ESMO Publishes Guidelines for the Management of Solid Tumor Brain Metastases

Emilie Le Rhun, MD

The European Association of Neuro-Oncology and ESMO have released clinical practice guidelines, which provide management recommendations for the diagnosis, treatment, and follow-up of patients with solid tumor brain metastases.

The practice guidelines, which were published in Annals of Oncology and provided by a multidisciplinary group of experts from institutions in Europe, cover clinical and pathological diagnosis, staging and risk assessment, and treatment and follow-up.

“[The] recommendations are based on available scientific data and the authors’ collective expert opinion, wrote lead expert Emilie Le Rhun, MD, of the Departments of Neurology and Neurosurgery, Clinical Neuroscience Center and Brain Tumor Center at the University Hospital Zurich in Zurich, Switzerland and coauthors in the publication.

Regarding diagnosis, pathology, and molecular biopsy, the panel made the following recommendations:

• Screening for brain metastases should be considered for patients with lung cancer with the possible exception of stage I non–small cell lung cancer (NSCLC), and for stage IV melanoma, and potentially also for patients with metastatic HER2-positive and triple-negative breast cancer;
• The presence of brain metastases should be explored by neuroimaging in all patients with cancer who present with clinical symptoms or signs of raised intracranial pressure, seizures, and new neurological deficits;
• The diagnostic work-up of patients with suspected brain metastases should include cranial MRI with pre- and post-contrast T1-weighted, T2-weighted- and/or T2-FLAIR and diffusion-weighted sequences;
• Histopathological and immunohistochemical work-up of brain metastases should follow local institutional algorithms
• In patients undergoing neurosurgical resection, treatment-relevant predictive biomarkers detected in the primary tumor or extra-central nervous system metastasis should be reconfirmed in the brain metastases;
• Cell-free tumor DNA in the blood or cerebrospinal fluid (CSF) analyses should not be routinely requested for the characterization or monitoring of brain metastases
• CSF studies including cytology should be carried out to rule out leptomeningeal metastasis if suspected based on clinical or neuroimaging findings.

Regarding general treatment considerations, the panel made the following recommendations:

Surgery

• Surgery should be considered when there is doubt on the neoplastic nature of a brain lesion, when no primary tumor is known, when more than one tumor is known, when the primary tumor rarely generates brain metastases or when changes in molecular profile compared with the primary tumor may impact clinical decision making;
• Single brain metastases should be considered for surgical resection;
• Multiple resectable brain metastases may be considered for surgical resection
• Surgery may be considered for patients requiring steroids, who are candidates for immune checkpoint inhibition;
• Surgery should be considered when there are acute symptoms of raised intracranial pressure;
• A postoperative MRI should be carried out within 48 hours after surgery to determine the extent of resection.

Radiotherapy

• Stereotactic radiosurgery (SRS) is recommended for patients with a limited number (1-4) of brain metastases;
• SRS may be considered for patients with a higher number of BMs (4-10) with a cumulative tumor volume less than 15 mL;
• SRS to the resection cavity is recommended after complete or incomplete resection of brain metastases;
• Postoperative whole brain radiotherapy (WBRT) after neurosurgical resection or after SRS should be discouraged;
• WBRT should be considered for treatment of multiple brain metastases not amenable to SRS, depending on the presence of neurological symptoms, size, number and location of brain metastases and the choice and availability of CNS-active systemic therapy;
• Supportive care with omission of WBRT should be considered in patients with multiple brain metastases not eligible for SRS and poor performance status;
• Prophylactic cranial irradiation is still recommended for patients with limited and extensive-stage small cell lung cancer (SCLC) with complete response to chemoradiotherapy.

Pharmacotherapy

• Systemic pharmacotherapy based on histological and molecular characteristics of the primary tumor and previous treatment should be considered for most patients with brain metastases;
• If feasible, molecular genetic work-up of brain metastases rather than primary tumor should be considered for selecting targeted therapy and immunotherapy in a tumor-specific manner;
• Systemic treatment of asymptomatic or oligosymptomatic brain metastases should be considered to delay WBRT in HER2-positive breast cancer patients with a preserved general status;
• For HER2-negative breast cancer patients with progressive brain metastases after local treatment, standard chemotherapy, such as capecitabine, eribulin or carboplatin and bevacizumab (Avastin), may be considered;
• Patients with NSCLC without actionable oncogenic driver alterations with asymptomatic or oligosymptomatic brain metastases should be treated by up-front immune checkpoint inhibition alone (PD-L1 ≥50%) or systemic chemotherapy combined with immune checkpoint inhibition (PD-L1 <50%);
• Patients with NSCLC with actionable oncogenic driver alterations, such as EGFR or ALK or ROS1 rearrangement, and asymptomatic or oligosymptomatic brain metastases, should be treated by up-front systemic targeted therapy;
• Patients with SCLC should be treated by platinum-based chemotherapy without or with immune checkpoint inhibition;
• The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) should be the preferred first-line treatment option not only in BRAF wild-type, but also in BRAF-mutated asymptomatic patients;
• Patients with multiple symptomatic BRAF-mutated brain metastases or patients requiring 4 mg of dexamethasone or more eligible for further treatment should receive dabrafenib (Tafinlar) plus trametinib (Mekinist).

Regarding integrated therapeutic approaches, the panel made the following recommendations:

• The multimodality treatment of brain metastases should be based on a careful individualized estimation of the different contributions from surgery, radiation oncology, and medical oncology;
• Therapeutic decisions should be discussed at a dedicated brain metastases board or at a disease-specific tumor board with participation of colleagues experienced in the management of CNS tumors;
• Randomized trials in patients with asymptomatic or oligosymptomatic brain metastases should be conducted to identify the optimal combined modality treatment of systemic therapy, including TKIs or immune checkpoint inhibition, with surgery or SRS.

Regarding monitoring and follow-up, the panel made the following recommendations:

• A detailed neurological examination should be carried out every 2 to 3 months or earlier when radiological progression is suspected and/or neurological symptoms or signs develop;
• Neurocognitive function and ability to consent should be regularly assessed
• Brain MRI should be carried out every 2 to 3 months or at any instance of suspected neurological progression;
• Advanced MR imaging techniques, such as MR spectroscopy and perfusion imaging and amino acid PET, should be considered for distinguishing treatment-related changes from tumor progression.

Finally, regarding supportive care, the panel made the following recommendations:

Steroids should only be considered in symptomatic patients;

Primary anticonvulsant prophylaxis should not be given;

If indicated, low-molecular-weight heparin should be considered as the first-line treatment for primary or secondary thromboprophylaxis and for the therapeutic treatment of venous thromboembolism in brain metastases patients.

Decisions on the competency to drive should take into account epilepsy but also cognitive and other neurological functions and need to adhere to national guidelines and law.

Reference

1. Rhun EL, Guckenberger M, Smits M, et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. Published online August 5, 2021. Accessed August 17, 2021. doi:10.1016/j.annonc.2021.07.016