Supporting information for practice points: surgery

Treatment of brain metastases should be determined in the context of a patient’s systemic disease status; the views of medical and radiation oncology should be sought. Note that surgery may be urgent if the patient has a reduced conscious state or there is midline shift or extensive mass effect.

Potential benefits and risks of surgical resection

Surgical resection provides its main benefits through direct removal of the targeted lesion. Resection may help to maintain quality of life, prevent death directly from the metastasis and prolong survival.¹² Potential benefits of surgery include:

• Relief of symptoms, including focal neurological deficit, seizures, and headache from raised intracranial pressure.
• Reduced steroid requirements.
• Histological diagnosis and verification of receptor status of metastases.
• Local control if extra-cranial disease is controlled.
• In cerebellar and periventricular metastases, to prevent risk of hydrocephalus.
• In posterior fossa metastases, to prevent brainstem compression from tumour growth or swelling post irradiation.

The potential benefits of surgical resection must be balanced with the risks of post-operative morbidity and mortality.

Surgical resection of brain metastases is associated with a range of risks and side-effects. Focal neurological deficit is a potential complication of surgery. The tumour may recur after surgery at local site or elsewhere in the brain.

General complications include haemorrhage, infection and seizures.

Anti-convulsant medication

A systematic review by Mikkelson et al (2010) assessed if prophylactic anti-convulsants decrease the risk of seizures in patients with metastatic brain tumours compared with no treatment.¹⁸ Only a single, underpowered randomised controlled trial (RCT) of melanoma patients with brain metastases was identified. The study did not detect a difference in seizure occurrence. The review concluded that there is a lack of clear and robust benefit from the routine prophylactic use of anti-convulsants.¹⁸

The Quality Standards Subcommittee of the American Academy of Neurology published a practice parameter on the use of prophylactic anti-convulsants in patients with primary and metastatic brain tumours (2000).¹⁹ The recommendations in the practice parameter were based on a systematic review and meta-analysis. The practice parameter concluded that in 12 studies (four RCTs and eight cohort studies) examining the use of prophylactic anti-convulsants to prevent first seizures in patients with brain metastases, none have demonstrated efficacy. A meta-analysis of the four RCTs reported no evidence of an effect on the frequency of first seizure in patients receiving anti-convulsant prophylaxis.

Specimen review

The choice of systemic therapy is usually based on the tissue characteristics of the primary tumour. A number of studies have shown that the immunophenotype of the distant breast cancer metastases may be different from that of the primary tumour.  The most frequent finding was that compared to primary tumours, oestrogen and progesterone receptors are more frequently negative in distant metastases, whereas HER2 (human epidermal growth factor receptor 2) is more often positive.¹²⁰

A pooled analysis of individual patient data from two large prospective trials undertaken included 289 patients with breast cancer primary tumour. The most frequent distant sites of metastases included in the studies were skin/soft tissue, bone or bone marrow and liver. Discordance in oestrogen, progesterone and HER2-receptors between the confirmed primary and recurrent breast cancer was 12.6%, 31.2% and 5.5% (all p<0.001).¹²¹

A retrospective analysis of 233 breast cancer patients reported receptor conversion rates for oestrogen (10.3%), progesterone (30%) and HER2 (5.2%) receptors. Of the 44 women with brain metastases, receptor conversion was noted at rates of 13.7% for oestrogen, 36.3% for progesterone and 2.3% for HER2. By comparison to other metastatic sites, receptor conversion was more frequent in brain, liver and gastro-intestinal metastases.¹²⁰

Steroid use

Steroids frequently cause a resolution or improvement of symptoms but side effects can be problematic and without further treatment neurological symptoms will recur.¹²² Steroids may be useful to manage symptoms and reduce cerebral oedema, particularly in the perioperative period.

A systematic review by Ryken et al 2010 addressed whether steroids improve neurologic symptoms in patients with metastatic brain tumours.¹²³ Of the two included studies, one provided evidence that the administration of steroids provides relief of symptoms in patients with symptomatic brain metastatic disease; however, recognising that there is no control group only the lowest grade of recommendation was made.¹²³

A randomised double-blind study, performed in two phases, was undertaken to compare dexamethasone doses of 4mg, 8mg and 16mg per day for the treatment of brain tumour oedema.²⁰ The first series compared 8mg dexamethasone per day to 16mg per day. The second series, compared 4mg day versus 16mg day. The study found that the administration of 4mg dexamethasone per day results in the same degree of improvement as administration of 16mg per day after one week of treatment in patients with no sign of impending herniation. Toxic effects were found to be dose-dependent and during a four-week period occurred more frequently in patients using 16mg per day.²⁰

A Cochrane review by Tsao et al (2012) assessed the effectiveness of steroids alone versus WBRT and steroids.⁴⁵ The review identified one RCT examining the use of WBRT and prednisone vs. prednisone alone and produced inconclusive results.⁴⁵

Driving

A person’s driving ability can be impaired by brain tumours, seizures and the associated treatment and medications used such as anti-convulsants. These impairments include affected vision, mobility, coordination, perception and judgement.¹²⁴

The national medical standards for licensing published by the national transport commission, Assessing fitness to drive: for commercial and private vehicle drivers, (Austroads 2012), have established criteria to assess a patient’s fitness to drive, which are based on the clinical management guidelines.²¹

The standards outline roles and responsibilities for patients, health professionals and the licensing authorities. Patients have a responsibility to report to their local licensing authority any long-term injury or illness that may affect their ability to drive; to respond honestly to questions about their health and its likely impact on their driving ability; and to comply with the requirements of a conditional license. Health professionals should assess a patient’s suitability to hold a license; provide information to patients on fitness to drive, the impact of their medical condition, and the patient’s responsibility to self-report new or recurring symptoms. Responsibility for all decisions regarding the licensing of drivers sits with the licensing authority.²¹

Patients may feel hostile towards the health professional when there is possibility of restrictions to their driving license, as it offers an important means of independence. In such circumstances, or situations where a health professional feels they cannot act objectively in assessing a patient’s fitness to drive, a health professional may choose to refer a patient to another practitioner or directly to the local licensing authority.

Health professionals may refer patients to social work services to discuss local transport support services available.

For more information on driving after brain injuries, or for access to current driving guidelines refer to: here.

Confidentiality, privacy and reporting

The duty to protect confidentiality applies to driver licensing authorities, however with respect to assessing and reporting fitness to drive, the duty to maintain confidentiality is legally qualified in certain circumstances in order to protect public safety. The health professional should consider reporting directly to the licensing authority in situations where the patient is either:

• Unable to appreciate the impact of their condition;
• Unable to take notice of the health professional’s recommendations due to cognitive impairment; or
• Continues to drive despite appropriate advice and is likely to endanger the public.²¹

Cerebellar/periventricular/posterior fossa metastases

Metastases to the cerebellum are generally not tolerated well, and carry a poorer prognosis compared to supratentorial metastases.  Lesions in the posterior fossa can lead to hydrocephalus, herniation, brainstem compression, and death.¹²⁵ Metastatic disease within the periventricular brain tissue may obstruct the flow of cerebrospinal fluid produced in the ventricles to the subarachnoid space and may lead to an obstructive or non-communication hydrocephalus.¹²⁶ Surgical management of patients with these metastases may be required.

Graded Prognostic Assessment (GPA)

The Breast-GPA is a prognostic index for breast cancer patients with brain metastases. The GPA was developed following the Radiation Therapy Oncology Group’s (RTOG) Recursive Partitioning Analysis as an updated index for patients with brain metastases.  The GPA was developed following the Radiation Therapy Oncology Group’s (RTOG) Recursive Partitioning Analysis as an updated index for patients with brain metastases.^23,24

The Breast-GPA was developed through retrospective analysis of 400 breast cancer patients treated for newly diagnosed brain metastases between 1993 and 2010, for prognostic factors for survival. Survival time was measured from the time of first treatment for brain metastases to the date of death or last follow-up. Prognostic factors were analysed by multivariate Cox regression and recursive partitioning analysis (RPA).^23,24

The median overall survival for all patients was 13.8 months. At the time of data collection, 95 (24%) of the 400 patients were alive, with a median follow-up time of 17.1 months. Seventy-seven per cent of HER2-positive patients received trastuzumab, and 82% of ER/PR-positive patients received hormonal therapies. Eighty-three per cent of patients (n=332) were treated with radiotherapy (WBRT alone, SRS alone or WBRT plus SRS); 16.8% of patients (n=67) were treated with surgery plus radiotherapy (WBRT and/or SRS). One patient underwent observation. Data for chemotherapy treatment was not available.²⁴

Multivariate Cox regression analysis identified the significant prognostic factors as KPS (p<0.0001), ER/PR status (p=0.0002), HER2 status (p<0.0001), and the interaction of ER/PR and HER2 (p=0.027).²⁴ Relative to patients with triple-negative breast cancer, the risk of death was 0.50 for Luminal A subtype; 0.38 for the HER2-positive subtype; and 0.35 for the Luminal B subtype. The prognostic factors identified as significant in the RPA analysis were consistent with the multivariate Cox regression analysis, with the addition of age for patients with KPS 60-80.²⁴ The number of brain metastases and whether extra-cranial metastases were present or absent were not significant prognostic factors.²⁴

Table 4 shows the Breast-GPA index for women with breast cancer and brain metastases. The sum of the relevant values for each prognostic factor is the GPA for the individual patient. A score of 4.0 correlates with the best prognosis and 0.0 the poorest.^23,24

Table 4: GPA index for women with breast cancer and brain metastases^23,24

Abbreviations: KPS – Karnofsky Performance Status; Basal – triple negative disease; HER2 – HER2-positive and ER/PR-negative; Luminal A – ER/PR-positive and HER2-negative; Luminal B – triple positive disease

The median survival times by GPA score were also estimated in the analysis. For GPA 0.0-1.0 median survival was 3.4 months (2.4-4.9). GPA score 1.5-2.0 had median survival of 7.7 months (4.8-9.7). Median survival for GPA score 2.5-3.0 was 15.1 months (10.8-17.9). GPA score 3.5-4.0 had median survival of 25.3 months (20.4-30.4).^23,24

Treatment is not a factor in the Breast-GPA, as it is intended to be useful in making treatment choices rather than evaluating outcomes after treatment. It was noted that when treatment was added to the final multivariate Cox regression analysis, no significant change to the direction or magnitude of the estimated hazard ratio was found.^23,24