Thema: Thalidomid zur Behandlung eines Glioblastoms?

Hat jemand Talidomid schon bei Glioblastom eingenommen? Welche Erfahrung haben Sie gemacht. Wir sind für jede Info dankbar.

hier der artikel den rosi gefunden hat. den quellenangaben zufolge ist der text 2000 entstanden, also schon 3 jahre alt und für onkologische Verhältnisse nicht mehr ganz aktuell.


Thalidomid in der Onkologie!?

Thalidomid wurde in den 60er Jahren unter dem Namen Contergan® als Sedativum eingesetzt. Dieser sedativ1e Effekt wurde einer Arbeit zur Pharmakokinetik der beiden Enantiomere von Thalidomid zufolge durch das (+)-R-Thalidomid verursacht. Die teratogenen und immunmodulatorischen Effekte sind vermutlich dem (-)-S-Enantiomer zuzuschreiben. Da im menschlichen Organismus eine rasche chirale Inversion zwischen den beiden Enantiomeren stattfindet, ist es nicht möglich, gezielt mit einem der beiden Enantiomere zu therapieren. [1]

Der Eingriff von Thalidomid in biologische Prozesse, so z.B. in die Ausbildung von Blutgefäßen oder in die Zellkommunikation ist für den sich entwickelnden Feten katastrophal, aber nicht notwendigerweise für den erwachsenen Organismus. Thalidomid hemmt die Produktion von TNF-a und beeinflusst die Regulierung der Zytokine durch die T-Zellen. Dadurch ließen sich immunmodulatorische und antiinflammatorische Eigenschaften erklären, die der Substanz neben einem antiangiogenen Effekt zugeschrieben werden [2].

Seit einiger Zeit ist Thalidomid in den USA für die Behandlung von Komplikationen des Erythema nodosum leprosum zugelassen [3].
Im Rahmen von Studien wird der Wirkstoff aber auch bei anderen Indikationen eingesetzt, z.B. zur Behandlung der Ulzeration von oropharyngalen Aphten, Diarrhöe oder Gewichtsverlust bei HIV-Infektion, (Auto-) Immunreaktionen, bei Behcet´s Syndrom, rheumatoider Arthritis und auch bei Krebs [2,4,5].

Gegenwärtig wird Thalidomid z.B. bei der Therapie des (trotz Hochdosistherapie) rezidivierenden Multiplen Myeloms eingesetzt [6,7]. Thalidomid ist aber kein Zytostatikum im engeren Sinne. Es wird angenommen, dass es durch die Inhibition der Angiogenese von tumorversorgenden Blutgefäßen wirkt [2]. Derzeit wird die Wirkung von Thalidomid bei anderen Tumoren, z.B. bei Brustkrebs, bei Kaposi´s Sarkom [2] und bei Hirnkrebs (Glioblastoma multiforme) [2,8] untersucht.

Wegen der bekannten Teratogenizität, ist die konsequente Empfängnisverhütung für weibliche Patienten in gebärfähigem Alter Bedingung zu einer Behandlung mit Thalidomid. Abgesehen davon wird der Wirkstoff auch mit peripheren Neuropathien in Verbindung gebracht, die während der Therapie auftraten. Beschrieben wird eine symmetrische schmerzliche Paresthesie der Hände und Füße mit Verminderung des Tastgefühls in den unteren Gliedmaßen. Zur Vermeidung eventueller irreversibler Schäden ist eine strenge Überwachung dieser Symptome auch durch den Patienten selbst unbedingt notwendig. Die potentielle Sedation des Medikamentes muss bedacht werden [2].

Im New England Journal of Medecine hat im Jahr 2000 ein intensiver Austausch zu dem Thema stattgefunden.

Thalidomid ist bisher nicht zugelassen und kann nur mit dem Zusatz "Therapieversuch" eingesetzt werden. Im Einzelfall kann Thalidomid unter Beachtung einiger Formalitäten (behördliche Bewilligung, Patientendossier) bei der Firma Grünenthal angefordert werden.

Firma Grünenthal, PF 50 04 44, 52088 Aachen
Herrn Zwingenberger (Tel. 0241 / 5691304)
Frau Erkens (Tel. 0241 / 5691111)

Literatur:
Tommy Eriksson: "Pharmacokinetics of the enantiomers of thalidomide", Dissertation in klinischer Pharmakologie an der medizinischen Fakultät der Lund University, S-221 85 Lund; 31.10.1997
Leonard Calabrese & Kenneth Resztak: "Thalidomide revisited: pharmacology and clinical applications", Exp. Opin. Invest. Drugs (1998) 7 (12): 2043-2060
Interview mit Thomas Herald Rea, M. D.: "Thalidomide resurfaces with FDA ruling", Dermatology Times Today, Februar 2000
Jeffrey M. Jacobson et al.: "Thalidomide for the treatment of oral aphtous ulcers in patients with human immunodifiency virus infection", New England Journal of Medecine, 336: (21): 1487
Calabrese L., Fleischer AB: "Thalidomide: current and potential clinical applications.", American Journal of Medecine, 108 (6) 487-95/2000 Apr 15
Singhal s., Mehta J., Desikan R. et al, "Antitumor activity of thalidomide in refractory multiple myeloma." N Engl J Med 1999; 341: 1565-71. [Erratum, N Engl J Med 2000; 342:364]
Rajkumar SV, Fonseca R., Dispenzieri A. et al: "Thalidomide in the treatment of relapsed and refractory myeloma." Blood 1999; 94: Suppl 1:316a.abstract
Howard A. Fine, William D. Figg et al.: "Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas", Journal of Clinical Oncology, Vol. 18, N° 4 (February), 2000: 708-715
Quelle: onkonet

Thalidomid kann NICHT mehr bei Grünthal angefordert werden, sondern muß jetzt vom Arzt bei einer anderen Firma angefordert werden. Es ist NICHT mehr kostenlos. So richtig klare Ergebnisse in der Glioblastomtherapie gibt es noch nicht.

Gruß

PD Dr. Mursch
Neurochirurgie
Zentralklinik Bad Berka

Arzneimittelforschung. 1967 May;17(5):646-8.

[Treatment of a 2nd degree astrocytoma with thalidomide (N-phthalylglutamic
acid amide]

[Article in German]

Buelens I.


Neurochirurgie. 1999 Nov;45(4):293-300.

[Cerebral tumors and neoangiogenesis ]

[Article in French]

Jouanneau E, Bachelot T.

Service de Neurochirurgie A, Hopital Pierre Wertheimer, Universite Lyon
I.

Angiogenesis, which is the development of new vessels arising from the
preestablished arborization, plays a fundamental role in tumor growth.
Angiogenesis is the combination of antagonistic factors: proangiogenesis
and antiangiogenesis factors. On the basis of the concept of relationship
between angiogenesis and tumor growth, a promising new way of research
is developing with the aim to control angiogenesis with an antitumor goal.
The results of the preclinical trials point out the potential of antiangiogenesis
agents in the fight against cancer. So, it was showed that tumor growth
in animal models of syngenic or human tumors is inhibited by inhibitors
of proangiogenic factors (like VEGF or FGF antibody ...) or by antiangiogenic
factors. Endostatin, which is a natural inhibitor of angiogenesis, seems
to be the most powerful molecule, able to achieve total and final regression
of preestablished tumors. However, there are only preliminary data. Clinical
trials are on the way. They should bring some answers concerning the place
of these antiangiogenesis agents in the traditional therapeutic strategy.
In neurooncology, just like in general cancerology, clinical trials have
began with different molecules like Marismastat or Thalidomid. A review
of the principal actors, preclinical and clinical trials in progress is
presented.


J Clin Oncol. 2000 Feb;18(4):708-15.

Comment in:
· J Clin Oncol. 2000 Oct 1;18(19):3453. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11013292>

Phase II trial of the antiangiogenic agent thalidomide in patients with
recurrent high-grade gliomas.

Fine HA, Figg WD, Jaeckle K, Wen PY, Kyritsis AP, Loeffler JS, Levin VA,
Black PM, Kaplan R, Pluda JM, Yung WK.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, and Departments
of Neurology, Surgery, and Radiation Oncology, Brigham and Women´s Hospital,
Harvard Medical School, Boston, MA, USA.

PURPOSE: Little progress has been made in the treatment of adult high-grade
gliomas over the last two decades, thus necessitating a search for novel
therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors,
which leads to the supposition that angiogenesis inhibition may represent
a potentially promising strategy in the treatment of these tumors. We present
the results of a phase II trial of thalidomide, a putative inhibitor of
angiogenesis, in the treatment of adults with previously irradiated, recurrent
high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis
of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme
who had radiographic demonstration of tumor progression after standard
external-beam radiotherapy with or without chemotherapy were eligible.
Patients were initially treated with thalidomide 800 mg/d with increases
in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg
was achieved. Patients were evaluated every 8 weeks for response by both
clinical and radiographic criteria. RESULTS: A total of 39 patients were
accrued, with 36 patients being assessable for both toxicity and response.
Thalidomide was well tolerated, with constipation and sedation being the
major toxicities. One patient developed a grade 2 peripheral neuropathy
after treatment with thalidomide for nearly a year. There were two objective
radiographic partial responses (6%), two minor responses (6%), and 12 patients
with stable disease (33%). Eight patients were alive more than 1 year after
starting thalidomide, although almost all with tumor progression. Changes
in serum levels of basic fibroblastic growth factor (bFGF) were correlated
with time to tumor progression and overall survival. CONCLUSION: Thalidomide
is a generally well-tolerated drug that may have antitumor activity in
a minority of patients with recurrent high-grade gliomas. Future studies
will better define the usefulness of thalidomide in newly diagnosed patients
with malignant gliomas and in combination with radiotherapy and chemotherapy.
Additionally, studies will be needed to confirm the potential utility of
changes in serum bFGF as a marker of antiangiogenic activity and/or glioma
growth.


J Neurooncol. 2001 Aug;54(1):31-8.

Phase II study of thalidomide in the treatment of recurrent glioblastoma
multiforme.

Marx GM, Pavlakis N, McCowatt S, Boyle FM, Levi JA, Bell DR, Cook R, Biggs
M, Little N, Wheeler HR.

Royal North Shore Hospital, University of Sydney, Australia.

Treatment options and prognosis remains poor for patients with recurrent
glioblastoma multiforme. These tumors are highly vascularised and over
express angiogenic factors such as vascular endothelial growth factor and
may potentially be responsive to antiangiogenic therapies. We present the
results of a phase II trial of Thalidomide, an antiangiogenic agent, in
the treatment of recurrent glioblastoma multiforme. Patients were treated
with 100 mg/day of Thalidomide, increased at weekly intervals by 100 mg
to a maximum tolerated dose of 500 mg/d. Forty-two patients were enrolled,
with 38 patients being assessable for response and 39 for toxicity. Two
patients (5%) achieved a partial response and 16 (42%) had stable disease.
The median survival was 31 weeks and the 1-year survival was 35%. Patients
who had a partial response or stable disease had either a stabilisation
or improvement in quality of life scores or performance status. Overall
Thalidomide was well tolerated with no grade 4 toxicities and no treatment
related deaths. The median maximum tolerated dose was 300 mg/day. The most
common toxicity was fatigue to which patients developed tachyphylaxis.
There was no correlation demonstrated with plasma vascular endothelial
growth factor levels and response or survival. Thalidomide is a well-tolerated
drug that may have some activity in the treatment of recurrent glioblastoma.
Optimum dosing with antiangiogenic agents is currently under investigation.
Chronic low dose therapy may be required to see conventional responses
or improvements in time to progression. The dose required to achieve optimal
biological impact may be better defined once we have established reliable
surrogate endpoints.


Cancer J. 2003 May-Jun;9(3):149-56.

Current chemotherapy for glioblastoma.

Parney IF, Chang SM.

Neuro-Oncology Service, Department of Neurological Surgery, University
of California San Francisco, San Francisco, California 94143-0350, USA.

INTRODUCTION: Glioblastoma multiforme continues to be associated with a
dismal prognosis, despite aggressive therapy. What limited therapeutic
impact that has been made has come via multimodality treatment in which
chemotherapy plays an important role. In this manuscript, we review current
chemotherapy options for glioblastomas. METHODS: The current literature
concerning glioblastoma multiforme chemotherapy was reviewed. In addition
to a review of landmark references, a MEDLINE search of the literature
published from January 2000 to November 2002 was performed using the key
words "chemotherapy AND malignant glioma" and limiting responses
to clinical trials. RESULTS: Several cytotoxic chemotherapeutic agents
that are efficacious in treating glioblastoma are in common clinical use.
These can be classified as first-line or second-line agents, depending
on their efficacy. In addition, cytostatic chemotherapy agents are beginning
to play a role in glioblastoma treatment. Finally, new methods to deliver
high chemotherapy doses to brain tumors hold promise for future therapies.
CONCLUSIONS: Despite the overall poor prognosis of patients with glioblastoma
multiforme, multimodality treatment and chemotherapy in particular improve
outcome, and chemotherapeutic options are beginning to have an increased
impact. Strategies currently in clinical trials may improve this impact
more in the future.