Considering that glioblastomas are among the most common and malignant brain tumors and have a very poor prognosis, optimizations of the current therapy are urgently needed. Two publications are attracting attention in this regard: one tested the addition of bevacizumab to standard chemoradiotherapy, the other used methadone to enhance the effect of chemotherapy.
(ag) Bevacizumab is indicated as monotherapy for the treatment of patients with recurrent glioblastoma (WHO grade IV) after prior therapy with temozolomide. However, radiotherapy plus temozolomide remains the standard of care in primary treatment, so a new phase III trial [1] tested the extent to which the addition of bevacizumab could improve treatment success in this population as well.
The total of 921 patients with newly diagnosed glioblastoma received either intravenous bevacizumab (n=458) or placebo (n=463) in addition to standard therapy. After treatment was stopped on day 28, six months of maintenance therapy with bevacizumab/placebo plus temozolomide was started. This was followed by the monotherapy phase with bevacizumab/placebo until progression or unsustainable toxicities.
No benefit in overall survival
While one of the co-primary endpoints, progression-free survival, showed a significant benefit of addition across all subgroups (10.6 vs. 6.2 months, HR 0.64, p<0.001), overall survival did not differ significantly (HR 0.88, p=0.1).
Regarding the secondary endpoints: Survival rates at one year were 72.4 with bevacizumab and 66.3% with placebo (p=0.049), and 33.9 and 30.1% at two years (p=0.24). More adverse events of grade three or higher occurred in the bevacizumab group.
Thus, although the addition significantly improved progression-free survival and did not negatively affect quality of life until progression, the increased side effects should be factored into the assessment, the authors concluded.
Methadone enhances the success of chemotherapy
A German report [2] in the field of glioblastoma also raises eyebrows: Glioblastoma cells have opioid receptors on their surface. After it was discovered that cAMP is crucial for proliferation, differentiation and apoptosis in certain tumors and that its downregulation (e.g. by means of opioid receptor agonists) could make the tumors more sensitive to anticancer treatments, this fact could now be demonstrated for the first time in glioblastomas. Specifically, methadone sensitizes glioblastomas and otherwise untreatable glioblastoma stem cells to doxorubicin-induced apoptosis. It increases doxorubicin uptake and decreases efflux (which is why smaller amounts of the cytostatic drug are needed and side effects are reduced). Friesen et al. were also able to show that doxorubicin increases the number of opioid receptors in the cancer cell, which in turn allows more methadone to bind in an escalating process.
Doxorubicin has already demonstrated efficacy in the treatment of malignant gliomas in in vitro and in vivo studies [3].
The authors conclude that opioid receptor activation may be a promising strategy to prevent tumor growth (via regulation of cAMP) and increase the efficacy of anticancer agents in the treatment of glioblastoma. Clinical studies in this direction are being planned.
Literature:
- Chinot OL, et al: N Engl J Med 2014; 370(8): 709-722.
- Friesen C, et al: Cell Cycle 2014; 13(10): 1560-1570.
- Fabel K, et al: Cancer 2001 Oct 1; 92(7): 1936-1942.
InFo ONCOLOGY & HEMATOLOGY 2014; 2(9): 6.
