NIHR Signal Whole brain radiotherapy provides little benefit for lung cancer that has spread

Published on 10 January 2017

Radiotherapy to the whole brain makes little difference to people with the commonest type of lung cancer that has spread to the brain and cannot be operated on.

This mainly UK-based trial found no difference in overall survival and quality of life among people who had whole brain radiotherapy plus usual supportive care compared with people who received supportive care alone.

This is the largest trial to assess the effect of this treatment in people with non-small cell lung cancer and multiple brain metastases (cancer deposits in the brain). Practice has been changing since early results of the trial were released. The final results reinforce the message that this treatment has little to offer most patients in this situation.

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Why was this study needed?

Non-small cell is the most common type of lung cancer. In about one third of these people the cancer spreads to the brain. Since the 1960s, standard treatment has included radiotherapy to the whole brain. However, people with brain metastases from lung cancer have poor survival outlook, and there’s been little research to show whether this type of radiotherapy makes an important difference.

This is the first large randomised study comparing whole brain radiotherapy and supportive care to supportive care alone in this patient group. The trial was designed to show whether supportive care alone was at least as good as that combined with whole brain radiotherapy. The researchers were interested in this because if radiotherapy does not improve length or quality of life, patients could be spared having to attend radiotherapy treatments and the associated side effects in their final stages of life.

What did this study do?

The QUARTZ randomised controlled trial included 538 people with lung cancer with brain metastases which could not be treated by surgery or targeted radiotherapy. Recruitment was from 69 UK and three Australian hospitals.

Patients were randomly assigned to supportive care alone or whole brain radiotherapy plus supportive care. Planned radiotherapy involved five treatments over five to eight days. Supportive care included the steroid dexamethasone, plus whatever palliative care treatment the cancer specialists thought necessary.

Quality of life was assessed by weekly telephone questionnaire. Researchers also looked at overall length of survival. They said they would consider supportive care as good as radiotherapy if radiotherapy gave fewer than seven additional days of life, adjusted for the quality of that extended life.

What did it find?

  • People who had radiotherapy had an average 4.7 additional quality-adjusted days of life compared to those who had supportive care alone. This fell short of the margin needed to show a difference and could have been down to chance (46.4 quality-adjusted days with radiotherapy compared with 41.7 with supportive care, 90% confidence interval [CI] -12.7 to 3.3).
  • When the researchers looked at length of life alone, there was also little difference between the two groups. People who had radiotherapy lived on average 9.2 weeks compared to 8.5 weeks for supportive care.
  • People who had radiotherapy were more likely to have episodes of drowsiness, to lose their hair, feel nauseous and have a dry or itchy scalp. There was no difference in the number with serious adverse events, which affected around a third of each group.
  • Younger people (under 60) and those who had better prognostic outlook at study start seemed more likely to benefit from radiotherapy. However, the numbers of patients in these groups were small so this finding should be interpreted with some caution.

What does current guidance say on this issue?

NICE guidance from 2011 states: “Consider palliative whole-brain radiotherapy for patients with symptomatic brain metastases with good performance status (WHO 0 or 1)”. This means people who have symptoms from their brain tumours but who are either fully active, or can carry out all but heavy physical work.

This study does not report on the WHO scale, but it included people with any level of functional impairment as defined by Karnofsky Performance Status (KPS). Over a third had KPS of less than 70, equivalent to being unable to carry out normal activity or any active work. Therefore the study was more inclusive.

What are the implications?

Cancer care is already changing after early reports from this trial. The full results provide confirmation to professionals, commissioners and patients that whole brain radiotherapy offers little benefit. Gain for most people is measured in days, rather than months of life.

The evidence might inform the NICE guidance on treatment of lung cancer. Avoiding radiotherapy if it doesn’t work could be better for patients and save the NHS some costs.

Citation and Funding

Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004-2014.

This study was funded by Cancer Research UK, the Medical Research Council Clinical Trials Unit at University College London and the National Health and Medical Research Council in Australia.

Bibliography

NICE. Lung cancer: diagnosis and management. CG121. London: National Institute for Health and Care Excellence; April 2011.

Tsao MN, Lloyd N, Wong RKS, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;(4):CD003869.

Why was this study needed?

Non-small cell is the most common type of lung cancer. In about one third of these people the cancer spreads to the brain. Since the 1960s, standard treatment has included radiotherapy to the whole brain. However, people with brain metastases from lung cancer have poor survival outlook, and there’s been little research to show whether this type of radiotherapy makes an important difference.

This is the first large randomised study comparing whole brain radiotherapy and supportive care to supportive care alone in this patient group. The trial was designed to show whether supportive care alone was at least as good as that combined with whole brain radiotherapy. The researchers were interested in this because if radiotherapy does not improve length or quality of life, patients could be spared having to attend radiotherapy treatments and the associated side effects in their final stages of life.

What did this study do?

The QUARTZ randomised controlled trial included 538 people with lung cancer with brain metastases which could not be treated by surgery or targeted radiotherapy. Recruitment was from 69 UK and three Australian hospitals.

Patients were randomly assigned to supportive care alone or whole brain radiotherapy plus supportive care. Planned radiotherapy involved five treatments over five to eight days. Supportive care included the steroid dexamethasone, plus whatever palliative care treatment the cancer specialists thought necessary.

Quality of life was assessed by weekly telephone questionnaire. Researchers also looked at overall length of survival. They said they would consider supportive care as good as radiotherapy if radiotherapy gave fewer than seven additional days of life, adjusted for the quality of that extended life.

What did it find?

  • People who had radiotherapy had an average 4.7 additional quality-adjusted days of life compared to those who had supportive care alone. This fell short of the margin needed to show a difference and could have been down to chance (46.4 quality-adjusted days with radiotherapy compared with 41.7 with supportive care, 90% confidence interval [CI] -12.7 to 3.3).
  • When the researchers looked at length of life alone, there was also little difference between the two groups. People who had radiotherapy lived on average 9.2 weeks compared to 8.5 weeks for supportive care.
  • People who had radiotherapy were more likely to have episodes of drowsiness, to lose their hair, feel nauseous and have a dry or itchy scalp. There was no difference in the number with serious adverse events, which affected around a third of each group.
  • Younger people (under 60) and those who had better prognostic outlook at study start seemed more likely to benefit from radiotherapy. However, the numbers of patients in these groups were small so this finding should be interpreted with some caution.

What does current guidance say on this issue?

NICE guidance from 2011 states: “Consider palliative whole-brain radiotherapy for patients with symptomatic brain metastases with good performance status (WHO 0 or 1)”. This means people who have symptoms from their brain tumours but who are either fully active, or can carry out all but heavy physical work.

This study does not report on the WHO scale, but it included people with any level of functional impairment as defined by Karnofsky Performance Status (KPS). Over a third had KPS of less than 70, equivalent to being unable to carry out normal activity or any active work. Therefore the study was more inclusive.

What are the implications?

Cancer care is already changing after early reports from this trial. The full results provide confirmation to professionals, commissioners and patients that whole brain radiotherapy offers little benefit. Gain for most people is measured in days, rather than months of life.

The evidence might inform the NICE guidance on treatment of lung cancer. Avoiding radiotherapy if it doesn’t work could be better for patients and save the NHS some costs.

Citation and Funding

Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004-2014.

This study was funded by Cancer Research UK, the Medical Research Council Clinical Trials Unit at University College London and the National Health and Medical Research Council in Australia.

Bibliography

NICE. Lung cancer: diagnosis and management. CG121. London: National Institute for Health and Care Excellence; April 2011.

Tsao MN, Lloyd N, Wong RKS, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;(4):CD003869.

Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial

Published on 9 September 2016

Mulvenna, P.,Nankivell, M.,Barton, R.,Faivre-Finn, C.,Wilson, P.,McColl, E.,Moore, B.,Brisbane, I.,Ardron, D.,Holt, T.,Morgan, S.,Lee, C.,Waite, K.,Bayman, N.,Pugh, C.,Sydes, B.,Stephens, R.,Parmar, M. K.,Langley, R. E.

Lancet , 2016

BACKGROUND: Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. METHODS: The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. FINDINGS: Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38-85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1.06, 95% CI 0.90-1.26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4.7 days (46.4 QALY days for the OSC plus WBRT group vs 41.7 QALY days for the OSC group), with two-sided 90% CI of -12.7 to 3.3. INTERPRETATION: Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. FUNDING: Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.

Quality adjusted life years are calculated to help people standardise the value of time. For example, someone in pain, or with little consciousness of their surroundings, might live longer than someone who was pain-free and alert to the end of their life, but most people would not say that their quality of life was as good. Treatment may increase quality of life due to fewer symptoms, or decrease quality of life due to more side effects or treatment burden. In this study this was combined with differences in length of life to give a quality adjusted day of life.

Expert commentary

Patients with brain metastases from non-small cell lung cancer have a poor prognosis. Treatment should focus on improving quality of life and survival, and reducing unnecessary interventions. Dexamethasone and whole brain radiotherapy have often been used with previously unknown benefit and harms. If whole brain radiotherapy does not increase survival or quality-of-life and causes drowsiness, hair loss, nausea, and dry/itchy scalp, then for many people this might not be a helpful intervention. For fitter patients, there may be a small survival advantage with whole brain radiotherapy. In this case, a discussion with their oncologist about the benefits and risks is needed.

Dr Jason Boland, Senior Clinical Lecturer and Honorary Consultant in Palliative Medicine, Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull