Chemoradiotherapy confers survival benefit in glioblastoma
Combining oral chemotherapy with radiotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with newly diagnosed glioblastoma compared with radiotherapy alone, according to a meta-analysis.
Five randomized controlled trials (n=1,655) evaluating the combined use of temozolomide (concomitant [75 mg/m2 from first to last day of radiotherapy] or adjuvant [150 mg/m2/day and 200 mg/m2/day for the first and second cycles, respectively]) and radiotherapy were included. The standard radiation schedule (60 Gy) was used, with some patients transitioning to an accelerated hyperfractionated irradiation course (70.4 Gy). [Medicine 2017;96:44(e8444)]
Chemoradiotherapy significantly improved OS (hazard ratio [HR], 0.70; p=0.002) and PFS (HR, 0.75; p=0.05) vs radiotherapy alone. However, the researchers indicated that the PFS data should be interpreted with caution as data regarding this were limited.
There was an increased risk of grade 3–4 haematological adverse events such as neutropenia (pooled risk ratio [RR], 46.23; p=0.007), leukopenia (pooled RR, 14.49; p<0.0001), and thrombocytopenia (pooled RR, 37.65; p=0.0004) with combination therapy vs radiotherapy alone. “[However], most of these toxicities could be managed by delaying the chemotherapy schedule or reducing the drug dose,” the researchers pointed out.
“Chemotherapy plays an important role in the treatment of malignant gliomas,” said the researchers, while radiotherapy with concurrent and adjuvant temozolomide was considered the standard treatment for adult patients with glioblastoma. [N Engl J Med 2005;352:997-1003]
Temozolomide is a novel oral alkylating agent that has been reported to show antitumour activity for newly diagnosed malignant gliomas. [Ann Oncol 2001;12:259-266; J Clin Oncol 2002;20:1375-1382] The findings show a clear survival advantage with temozolomide and radiotherapy despite controversy surrounding the efficiency of adjuvant chemotherapy plus radiotherapy. [N Engl J Med 2005;352:987-996; J Clin Oncol 2003;21:1485-491]
Previous studies have also shown the efficiency of difluoromethylornithine and marimastat when combined with other chemotherapeutic agents such as BCNU* or other polyamine inhibitors for glioblastoma treatment. [J Neurooncol 2006;78:295-302; Nat Rev Cancer 2003;3:489-501; J Clin Oncol 2002;20:1383-1388] “Taken together … [difluoromethylornithine and marimastat] may contribute to the response of chemotherapy or/and radiotherapy in [glioblastoma] patients,” said the researchers.
It is important to establish treatment alternatives for glioblastoma given its poor prognosis despite advances in treatment. [JAMA 2005;293:615-617; J Clin Oncol 2006;24:1253-1265] Given the small populations in the included studies, different study designs, and lack of comprehensive evaluation on adverse events which could exaggerate the benefits of combined therapy, the researchers recommended randomized controlled trials to further evaluate the efficiency of chemoradiotherapy in this setting.
Radioresistance in glioma stem cells could be attributed to the activation of DNA-damage response pathways, [Nature 2006;444:756-760] whereas chemoresistance may be due partly to the overexpression of MGMT**. [Mol Cancer 2006;5:67; Glia 2006;54:850-860]
“[MGMT] has been considered as a predictive marker in response to [temozolomide] in patients with newly diagnosed [glioblastoma],” said the researchers, citing trials showing MGMT promoter methylation as a strong prognostic marker for survival in malignant gliomas irrespective of chemotherapy or radiotherapy. [N Engl J Med 2005;352:997-1003; Neurol India 2011;59:229-235]
However, other studies noted that MGMT promoter methylation alone was insufficient in determining the sensitivity of grade III gliomas to alkylating agents due to other factors that could influence MGMT protein expression. [Crit Rev Oncol Hematol 2006;60:99-111; PloS One 2011;6:e17156]
“[F]urther studies are needed to investigate the correlation between MGMT promoter methylation and the treatment outcome,” added the researchers.