Where Does Whole Brain Radiation Fit in Lung Cancer Management?

Management of brain metastases from lung cancer and several other primary cancers has been evolving over the past decade, with greater research, wider availability, and more general reliance on stereotactic radiosurgery (SRS) for management of brain metastases, which in turn has been associated with a greater avoidance of whole brain radiation therapy (WBRT), at least for patients with a limited number of brain metastases. This preference has been shared by radiation oncologists and medical oncologists, as well as patients and caregivers who increasingly recognize the appeal of avoiding WBRT if feasible.

This is based on multiple concerns. In addition to potential short-term side effects including fatigue, headache, alopecia, and possibly confusion, there is a greater concern for long-term neurocognitive deficits that may have been less concerning when fewer patients lived for one or several years after initial treatment for brain metastases. The potential to treat brain lesions with a single treatment or potentially simply not pursuing treatment for brain metastases also obviates a wait of often several weeks before systemic therapy is initiated.

Updates From ASCO 2015

In this setting of controversy and evolving practice, we saw two important presentations at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) that focus on management options for WBRT for patients with brain metastases. The first, looking at patients exclusively with non-small cell lung cancer metastatic to the brain, asked whether WBRT, along with corticosteroids and other supportive care, provides significant benefit in terms of quality-adjusted life-years compared with corticosteroids alone. Conducted by the United Kingdom's Medical Research Council, the QUARTZ study^[1] accrued 538 patients over a period of nearly 7.5 years, as it was clearly challenging for patients and physicians to accept a randomization that would exclude radiation for half of the patients with identified metastatic disease to the brain. In addition, the patients enrolled were more likely than a historical cross-section^[2] to have a poor performance status or other negative risk factors. WBRT was administered as 20 Gy over five fractions, though it is more common in the United States and many other parts of the world to administer smaller fractions over 2 or more weeks. The study generated significant interest and debate, revealing no significant difference in overall survival (OS) or quality of life, though it was notable that median survival was disappointingly poor in both arms (9.3 vs 8.1 weeks for the WBRT and steroids/supportive care–alone arms, respectively).

The second trial, NCCTG (now Alliance) N0574,^[3] included patients with brain metastases from multiple types of primary tumors. It evaluated the incremental benefit of WBRT delivered to 30 Gy over 12 fractions, on top of SRS for patients with one to three brain metastases, to see whether these benefits exceed the risk for cognitive deficits from WBRT. Over more than a decade (2002-2013), the study randomly assigned 213 patients with a performance status of 0-2, of whom 72% had lung cancer. It included multiple interval cognitive tests along with review of imaging and survival outcomes. The investigators found that cognitive decline on a range of detailed tests was far more common at 3 months from the start of treatments among patients assigned to WBRT (91.7% vs 63.5% experiencing decline; P = .0007). On the other hand, intracranial progression was far more common with SRS alone at 3 months (24.7% vs 6.3%) and 6 months (35.4% vs 11.6%; P < .0001). There was no significant difference in OS between the two arms (7.4 vs 10.4 months; hazard ratio [HR] = 1.02; P = NS).

The Role of WBRT Moving Forward

How should we interpret these results as we manage our all-too-common patients with brain metastases from lung cancer? Is there still a potential role for WBRT?

Here, it is critical to bear in mind the populations being studied and not generalize too broadly. The selection bias of patients is suggested by the very prolonged accrual intervals for both trials and the very different survival results. If we consider the results we might expect to see in these trials, it is instructive to consider a retrospective analysis^[2] of over 1200 patients with brain metastases from RTOG trials that divided patients into three distinct groups based on recursive partitioning analysis (RPA) in which the most favorable group (younger than 65, Karnofsky performance status [KPS] > 70, primary tumor controlled, brain as only site of metastatic spread) had a median OS of 7.1 months, those in the least favorable group (KPS < 70) had a median OS of only 2.3 months, and the majority fell between these two groups with a median OS of 4.2 months.

The QUARTZ trial demonstrated no survival benefit from WBRT, but it is notable that both groups had a survival comparable to the least favorable subgroup in the RTOG RPA categorization. Although the designation of patients within the Medical Research Council study corroborated that far more patients would fit in this subgroup (34%) than in the much larger RTOG population (15%), we know that performance status assignment is a subjective consideration. Given the exceptionally poor survival of both arms, we should presume that the clear majority of patients in the QUARTZ study were selected as likely having a particularly poor prognosis, which enabled them and their oncologists to feel comfortable forgoing the prevailing standard of care of local therapy to their known brain metastases. The dose/schedule of 20 Gy/five fractions may also be suboptimal, but it is probably less of a factor than the extremely poor-risk population included in the study. What is most evident from this study is that patients who appear to be the most appropriate candidates for hospice, with a poor performance status and an anticipated survival of just a few months, do not benefit from WBRT and can pursue steroids and supportive care alone. Given the poor survival of the trial population and the skewed measures showing unusually poor risk, we should not extrapolate these conclusions to fitter patients who are better candidates for potentially effective systemic therapies.

Reviewing the results of the NCCTG N0574 trial, we see that these patients were on the other end of the spectrum, with a survival exceeding 7 months. Although the median OS was numerically striking in favor of the arm that received SRS alone, this is really an isolated time point in otherwise overlapping survival curves, as reflected by the HR for OS of 1.02, consistent with no difference at all in OS. Given the greater risk of cognitive deficits with WBRT, it is appropriate to be far more judicious about WBRT for this selected population with just one to three brain metastases, who are the patients most likely to demonstrate prolonged survival, albeit with recognized greater risk for new lesions that may be associated with headaches, seizures, and other symptoms of recurrent brain metastases, and which may in turn necessitate salvage WBRT.

For those with a good performance status and many metastatic lesions, WBRT arguably remains the most appropriate tool for the job.

We cannot presume that these same results would hold for patients with five or eight or more than 10 brain lesions, though the growing body of evidence for treating such patients with SRS highlights the feasibility of this approach for patients with more than three but still a limited number of brain metastases.^[4]

The results from the NCCTG trial lead me to favor SRS for patients with up to three (and probably a few more) brain lesions. As that number rises, however, the probability of further brain lesions becomes ever greater as well. I would therefore contend that we should not conclude that it is appropriate to omit WBRT for all patients with brain metastases. For those with a good performance status and many metastatic lesions, WBRT arguably remains the most appropriate tool for the job.

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