In the JournalsPerspective

Adjuvant whole-brain radiotherapy ‘should not be recommended’ for certain patients with melanoma brain metastases

Patients who underwent definitive local treatment of one to three melanoma brain metastases did not attain significant clinical benefit from adjuvant whole-brain radiotherapy, according to results of a randomized phase 3 trial published in Journal of Clinical Oncology.

However, the local failure rate appeared significantly lower with whole-brain radiotherapy (WBRT) compared with observation alone.

“For patients who have had definitive local treatment of one to three melanoma brain metastases using either surgery or stereotactic radiosurgery, adjuvant WBRT does not provide any significant clinical benefit and should not be recommended,” Angela M. Hong, MBBS, PhD, researcher at Melanoma Institute Australia and clinical professor of medicine at University of Sydney Central Clinical School, and colleagues wrote.

Brain metastases are common among patients with high-risk melanoma, and those with a small number of metastases can be treated effectively with surgery or stereotactic radiosurgery. However, these patients have a high risk for developing new brain metastases.

The role of adjuvant WBRT in reducing new metastases among these patients has not been established.

For this reason, Hong and colleagues randomly assigned 215 patients (median age, 64 years; 66% men) who underwent local treatment for one to three melanoma brain metastases to adjuvant WBRT (n = 107) or observation (n = 108). The researchers excluded six patients in the WBRT group and one in the observation group who withdrew consent for additional data. One patient died of thromboembolism before collection of baseline data but was included in the OS analysis.

More than 90% of patients had an ECOG performance status of 0 to 1, 67% had extracranial disease at the time of random assignment and 60% had one melanoma brain metastasis.

Distant intracranial failure within 1 year served as the primary endpoint. Time to intracranial failure, survival and time to deterioration in performance status served as secondary endpoints.

Ninety-seven percent of patients in the WBRT group completed treatment, and 95% of them received 30 Gy in 10 fractions. Twenty-four patients underwent hippocampal avoidance WBRT.

Median follow-up was 48.1 months (range, 39.6-68).

Results showed 42% of patients who received WBRT and 50.5% who underwent observation developed distant intracranial failure within 1 year (OR = 0.71; 95% CI, 0.41-1.23). Distant intracranial failure rates increased to 52% in the WBRT group and 57.9% in the observation group for the total follow-up period, which did not represent a significant difference (OR = 0.79; 95% CI, 0.45-1.36). However, researchers observed a significantly lower local failure rate after WBRT compared with observation (20% vs. 33.6%; P = .03).

Patients in the WBRT group had a median time to deterioration in performance status of 3.8 months vs. 4.4 months in the observation group. The researchers observed no significant differences in the rate of neurological death (43.6% vs. 45.8%) or median OS (16.5 months vs. 13 months) between the groups. The 1-year mortality rate was 41.5% in the WBRT group and 51.4% in the observation group.

WBRT appeared associated with higher rates of grade 1 to grade 2 adverse events in the first 2 to 4 months after treatment, including fatigue, anorexia, nausea, dermatitis and alopecia.

The study’s recruitment period of 8.5 years coincided with the revolution in systemic therapy for metastatic melanoma, which served as its primary limitation.

“The role of radiation therapy for melanoma brain metastases in combination with other treatments has become more complex with recent advances in stereotactic radiosurgery technology and intracranially effective systemic therapies,” Hong and colleagues wrote. “There are ongoing randomized trials defining the role of combining radiation therapy with BRAF-directed targeted therapy or immune checkpoint inhibitors in melanoma brain metastases. Multidisciplinary team input that considers all available treatment modalities has become essential in determining the most appropriate management of patients with melanoma brain metastases.” – by Jennifer Southall

Disclosures: The study was funded by grants from Cancer Australia and Cancer Research UK. Hong reports a consultant/advisory role with Amgen. Please see the study for all authors’ relevant financial disclosures.

Patients who underwent definitive local treatment of one to three melanoma brain metastases did not attain significant clinical benefit from adjuvant whole-brain radiotherapy, according to results of a randomized phase 3 trial published in Journal of Clinical Oncology.

However, the local failure rate appeared significantly lower with whole-brain radiotherapy (WBRT) compared with observation alone.

“For patients who have had definitive local treatment of one to three melanoma brain metastases using either surgery or stereotactic radiosurgery, adjuvant WBRT does not provide any significant clinical benefit and should not be recommended,” Angela M. Hong, MBBS, PhD, researcher at Melanoma Institute Australia and clinical professor of medicine at University of Sydney Central Clinical School, and colleagues wrote.

Brain metastases are common among patients with high-risk melanoma, and those with a small number of metastases can be treated effectively with surgery or stereotactic radiosurgery. However, these patients have a high risk for developing new brain metastases.

The role of adjuvant WBRT in reducing new metastases among these patients has not been established.

For this reason, Hong and colleagues randomly assigned 215 patients (median age, 64 years; 66% men) who underwent local treatment for one to three melanoma brain metastases to adjuvant WBRT (n = 107) or observation (n = 108). The researchers excluded six patients in the WBRT group and one in the observation group who withdrew consent for additional data. One patient died of thromboembolism before collection of baseline data but was included in the OS analysis.

More than 90% of patients had an ECOG performance status of 0 to 1, 67% had extracranial disease at the time of random assignment and 60% had one melanoma brain metastasis.

Distant intracranial failure within 1 year served as the primary endpoint. Time to intracranial failure, survival and time to deterioration in performance status served as secondary endpoints.

Ninety-seven percent of patients in the WBRT group completed treatment, and 95% of them received 30 Gy in 10 fractions. Twenty-four patients underwent hippocampal avoidance WBRT.

Median follow-up was 48.1 months (range, 39.6-68).

Results showed 42% of patients who received WBRT and 50.5% who underwent observation developed distant intracranial failure within 1 year (OR = 0.71; 95% CI, 0.41-1.23). Distant intracranial failure rates increased to 52% in the WBRT group and 57.9% in the observation group for the total follow-up period, which did not represent a significant difference (OR = 0.79; 95% CI, 0.45-1.36). However, researchers observed a significantly lower local failure rate after WBRT compared with observation (20% vs. 33.6%; P = .03).

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Patients in the WBRT group had a median time to deterioration in performance status of 3.8 months vs. 4.4 months in the observation group. The researchers observed no significant differences in the rate of neurological death (43.6% vs. 45.8%) or median OS (16.5 months vs. 13 months) between the groups. The 1-year mortality rate was 41.5% in the WBRT group and 51.4% in the observation group.

WBRT appeared associated with higher rates of grade 1 to grade 2 adverse events in the first 2 to 4 months after treatment, including fatigue, anorexia, nausea, dermatitis and alopecia.

The study’s recruitment period of 8.5 years coincided with the revolution in systemic therapy for metastatic melanoma, which served as its primary limitation.

“The role of radiation therapy for melanoma brain metastases in combination with other treatments has become more complex with recent advances in stereotactic radiosurgery technology and intracranially effective systemic therapies,” Hong and colleagues wrote. “There are ongoing randomized trials defining the role of combining radiation therapy with BRAF-directed targeted therapy or immune checkpoint inhibitors in melanoma brain metastases. Multidisciplinary team input that considers all available treatment modalities has become essential in determining the most appropriate management of patients with melanoma brain metastases.” – by Jennifer Southall

Disclosures: The study was funded by grants from Cancer Australia and Cancer Research UK. Hong reports a consultant/advisory role with Amgen. Please see the study for all authors’ relevant financial disclosures.

    Perspective
    John Suh

    John Suh

    Although the use of adjuvant WBRT has been shown to improve intracranial control after surgery or stereotactic radiosurgery, routine use of WBRT for melanoma brain metastases has been challenged given its lack of survival benefit, known neurocognitive effects and ‘radioresistance’ to conventional radiation therapy. Additionally, the importance of tumor type on overall prognosis has been demonstrated via the diagnosis-specific graded prognostic assessment, also known as DS-GPA.

    In this multicenter, phase 3 trial from the Australia and New Zealand Melanoma Trials Group, researchers observed no significant difference in the distant intracranial failure rate within 12 months, OS, deterioration in performance status and neurologic death with the addition of WBRT. Local failure however, was significantly lower with WBRT.

    The results of this study confirm that routine use of WBRT for one to three melanoma brain metastases after definitive local therapy should be avoided. Because local failure improved with WBRT, patients who undergo local therapy for one to three brain metastases should be considered for some type of adjuvant therapy, such as targeted therapy or immunotherapy and stereotactic radiosurgery if the patient undergoes surgery. Given the emergence of BRAF-directed therapies and immune checkpoint inhibitors during the course of this study, the impact of these therapies on the results is not known.

    A plethora of treatment options for patients with brain metastases from melanoma exist; therefore, a multidisciplinary approach is strongly recommended to help optimize outcomes. Enrollment on clinical trials is paramount to better understand and treat this common manifestation of metastatic melanoma.

    References:

    Andrews DW, et al. Lancet. 2004;363:1665-1672.

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

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

    Patchell RA, et al. JAMA. 1998;280:1485-1489.

    Sperduto PW, et al. Int J Radiat Oncol Biol Phys. 2010;doi:10.1016/j.ijrobp.2009.08.025.

    • John Suh, MD
    • HemOnc Today Editorial Board Member
      Cleveland Clinic

    Disclosures: Suh reports no relevant financial disclosures.