Point/Counter

Does WBRT still have a role for limited brain metastases?

Click here to read the Cover Story, “Larger trials needed to confirm benefit of targeted therapies, immunotherapy for brain metastases.’”

POINT

Yes.

The Choosing Wisely recommendation from the American Society for Radiation Oncology (ASTRO) states to not “routinely add adjuvant WBRT to stereotactic radiosurgery for limited brain metastases.” This has been interpreted as the demise of WBRT in limited metastatic disease, which has been reinforced by the QUARTZ trial, which showed no OS or quality-of-life benefit with WBRT compared with supportive care in a hospice-eligible patient population. However, we believe that this is an extreme viewpoint, and the decision to offer WBRT should entail considerable personalization that requires a very balanced approach with an honest and open risk-benefit discussion with the patient.

Melissa A.L. Vyfhuis, MD, PhD
Melissa A.L. Vyfhuis

Randomized trials have consistently demonstrated the benefits of WBRT in combination with locally aggressive treatment (eg, surgery or SRS), typically in the form of improved local control, decreased intracranial progression and reduction of neurologic deaths. The benefits of WBRT are now perceived and presented in a dilutionary manner due to the lack of OS benefit, the high local control offered by SRS and neurocognitive toxicity. However, the exact clinically relevant magnitude of this toxicity remains poorly elucidated, and the various strategies available to mitigate cognitive dysfunction are used relatively infrequently in standard practice.

The Alliance study — a large randomized trial that investigated the addition of WBRT to SRS on cognitive dysfunction among patients with a limited number of brain metastases — showed an unacceptably high 3-month rate of cognitive decline in the SRS-alone arm at 63.5% (close to the 65% “unacceptable” rate from WBRT speculated as the trial hypothesis); however, statistically better than the 91.7% rate observed for WBRT plus SRS. A simple explanation for this high rate of cognitive impairment in the SRS cohort could be the high rate of intracranial failures at 3 months (24.7% vs. 6.4%; P < .001), cognitive dysfunction from disease progression, the need for repetitive salvage brain treatments or the effects of SRS itself.

Radiation oncologists are counseled to strongly consider omitting WBRT in combination with SRS among patients with limited metastatic disease, despite the dramatic increase in intracranial progression and the possibility of an OS benefit in appropriately selected patients — eg, those with a favorable graded prognostic assessment score and well-controlled extracranial disease. With improvements in systemic treatments, intracranial control becomes even more crucial and has a greater likelihood of impacting survival.

If one is to abandon WBRT based on the Alliance cognitive test score change results, then the extremely high rates of cognitive decline associated with SRS in that trial must be part of the informed written medical procedure consent form. We posit that advances in radiation delivery through hippocampal-avoidance WBRT and pharmacological interventions will likely result in reconsideration of this blanket exclusion. Further clinical trials are needed — and are underway — to discern the specific subset of patients likely to benefit from WBRT. In the meantime, treatment selection should include a comprehensive, unbiased and transparent discussion of trade-offs.

References:

Brown PD, et al. JAMA. 2016;doi:10.1001/jama.2016.9839.

Mulvenna P, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)30825-X.

Melissa A.L. Vyfhuis, MD, PhD, is chief resident in the department of radiation oncology at University of Maryland Medical Center. She can be reached at mvyfhuis@umm.edu. Andrew B. Lassman, MD, is the John Harris associate professor of neurology and chief of neuro-oncology at Columbia University. He can be reached at abl7@cumc.columbia.edu. Minesh Mehta, MD, is deputy director and chief of radiation oncology at Miami Cancer Institute. He can be reached at mineshm@baptisthealth.net. Disclosures: Vyfhuis reports no relevant financial disclosures. Lassman reports honoraria from AbbVie, Celgene, Cortice, Kadmon, Novocure, prIME Oncology Sapience and WebMD. Mehta reports consultant roles with AbbVie, AstraZeneca, Celgene, Oncoceutics, Tocagen and Varian; and a data and safety monitoring board role with Monteris.

COUNTER

No.

For decades, two forms of external, brain-directed radiation have been used for brain metastases: WBRT — in which the entire brain is treated with radiation over 1 to 3 weeks — and stereotactic radiation, in which only the visualized metastases are targeted, typically over the course of 1 to 5 days.

Ayal A. Aizer, MD, MHS
Ayal A. Aizer

Multiple randomized studies of surgery and/or stereotactic radiation alone vs. with WBRT define the advantages and disadvantages of WBRT. Although all studies showed that WBRT improved intracranial disease control, no studies demonstrated WBRT improved OS. In addition, multiple studies — which used sensitive measures of fatigue, quality of life and neurocognitive function — showed that WBRT had deleterious effects on these outcomes. Even using a cognitive decline definition of a standard deviation drop (a substantial deterioration) on cognitive testing from baseline, approximately 35% to 52% of patients will have cognitive impairment after WBRT.

These studies illustrate the doubtful significance of preventing new metastases in the brain, which is especially true given the vigorous imaging-based surveillance patients receive after brain-directed radiation. Close follow-up imaging allows most distant intracranial recurrences to be salvaged effectively. Also, the substantial competing risk for systemic death mitigates the clinical impact of subtle intracranial recurrence. Moreover, an increasing number of systemic agents can achieve effective intracranial penetration, further decreasing the impact of radiotherapeutic prophylaxis of the uninvolved brain.

Partially due to a lack of clinical trials, WBRT had been indicated for poor-prognosis patients with brain metastases. The QUARTZ trial — which included patients with NSCLC and brain metastases who harbored a guarded prognosis and were not candidates for surgery or stereotactic radiation — showed no survival or quality-of-life advantage with WBRT. Therefore, WBRT provided no benefit compared with best supportive care among patients with NSCLC and asymptomatic brain metastases who have a limited life expectancy.

If upfront stereotactic radiation is selected as management and rapid distant intracranial failure occurs, WBRT can, in most cases, be safely employed as salvage therapy, sparing the majority of patients from its harmful effects. In addition, the use of upfront brain-directed stereotactic radiation permits earlier resumption of systemic therapy given the shorter duration of treatment and recovery time. Because systemic progression is the primary cause of mortality among these patients, avoiding delays in systemic therapy administration is of great importance.

The use of memantine with WBRT and a hippocampal-sparing WBRT technique may minimize neurocognitive toxicity. Administration of memantine is backed by a placebo-controlled randomized trial; however, a significant percentage of patients still experienced neurocognitive decline. In addition, hippocampal-sparing WBRT is supported only by single-arm phase 2 data.

Numerous randomized studies have shown no benefit with the addition of WBRT to local, brain-directed therapy for a limited number of brain metastases. In addition, modern studies have elucidated the significant harm that WBRT can impart on patient quality of life and neurocognitive function. Upfront stereotactic radiation remains the most optimal approach for patients with a limited number of brain metastases.

References:

Aoyama H, et al. JAMA. 2006;doi:10.1001/jama.295.21.2483.

Brown PD, et al. JAMA. 2016;doi:10.1001/jama.2016.9839.

Brown PD, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30441-2.

Brown PD, et al. Neuro Oncol. 2013;doi:10.1093/neuonc/not114.

Cagney DN, et al. Neuro Oncol. 2017;doi:10.1093/neuonc/nox077.

Chang EL, et al. Lancet Oncol. 2009;doi:10.1016/S1470-2045(09)70263-3.

Gondi V, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2014.57.2909.

Iuchi T, et al. Lung Cancer. 2013;doi:10.1016/j.lungcan.2013.08.016.

Kayama T, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.34.15_suppl.2003.

Knisely JP, et al. J Neurosurg. 2012;doi:10.3171/2012.5.JNS111929.

Kocher M, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.30.1655.

Lin NU, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2007.12.3588.

Long GV, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.62.9345.

Mulvenna P, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)30825-X.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Version 5.2017. www.nccn.org.

Patchell RA, et al. JAMA. 1998 doi:10.1001/jama.280.17.1485.

Shaw AT, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(15)00488-X.

Soffietti R, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2011.41.0639.

Ayal A. Aizer, MD, MHS, is assistant professor of radiation oncology in the department of radiation oncology at Dana-Farber/Brigham and Women’s Cancer Center and Harvard Medical School. He can be reached at ayal_aizer@dfci.harvard.edu. Paul D. Brown, MD, is professor of radiation oncology in the department of radiation oncology at Mayo Clinic. He can be reached at brown.paul@mayo.edu. Disclosures: Aizer reports research funding from Varian Medical Systems. Brown reports honoraria from Up to Date and Varian Medical Systems.

Click here to read the Cover Story, “Larger trials needed to confirm benefit of targeted therapies, immunotherapy for brain metastases.’”

POINT

Yes.

The Choosing Wisely recommendation from the American Society for Radiation Oncology (ASTRO) states to not “routinely add adjuvant WBRT to stereotactic radiosurgery for limited brain metastases.” This has been interpreted as the demise of WBRT in limited metastatic disease, which has been reinforced by the QUARTZ trial, which showed no OS or quality-of-life benefit with WBRT compared with supportive care in a hospice-eligible patient population. However, we believe that this is an extreme viewpoint, and the decision to offer WBRT should entail considerable personalization that requires a very balanced approach with an honest and open risk-benefit discussion with the patient.

Melissa A.L. Vyfhuis, MD, PhD
Melissa A.L. Vyfhuis

Randomized trials have consistently demonstrated the benefits of WBRT in combination with locally aggressive treatment (eg, surgery or SRS), typically in the form of improved local control, decreased intracranial progression and reduction of neurologic deaths. The benefits of WBRT are now perceived and presented in a dilutionary manner due to the lack of OS benefit, the high local control offered by SRS and neurocognitive toxicity. However, the exact clinically relevant magnitude of this toxicity remains poorly elucidated, and the various strategies available to mitigate cognitive dysfunction are used relatively infrequently in standard practice.

The Alliance study — a large randomized trial that investigated the addition of WBRT to SRS on cognitive dysfunction among patients with a limited number of brain metastases — showed an unacceptably high 3-month rate of cognitive decline in the SRS-alone arm at 63.5% (close to the 65% “unacceptable” rate from WBRT speculated as the trial hypothesis); however, statistically better than the 91.7% rate observed for WBRT plus SRS. A simple explanation for this high rate of cognitive impairment in the SRS cohort could be the high rate of intracranial failures at 3 months (24.7% vs. 6.4%; P < .001), cognitive dysfunction from disease progression, the need for repetitive salvage brain treatments or the effects of SRS itself.

Radiation oncologists are counseled to strongly consider omitting WBRT in combination with SRS among patients with limited metastatic disease, despite the dramatic increase in intracranial progression and the possibility of an OS benefit in appropriately selected patients — eg, those with a favorable graded prognostic assessment score and well-controlled extracranial disease. With improvements in systemic treatments, intracranial control becomes even more crucial and has a greater likelihood of impacting survival.

If one is to abandon WBRT based on the Alliance cognitive test score change results, then the extremely high rates of cognitive decline associated with SRS in that trial must be part of the informed written medical procedure consent form. We posit that advances in radiation delivery through hippocampal-avoidance WBRT and pharmacological interventions will likely result in reconsideration of this blanket exclusion. Further clinical trials are needed — and are underway — to discern the specific subset of patients likely to benefit from WBRT. In the meantime, treatment selection should include a comprehensive, unbiased and transparent discussion of trade-offs.

References:

Brown PD, et al. JAMA. 2016;doi:10.1001/jama.2016.9839.

Mulvenna P, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)30825-X.

Melissa A.L. Vyfhuis, MD, PhD, is chief resident in the department of radiation oncology at University of Maryland Medical Center. She can be reached at mvyfhuis@umm.edu. Andrew B. Lassman, MD, is the John Harris associate professor of neurology and chief of neuro-oncology at Columbia University. He can be reached at abl7@cumc.columbia.edu. Minesh Mehta, MD, is deputy director and chief of radiation oncology at Miami Cancer Institute. He can be reached at mineshm@baptisthealth.net. Disclosures: Vyfhuis reports no relevant financial disclosures. Lassman reports honoraria from AbbVie, Celgene, Cortice, Kadmon, Novocure, prIME Oncology Sapience and WebMD. Mehta reports consultant roles with AbbVie, AstraZeneca, Celgene, Oncoceutics, Tocagen and Varian; and a data and safety monitoring board role with Monteris.

PAGE BREAK

COUNTER

No.

For decades, two forms of external, brain-directed radiation have been used for brain metastases: WBRT — in which the entire brain is treated with radiation over 1 to 3 weeks — and stereotactic radiation, in which only the visualized metastases are targeted, typically over the course of 1 to 5 days.

Ayal A. Aizer, MD, MHS
Ayal A. Aizer

Multiple randomized studies of surgery and/or stereotactic radiation alone vs. with WBRT define the advantages and disadvantages of WBRT. Although all studies showed that WBRT improved intracranial disease control, no studies demonstrated WBRT improved OS. In addition, multiple studies — which used sensitive measures of fatigue, quality of life and neurocognitive function — showed that WBRT had deleterious effects on these outcomes. Even using a cognitive decline definition of a standard deviation drop (a substantial deterioration) on cognitive testing from baseline, approximately 35% to 52% of patients will have cognitive impairment after WBRT.

These studies illustrate the doubtful significance of preventing new metastases in the brain, which is especially true given the vigorous imaging-based surveillance patients receive after brain-directed radiation. Close follow-up imaging allows most distant intracranial recurrences to be salvaged effectively. Also, the substantial competing risk for systemic death mitigates the clinical impact of subtle intracranial recurrence. Moreover, an increasing number of systemic agents can achieve effective intracranial penetration, further decreasing the impact of radiotherapeutic prophylaxis of the uninvolved brain.

PAGE BREAK

Partially due to a lack of clinical trials, WBRT had been indicated for poor-prognosis patients with brain metastases. The QUARTZ trial — which included patients with NSCLC and brain metastases who harbored a guarded prognosis and were not candidates for surgery or stereotactic radiation — showed no survival or quality-of-life advantage with WBRT. Therefore, WBRT provided no benefit compared with best supportive care among patients with NSCLC and asymptomatic brain metastases who have a limited life expectancy.

If upfront stereotactic radiation is selected as management and rapid distant intracranial failure occurs, WBRT can, in most cases, be safely employed as salvage therapy, sparing the majority of patients from its harmful effects. In addition, the use of upfront brain-directed stereotactic radiation permits earlier resumption of systemic therapy given the shorter duration of treatment and recovery time. Because systemic progression is the primary cause of mortality among these patients, avoiding delays in systemic therapy administration is of great importance.

The use of memantine with WBRT and a hippocampal-sparing WBRT technique may minimize neurocognitive toxicity. Administration of memantine is backed by a placebo-controlled randomized trial; however, a significant percentage of patients still experienced neurocognitive decline. In addition, hippocampal-sparing WBRT is supported only by single-arm phase 2 data.

Numerous randomized studies have shown no benefit with the addition of WBRT to local, brain-directed therapy for a limited number of brain metastases. In addition, modern studies have elucidated the significant harm that WBRT can impart on patient quality of life and neurocognitive function. Upfront stereotactic radiation remains the most optimal approach for patients with a limited number of brain metastases.

References:

Aoyama H, et al. JAMA. 2006;doi:10.1001/jama.295.21.2483.

Brown PD, et al. JAMA. 2016;doi:10.1001/jama.2016.9839.

Brown PD, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30441-2.

Brown PD, et al. Neuro Oncol. 2013;doi:10.1093/neuonc/not114.

Cagney DN, et al. Neuro Oncol. 2017;doi:10.1093/neuonc/nox077.

Chang EL, et al. Lancet Oncol. 2009;doi:10.1016/S1470-2045(09)70263-3.

Gondi V, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2014.57.2909.

Iuchi T, et al. Lung Cancer. 2013;doi:10.1016/j.lungcan.2013.08.016.

Kayama T, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.34.15_suppl.2003.

Knisely JP, et al. J Neurosurg. 2012;doi:10.3171/2012.5.JNS111929.

Kocher M, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2010.30.1655.

Lin NU, et al. J Clin Oncol. 2008;doi:10.1200/JCO.2007.12.3588.

Long GV, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.62.9345.

Mulvenna P, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)30825-X.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Version 5.2017. www.nccn.org.

Patchell RA, et al. JAMA. 1998 doi:10.1001/jama.280.17.1485.

Shaw AT, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(15)00488-X.

Soffietti R, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2011.41.0639.

Ayal A. Aizer, MD, MHS, is assistant professor of radiation oncology in the department of radiation oncology at Dana-Farber/Brigham and Women’s Cancer Center and Harvard Medical School. He can be reached at ayal_aizer@dfci.harvard.edu. Paul D. Brown, MD, is professor of radiation oncology in the department of radiation oncology at Mayo Clinic. He can be reached at brown.paul@mayo.edu. Disclosures: Aizer reports research funding from Varian Medical Systems. Brown reports honoraria from Up to Date and Varian Medical Systems.