Effect of temozolomide on central nervous system relapse in patients with advanced melanoma
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Abstract:
Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma.Keywords:
Temozolomide
The effect of temozolomide (TMZ) and radiotherapy (RT) in the treatment of glioblastoma multiforme (GBM) has been well documented in randomized controlled trials. Here we present our findings on the effect of TMZ added to RT at a population level. The Cancer Registry of Norway was searched for patients with a GBM diagnosis from January 1, 2000 to December 31, 2007. Subsequently, the prescriptions registered to these patients were obtained from the Norwegian Prescription Database. The data were analyzed according to era (pre-TMZ introduction or post-TMZ introduction) and according to treatment received. Furthermore, a matching procedure was utilized to reduce the bias between the RT + TMZ and RT alone treatments so that the effect of TMZ could be better scrutinized. We identified 1157 GBM patients. The median overall survival (OS), in months, was 8.3 (95% confidence interval: 7.6-9.0) and 10.1 (95% confidence interval: 9.1-11.0) in the pre-TMZ and TMZ eras, respectively (P < .001). By treatment, we found median OS for the control, RT alone, and RT + TMZ groups to be 2.5, 9.0, and 16.2 months, respectively (P < .001). Two-year survival was 0%, 4%, and 25%, respectively. The effect of age on TMZ effect was insignificant. In the matched group analysis, TMZ provided a 7.6-month OS benefit. Our population data reproduce the beneficial effect of TMZ from randomized controlled trials with a median OS of 16.2 months and 25% 2-year survival.
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Purpose or ObjectiveRadiation therapy (RT) is a mainstay of treatment for primary and metastatic brain tumours.Various toxicities, ranging from asymptomatic to fatal, occur in the central nervous system after RT to the brain.MR imaging is useful in detecting these toxicities and complications.White matter changes in the brain after RT is well-known and is seen on T2-weighted or FLAIR MR images.The purpose of this study was to evaluate post-RT imaging changes using FLAIR T2-weighted MR images in adult primary brain tumour patients previously treated with RT.We aimed to see if any correlation existed between isodose of the delivered doses and subsequent T2 changes post-RT. Material and MethodsBetween Sept.2012 and Dec.2016, we retrospectively analysed records of all newly diagnosed low grade brain tumours who received RT to brain (with/without concurrent Temozolomide-TMZ).Fourteen patients who had MR images consisting of T2/FLAIR sequences, available from 6-24 months after RT completion were taken for the final analysis.In all patients RT was initiated 4-6 weeks after surgery/biopsy.Two patients were treated using IMRT while 12 patients were treated using partial arc VMAT.Concurrent TMZ to a dose of 75mg/m2 was given in 6 patients.Imaging datasets 6-24 months post-RT were analysed.The MR sequences included T2-FLAIR weighted images with a slice thickness of 2-3mm, which was reviewed by a radiologist and a radiation oncologist.These images were then fused with RT planning MRI on the BrainLab (BrainLab AG, Feldkirchen, Germany).The identified white matter changes were contoured on the FLAIR sequences.The MR images prior to RT were also reviewed to exclude preexisting hyperintensity related to peritumoral edema, tumour infiltration or post-operative changes. ResultsFinal analysis included 14 patients.Median age was 48.5yrs (3-63yrs) at time of RT.Histological diagnoses were astrocytoma (n=10), oligodendroglioma(n=3) and ependymoma(n=1).One patient had grade 1 histology while all others had grade 2 histology.Median dose was 55.9Gy (45 -60Gy) at 1.8-2Gy per fraction, 5 days a week.Mean PTV volume (vol.) was 305.6±358.6cc(32.5 -1461.4cc).Mean vol. of the contoured T2 changes was 60. 9±54.9cc(0.93 -145cc).Percentage isodose encompassing 100% of T2 change vol.was 63.3±28.5% (19 -98.7%) but there was no significant correlation between the delivered dose to the PTV and the percent isodose (p=0.61).There was however, a significant correlation between the PTV and the T2 change vol.(p=0.02). ConclusionThis retrospective analysis showed that though there was significant post-RT T2 changes in the brain parenchyma, these changes were not confined to any specific isodose but were distributed from low to high dose regions.It will be imperative to study further if post-RT changes on T2-FLAIR carry significance in terms of white matter changes, which can bear correlation to toxicities vis-a-vis residual disease progression or recurrence.
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ÖZETGİRİŞ ve AMAÇ: Grade IV gliom olan glioblastoma multiforme (GBM), yetişkinlerde en sık görülen primer beyin tümörüdür.Biyopsi veya rezeksiyonu takiben, radyoterapi (RT) eş zamanlı ve adjuvan temozolomid (TMZ) kullanımı (6 kür), yeni teşhis edilmiş GBM vakaları için standart tedavi haline gelmiştir.Orijinal tedavi rejimi 6 kür TEMODAL kullanımını içermesine rağmen, bazı merkezler daha iyi sonuç elde etme umuduyla progrese olmayan hastalarda 12 veya daha fazla kür tedavi uygulamaktadır.Butedavi yaklaşımı tartışmalıdır.Çalışmamızın temel amacı, hastalıksız sağkalım (DFS) ve genel sağ kalım (OS) açısından standart kombine tedavi yaklaşımı ile tedavi edilen hastalarda TEMODAL tedavisinin uzatılmasının (6 aydan 12 aya kadar
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