Maintenance Therapy with 13-cis Retinoid Acid in High-Grade Glioma at Complete Response After First-Line Multimodal Therapy – A Phase-II Study

Wismeth, C.; Hau, Peter; Fabel, Klaus; Baumgart, U.; Hirschmann, Birgit; Koch, Horst J.; Jauch, T.; Grauer, Oliver; Drechsel, Lisa; Brawanski, Alexander; Bogdahn, Ulrich; Steinbrecher, Andreas

doi:10.1023/b:neon.0000024748.26608.2f

Cited by 25 publications

(18 citation statements)

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“…It is conceivable that ATRA effects are limited in recurrent tumors with significant tumor burden as in previous clinical studies, which only included patients with recurrent tumor disease (38,40). It is thus tempting to speculate that patients, which underwent first-line therapy and feature low tumor burden could profit from ATRA therapy (41). In addition, it cannot be excluded that some tumor cells might be endowed with an ATRA-resistant phenotype caused by ATRA-metabolizing enzymes, which are culprits of ATRA resistance in other tumor entities (42,43).…”

Section: Discussionmentioning

confidence: 99%

Differentiation Therapy Exerts Antitumor Effects on Stem-like Glioma Cells

Campos

Wan

Farhadi

et al. 2010

Clinical Cancer Research

288

285

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Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications.Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model.Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo.Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma. Clin Cancer Res; 16(10); 2715-28. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Differentiation Therapy Exerts Antitumor Effects on Stem-like Glioma Cells

Campos

Wan

Farhadi

et al. 2010

Clinical Cancer Research

288

285

View full text Add to dashboard Cite

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“…It may also increase the sensitivity of glioblastoma cells to conventional chemotherapy 17 . As a single agent, cisretinoic acid has shown modest benefits in maintaining remission in malignant glioma [18][19][20] . Combination therapy with temozolomide and cis-retinoic acid at recurrence has shown considerable promise, yielding a 6-month progression-free survival (pfs-6) of 43% in a large phase ii study from the North American Brain Tumor Consortium 21 .…”

Section: Discussionmentioning

confidence: 99%

Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

et al. 2012

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Objective: To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (TMZ) with cis-retinoic acid (CRA) for patients with glioblastoma. Methods: This retrospective population-based review considered the charts of all patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002–2008. Consecutive patients came from a population-based referral centre and provincial cancer registry. All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and TMZ 75 mg/m2 daily, followed by TMZ 150–200 mg/m2 for days 1–5, repeated every 28 days for up to 24 cycles, and CRA 50 mg/m2 twice daily for days 1–21, repeated every 28 days. The main outcome measures were safety, tolerability, and effectiveness of long-term TMZ and CRA. Results: Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant TMZ. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of TMZ and 3 cycles of CRA. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years. Conclusions: Extended adjuvant TMZ and CRA is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant TMZ. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.

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“…RA was once a prospective treatment for malignant glioma [246][247][248][249], but has not proved to be an effective treatment, mostly due to side effects and resistance. There is no doubt that RA is successful in cell culture models of gliomas.…”

Section: Downstream Effectors Of Retinoic Acid Signaling Related To Nmentioning

confidence: 99%