Multi-disciplinary management for patients with oligometastases to the brain: results of a 5 year cohort study

Brain metastases occur in approximately 20-30% of all cancer patients and have an incidence at least four times higher than primary brain tumours[1]. The common primary sites that metastasise to the brain are lung (45-50%), breast (10-30%), melanoma (5-20%), renal cell (7%) and gastrointestinal tumours (6%). Presentation in the context of an unknown primary also makes up a small proportion of cases (5%)[1‐3]. Recent epidemiological data have suggested a very significant increase in brain metastases in patients with common tumour types, primarily related to improved systemic treatment[4].

Historically, brain metastases were considered to be associated with a uniformly poor prognosis and whole brain radiotherapy was the mainstay of treatment. This view has changed gradually in the last two decades with increasing interest in the use of surgery and radiosurgery (RS). Randomised trial evidence now supports the use of surgery and RS in addition to WBRT to improve survival in patients with a single metastasis[5‐7]. An increased focus on local treatment for oligometastatic disease is increasingly relevant due to improved systemic therapies in several common cancers, leading to better control of extra-cranial disease and earlier diagnosis of brain metastases due to more widespread use of MRI. In addition, development in radiotherapy technology has made RS more widely available thereby providing a local treatment option for some patients in whom surgery would not be deemed appropriate. An increasing proportion of patients with brain metastases may therefore be candidates for more aggressive local management aimed at optimising local control in brain.

Patient selection for treatment of brain metastases has been addressed by several different approaches to stratification according to prognostic factors[8‐10]. The RTOG Prognostic Assessment (RPA) classification is the most widely used and validated. Class 1 and 2 patients are usually considered appropriate for aggressive treatment[11]. Recent publications have suggested additional subdivision based on more detailed information on the status of non-brain metastatic sites and/or tumour biology, which may refine this approach and improve selection further[10, 12, 13].

Recent randomised studies have added important data on the role of surgery and RS with or without whole brain radiotherapy in good prognosis patients with oligometastases. Data from EORTC 22952–26001 suggest equivalent survival following either modality (10.7 and 10.9 months) and local control rates of 69% and 41% at the treated lesion using RS or surgery respectively[14]. Although local and distant recurrences in the brain were reduced with the addition of WBRT, this did not impact on survival. The authors suggest that with MRI-based follow up, salvage treatment is effective in preventing neurologic progression as a cause of death. Design of this study reflects that fact that many clinicians are moving away from routine use of adjuvant WBRT because of a concern about induction of neurocognitive deficit. Neurocognitive decline in a specific verbal memory domain at 4 months after brain metastases treatment was significantly associated with WBRT in a randomised study[15]. However, very few studies have addressed this issue and several data sets support the view that uncontrolled metastatic disease is a more significant contributor to cognitive problems and poor quality of life[16, 17].

In the UK and other countries where there has been increasing site specialisation among oncologists based on primary disease site, there are specific issues in managing patients with brain metastases since they present to their site specialist team, often without links to a neuro-oncology unit. Whilst management outside a neuro-oncology setting may be appropriate for poor prognosis patients, for others lack of access to a comprehensive neuro-oncology opinion may impact on management and outcomes. Lack of specialist management may also limit information that is gathered at follow up and reduce access to new treatment approaches within clinical studies.

Multidisciplinary team working is well established in the management of cancer and joint surgical/ oncology consultations may have a role, particularly where there are several different treatment strategies that have to be balanced against the individual’s circumstances. In view of the changing demographics of metastatic brain disease we established a multi-disciplinary brain metastases clinic in February 2007 specifically for patients with good prognostic features with the hypothesis that improving the process of care could improve clinical management and outcomes in such patients.

Changes in the approach to managing systemic disease in common tumour types associated with brain metastases and the evolving treatment options led us to set up a specific multi-disciplinary clinic to manage good prognosis brain metastases cases with the view that improving the process of care could improve outcomes in this group.

The clinic has proven feasible to run with the same oncologist, neurosurgeon and nurse specialist providing continuity of care. The vast majority of patients seen have met the referral criteria and aggressive local therapy to their brain metastases has been appropriate. Only a small number of patients in RPA class 3 attended the clinic either because they had deteriorated in the time since the referral was made or they had requested a second opinion regarding their management. Patient numbers increased significantly over the last two years which is likely to reflect the time taken to build relationships between site specific teams and the increasing acceptance of locally aggressive management of brain metastases in selected patients within the oncology community. Currently there are approximately 10 patients per clinic and as our referral rate continues to increase we plan to increase to weekly clinics. In view of this continuing increase in referrals it seems likely that not all potentially eligible patients are presently being considered for localised therapy. A regional audit of brain metastases patients would be required to evaluate what fraction of potentially appropriate referrals are seen.

Brain metastases were the first presentation of cancer in 25% and standard site-specific cancer referral pathways do not generally include such patients, particularly where diagnostic uncertainty exists regarding the primary. We have found that managing such patients through the brain metastases clinic has streamlined the organisation of staging investigations and onward referral to the appropriate local site-specific oncologist. Furthermore, we have found that most patients with a new cancer diagnosis find it helpful to receive some general information regarding their cancer and possible further treatment options which is more feasible within our clinic compared to a standard neurosurgical clinic. Support for the patient and their family from the brain metastases specialist nurse in the period prior to seeing the systemic oncologist has proved useful. Concerns regarding the potential of a “metastases-specific” clinic to compromise the decision-making autonomy of systemic oncologists could be seen as a barrier to the development of such services but we are clear to all patients that the systemic oncologist maintains overall responsibility for their care and we have not experienced any conflicts. We have also found that patients are happy to attend both their systemic oncology and brain metastases follow-up clinics. As patients are of good performance status, the extra clinic visit above standard care does not appear to be a particular burden and over 90% attended regular follow-up with us whilst they remained fit enough for further treatment. Good communication between specialists is obviously paramount when disease progression occurs and to ensure that imaging is not duplicated. This was achieved by letter and phone call/ email if appropriate.

This is a deliberately highly selected group, but nevertheless our outcomes are encouraging and represent a fairly typical cancer centre, treating patients referred from routine oncology practice. The 18 month median overall survival of our patients (RPA class 1 or 2) is considerably better than the 7 and 4 months reported in 2000 by Gaspar et al. (RPA class 1 and 2)[11]. These patients had been treated in RTOG 91–04 and patient profiles were similar to ours but localised treatment was not given. This serves to emphasise the importance of localised therapy for brain metastases in appropriate patients and the considerable improvements in the treatment of systemic disease in the last decade. In some common tumour sites effective systemic agents do not reach sites of CNS disease and patients are at risk of neurologic death despite controlled disease elsewhere[19] which underlines the growing need to address CNS disease separately. Without streamlined multidisciplinary management pathways for patients with brain metastases the potential survival benefits of further improvements in systemic therapies may not be realised; with further improvements in survival from systemic metastases more patients are likely to live to develop brain metastases.

There are no trials offering a direct comparison between surgery and RS for oligometastases although available data suggest that local control rates are similar[5, 20, 21]. A joint surgical/ oncology clinic can reduce clinician bias in treatment decisions in other cancer types[22, 23] and we feel that the combined surgical and oncology aspect of our clinic has been beneficial in tailoring treatment to the complex needs of patients with brain metastases. It should be noted in our group that patients treated with primary surgery included patients presenting in emergency settings who may be expected to do less well, whereas those treated with RS were stable pre-treatment.

In the UK, the National Institute for Clinical Excellence (NICE) guidance recommends that referral to neuro-oncology is made for patients in whom brain metastasis is the first presentation of disease or those with a single metastasis and that RS should be available to patients with 1–2 metastases as an alternative to surgery. Until recently RS has been available in only a limited number of centres and there is concern that a substantial proportion of patients have not had ready access to RS. The recent expansion in the number of centres with RS technology should reduce access issues but this underlines the need to identify these patients appropriately[24]. At the same time the availability of RS technologies is encouraging treatment of patients with larger numbers of brain metastases which may define additional sub-groups of patients for whom this is effective treatment, but this is reliant on comprehensive follow-up of patient outcomes[25, 26].

The debate continues regarding whether WBRT should be routinely offered following localised therapy for oligometastases to the brain[27]. Data from the EORTC 22952–26001 study have shown that whilst “adjuvant” WBRT was associated with a lower rate of intracranial progression and neurological death, overall survival and functional independence were not improved and that WBRT may negatively impact upon some aspects of quality of life[14, 28]. Our policy was to withhold WBRT immediately after localised treatment unless there was evidence of residual disease. 44% of deaths in our study were from neurological causes with the majority of other deaths due to progressive malignancy elsewhere or thromboembolic events, which is consistent with outcomes in the control arm of the EORTC study[14]. 45% of our patients did not require WBRT in their treatment course. Structured MRI follow-up is however essential to identify disease progression in the brain when treatment options were available. The American College of Radiology recommends 3 monthly MRI in the first instance extending to every 4–6 months[29]. Each centre providing a brain metastases service should develop a general policy with regard to WBRT and follow-up.

Although our outcome results are promising, clearly our patient group was highly selected and there are limitations to our analysis. Significant bias prevents and non-randomisation prevents efficacy comparisons between treatments which was not the purpose this report. Due to small numbers, we were unable to calculate survival of less common primary tumours. Quality of life and neuropsychology data was not available, specifically level of functional independence influenced by neurological symptoms. We did not observe significant treatment related toxicity from radiation-based treatments but data on early toxicity following surgery were not available.

Future advantages of treating patients in a specific clinic setting include long-term collection of functional outcome and treatment toxicity. We have now developed a formal database to prospectively collect data and all patients will be offered neuropsychology assessment. The clinic also offers a pathway to support the evaluation of MRI screening in patients at high risk of brain metastases and we will shortly begin evaluating such a policy in high risk patients with metastatic breast cancer (HER-2 positive, hormone negative in the first instance). A dedicated brain metastases clinic should also facilitate trial participation in good prognosis patients and provide a reliable means of documenting long-term outcomes. Emerging research topics in radiation therapy are whether it is the number or volume of metastases that should be used to define patients who likely to benefit from RS, the use of RS to the tumour bed following surgery and the merits of reducing radiotherapy to radiosensitive regions relevant to changes in memory domains, such as the hippocampus[30‐32]. Historically patients with brain metastases have been excluded from studies of novel systemic agents, but the advent of small molecule targeted agents that penetrate CNS and the emergence of a good prognosis sub-group of brain metastases patients should change this. Within this group of patients there are very important questions to be addressed including whether novel agents can be selected based on primary tumour molecular genetics and whether the agents that target neo-angiogenesis will be effective in brain metastases.

The epidemiology of brain metastases is changing. Effective systemic treatments are prolonging survival in common cancers producing a population of “good prognosis” patients with brain metastases who benefit from multi-disciplinary management and rapid access to effective local treatment modalities. We found that a dedicated joint clinic for such patients staffed by a specific interested neurosurgeon, neuro-oncologist and specialist nurse is feasible and effective. We did not experience significant issues with communication/ decision making between systemic oncology and neuro-oncology teams, probably a result of the fact that multidisciplinary teamwork is now standard for many aspects of cancer care. In our experience there is a sufficient need and promising survival data to support a dedicated clinic and continuing patient follow-up in this setting also offers the opportunity to better define management strategies and further research for this patient group. We would encourage other neurosurgical/ oncology centres to develop similar models of care.