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When Temozolomide Alone Fails: Adding Procarbazine in Salvage Therapy of Glioma

Published online by Cambridge University Press:  02 December 2014

Fleur Huang ,
Petr Kavan ,
Marie-Christine Guiot ,
Yelena Markovic  and
David Roberge
Fleur Huang
Affiliation:
Division of Radiation Oncology, McGill University Health Centre, Montreal Neurological Hospital, Montreal, Quebec, Canada
Petr Kavan
Affiliation:
Department of Oncology, McGill University Health Centre, Montreal Neurological Hospital, Montreal, Quebec, Canada
Marie-Christine Guiot
Affiliation:
Department of Pathology, McGill University Health Centre, Montreal Neurological Hospital, Montreal, Quebec, Canada
Yelena Markovic
Affiliation:
Department of Pathology, McGill University Health Centre, Montreal Neurological Hospital, Montreal, Quebec, Canada
David Roberge
Affiliation:
Division of Radiation Oncology, McGill University Health Centre, Montreal Neurological Hospital, Montreal, Quebec, Canada
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Abstract

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Background:

Since temozolomide (TMZ) entry into routine practice in the first-line management of glial tumors, post-TMZ recurrences present a growing challenge. Without standard chemotherapy for TMZ failure, care in such palliative settings requires consideration not only of efficacy but of toxicity and convenience.

Methods:

At our institution, a combination regimen has been used: oral alkylating agents procarbazine (PCB) (100-150 mg/m2/day) and TMZ (150-200 mg/m2/day) administered on days 1-5 of a 28-day cycle. This treatment has been initiated upon radiological and/or clinical disease progression, and continued until evidence of further progression or toxicity. We retrospectively reviewed our experence with this regimen.

Results:

Since November 2004, 17 patients (median age 53) were treated for histologically confirmed glioma (glioblastoma multiforme (GBM), N=12; Grade 3 glioma, N=3; Grade 2 glioma, N=2) after a median of 2 recurrences. TMZ was previously given either as adjuvant therapy (post-chemoradiotherapy maintenance in 8 of 13 cases) or as salvage monotherapy (4 cases). Of 16 evaluable cases, 14 (13 high grade tumors) showed O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Two patients achieved partial response and one had complete response by RECIST criteria. Disease progressed after a median of 4 cycles (range 1 to 11+), with an actuarial progression-free survival of 42% after 6 cycles. Grade 3/4 toxicity was rare, and no dose reductions were needed. One patient discontinued treatment due to procarbazine hypersensitivity.

Conclusion:

Combination PCB-TMZ is well-tolerated, with modest activity in TMZ-exposed glioma.

Résumé:

<span class='bold'>RÉSUMÉ:</span><span class='bold'><span class='italic'>Contexte:</span></span>

Depuis que le témozolomide (TMZ) est utilisé de routine comme traitement majeur des tumeurs gliales, les rechutes après le traitement par le TMZ presentment un défi de plus en plus grand. Quand on fait face à un échec du traitement par le TMZ et en l’absence de chimiothérapie standard, on doit considerer non seulement l’efficacité mais aussi la toxicité et les aspects pratiques du traitement dans ce contexte palliatif.

<span class='bold'><span class='italic'>Méthodes:</span></span>

Dans notre institution, nous avons utilisé un traitement d’association : deux agents alkylants oraux, la procarbazine (PCB) (100–150 mg/m2/ j) et le TMZ (150–200 mg/m2/ j), administrés aux jours 1–5 d’un cycle de 28 jours. Ce traitement était commencé lorsqu’on observait une progression radiologique et/ou clinique de la tumeur et il était maintenu jusqu’à ce qu’on observe une progression plus marquée ou de la toxicité. Nous avons fait une revue rétrospective de ce mode de traitement.

<span class='bold'><span class='italic'>Résultats:</span></span>

Depuis novembre 2004, 17 patients dont l’âge médian était de 53 ans ont été traités pour un gliome confirmé par l’histologie (glioblastome muliforme (GBM) N = 12; gliome de grade 3, N = 3; gliome de grade 2, N = 2) après un nombre de rechutes médian de 2. Le TMZ avait été donné antérieurement soit comme traitement adjuvant (traitement d’entretien post–chimioradiothérapie chez 8 patients sur 13) ou en monothérapie comme traitement de rattrapage (chez 4 patients). Chez 14 (13 cas de tumeurs de haut grade) des 16 patients évaluables, on a observé une méthylation du promoteur de l’O–6–méthylguanine–DNA méthyltransférase (MGMT). Deux patients ont eu une réponse partielle et un a eu une réponse complete selon les critères RECIST. La maladie a progressé après 1 à 11 cycles ou plus, médiane de 4 cycles, avec une survie actuarielle sans progression de 42% après 6 cycles. Une toxicité de grade 3/4 était rare et aucune réduction de dose n’a été nécessaire. Un patient a cessé le traitement à cause d’une hypersensibilité à la procarbazine.

<span class='bold'><span class='italic'>Conclusion:</span></span>

La combinaison PCB–TMZ est bien tolérée et son efficacité sur les gliomes qui ont déjà été exposés au TMZ est modeste.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 35 , Issue 2 , May 2008 , pp. 192 - 197
Copyright
Copyright © The Canadian Journal of Neurological 2008

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