Metastatic melanoma: prognostic factors and survival in patients with brain metastases

Malignant melanoma is the fifth most common cancer in the UK. Although the majority of patients present with early stage, operable disease, up to 20% have metastases at presentation [1]. Brain metastases occur in approximately 44% patients with metastatic melanoma, with a median overall survival (OS) of just 4 months [2]. Traditionally, brain metastases from melanoma have been deemed incurable by systemic therapy. Poor response rates to chemotherapy are most likely due to low drug concentrations accessing malignant cells owing to the protective nature of the blood–brain barrier [1]. There is evidence for the efficacy of novel systemic agents, both targeted BRAF inhibition and immunotherapy, in brain metastases from melanoma [1, 3‐5]. Local treatment options include neurosurgery and radiotherapy. The latter is available for administration in two different forms; stereotactic radiosurgery (SRS) for patients with low-volume, low count brain metastases [6], or whole brain radiotherapy (WBRT) for patients with more widely disseminated intracranial disease. The evidence base for the efficacy of WBRT in the treatment of melanoma brain metastases is inconclusive. Many studies have shown no improvement in OS [7‐9]. It has been hypothesised that this may be due to the resistant nature of melanoma cells to non-SRS radiation, having some ability to repair themselves following radiation insult [9, 10]. Other analyses suggest that WBRT may provide some benefit to intracranial control, particularly when used in combination with SRS and when there is stable extracranial disease [11]. In the absence of definitive guidance, clinicians can utilise a variety of prognostic tools to inform treatment decisions. The melanoma-specific Graded Prognostic Assessment (msGPA) [12] is one such tool that allocates patients into four categories according to number of brain metastases and their Karnofsky performance status (KPS). Patients with a higher msGPA score have a better OS [12]. The relevance of this tool to the modern day patient population, with its access to novel systemic therapies, has not been validated. One criticism of the msGPA is that it does not take into account patient age, presence of extracranial disease, leptomeningeal disease, aggregate brain tumour volume or BRAF status, all of which may be potential important prognostic indicators [2, 4, 13‐15].

We aim to assess the validity of the msGPA in the modern day patient population. Important prognostic factors that influence the survival of patients with brain metastases from melanoma will be identified. The efficacy of SRS combined with other systemic therapies versus WBRT will be assessed.

Patients undergoing treatment for brain metastases in metastatic melanoma at the Rosemere Cancer Centre, within the Lancashire and South Cumbria Cancer Network (LSCCN), seen in the medical oncology clinic between 2011 and 2016 were identified (n = 57). The hospital database system was used to obtain clinic letters, scan results, BRAF testing outcomes and treatment regimes. The information was collated using Microsoft Excel (2010) software. When exact dates were unavailable, the 15th of the month was used. BRAF-mutant positive patients (n = 4) who presented prior to the availability of BRAF inhibitors were excluded to enable the efficacy of novel targeted therapies to be assessed.

Treatment of intracranial and extracranial disease was determined by BRAF status, symptoms including performance status, previous treatment, number of brain metastases, patients’ preferences and availability and funding of drugs as determined in the UK by the National Institute for Health and Care Excellence and the UK National Cancer Drugs Fund. In 2011 single agent BRAF inhibition was available in the UK as first line treatment, and subsequently in combination with MEK inhibition in July 2016. Second line ipilimumab was available in 2011 and first line in 2014. PD1 antibodies were available from the end of 2015 in both untreated and previously treated patients. Combination immunotherapy was not available during the time period of this audit nor were any clinical trials available for patients with brain metastases. Patients’ history and radiology were discussed at both a specialist skin and brain multidisciplinary team meeting to determine suitability for neurosurgery and radiotherapy including stereotactic treatment. Generally, patients with multiple brain metastases from BRAF positive melanoma would be offered BRAF inhibition (±MEK inhibition) as first line, followed by either systemic immunotherapy or whole brain radiotherapy second line. Patients with BRAF negative melanoma would be assessed for surgery and/or stereotactic radiotherapy as first line treatment and then offered systemic immunotherapy if available and not received previously. Patients ineligible for surgery or stereotactic radiotherapy and those patients who had exhausted previous systemic treatment options were assessed for whole brain radiotherapy.

StatsDirect [16] software was used to perform survival analysis according to BRAF status, msGPA score and radiotherapy modality. Kaplan-Meier (KM) curves [17] were generated and tested for statistical significance using peto’s log rank [18] technique. Where confidence intervals (CI) are quoted, Andersens 95% CI are used. Survival is quoted in months, standardised to a 30 day period to allow comparison.

Univariate and multivariate analysis were performed using Cox regression [19]. Prognostic factors tested included age, sex, BRAF status, KPS, msGPA, presence of extra cranial disease and presence of neurological symptoms. Factors that showed statistical significance (p < 0.05) on univariate testing were run in multivariate analysis in various combinations to determine if these associations maintained statistical significance when other factors were taken into account.