Elsevier

Clinical Oncology

Volume 25, Issue 3, March 2013, Pages e23-e30
Clinical Oncology

Original Article
Interim Data from the Medical Research Council QUARTZ Trial: Does Whole Brain Radiotherapy Affect the Survival and Quality of Life of Patients with Brain Metastases from Non-small Cell Lung Cancer?

https://doi.org/10.1016/j.clon.2012.11.002Get rights and content

Abstract

Aims

Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life.

Materials and methods

QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data.

Results

Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62–73), 60% male, 50% with a Karnofsky performance status <70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39–61), OSC 51 days (95% confidence interval 27–57) – hazard ratio 1.11 (95% confidence interval 0.80–1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference −1 day (95% confidence interval −12.0 to +13.2 days).

Conclusion

These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question.

Introduction

It is estimated that primary lung tumours account for 50% of all metastatic brain tumours [1], [2] and over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases [3], [4]. With modern imaging techniques for detecting brain metastases and prolonged survival of lung cancer patients due to improvements in both local and systemic approaches, the prevalence of brain metastases will probably increase. Patients with brain metastases from an underlying lung primary seem to fare less well in terms of overall survival compared with other primary tumour sites, such as breast and colonic malignancies [5], [6], with a median survival of less than 3 months.

Based on observational, non-randomised and cohort studies [7], [8], the standard management of inoperable brain metastases is generally considered to be treatment with steroids and whole brain radiotherapy (WBRT), although there are no randomised studies demonstrating that WBRT in addition to optimal supportive care (OSC) improves survival or quality of life. The potential benefits of WBRT are improvement or stabilisation of neurological symptoms, improved quality of life and performance status, and a reduction in the dose of steroids needed to control symptoms, although reports suggest that physicians overestimate the benefits of WBRT and that symptoms may deteriorate after WBRT [9]. Potential toxicities associated with WBRT include hair loss, headaches, nausea, weakness and fatigue. Previous randomised clinical trials evaluating WBRT for metastases have concentrated on the radiation dose and fractionation schemes [10], [11], [12], [13] rather than the efficacy of the therapy itself and a Cochrane systematic review assessing the effectiveness of WBRT for multiple brain metastases concluded that trials were needed to compare OSC and OSC + WBRT [14]. In view of the high incidence of NSCLC patients developing brain metastases, their poor survival and the lack of randomised evidence regarding the value of WBRT, the UK Medical Research Council Clinical Trials Unit supported by the UK National Cancer Research Institute Lung Clinical Studies Group initiated the QUARTZ Trial (Quality of Life after Radiotherapy for Brain Metastases), a randomised phase III trial comparing OSC + WBRT versus OSC alone for patients with brain metastases from NSCLC.

It was recognised from the onset that recruitment of both centres and patients to the trial was going to be challenging due to the strong views in favour of and against WBRT in this clinical setting. Recruitment to the trial has been below the original predictions, despite continued efforts by the trial management group (TMG) to aid and support open centres, including telephone workshops for investigators to share experiences about approaching potential patients and debates about the trial and challenges in recruitment at national meetings. Three years after opening, the trial was threatened with both the loss of funding and early termination. One of the main barriers to recruitment seemed to be a lack of any preliminary randomised data to support the trial's hypothesis (that omitting WBRT would not be detrimental), which could be used by doctors and patients to make an informed decision about participation in the trial. This lack of preliminary data led to challenging conversations for clinicians faced with colleagues or patients/carers who had strong opinions as to which treatment would be better. The TMG therefore took the unusual step of formally requesting that the independent trial steering committee (TSC) release data from the first cohort of patients. In order to minimise bias, neither the TMG nor the TSC were aware of the interim data when the request was being considered. It was agreed that the interim data would initially be released to, and discussed by, the trial investigators in a closed meeting with experienced statisticians present to stress the limitations of early data and to caution against over interpretation. Following this, the interim data would be made publically available through a peer-reviewed publication; the release of data was supported by the patient representative on the TMG.

Section snippets

Materials and Methods

QUARTZ is designed as a pragmatic trial, such that any patient with inoperable brain metastases confirmed on computed tomography or magnetic resonance imaging from a histologically or cytologically confirmed NSCLC, for whom the clinician and patient is uncertain of the benefit of WBRT, is eligible. All patients are assessed by a multidisciplinary lung/neuro-oncology team, as appropriate, to determine inoperability and trial eligibility. Previous treatment with systemic chemotherapy or epidermal

Results

Between March 2007 and April 2010, 151 patients were randomly assigned from 78 centres in the UK and Australia (75 to OSC + WBRT and 76 to OSC alone). All randomly assigned patients were included in these analyses and overall data compliance was good, with over 90% of expected case report forms received and over 80% of expected quality of life forms completely filled in. Participants' baseline demographics (Table 1) included 91 (60%) men; the median age at randomisation was 67 years

Discussion

The aim of the release of interim data from the QUARTZ trial was to provide information to clinicians, potential participants and their families, which could be used to inform the decision about participating in QUARTZ. Despite widespread support for the trial, over 70 centres open to recruitment in the UK and Australia and an active TMG who publicised the trial through publications, presentations at academic meetings and workshops designed to share experiences of recruiting patients to QUARTZ,

Conclusion

The key clinical message from this paper is that early data from the QUARTZ trial show no evidence of a clear detriment in terms of either quality of life or overall survival in either arm of this trial. It must be stressed that these are early data and therefore cannot be taken as definitive evidence. The 95% confidence interval around the estimate of difference in QALY of 1 day ranges from −12 days to +13 days and thus further patients are required to produce a reliable result.

Although

Acknowledgements

The authors wish to thank all the patients and participating centres, the QUARTZ Independent Data Monitoring Committee and the QUARTZ Trial Steering Committee for their support.

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