Temozolomide, Radiotherapy Comparable For Low-Grade, High-Risk Glioma

Patients with low-grade glioma with a high-risk feature have similar short-term outcomes from primary temozolomide or primary radiotherapy

medwireNews: A phase III trial has failed to show progression-free survival (PFS) or health-related quality of life (HRQoL) benefits with primary temozolomide over standard radiotherapy for the treatment of patients with low-grade, high-risk glioma.

The open-label EORTC 22033-26033 study included 477 patients in 19 countries with WHO grade II astrocytoma, oligoastrocytoma or oligodendroglioma but at least one high-risk feature, such as age over 40 years, progressive disease, a tumour at least 5 cm in diameter or crossing the midline, or neurological symptoms.

The first of the two reports published in The Lancet Oncology shows that, after a median follow-up of 48 months, PFS was 39 months for the 237 patients randomly assigned to receive up to 12 cycles of dose-dense oral temozolomide 75 mg/m2 once daily for 21 days of a 28-day cycle.

And this did not significantly differ from the PFS of 46 months in the patients who were assigned to receive up to 50.4 Gy of conformal radiotherapy given in 1.8 Gy doses 5 days a week for up to 6.5 weeks.

Further analysis of 318 patients with molecularly defined glioma indicated that patients whose tumours had IDH1 or IDH2 mutations without the 1p/19q co-deletion had better PFS with radiotherapy than with temozolomide (hazard ratio [HR]=1.86), say Brigitta Baumert, from Maastricht University Medical Centre in the Netherlands, and co-investigators.

They believe the “optimal treatment strategy” for such patients, who are known to have a more favourable prognosis, therefore “remains controversial” and might include initial chemotherapy.

By contrast, the choice of treatment did not significantly alter PFS for those whose tumours had IDH mutations with the 1p/19q co-deletion or were wild-type for IDH1 and IDH2, previously associated with a poor prognosis, indicating that “novel or more intensive treatment strategies are warranted even at the cost of some toxicity”, the researchers suggest.

In the second report, Jaap Reijneveld, from VU University Medical Centre in Amsterdam, the Netherlands, and co-workers failed to find a significant difference between the temozolomide and radiotherapy groups for the study’s secondary endpoints of HRQoL and global cognitive functioning.

HRQoL, as measured by the EORTC’s QLQ-C30 and Brain Cancer Module over 36 months, was comparable overall between the groups and the small differences detected, such as a greater communication deficit with radiation, were not clinically relevant, the researchers say.

Similarly, Mini–Mental State Examination results over 36 months were comparable between the groups in both overall analysis and longitudinal analysis.

“Our results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma”, they conclude.

Noting that 14% of the temozolomide group and 13% of the radiotherapy group had significant impairment at baseline, the team emphasizes that “HRQOL of patients with low-grade glioma is compromised in all patients already at the time of diagnosis and treatment initiation, and does not return to levels similar to those in healthy controls even after successful treatment.”

In a linked comment, Roberta Rudà, from the University of Turin in Italy, accepts the trial authors’ conclusion that the EORTC results do not support the use of temozolomide over radiotherapy alone, but cautions that “we must be aware that these are short-term results, and will need definitive validation in the long term.”

Comparing the EORTC study results with those of an earlier trial showing a PFS advantage with the addition of procarbazine, lomustine and vincristine (PCV) chemotherapy to radiotherapy in a similar patient population, she adds: “The question now is whether a salvage treatment with radiotherapy at relapse after upfront chemotherapy alone will bring the same overall survival of radiotherapy plus PCV.”

 

References

Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol; Advance online publication 26 September 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30313-8

Reijneveld JC, Taphoorn MJB, Coens C, et al. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol; Advance online publication 26 September 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30305-9

Rudà R. Does an optimum treatment for high-risk low-grade gliomas exist? Lancet Oncol; Advance online publication 26 September 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30434-X

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