Brain metastases (BM) are common and can be detrimental in patients with primary cancers. Lung cancer accounts for over 40% of BM cases and breast cancer is responsible for 10% to 20% of BM. Typically, patients present with oligometastatic disease—1 to 3 intracranial metastases. Stereotactic radiosurgery (SRS) is often used to good effect in treating these tumors. To investigate intracranial tumor progression control, researchers have conducted randomized clinical trials (RCTs) in which whole brain radiotherapy (WBRT) was added to the clinical regimen following SRS. RCTs demonstrated that WBRT did in fact show improvement in intracranial tumor control; however, WBRT does not confer a survival advantage. In fact, previous RCTs have suggested that WBRT may cause deterioration of cognitive function and quality of life (QOL).1–3
Brown et al1 conducted the largest, multi-institutional study utilizing a plethora of cognitive and QOL assessments to determine the effects of WBRT. They enrolled 213 randomized participants with 1 to 3 BM at 34 participating institutions. One group underwent SRS alone and the second group had SRS plus WBRT that began within 14 days of SRS. The WBRT dose regimen was 30 Gy in 12 fractions and the SRS dose was 18 to 22 Gy in the SRS plus WBRT group, and 20 to 24 Gy in SRS alone. Baseline evaluations were made starting at week 6 and subsequently at months 3, 6, 9, and eventually, at month 60. QOL was assessed using the Functional Assessment of Cancer Therapy-Brain. Scores ranged between 0 and 200 where higher scores signified better QOL. The Barthel Index of Activities of Daily Living (ADL Index) was used to determine functional independence where a score of 100 indicated complete independence and a lower score demonstrated the need for supervision and assistance. Seven other assessments were used to evaluate immediate memory, fine motor control, delayed memory, and other cognitive abilities. The primary endpoint was deemed to be cognitive deterioration at 3 months after SRS defined as a decline in any of the cognitive tests. Secondary endpoints included time to intracranial failure, overall survival, QOL, as well as other parameters.
Brown et al1 showed that there was significantly more cognitive deterioration at the 3-month evaluation mark in the SRS plus WBRT group. Additionally, this group showed to have decline in immediate memory, delayed memory, and verbal fluency when compared to the SRS alone group. The SRS alone group demonstrated a significantly better QOL and functional well-being; however, time to intracranial tumor progression was significantly shorter for SRS alone vs SRS plus WBRT. Intracranial tumor control rates at 3 months were higher (93.7%) in SRS plus WBRT vs (75.3%) SRS alone. The 6- and 12-month control rates were also significantly higher in SRS plus WBRT vs SRS alone (32.4% vs 7.8%, respectively). For long-term survivors—defined as evaluable patients who survived past 12 months—the intracranial tumor control rate at 12 months in SRS plus WBRT vs SRS alone was 89.5% vs 20.0%, respectively. Cognitive deterioration, however, occurred more often in the SRS plus WBRT group. Decline in intermediate memory was most pronounced at 3 months; deterioration in fine motor control was most pronounced at 6 months.
The study by Brown et al1 gives some insight into the controversial issue of WBRT. Although the SRS plus WBRT group had a higher intracranial tumor control rate, patients experienced significant cognitive decline and no improvement in survival occurred. Chang et al2 (Figure) conducted a randomized controlled trial similar to Brown et al,1 where the study was forced to be halted due to the high probability (96%) that patients randomly assigned to receive SRS plus WBRT (n = 28), vs patients in the SRS alone group (n = 30), were likely to show a significant decline in learning and memory function at 4 months. Aoyama et al3 on the other hand believes that WBRT should be considered for patients’ BMs from nonsmall-cell lung cancer and has a favorable prognosis. Studies have been done to avoid the hippocampal neural stem-cell area during WBRT to preserve memory and cognitive functions. Gondi et al4 demonstrated that the mean relative decline in the Hopkins Verbal Learning Test–Revised Delayed Recall at 4 months was significantly lower when avoiding the hippocampal compartment, but QOL did not change.
Figure. A, Actuarial time to death (all causes). SRS: stereotactic radiosurgery; WBRT: whole brain radiotherapy. B, Actuarial freedom from local tumor progression. SRS: stereotactic radiosurgery; WBRT: whole brain radiotherapy. Reprinted from Lancet Oncology,2 Copyright (2009), with permission from Elsevier.
The study by Brown et al1 lends more emphasis to the necessity to balance the need for tumor control and potential cognitive decline when deciding to administer WBRT. New, promising research in radiosensitizer drugs may allow for lower doses of radiation to normal brain while improving tumor control.5 Refinements in neuroimaging and increasing use of SRS in treating multiple metastases may offer benefit as well.6 Indeed, in patients with cancer, cognitive dysfunction can greatly lower patients’ abilities to carry out basic activities of daily living, increase strain on families and other support systems, and decrease eligibility in potentially effective clinical trials. These various treatment strategies should be carefully evaluated when considering SRS plus WBRT.
Julia R. Schneider, BS
Shamik Chakraborty, MD
John A. Boockvar, MD
Department of Neurosurgery Lenox Hill Hospital and Hofstra Northwell School of Medicine New York, New York