Extended Adjuvant Temozolomide with cis-Retinoic Acid for Adult Glioblastoma

Abstract

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.

Severe Cholestatic Hepatitis due to Temozolomide

“… 3 The study by the Manitoba Cancer Center with 116 patients treated with adjuvant temozolomide and cis -retinoic acid for up to 24 cycles or until evidence of disease progression documented 13 patients with elevated transaminases and three cases of elevated bilirubin, but none of these patients discontinued therapy. 10 Our case closely resembles the lethal case of cholestatic hepatitis reported by Sarganas in relation to type of liver injury and the absence of previous liver pathology, 7 but differs regarding the time of onset of liver toxicity: While Sarganas reported the appearance of symptoms at the end of therapy, we observed the start of transaminase elevation after 3 weeks of therapy. The authors reviewed data from the Food and Drug Administration (FDA) adverse event reporting system and recognized seven cases of temozolomide-induced liver injury, but in two cases other drugs potentially responsible for liver toxicity were involved.…”

Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells

“…22 We found that the tumors with high Mcl-1 were significantly correlated with tumors samples with high BNIP3 expression as determined by immunohistochemistry (Fig. 9B, Table 1).…”

“…FBW7 has been shown to be important in the degradation of Mcl-1 through the ubiquitination/proteosome pathway. 22 FBW7 has also been shown to be involved in the degradation of HIF-1 23 suggesting it plays a role in eliminating cell survival mechanisms under prolonged hypoxic conditions.…”

Daily Lifestyle Modifications to Improve Quality of Life and Survival in Glioblastoma: A Review

“…A third phase II trial evaluating oral all-trans-retinoic acid use in recurrent glioblastoma showed no significant effect on tumor progression or survival [ 51 ]. Of patients receiving CRA along with temozolomide during the initial treatment of glioblastoma, none had improved progression-free or overall survival compared to those receiving temozolomide alone [ 52 ]. There is one ongoing clinical trial evaluating whether isotretinoin can help control glioblastoma when given with temozolomide (NCT00555399).…”