More info and more to come!
I will try to review the intrathecal herceptin articles tonight and send summaries They are listed below and after that more info on intrathecal herceptin and even practioners utilizing it (did her2support search)
Intrathecal trastuzumab and thiotepa for leptomeningeal spread of breast cancer.
Ferrario C, Davidson A, Bouganim N, Aloyz R, Panasci LC.
Ann Oncol. 2009 Apr;20(4):792-5. Epub 2009 Feb 17. No abstract available.
PMID: 19223574 [PubMed - in process]
Related Articles
2:
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. 2009 May;63(6):1157-9. Epub 2008 Nov 6. No abstract available.
PMID: 18987856 [PubMed - indexed for MEDLINE]
Related Articles
3:
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]
Related Articles
4:
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]
Related Articles
5:
[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]
Related Articles
6:
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]
Related Articles
7:
Breast cancer (metastatic).
Stebbing J, Slater S, Slevin M.
Clin Evid (Online). 2007 Feb 1;2007. pii: 0811.
PMID: 19454050 [PubMed - in process]
Related Articles
8:
Care with intrathecal trastuzumab.
Siderov J.
Lancet Oncol. 2006 Nov;7(11):888. No abstract available.
PMID: 17081914 [PubMed - indexed for MEDLINE]
Related Articles
9:
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]
Related Articles
10:
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]
Related Articles
11:
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]
Related Articles
12:
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]
Related Articles Free article at journal site
Items
^^^^^^
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]
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, 02:51 PM #10
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,773
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
Thread Tools Search this Thread Rate Thread Display Modes
04-06-2006, 05:52 PM #1
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,773
Herceptin is now being tried intrathecally (injected into the brain via the CSF)
I posted this to the wrong forum--there is no clinical trial--yet.
Herceptin is now being tried intrathecally (injected into the brain via the CSF)
--CSF is the cerebral spinal fluid that bathes the brain and circulates around the parts of the brain and spinal cord
--carcinomatosis just means "widespread cancer"
leptomeningeal or meningeal involvement is different than parenchymal involvement as I explained in an earlier post (parenchymal means within the tissue of the brain itself rather than on its outside linings/covers)
Here is the abstract:
Oncol Rep. 2006 May;15(5):1373-7. Links
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, Lassig D, Schoenberg S, Heinemann V.
Department of Internal Medicine III, University of Munich - Klinikum Grosshadern, D-81377 Munich, Germany.
joachim.stemmler@med.uni-muenchen.de.
Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old female presenting with HER2-overexpressing MBC and suffering from meningeal carcinomatosis was treated with the humanized antibody trastuzumab directed to HER2 by intrathecal administration. The patient was diagnosed with HER2-overexpressing stage III breast cancer in December 2003. In August 2004, the patient developed a singular intracerebral metastasis which was resected by neurosurgery followed by whole-brain radiotherapy. Since MRI and cerebrospinal fluid (CSF) analyses indicated meningeal carcinomatosis, the patient was commenced on trastuzumab (6 mg/kg q3w) and capecitabine (2.500 mg/m(2) d1-14, q3w). Prompted by clinical deterioration, 5 repeated doses of intrathecal methotrexate (15 mg/dose) were administered, yet without clinical improvement. There is initial evidence that trastuzumab does not reach an adequate concentration in CSF after intravenous application. Nevertheless, infiltration of trastuzumab into CSF is facilitated under conditions of an impaired blood-brain barrier, as it is known for meningeal carcinomatosis. For patients with leptomeningeal disease, intrathecal application of trastuzumab may provide an interesting therapeutical approach for patients with HER2 overexpressing metastatic breast cancer. Therefore, an Ommaya reservoir for intrathecal treatment with trastuzumab was placed surgically and intrathecal therapy was begun with escalating doses of trastuzumab (5-20 mg), which proved to be effective and well tolerated by the patient. Within 2 weeks after treatment, the patients' condition improved significantly and cell counts in CSF obtained from the Ommaya reservoir remained low for 11 months after first diagnosis of meningeal carcinomatosis when clinical symptoms and MRI indicated progression of meningeal and cerebral disease.
PMID: 16596213 [PubMed - in process]
04-06-2006, 09:11 PM #2
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,773
I remember a previous post asking about leptomeningeal spread of breast cancer
and found this article about experimental work in mice similar to the article above. In mice it had to be injected locally, not in the lumbar (back) region:
Clinical Cancer Research Vol. 7, 2050-2056, July 2001
© 2001 American Association for Cancer Research
Regular Articles
Treatment of Meningeal Breast Cancer Xenografts in the Rat Using an Anti-P185/HER2 Antibody1
Ira Bergman2, Mamdouha A. Barmada, Judith A. Griffin and Dennis J. Slamon
Departments of Pediatrics [I. B., J. A. G.], Neurology [I. B.], and Pathology [M. A. B.] University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; and Division of Hematology and Oncology, UCLA School of Medicine, Los Angeles, California 90024 [D. J. S.]
The metastatic spread of breast cancer to the leptomeninges (LM) is a painful, debilitating, and usually lethal condition. Current therapies are generally ineffective or extremely toxic. The current study evaluated monoclonal antibody therapy in an animal model of LM human breast cancer. Monoclonal antibody 4D5, which recognizes the extracellular domain of the HER2/neu receptor, was administered into the cerebrospinal fluid of athymic rats implanted with human breast cancer cell lines. Continuous intraventricular administration of 4D5 inhibited growth of SKBR3 cells that overexpress HER2/neu but not of MCF7 cells, which do not. Inhibition was dose-dependent, with higher doses of 4D5 producing an improved response. i.p. administration of cisplatin in addition to 4D5 did not improve results. Continuous administration of 4D5 into the lumbar, as opposed to the ventricular intrathecal space, was not therapeutically effective. Treatment with 4D5 did not result in outgrowth of cells lacking expression of the HER2/neu receptor. These results suggest that 4D5, administered regionally, may palliate LM metastases from HER2/neu-overexpressing breast carcinoma.
11-27-2006, 06:04 AM #13
aviv
Member
Join Date: Nov 2006
Posts: 8
Question about Intrathecal Herceptin treatment
I also wanted to ask you all about IT Herceptin-
My mom has 8 brain lesion (~1.5cm) - probably more, since we ran CAT scan, rather than MRI.
Some of them are deep in the brain (frontal, perietal, temporal and occipital areas).
Is there any knowledge if IT Herceptin would fit that condition- would it reach these deep mets- or, would it only work for the areas nearby the intrathecal fluid, and the mets that are on the surface of the brain?
Also, I've checked around here- as expected, no one is conducting trials/treatments on IT Herceptin around.
I tried to get Dr Stemmler (the one who ran this trial), got no response thus far-
Has anyone found a place other than Germany that runs these treatments?
Thanks!!!
11-27-2006, 06:39 AM #14
mkrny
Senior Member
Join Date: Mar 2006
Location: LI, NY
Posts: 38
From what I see any work w/ IT herceptin is pre-trial. Very experimental at this point w/ unknown end results from a statistical perspective (4 patients isn't enough for oncs to hang their hat on performance).
We have a neuro-onc on Long Island in NY (Dr Demopoulos) that is giving it to one patient currently and my Maryann is likely to be his second patient on it. I can provide contact info if desired.
Is radio surgery (e.g. Gamma-knife, Cyberknife, ...) an option to attack the multiple brain met spots you mom has?
11-27-2006, 06:55 AM #15
aviv
Member
Join Date: Nov 2006
Posts: 8
mkrny: she had already gone through WBR on May.
Our radiology doc carefully checked her images from the past few months (CTs, MRI), and concluded that since the lesions are growing fast, it's useless to try stereotactic radiation- since while concetrating radiation on individual tumors, others would rapidly grow, and eventually she'll get the same amount of radiation as if she would in the case of repetitive WBR- so he suggests only second WBR.
I fear from additional WBR, as it may severly affect her- so as long as she can bear the pain with steroids, we'll postpone the second WBR.
Please, do forward the contact of Dr Demopoulos.
11-27-2006, 08:17 AM #16
mkrny
Senior Member
Join Date: Mar 2006
Location: LI, NY
Posts: 38
Here's his contact info:
Dr Alexis Demopoulos
Director, Neuro-Oncology
North Shore/LIJ - North Shore University Hospital
300 Community Dr
Manhasset, NY 11030
516.562.3065
Our prayers are with you,
11-27-2006, 11:02 AM #17
aviv
Member
Join Date: Nov 2006
Posts: 8
thanks! already contacted him and he referred me to someone in the area. i'll keep you posted if there's any progress on the IT Herceptin area with us.
ASCO abstract: most important to STAY on herceptin once have brain mets!!!
Abstract No:
11507
Citation:
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 11507
Author(s):
B. Nam, K. Lee, T. Kim, J. Ro
Abstract:
Background: Brain metastases (BM) occur in as many as one-third of patients with metastatic breast cancer (MBC). Incidences and prognoses by triple receptor subtypes in BM have not been well delineated. Methods: Retrospectively, prognoses were assessed according to clinical characteristics, triple receptor subtypes, and receipt of trastuzumab therapy by univariate and multivariate analyses. ER/PR/HER2 were tested by IHC with HER2 FISH for IHC 2+ and for all 118 consecutive primary BC. Results: Between 8/2001 and 4/2006, 138 of 805 pts (17.1%) with MBC presented with BM at NCC Korea. More pts with triple negative and HER2+ tumors developed BM (see table). The median age was 47 years. They were single (9%), multiple (80%), or leptomeningeal disease with or without multiple BM (11%). As initial therapy, 104 pts received WBRT, 8, intrathecal therapy (IT), 9, WBRT with IT, and 17 others. Of 56 HER2+ pts, 45 received trastuzumab either before (n=25) or after (n=13), or continuously before and after BM diagnosed (n=7). By 10/2006, 117 pts died with a median survival of 4.5 months. Multivariate analyses indicated age, tumor receptor subtypes, leptomeningeal presentation and number of extracranial disease sites as significant factors. Receipt of trastuzumab therapy after BM was a significant variable for survival in HER2+ diseases (3.8 vs. 13.4 mo, p=0.0000). Pts with triple negative subtype lived shortest compared with other types (p=0.0035). Conclusions: More pts with triple negative and HER2+ disease developed BM. HER2+ disease gained a significant survival benefit by trastuzumab therapy. Supported by NCC Grant 0610240 and 0510520.
Triple receptor status Brain metastasis
N (%) Metastatic breast cancer
N (%) Early breast cancer
N (%) P-value
ER or PR+/HER2- 23/126 (18.2) 254/556 (45.7) 68/118 (57.6) <0.0001
ER or PR+/HER2+ 19/126 (15.0) 73/556 (13.1) 16/118 (13.5)
ER and PR-/HER2+ 37/126 (29.4) 91/556 (16.4) 15/118 (12.7)
ER and PR-/HER2- 47/126 (37.3) 138/556 (24.9) 19/118 (16.1)
Unknown/total 12/138 111/667 0/118
06-01-2007, 02:26 PM #2
StephN
Senior Member
Join Date: Nov 2004
Location: Seattle
Posts: 2,138
Some questions
Good info, but I am not sure why. This abstract leaves open several questions in my mind.
1. I ASSUME all these patients had mets in other places. There is a reference to the number of extracranial sites as a factor. It does not say what drugs they were on before, during or after brain mets treatment. Some drugs are felt to make the blood/brain barrier a little flabby and allow some Herceptin penetration.
2. The other main question is whether the use of Herceptin was for keeping the other mets under control so that there are less cancer cells to get into the brain. This is only sensible and does not need a study.
The conclusion that a person with brain mets who has the benefit of Herceptin will live longer is obvious to us on this board. We who participate here are only a small number, but our survival rate seems much higher than the 13.4 months in the study.
06-01-2007, 06:57 PM #3
Adriana Mangus
Senior Member
Join Date: May 2006
Location: California
Posts: 315
More studies are needed
I believe this is a preliminary results based on a small number of participants.
I agree with Stephanie, did the participants had mets to other organs, where?
How long?
Is the addition of herceptin helpful to the "late" development of Brain mets, regardless of mets to other organs, and if so in average how long did it take to develop brain mets, after the addition of herceptin.
What is clear to me is that herceptin is a clear winner vs bc, what I still do not know is whether regardless of receptors i.e. _ or +, brain mets will follow.
My onc believes (he's the head of Onc Dept, and has traveled extensively to other countries that dispensed herceptin), that no matter what your pathology reports results are, "thanks" to herceptin, brain mets will develop soon or later due to Her2 positive patients longevity. Hard to believe, uh??? What a price to pay to be alive? Does it make sense to you. Still do not want to believe it.
06-02-2007, 05:43 AM #4
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,773
as this has only been released as an abstract so far
unable to speculate.
138 is not such a small number of patients from a single institution to provide meaningful info
as to what other sites, how many...they state it was a significant factor/variable in their statistical correlation but more details can only follow once
information disseminated
Stay tuned for more info...perhaps someone at ASCO will hear this presentation and comment
06-02-2007, 01:04 PM #5
Hopeful
Senior Member
Join Date: Aug 2006
Posts: 1,571
Adriana,
Your onc certainly is a jolly old soul. It does not make sense to me, and I certainly don't interpret the current statistics that way.
FWIW, I read an article about aromatase production the other day, and was surprised to learn that a good amount of it is actually produced in the brain. That being the case, I would expect more hormone positive patients to develop brain mets, but the stats all show the opposite. So, who knows?
Hopeful
06-11-2007, 11:10 PM #6
Lani
Senior Member
Join Date: Mar 2006
Posts: 2,773
hot off the press--article discusses whether difference extracranial control, WBRT
effect, etc
: J Neurooncol. 2007 Jun 8; [Epub ahead of print] Links
Trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer.
Bartsch R, Rottenfusser A, Wenzel C, Dieckmann K, Pluschnig U, Altorjai G, Rudas M, Mader RM, Poetter R, Zielinski CC, Steger GG.
Department of Medicine 1 and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria,guenther.steger@meduniwien.ac.at.
Background: Brain metastases are frequently encountered in Her2 positive advanced breast cancer. It is still not clear, if trastuzumab treatment should be continued following their diagnosis. In this analysis we evaluated if trastuzumab was able to influence time to in-brain progression (TTP) and overall survival (OS). For this reason, we compared patients who continued on trastuzumab with a historical control group. Patients and Methods: Seventeen Her2 positive patients receiving whole brain radiotherapy for brain metastases and continuing on trastuzumab were identified. As historical control group, thirty-six patients treated before 2002 were identified from a breast cancer database. We performed a multivariate analysis (Cox regression) to explore which factors were potentially able to significantly influence TTP and OS. Results: Median TTP was 6 months, range 1-33+ months. Median OS was 7 months, range 1-38 months. Seventeen patients received trastuzumab after WBRT. Factors associated with prolonged TTP were KPS (p = 0.001), and intensified local treatment (p = 0.004). A trend towards longer TTP was observed in patients treated with trastuzumab (p = 0.068). OS was significantly influenced by KPS (p < 0.001), and continued antibody therapy (p = 0.001). Conclusion: Two parameters were significantly associated with prolonged OS: KPS and trastuzumab. While there was a trend towards prolonged TTP in patients with trastuzumab treatment after WBRT, this did not reach statistical significance. It appears therefore reasonable to suggest continuation of antibody therapy in patients with good performance status despite disease spreading to the brain. Concerning activity of trastuzumab in brain metastases themselves, no final conclusion is possible.
PMID: 17557136 [PubMed - as supplied by publisher]
Linear Mode
