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Whole brain radiotherapy (WBRT) has been utilized in patients with brain metastases (BMs) for decades, but recent evidence has called into question the value of WBRT. As a result, clinicians are left wondering which, if any patients with BMs should receive WBRT. We believe that the answer can be found by revisiting the original rationale for WBRT and what trials have revealed about its benefits and limitations. In the realm of big data, we believe that WBRT will evolve to find its new place in contemporary cancer management.
For patients with ‘limited’ BMs who have undergone open surgical resection and/or stereotactic radiosurgery (SRS), WBRT serves as an adjuvant therapy to improve local and regional control. In essence, irradiating the whole brain ‘boosts’ the tumor bed and aims to sterilize the brain of metastatic disease that is present but clinically undetectable, so called “micrometastatic disease”. Trials have demonstrated that WBRT achieves both of these objectives.
This rationale for WBRT was validated in a landmark trial in the 1990s by Patchell et al.1 Although the addition of WBRT in patients with single BMs improved locoregional control and neurological death, it failed to improve overall survival (although it was not powered to do so). The inclusion criteria for this trial are noteworthy in that all patients had a single BM and a Karnofsky performance score (KPS) over 70.1 Several other key trials have confirmed that WBRT improves local control and decreases failure at distant sites (Table 1).1-4
The associated neurocognitive detriment of WBRT has also become increasingly clear.3 While there are several promising future mediators of WBRT-induced toxicity, they remain in relatively early stages of clinical validation and utilization. Thus while adding WBRT to SRS unequivocally improves local control and prevents new BM, WBRT results in neurotoxicity and does not improve survival among the heterogeneous populations studied. It is therefore not surprising that the popularity of SRS has increased dramatically and the use of WBRT has waned in recent years.
Should WBRT ever be used in patients with limited BMs? From the modern SRS era, prospective data do exist demonstrating improved survival in select patients with <4BMs.5 We believe that big data will ultimately serve to analyze the numerous variables involved in survival in patients with BMs and define a population of patients for whom WBRT will become the standard of care. Until then patient selection must include more than merely the total number of BMs: we should select patients with a sufficient risk of intracranial micrometastatic or leptomeningeal disease. Consider that in the case of small lung cancer, WBRT remains the current standard of care even in the presence of 1-3 BMs. Are there any parallel clinical scenarios where patients with limited alternative histology BMs should be offered WBRT? Tumor histology is a key driver in the frequency, distribution, volume, and radiosensitivity of BMs: all factors critical to the risk of additional intracranial disease and the potential benefit of WBRT. In the coming years, tumor biology and not just histology will factor more into this equation.6 Existing evidence evaluating WBRT fails to incorporate some of the key drivers of regional brain failure that should be considered with individual patients during decision-making: expected survival, symptoms, histology, biology, active/refractory systemic disease, and the timing of WBRT (especially when it delays the utilization of systemic therapy).
Another population of patients with tumors greater than 4cm, leptomeningeal carcinomatosis, or more than 3 BMs is an unfavorable group that has been considered not eligible for SRS. The QUARTZ trial recently compared optimal supportive care with or without WBRT (20 Gy in 5 fractions) in patients with BMs from non-small cell lung cancer “not amenable to SRS”.7 30% of patients had a single BM, 38% had KPS < 70, and 5% were Recursive Partitioning Analysis class I. Despite accruing over 500 patients, their results demonstrated no difference in overall survival or quality of life (QOL) between groups. While we await the publication of the details of this trial, it has led many physicians to question the utility of WBRT altogether.
Although we commend the QUARTZ trial researchers for their effort to define the role for WBRT in a clinically meaningful way, the results of the trial may not come as a surprise to many. As the number of patients eligible for SRS alone increases, the prognosis of patients with tumors “not amenable to SRS” will continue to worsen (akin to the Will Rogers phenomenon). In a patient population with such a poor prognosis (high volume disease and poor KPS), it is unlikely that any current therapy would provide a dramatic improvement in survival.
While the neurocognitive impairment following WBRT has been evaluated in recent years, we should continue to weigh the potential morbidity of WBRT against that from intracranial disease progression. Although the QUARTZ trial failed to demonstrate a difference in QOL between arms, we believe that the potential for WBRT to affect QOL between arms is dependent on the distribution, volume, and clinical symptoms associated with BMs, and evaluating such a question is difficult in a heterogeneous patient population. Tumor biology will drive systemic therapy and even intracranial disease responses, but QUARTZ was not designed to account for differences in tumor biology.
Should WBRT be used in patients with BMs not amenable to SRS? Most clinicians would say yes, but there is surprisingly little evidence to guide them. Even in patients with > 4 brain metastases or poor KPS, SRS offers several logistic advantages over WBRT, including a single day of effective treatment permitting earlier systemic therapy. While big data analyses could provide this crucial information in the future, it is unlikely to incorporate individualized patient treatment preferences any time soon. In the end, an individualized treatment decision based on patient-specific factors cannot be overemphasized. Any discussion with a patient should not only include details of the disease process, but also of the individual’s desires, fears, and expectations. WBRT should be utilized in patients desiring it after a frank discussion on the goals and expectations of therapy.
Authors’ disclosure of potential conflicts of interest
The authors reported no conflict of interest.
Author contributionsConception and design: Daniel M. Trifiletti, Jason P. Sheehan, James M. Larner.
Manuscript writing: Daniel M. Trifiletti, Jason P. Sheehan, James M. Larner.
Final approval of manuscript: Daniel M. Trifiletti, Jason P. Sheehan, James M. Larner.