Radiation dose escalation for malignant glioma

Background
This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour (cancer) in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. It affects about 5 in 100,000 people per year in Europe and North America. A number of studies have investigated the best strategy to give radiation to people with HGG, this review looks at these studies to see what they found. Due to toxicity, radiation is not given all in one day. In order to balance toxicity and tumour control, smaller doses of radiation are given over several days.

Conventional radiotherapy involves giving daily radiation dose (called a fraction) of 180 cGy to 200 cGy per day. Hypofractionated radiotherapy refers to the use of a higher daily dose of radiation (greater than 200 cGy per day) which typically reduces the overall number of fractions and the overall treatment time.

Hyperfractionated radiotherapy refers to the use of a lower daily dose of radiation (less than 180 cGy per day), a greater number of fractions and multiple fractions delivered per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy (beam of radiation directed from outside the body), in the same time frame. The aim with this approach is to reduce the potential for late toxicity, which is a side affect occurring more than 3 month after treatment is completed.

Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions.

The aim of the review
To examine the effectiveness and safety of external beam radiation dose escalation (higher radiation doses) in people newly diagnosed with HGG.

What are the main findings?
We found 11 trials (1537 participants in the relevant treatment groups for this review). People with a poor prognosis (likelihood of recovery) generally were not eligible for entry into the clinical trials based on their poor level of health. There was an overall survival benefit for people with HGG receiving postoperative (after surgery to remove some or all of the tumour) conventional radiotherapy compared to the participants receiving supportive care after surgery. Hypofractionated radiotherapy has similar effectiveness for survival as compared to conventional radiotherapy, particularly for people aged 60 years and older with glioblastoma. There were no clear differences in side effects between these different treatment groups. There was insufficient data regarding other outcomes, namely progression free survival (survival without the cancer getting worse) and quality of life between these different treatment groups.

There are insufficient data regarding the outcomes of survival, side effects, progression free survival and quality of life for hyperfractionation versus conventionally fractionated radiation and for accelerated radiation versus conventionally fractionated radiation.

Certainty of the evidence
The certainty of the evidence ranged from very low to high. Some of the trials were at a higher risk of bias due to missing details regarding how they divided participants into treatment groups, how many patients were lost to follow-up (after care) and possible selective reporting of outcomes such as side effects.

Only five of the 11 included trials were published after the year 2000. Most trials included in the analysis were published before 2000 and are now considered out of date. These older trials did not distinguish between the various subtypes of HGG, and they used outdated radiotherapy techniques such as whole brain radiotherapy rather than local radiotherapy (targeted only to the tumour and not the whole brain).

What are the conclusions?
Postoperative conventional daily radiotherapy improves survival for adults with good functional well-being and HGG compared to no postoperative radiotherapy. Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for people aged 60 years and older with glioblastoma. Since the last version of this review in 2016, we found no new relevant studies for inclusion.

Authors' conclusions: 

Postoperative conventional daily radiotherapy probably improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy.

Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for individuals aged 60 years and older with glioblastoma.

There are insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy).

There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These HGG individuals with poor prognosis have generally been excluded from randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these people with poor prognosis.

Since the last version of this review, we found no new relevant studies. The search identified three new trials, but all were excluded as none had a conventionally fractionated radiotherapy arm.

Read the full abstract...
Background: 

This is an updated version of the original Cochrane Review published in Issue 8, 2016.

High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. Studies have investigated the best strategy to give radiation to people with HGG. Conventional fractionated radiotherapy involves giving a daily radiation dose (called a fraction) of 180 cGy to 200 cGy. Hypofractionated radiotherapy uses higher daily doses, which reduces the overall number of fractions and treatment time. Hyperfractionated radiotherapy which uses a lower daily dose with a greater number of fractions and multiple fractions per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy in the same time frame. The aim is to reduce the potential for late toxicity. Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions.

Objectives: 

To assess the effects of postoperative external beam radiation dose escalation in adults with HGG.

Search strategy: 

We searched CENTRAL, MEDLINE Ovid and Embase Ovid to August 2019 for relevant randomised phase III trials.

Selection criteria: 

We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens: daily conventionally fractionated radiotherapy versus no radiotherapy; hypofractionated radiotherapy versus daily conventionally fractionated radiotherapy; hyperfractionated radiotherapy versus daily conventionally fractionated radiotherapy or accelerated radiotherapy versus daily conventionally fractionated radiotherapy.

Data collection and analysis: 

The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach.

Main results: 

Since the last version of this review, we identified no new relevant trials for inclusion. We included 11 randomised controlled trials (RCTs) with 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for people with HGG receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 favouring postoperative radiotherapy (95% confidence interval (CI) 1.58 to 2.55; P < 0.00001; moderate-certainty evidence). Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data.

Overall survival was similar between hypofractionated and conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17; P = 0.63; very low-certainty evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one participant in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data.

Overall survival was similar between hypofractionated and conventional radiotherapy in the subset of two trials (293 participants) which included participants aged 60 years and older with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46; P = 0.21; high-certainty evidence).

There were two trials which compared hyperfractionated radiotherapy versus conventional radiation and one trial which compared accelerated radiotherapy versus conventional radiation. However, the results could not be pooled.

The conventionally fractionated radiotherapy regimens were 4500 cGy to 6000 cGy given in 180 cGy to 200 cGy daily fractions, over five to six weeks.

All trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher.

The risk of selection bias was generally low among these RCTs. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life.

Share/Save