we present clinical evidence that trastuzumab levels in cerebrospinal fluid are increased under conditions of an impaired blood-brain barrier such as meningeal carcinomatosis or radiotherapy. This evidence supports the concept of continuing trastuzumab therapy in patients with brain metastases treated by radiotherapy. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum.
PMID: 17159499 [PubMed - indexed for MEDLINE]

You might want to go up to the Search function on the yellow bar above and put in Lani and brain mets..I have posted on various treatments

[Lani]

here is info I just quickly gathered on Boswellia Serrata and intrathecal herceptin
from a 9/06 thread I started--I recently read a post from someone who thanked me for providing the info--she had used Boswellia and had a 40% decrease in the size of her brain mets and a long period of stable disease (couldn't find the post, but found these by putting Boswellia into the search function above). I also post my info on intrathecal (injected into the cerebrospinal fluid so it doesn't have to cross the blood-brain barrier) herceptin:
Here is the first post:

for those with brain mets (and those scared of developing brain metastases)

a most remarkable article--I felt it inappropriate to place it with interesting articles as only one tenth as many her2support readers view those posts and it is my impression that there are some out there who could definitely need this news, published in a very respectable journal

I was happy to see an email address attached to the abstract and have forwarded on more information...


1: J Neurooncol. 2006 Sep 26; [Epub ahead of print] Links
A lipoxygenase inhibitor in breast cancer brain metastases.

Flavin DF.
Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT, 06831, USA, Dana_FK@hotmail.com.
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.
PMID: 17001517 [PubMed - as supplied by publisher]






hmerch
Member

Join Date: Apr 2006
Posts: 5





I contacted Dr. Flavin for my mother who has brain mets and she said that Boswellia serrata should be used right away at 800mg 3 times a day.

My understanding from my conversation with her was that those of her patients who are using this had regression of brain mets. She also has a few patients who are met free now for a few years.

This sounds pretty great and I'm going to get this for my mom if her onc allows it, but I am curious if anyone else has used this compound and if so what has been your success?

Thanks,
Hina














10-27-2006, 03:31 PM
#15
heblaj01
Senior Member

Join Date: Apr 2006
Posts: 543



Caution: possible interaction of Boswellia with some chemo drugs

In checking the pharmacokinetics of Boswellia Serrata I found this article which describes it as an iinhibitor of P450 enzymes which are required in the liver to metabolize some chemo drugs such as Navelbine.
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
Analysis of frankincense from various Boswellia species with inhibitory activity on human drug metabolising cytochrome P450 enzymes using liquid chromatography mass spectrometry after automated on-line extraction.
The abstract does not state if the inhibition is occuring only in he gut or in the liver or both.
If the inhibition is restricted to the gut then intravenous chemo drugs would not be affected.
If however the inhibition is in the liver the consequences could be lowered effectiveness of the chemo treatment & possibly higher level of side effects due to longer persitance of the drug in the body & higher accumulation.

I hope this will turn out to be a false alert for most of those planing to use Boswellia but it needs to be clarified by someone with the right background such as Lani.


heblaj01
Senior Member

Join Date: Apr 2006
Posts: 543





This article posted by Lani is most interesting for members of this forum since it deals with metastatic brain cancer from breast.

It appears that Boswella Serrata might also be usefull for primary brain tumors since a phase 2 clinical trial is under preparation:

http://www.clinicaltrials.gov/ct/gui/show/NCT00243022
Boswellia Serrata Combined With a Low-Fat, Vegan Diet or a Standard Diet Alone in Treating Patients Who Have Undergone Surgery and Radiation Therapy for Newly Diagnosed Glioblastoma Multiforme





from my 11/06 post:



Here are two articles on IT herceptin--the latest(hot-off-the-press) I do not yet have access to:
1: Lancet Oncol. 2006 Nov;7(11):888. Links
Care with intrathecal trastuzumab.

Siderov J.
PMID: 17081914 [PubMed - in process]

Related Links
Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.[Oncol Rep. 2006]

Hope this helps!

PS I have very little internet access at the moment(visiting for the holidays), so sorry not to post more info on this
















11-22-2006, 03:50 PM
#9
Lani
Senior Member

Join Date: Mar 2006
Posts: 1,988



got it!

The Lancet Oncology
Volume 7 • Number 11 • November 2006
Copyright © 2006 Elsevier






Reflection and Reaction
Care with intrathecal trastuzumab


Jim Siderova
a Cancer Services, Austin Health, Studley Road, Heidelberg, VIC, Australia 3084

E-mail address: jim.siderov@austin.org.au




PII S1470-2045(06)70917-2

I read with interest the Case Report on the use of intrathecal trastuzumab published in The Lancet Oncology because it is an uncommon method of administration for a monoclonal antibody.[1] I wish to point out a potential issue with the intrathecal administration of trastuzumab.

In Australia and the UK, trastuzumab is supplied in vials of 150 mg powder,2, 3 which contains histidine, trehalose dihydrate, and polysorbate, among other excipients. Once reconstituted with water for injection, the resultant solution is free of preservatives. In the USA, trastuzumab is supplied in vials of 440 mg powder,[4] together with 20-mL bacteriostatic water for reconstitution. This bacteriostatic water contains 1·1% benzyl alcohol—a preservative.

Products that contain preservatives, particularly benzyl alcohol, should not be administered intrathecally because of the risks of anaphylaxis and potential for neurotoxicity from the preservative agent.[5] Reported events include paraparesis, fibrosis of the cauda equina, and segmental demyelination of the dorsal and ventral roots.[5]

Thus, colleagues in the USA who might consider treatment with trastuzumab intrathecally should do so without the use of the diluent provided.

Intrathecal administration is an important component of the management of malignant disease, but products injected in this way should not contain preservatives, especially benzyl alcohol. Physicians, pharmacists, and nurses involved in the preparation or administration of intrathecal treatment should ensure that preservative-free products are used.

I declare no conflicts of interest.
















11-22-2006, 03:51 PM
#10
Lani
Senior Member

Join Date: Mar 2006
Posts: 1,988



references

REFERENCES:

1 Platini C, Long J, Walter S: Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 7. 778-780.2006; Full Text
2 Roche products Pty Ltd: Herceptin (trastuzumab) Australian approved product information. Therapeutic Goods Administration approved amendment, Roche products Pty Ltd Sydney 21 April, 2006.
3 Electronic Medicines Compendium: (accessed Sept 20, 2006) http://emc.medicines.org.uk/emc/indu...ocumentid=3567
4 In: McEvoy GK, ed. American Hospital Formulary Service (AHFS) Drug Information, American Society of Health-System Pharmacists Bethesda 2006: 1209-1215.
5 Hetherington NJ, Dooley MJ: Potential for patient harm from intrathecal administration of preserved solutions. Med J Aust 173. 141-143.2000; Abstract

01-07-2008, 07:08 PM #3
Lani
Senior Member

Join Date: Mar 2006
Posts: 2,508
another article I just refound:
Anticancer Drugs. 2007 Jan;18(1):23-8. Links
Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.

Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V.
Medical Department III, Ludwig-Maximilians University of Munich, Clinic Grosshadern, Munich, Germany. Joachim.Stemmler@med.uni-muenchen.de
Patients receiving trastuzumab for HER2-overexpressing metastatic breast cancer seem to suffer from an increased risk of brain metastases, even in cases with responsive disease. To evaluate whether trastuzumab is able to penetrate the blood-brain barrier, we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. At different time points, trastuzumab levels in the serum and cerebrospinal fluid were measured using a newly developed immunoenzymatic test for trastuzumab. Six out of eight patients were evaluable for determination of trastuzumab level in the serum and cerebrospinal fluid. Before radiotherapy, median trastuzumab level in the serum was 52 054 ng/ml compared with 124 ng/ml in cerebrospinal fluid (ratio 420 : 1). After completion of radiotherapy, median trastuzumab level was 20 185 ng/ml in the serum and 226 ng/ml in cerebrospinal fluid, respectively (ratio 76 : 1). With concomitant meningeal carcinomatosis, trastuzumab level in the serum after radiotherapy was 17 431 and 356 ng/ml in cerebrospinal fluid (ratio 49 : 1). For the first time, we present clinical evidence that trastuzumab levels in cerebrospinal fluid are increased under conditions of an impaired blood-brain barrier such as meningeal carcinomatosis or radiotherapy. This evidence supports the concept of continuing trastuzumab therapy in patients with brain metastases treated by radiotherapy. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum.
PMID: 17159499 [PubMed - indexed for MEDLINE]

[CourtneyL]

I read the article from Dr. Flavin regarding Boswellia with great interest. I recently wrote Dr. Flavin to ask if there were any counterindications to taking Boswellia with Tykerb and here is what she wrote back:

"We find that the boswelli will reduce tumors in the brain in 3 months but if the patients stay on tykerb or trastuzamab, the tumors then return in 3 more months. We have seen when the patients are not on a HER2 blocker, the Boswellia keeps the tumors regressed as long as the patients take the 1 gram of Boswellia 3 x/day. There are no side effects with this drug."

Has anyone on this site had positive results with Boswellia? Negative results? Any results? I am wondering if I should supplement my treatment with it.

[Lani]

I see that you are from San Francisco. Have you consulted with the gamma/cyberknife people at UCSF as to whether your tumors are too numerous or large to consider treating them that way.

I have met Penny Sneed,MD a radiation oncologist who I believe specializes in the gamma/cyberknife treatment of brain mets from primarily breast cancer among other metastatic diseases and is listed with Breast Cancer Clinic at UCSF. Perhaps she could also discuss with you whether any of her her2+ patients have been treated with intrathecal herceptin and/or Boswellia and/or Tykerb either before or after her treatments and how they have fared.