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Whole-brain radiotherapy provides little benefit for NSCLC with brain metastases
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Whole-brain radiotherapy failed to extend OS and improve quality of life among patients with non–small cell lung cancer and brain metastases, according to the results of a randomized phase 3 noninferiority trial.
Approximately 30% of patients with NSCLC will develop brain metastases, which are primarily treated with whole-brain radiotherapy and steroids such as dexamethasone. Whole-brain radiotherapy is associated with substantial toxicity and cognitive functioning defects.
“Whole-brain radiotherapy was widely adopted into clinical practice based on the assumption it improves tumor control in patients with brain metastases,” Paula Mulvenna, MBBS, MRCP, FRCR, consultant clinical oncologist at Newcastle Hospitals NHS Foundation Trust in Newcastle-upon-Tyne, England, said in a press release. “But in our lung cancer clinics, we were not seeing the improvements we had hoped for our patients. Survival times are poor and have hardly changed since the 1980s.”
No randomized trials have been conducted to determine whether whole-brain radiotherapy improves OS or quality of life in patients with brain metastases.
Mulvenna and colleagues conducted the Quality of Life after Treatment for Brain Metastases (QUARTZ) trial to determine whether whole-brain radiotherapy could be omitted from the treatment of patients with NSCLC and brain metastases without significant OS or quality-of-life detriments.
The researchers randomly assigned 538 patients (median age, 66 years; range, 38-85; 58% men) unsuitable for surgery or stereotactic radiotherapy to optimal supportive care with dexamethasone plus whole-brain radiotherapy (20 Gy in five daily fractions) or optimal supportive care alone (n = 269 for both).
Dexamethasone dose was determined by patient symptoms and titrated downward based on symptom improvements.
Patients completed weekly quality-of-life questionnaires prior to randomization and for up to 12 weeks after randomization, with monthly questionnaires administered thereafter.
Quality-adjusted life years (QALYs) served as the primary outcome measure. The researchers considered optimal supportive care alone noninferior if it was no more than 7 QALY days worse than treatment with whole-brain radiotherapy.
Patients assigned whole-brain radiotherapy plus optimal supportive care had a mean QALY of 46.4 (3.66) days, compared with 41.7 (3.23) days for optimal supportive care alone. This represented a difference of –4.7 QALY days in favor of radiotherapy (90% CI, –12.7 to 3.3).
More patients assigned whole-brain radiotherapy experienced moderate to severe episodes of drowsiness (42% vs. 28%; P = .0151), hair loss (34% vs. 1%; P = .0001), nausea (10% vs. 2%; P = .0067), and dry or itchy scalp (7% vs. 1%; P = .0057).
Eighty-nine patients assigned whole-brain radiotherapy and 82 patients assigned optimal supportive care alone reported at least one serious adverse event. The most common serious adverse events in both groups included infections (whole-brain radiotherapy, n = 17; optimal supportive care, n = 16), neurological events (n = 18; n = 31), and pulmonary or respiratory events (n = 22; n = 12).
The researchers did not observe a significant difference in median OS based on treatment with whole-brain radiotherapy or optimal supportive care alone (9.2 weeks vs. 8.5 weeks; HR = 1.06; 95% CI, 0.9-1.26).
A total of 536 patients died (whole-brain radiotherapy, n = 267; optimal supportive care, n = 269), with 98% of deaths (n = 519) considered disease related.
Overall quality of life or dexamethasone use did not significantly differ between the arms. Sixty-six percent of patients in the whole-brain radiotherapy arm and 68% of patients in the optimal supportive care arm received a dexamethasone dose reduction during the first 8 weeks of treatment.
“Whole-brain radiotherapy cannot be considered as the standard treatment for all patients with brain metastases because it does not extend survival, improve quality of life or reduce steroid use,” Ruth E. Langley, MD, senior clinical scientist at Medical Research Council Clinical Trials Unit of University College London, said in a press release. “Over time, there has been a shift away from using whole-brain radiotherapy in favor of radiosurgery, which has minimal side effects. Our results could further restrict its use.”
Whole-brain radiotherapy may continue to be appropriate for select patients with NSCLC and brain metastases, Cécile Le Pechoux, MD, Frederic Dhermain, MD, and Benjamin Besse, MD, radiation oncologists at Institut Gustave Roussy in Paris, wrote in an accompanying editorial.
“Improved survival with whole-brain radiotherapy was indeed shown for younger patients, particularly those younger than 60 years, and there was a trend toward better outcome in patients with a Karnofsky Performance Status of less than 70 and those with controlled primary NSCLC,” they wrote. “We believe that optimized whole-brain radiotherapy, given at the right time to appropriate patients, could lead to more individualized strategies. Both systemic and local treatments of brain metastases need to be discussed with patients, taking into account the results of this trial, classic prognostic factors and the molecular status.” – by Cameron Kelsall
Disclosures: Langley and four other study researchers report employment with the Medical Research Council Clinical Trials Unit at University College London, which received a funding grant from Cancer Research U.K. for this study. Mulvenna and the other researchers report no relevant financial disclosures. Le Pechoux, Dhermain and Besse report no relevant financial disclosures.
Perspective
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For many years, whole-brain radiation therapy (WBRT) has been the treatment of choice for patients with brain metastases given its ease of delivery and availability, benefit in improving neurologic symptoms and improvement in intracranial control. The emergence of stereotactic radiosurgery (SRS) and the concern regarding the neurocognitive decline after WBRT have led some to question the routine use of WBRT. Until the publication by Mulvenna and colleagues in The Lancet Oncology, no large prospective study compared WBRT with best supportive care, which is relevant given the limited prognosis for some patients and the focus on optimizing quality of life.
The Quality of Life after Treatment for Brain Metastases (QUARTZ) study was a multicenter, noninferiority phase 3 trial. Researchers enrolled 538 patients between 2007 and 2014 with brain metastases from non–small cell lung cancer. Patients were randomly assigned to receive WBRT (20 Gy in 5 fractions) or best supportive care, including dexamethasone. The primary endpoint was quality-adjusted life years (QALY), generated from OS and weekly questionnaires by patients. Eligibility was based upon a multidisciplinary tumor board recommendation that either surgery or SRS was unsuitable. In addition, the physician or patient needed to have uncertainty about the value of WBRT.
The trial — which required an unplanned interim analysis and conversion to a one-sided hypothesis test from the initial cohort of 151 patients — found that WBRT did not improve OS, quality of life, dexamethasone use or rate of serious adverse events compared with supportive care. The difference in mean QALYs — 4.7 days — was not significant between the two arms.
Because the effects of WBRT are not immediate, the lack of benefit in quality of life was not surprising, given the very short survival of poor-prognosis patients enrolled. In addition, only 35% of patients started WBRT within 7 days of randomization, and 11% of patients never received WBRT due to rapid disease progression or death. The vast majority (98%) of patients in both arms received dexamethasone at a dose of 8 mg per day, which most likely impacted weekly symptoms and quality-of-life responses. Finally, the tool used to measure quality of life — EQ-5D 3L — is not specific for patients with brain tumors and has measures that may be influenced by high-dose steroid use.
The lack of survival benefit also is not surprising given the eligibility requirements and noninferiority study design. The vast majority of patients had a graded prognostic assessment (GPA) of 0-1 and 1.5-2. Based on the disease-specific GPA, one would have expected survivals of 17 weeks rather than the 8 to 9 weeks reported on the QUARTZ trial. Not surprisingly, younger patients and those with a Karnofsky performance score of greater than 70 had improved survival with the addition of WBRT.
The QUARTZ study strongly corroborates the influence of patient selection on outcomes in brain metastasis clinical trials, and adds to the growing literature guiding the management of this patient population. Many of the patients on this trial were appropriate for hospice, which underscores the importance of best supportive care rather than WBRT in select patients with brain metastases. Given the importance and emphasis on affordable care, all patients with brain metastases should be carefully assessed by a multidisciplinary team to optimize treatment selection, which should include hospice. The emergence of biologic and molecular targets will continue to improve our understanding of this disease through the prudent utilization of current and emerging therapies.
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