Patient centred approach to themanagement of cerebral

metastasesRAD Magazine, 38, 445, 21-22

by Michael D JenkinsonConsultant neurosurgeon,

The Walton Centre for Neurology andNeurosurgery, Liverpool

Dr Brian HaylockConsultant clinical oncologist,

Clatterbridge Centre for Oncology, Wirral

michael.jenkinson@thewaltoncentre.nhs.uk

IntroductionBrain metastases cause significant mortality andmorbidity, including cognitive impairment, andaffect 10-40% of all cancer patients.1,2 They arethe commonest intracranial tumour, accountingfor an estimated 27,000 cases a year in the UK.Improved neuro-imaging facilities, an ageing pop-ulation and better systemic treatment for the pri-mary disease3 are all contributory factors to therising incidence.

Historically there was a fairly nihilisticapproach to patients with cerebral metastasis,which reflected the lack of effective systemictreatments in the past for the most frequent pri-mary disease lung cancer, ie the pre-platinoidera. These patients were often managed withsymptom control only and inevitably died fromneurological progression. Modern treatmentstrategies with modern chemotherapeutic regimesand targeted radiotherapy are therefore aimed atmore aggressive palliation to produce a betterquality survival and minimise the physical andcognitive morbidity, if not necessarily leading to asignificant increase in overall survival. A multi-disciplinary team (MDT) approach with contri-bution from neurosurgeons, clinical/radiationoncologists, palliative care physicians, specialistnurses and neuro-radiologists determines theindividual treatment plan for each patient, util-ising surgery, stereotactic radiosurgery (SRS) andwhole brain radiotherapy (WBRT) in the man-agement of brain metastases.Prognosis of cerebral metastasisLung and breast cancer account for approximately two-thirds4 of brain metastases patients. Renal cell carcinomaand malignant melanoma also frequently metastasise to thebrain, while gastric and prostate cancer are rarely associatedwith central nervous system (CNS) spread.5 Approximately20% of brain metastases can be described as precocious(found before the primary tumour) or synchronous (foundwithin two months of the primary tumour); the remaining80% are metachronous, arising in patients with a knownprimary tumour. Improved systemic control in certain can-cers, eg HER-2 positive breast cancer, and other biologicalagents, have changed the natural history of the diseaseresulting in increased CNS progression6,7 and this has re-

focused efforts on developing and delivering more effectivetreatment for brain metastasis. Nevertheless, the prognosisfor brain metastases remains poor; the majority of patientswho develop cerebral metastases will also have systemicprogression and are not suitable for active oncological treat-ment and the median survival is one to two months.

In routine clinical practice the median overall survival oftreated brain metastases is approximately six months,whereas in clinical trials (that are inevitably subject topatient selection bias) the median overall survival is oftenreported as seven to 10 months.8

Current treatment strategiesTreatment strategies aim to improve locoregional control ofcerebral metastasis and utilise surgery, radiosurgery andwhole brain radiotherapy in various combinations. Many ofthe clinical trials had small patient numbers and oftenreported no significant difference in overall survival whencomparing surgery, SRS and WBRT in various combinations(see Jenkinson et al for a summary table).9 The lack of supe-riority of one treatment combination over another may be areflection of the systemic cancer, and the lack of disease-specific randomised clinical trials. Moreover, in routine clin-ical practice they are often used sequentially and incombination to achieve intracranial disease control(figure 1).

B

Surv

ival

with

PS

2(%

)

60 12 18 24 30 36 42 48 54 60

100

80

60

40

20

60 12 18 24 30 36 42 48 54 60

100

80

60

40

20

Time (months)RandomisedtreatmentObservationWBRT

Over

all s

urvi

val (

%)

Time (months)

0 N No. of patients at risk

RandomisedtreatmentObservationWBRT

149 179 112 71 41 29 19 14 11 8 5 1 152 180 118 73 52 34 25 17 13 10 9 7

143 179 117 75 44 31 22 15 12 9 7 3 149 180 124 80 61 38 25 18 15 11 9 7

0 N No. of patients at risk

ObservationWBRT

ObservationWBRT

A

FIGURE 1Kaplan-Meier overall survival curves. (A) WHO per-formance score ≤2 and (B) overall survival afterobservation or WBRT (from Kocher et al13).

The benefits of locoregional control as a means to poten-tially prolong survival must be balanced against patientquality of life and neurological function. Local control can beachieved through microsurgery or SRS (table 1). Surgerycan be used for lesions of any size, while SRS is typicallyrestricted to tumours ≤3cm diameter, with no significantmass effect and no associated hydrocephalus. Surgery hasthe advantage of immediate relief of mass effect and lowercorticosteroid requirement compared to SRS, but has highercomplication and mortality rates often dictated by tumourlocation. Regional control can be achieved through WBRT,but this may be at the expense of neurocognitive impair-ment and several recent studies have demonstrated thatomission of WBRT and treatment with SRS alone preservesneurocognition for longer.10,11

These findings may represent the start of a paradigmshift away from WBRT in the treatment of brain metastasis,and Dr Minesh Mehta has proposed the so-called ‘dandelioneffect’; that is, should we treat the whole lawn (WBRT) orweed selectively (surgery and SRS) to preserve cognitivefunction.12 The recently published EORTC 22952-22601study13 demonstrated that omission of WBRT resulted in ahigher intracranial failure rate and increased risk of neuro-logical death compared to patients receiving WBRT.Interestingly in this study, WBRT did not prolong overallsurvival or functional independence (figure 2).Patient selection for aggressive treatmentGiven the generally poor prognosis for patients with brainmetastases, careful selection of suitable patients for treat-ment of brain metastases is essential to avoid unnecessaryrisk to those unlikely to benefit from aggressive treatment.Clinical and functional status, the primary site histologyand primary disease control, and imaging features all con-tribute to the clinical decision making process.

Patients likely to benefit from more aggressive local treat-ment, ie resection or SRS, are those with good functionalstatus and controlled primary and extracranial disease.Performance status is a key factor for determining suitabil-ity for treatment and prognosis, and the Karnofsky perfor-mance status (KPS) forms part of the numerous scoringsystems that have been developed to predict prognosis. Therecursive partitioning analysis (RPA) classification systemis the most utilised in routine clinical practice, and placespatients into one of three prognostic classes (I, II and III)based in KPS, age, status of primary tumour and extent ofextracranial disease (table 2).14 While histopathology of theprimary tumour was not a component of the RPA scales,the recently published disease-specific graded prognosticassessment (DS-GPA) scale demonstrated that the numberof relevant prognostic factors varies according to primary

Microsurgery Stereotacticradiosurgery

Advantages • Tissue for diagnosis• Relief of mass effect• Large tumours

• Minimally invasive• Day case• Deep and multiple

tumours• Avoids general

anaesthesia

Disadvantage • Longer hospital stay• Surgical risk, eg

haemorrhage,infection,neurological deficit

• Longer time toresolve masseffect

• Smaller tumours

Class Clinical parameters Median OS(months)

I <65 years; KPS ≥70; controlled primary;no extracranial spread

7.1

II ≥65 years; KPS ≥70; uncontrolledprimary; extracranial spread

4.2

III KPS <70 2.3

TABLE 1Advantages and disadvantages of microsurgery andstereotactic radiosurgery for local disease control.

TABLE 2Components of RPA classification use to determineprognosis in cerebral metastasis.14

FIGURE 2Patient with malignant melanoma metastases sevenyears after the initial skin cancer. (A) At presenta-tion the right temporal and parasagittal metastaseswere resected and the patient received WBRT(30Gy/10F). (B) Six weeks after WBRT MRI showedthe left frontal metastasis had increased in size andtwo new small metastases were present – these weretreated with SRS (20Gy to 80% isodose using theNovalis TX). (C) Three months post-SRS the threetreated metastases are controlled. (D) Six monthspost-SRS the resected parasagittal tumour hasrecurred – this was treated with SRS tostabilise the brain disease.

tumour types, eg in lung cancer age, KPS, extracranial dis-ease and number of metastases are all prognostic, whereasin breast cancer KPS is the only prognostic factor.8 The DS-GPA appears to show better accuracy in predicting progno-sis, but has not been applied to prospective clinical data. ConclusionsDespite an extensive published literature on the manage-ment of cerebral metastases, there are relatively few goodquality studies. Brain metastases are extremely heteroge-neous and patient selection is critical and no single treat-ment option is suitable for all patients. The currentliterature evidence supports the following:1, Treatment should be patient centred and take into

account:a. Primary cancer site and timing or progression, eg

breast tends to have better prognosis than lungcancer;

b. The relative radiosensitivity (eg lung) or radioresistance (eg renal, melanoma) of the metastasis;

c. Performance status, systemic disease control,cognitive function and quality of life.

2, Surgery and radiosurgery are equivalent treatments forobtaining local control when used in combination withWBRT.

3, If WBRT is omitted, SRS provides better local controlthan surgery.

4, Withholding WBRT is associated with increased risk ofintracranial failure and neurological death and patientsshould undergo surveillance MRI and have salvage treat-ment (eg resection, WBRT) available.

5, WBRT still has clear benefits in reducing intracranialrelapse rate and neurological progression.

6, WBRT is effective in treating high volume brain disease.Future developmentsFuture clinical trials are likely to be disease-specific, indeedthe ongoing MRC QUARTZ trial is comparing WBRT withpalliative care in newly diagnosed primary non-small celllung cancer to determine whether WBRT provides anysymptom control or survival advantage – the interim analy-sis suggests that it does not. In metastatic malignantmelanoma, there is an ongoing trial of local treatment(surgery or SRS) followed by randomisation to observation orWBRT for this relatively radioresistant tumour.

The neurocognitive impact of WBRT is more apparent in

those surviving greater than six months. Techniques to ame-liorate the potential cognitive toxicity of WBRT in additionto fractionation include hippocampal sparing and stereotac-tic radiotherapy (SRT), hypofractionated to the surgicalresection cavity, and clinical trials are in development inthese areas.Conflict of interest statementThe authors declare no actual or potential conflicts ofinterest.

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