For people diagnosed with glioblastoma (GBM), treatment options can depend on the particular characteristics of their tumour. One of these is MGMT methylation, which is found in around 40% of glioblastomas.

We know that people with MGMT-methylated glioblastoma tend to respond better to the chemotherapy drug temozolomide (TMZ). The current standard treatment for newly diagnosed glioblastoma includes radiotherapy and temozolomide chemotherapy.

When glioblastoma recurs, lomustine is one of the chemotherapy drugs commonly used. Researchers have also been exploring whether using lomustine and temozolomide together earlier in treatment could improve outcomes for people with MGMT-methylated glioblastoma.

What did the NOA-09 trial find?

The idea of combining temozolomide and lomustine is not new.

In 2006, a German research group published results from a small clinical trial, UKT-03, which suggested that using the two chemotherapy drugs together could improve survival.

This was followed by the CeTeG/NOA-09 clinical trial, which compared combined lomustine and temozolomide with temozolomide alone in people with newly diagnosed MGMT-methylated glioblastoma.

The results again suggested that people receiving combined lomustine and temozolomide may live longer than those receiving temozolomide alone.

However, NOA-09 was a relatively small trial and the findings were not conclusive.

Outcomes have also been reported for patients treated with this approach in routine clinical care in Germany.

What is happening in the UK?

A few centres in the UK now offer combined temozolomide and lomustine to patients with newly diagnosed MGMT-methylated glioblastoma.

We collected data from 41 patients treated at three UK centres between 2020 and 2024: Imperial, Plymouth and The London Clinic. Most of the patients were treated at Imperial, and most were treated during 2023 and 2024.

All had newly diagnosed MGMT-methylated glioblastoma and all received radiotherapy and chemotherapy. The median age was 53, although four patients were aged 70. Most had undergone a partial resection of their tumour.

We looked at several factors including:

• age and sex
• extent of tumour resection
• treatment received
• survival
• time to disease progression
• treatment and survival following progression.

We then compared the survival of these patients with their predicted survival, calculated using an online survival prediction model developed from pooled clinical trial data.

What did we find?

At a median follow-up of 33 months:

• median overall survival was 37 months
• 68% of patients were alive at two years
• 56% were alive at three years.

For comparison, the online prediction model estimated a median survival of 21 months, with 44% of patients predicted to be alive at two years.

These results suggest that combined temozolomide and lomustine may improve survival for some people with MGMT-methylated glioblastoma.

However, it is important to be clear that these results are not conclusive.

The group included only 41 patients and the findings compare their actual survival with predicted survival rather than results from a larger clinical trial. The results are therefore suggestive and further research is needed.

How is the treatment being used?

In routine clinical practice, we have made some pragmatic changes to the original trial protocol.

We now routinely start combined chemotherapy after the initial chemoradiotherapy with temozolomide.

We have also reduced the starting dose of lomustine to 80 mg/m².

What about combining this treatment with Optune?

We also looked at the very small number of patients who received combined temozolomide and lomustine alongside Optune.

Outcomes in this group appeared to be very good. However, the number of patients is very small, so it is not possible to draw firm conclusions from these results.

The findings are also in line with results reported from patients treated in routine clinical care in Germany.

What happens next?

These results are not conclusive, but they are suggestive and offer a potential route to better treatment for a subgroup of people with glioblastoma.

Several centres in the UK are now using combined temozolomide and lomustine, and we have shared our treatment protocol with them. We are keen to bring together and publish updated results from these centres as more patients are treated.

In the meantime, we are planning a simple clinical study to help us understand outcomes better and answer some of the questions that remain.

Further research will be needed before we can draw firm conclusions about the benefit of combined temozolomide and lomustine, but the results so far are encouraging.

Further information

Professor Ulrich Herrlinger and the Bonn research group
https://bonn-neuroscience.de/bcn-groups/herrlinger-group/

Dr Matt Williams, Imperial College London
https://profiles.imperial.ac.uk/matthew.williams

CeTeG/NOA-09 trial – The Lancet
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31791-4/abstract

Glioblastoma survival prediction tool
https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/

German real-world study – Neuro-Oncology Advances
https://academic.oup.com/noa/article/4/1/vdac137/6674265 

This article is intended to provide general information about current research and treatment approaches. It should not replace advice from your own healthcare team.