IN ELDERLY PATIENTS WITH LUNG CANCER AND BRAIN METASTASES AVOID BRAIN RT

LONDON ― Whole-brain radiotherapy (WBRT) provides "little additional clinically significant benefit" for patients with non–small cell lung cancer (NSCLC) with brain metastases, according to the investigators of the first large-scale randomized controlled trial of its kind.

Notably, all the patients were unsuitable for surgical resection or stereotactic radiotherapy, owing to widespread metastases.

WBRT can and should be omitted in these patients, conclude the study authors, who are led by Paula Mulvenna, MBBS, an oncologist and palliative care specialist with the Newcastle Hospitals NHS Foundation Trust in the United Kingdom.

The results, which come from the Quality of Life after Treatment for Brain Metastases (QUARTZ) study, were presented September 5 at the European Respiratory Society (ERS) International Congress 2016 and were simultaneously published online in the Lancet.

The results are in step with a transition in modalities that is taking place in radiation oncology in the treatment of brain metastases, even though the patients in the current study were not candidates for focal therapy, said senior author Ruth Langley, MBBS, PhD, Medical Research Council Clinical Trials Unit at University College London.

"Over time, there's been a shift away from using whole-brain radiation in favor of radiosurgery, which has minimal side effects. Our results could further restrict its [WBRT's] use," she said in a press statement.

However, there is one group of a patients who may be exempt from the recommendation not to use WBRT in this setting – those younger than 60 years, the authors point out.

"For younger patients, WBRT might offer a survival advantage," the authors write.

The authors of an accompanying editorial also highlight this point. Three lung cancer experts from the Gustave Roussy Cancer Campus, Villejuif France, suggest there is still a place for WBRT in patients with NSCLC and brain metastases. "We believe that optimized WBRT, given at the right time to appropriate patients, could lead to more individualized strategies."

The editorialists emphasize the significantly improved survival in patients younger than 60 years who receive radiation. The median overall survival was 10.4 weeks (95% confidence interval [CI, 6.3 - 13.4) vs 7.6 weeks (95% CI, 4.6 - 10.1) for the optimal supportive care (OSC) plus WBRT and OSC alone groups, respectively

They also highlight a trend for better survival outcomes in fitter patients (a Karnosky Performance Status score of at least 70) and in those with controlled primary NSCLC.

Thus, the editorialists believe there is still room for clinician discretion in making judgements about possible beneficiaries of WBRT in this setting.

Study Details

The QUARTZ study is a noninferiority phase 3 randomized trial that enrolled patients from 2007 to 2014 at 69 United Kingdom and three Australian centers.

Despite the widespread use of WBRT in lung cancer patients with substantial brain metastases, there has never been a major trial powered to authoritatively compare the intervention with supportive care alone.

In the trial, there was no difference in overall survival (hazard ratio, 1.06; 95% CI, 0.90 - 1.26), overall quality of life, or steroid (dexamethasone) use between patients randomly allocated to OSC plus WBRT (n = 269) and those who received OSC alone (n = 269).

There was also no evidence of a difference in the rate of serious adverse events between the two groups. The median age of the participants was 66 years.

Notably, the primary outcome of the trial was quality-adjusted life-years (QALYs), which was generated from overall survival and patients' weekly completion of a standard questionnaire on well-being.

The difference between the mean QALYs for the two groups was 4.7 days, which was within range of 7 QALY days for supportive care to be considered noninferior. Specifically, the OSC alone group had 41.7 QALY days vs 46.4 QALY days for the WBRT plus OSC group.

In summary, WBRT conferred an advantage in terms of quality days, but only a small one.

The trial is a reminder of the swift deadliness of advanced lung cancer. At the time of the analysis, 536 of the 538 patients had died. The estimated median survival was 9.2 weeks for patients who received OSC plus WBRT and 8.5 weeks for those who received OSC.

Treatment Approaches Changing

The authors and the editorialists highlight considerable changes since the start of QUARTZ in the systemic treatment of patients with advanced NSCLC. Targeted drugs such as EGFR tyrosine kinase inhibitors (TKIs) or ALK inhibitors have demonstrated "intracranial efficacy" and should be used as first-line treatment in cases of EGFR mutation or ALK rearrangement.

Regardless of how the results are interpreted, QUARTZ is a trial that was long overdue.

Up to 30% of all patients with NSCLC will present with or develop brain metastases, say the authors.

Despite the large numbers of patients, the routine practice of giving WBRT in combination with steroids (usually dexamethasone) in this setting is based "mainly on reports from the 1950s–60s," the study authors point out.

"Whole-brain radiotherapy was widely adopted into clinical practice based on the assumption it improves tumor control in patients with brain metastases. But in our lung cancer clinics, we were not seeing the improvements we had hoped for in our patients," said study Dr Mulvenna in a press statement

Remarkably, there has only been one small randomized controlled trial (with 48 patients), conducted by the Eastern Cooperative Oncology Group and published in 1971, specifically addressing the efficacy of supportive care plus WBRT compared with supportive care alone. The investigators concluded that WBRT was not justified as standard treatment because the survival benefit was so small.

"Nevertheless, WBRT remained standard practice," the QUARTZ authors observe.

In recent years, the potential treatment options for metastatic brain disease from NSCLC increasingly include neurosurgery and stereotactic radiosurgery.

Thus far, only patients with a single brain metastasis have been shown to gain a statistically significant survival benefit when WBRT is combined with focal (surgical or stereotactic) management of the intracranial disease, the study authors point out.

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