ESMO Perceptorship in Lung CancerManchester

7th – 9th March 2018

Dr Catherine McBain

Consultant Clinical Oncologist

The Christie NHS FT

Up to 50% of all lung cancer patients develop brain mets; incidence is increasing

Role of surgery and SRS established for some time

Benefit confined to those with controlled / radically treated systemic disease

But:

The boundaries of radically treatable / controllable systemic disease are changing

Synchronous presentation is common

Learning more about different disease subtypes

Falling enthusiasm for whole brain radiotherapy

The Lancet, Volume 388, Issue 10055, 22–28 October 2016, Pages 2004-2014

Patients approached if:

• There was uncertainty in the clinicians’ or patients’ minds

about the potential benefit of WBRT

• A multidisciplinary team that included both neurosurgeons

and radiation oncologists had concluded that the patient was

unsuitable for either surgery or stereotactic radiotherapy

The QUARTZ study

The Lancet, Volume 388, Issue 10055, 22–28 October 2016, Pages 2004-2014

Patients approached if:

• There was uncertainty in the clinicians’ or patients’ minds

about the potential benefit of WBRT

• A multidisciplinary team that included both neurosurgeons

and radiation oncologists had concluded that the patient was

unsuitable for either surgery or stereotactic radiotherapy

The QUARTZ study

Benefits of surgery

Benefits of SRS (Stereotactic radiosurgery /

stereotactic radiotherapy)

Patient selection: Who gets what and why?

Treatment after neurosurgical resection

Author Year No of

pts

Surgery +

WBRT

WBRT

alone

Patchell 1990 48 10 3.75

Vecht 1993 63 10 6

Mintz 1996 84 5.6 6.3 (ns)

Survival benefit limited to patients with controlled

extra-cranial disease

Patchell RA et al. NEJM 1990;322:494-500

Vecht CJ et al. Ann Neurol 1993;33:583-90

Mintz AH et al. Cancer 1996;78:1470-6

• Two phase III RCTs: 3 or 4 mets, KPS ≥ 70

• Adding SRS to WBRT resulted in:

• Improved KPS at 6 months

• ↓ steroid requirements

• Survival benefit in:

➢Solitary metastasis - median survival 6.5 vs 4.9

months

➢RPA class I (age < 65, KPS ≥ 70, no extracranial

disease) – median survival 11.6 vs 9.6 months

Andrews DW et al. Lancet 2004;363:1665-1672

Kondziolka D et al. Int J Radiat Oncol Biol Phys 1999;45(2):427-34

Gamma knife

Cyberknife

Linacc-based / Novalis Tx

Methods of SRS delivery: Gamma knife

Methods of SRS deliveryLinear-accelerator based: Novalis TX

No RCTs

Retrospective series of 206 pts

2 year survival: 20% vs 14% (ns)

Survival depended on:◦ Age, KPS, no extracranial mets, RPA class,

interval from diagnosis to treatment

It is generally accepted that surgery = SRS

Rades D et al. Cancer 2007;109:2515 - 2521

Extra-cranial disease◦ Controlled / controllable / progressing◦ Prognosis

Intra-cranial disease:◦ Number / volume / location of metastases◦ Mass effect◦ Certainty of diagnosis

Patient-related factors◦ Performance status◦ Preference◦ Intercurrent medical problems e.g. COPD

1997

1200 patients

•Age < 65

•KP ≥ 70

•Controlled

primary

•No extracranial

mets

RPA class I-III

‘General’ RPA*

*Gaspar L Int J Rad Oncol Biol Phys 1997;37:745-751

#Sperduto PW et al Int J Radiation Oncol Biol Phys 2010:77;655-661

#Sperduto PW et al JCO 2012;30(4):419-425

$Sperduto PW et al JAMA Oncology 2017:3:827-832

2010

4,259 patients

• Age

• KP

• Primary tumour

type

• Treatment

• Number of brain

mets

Disease-specific GPA#

2017

2,186 patients

• Tumour sub-type

• EGFR / ALK mut

• KP

• Age

• Number of mets

• Extra-cranial

disease

Disease specific,

Mutation-specific GPA $

Sperduto PW et al; JAMA Oncology; 2017; 3(6) 827-31

46.8 5.36.9

➢ 5% of NSCLC have ALK-rearranged NSCLC

➢Brain mets are common in this sub-population

➢ 90 patients, diagnosed in 6 US institutions 2007 - 14

➢Median follow-up 38.1 months from diagnosis;

➢ 16 months from diagnosis of brain metastases

Johung KL et al; J Clin Oncol; 2016; 34(2): 123-129

30% had brain metastases at presentation i.e. synchronous

74% stage 4 at diagnosis

47% had ≥ 4 mets

Systemic disease classified as:◦ Stable

◦ Oligoprogressive (≤ 4 sites of worsening extracranial disease)

◦ Progressive

Median OS after diagnosis of brain metastases:

49.5 months

1 year overall survival: 72% 2 year overall survival 66%

Survival most prolonged in patients with no extracranial disease (median survival not reached vs 32.6 months for patients with extracranial mets)

A combination of SRS, WBRT and surgery◦ 64 had SRS, 45 WBRT, 17 resections

◦ many had > 1 treatment type, or more than one episode e.g. of SRS

KP > 90

No extracranial metastases

No previous TKI treatment

Not prognostic:

• Number of mets

• Age

• Smoking history

• Initial type of radiotherapy

Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical

If they are going to have prolonged survival, sparing of late toxicity is vital

Consider first-line SRS, close CNS observation and treatment of emergent CNS disease

Year SRS /

Sx

No of

pts

Med OS 5yr OS

Flannery 2008 SRS 42 18mo 21%

Bonnette 2001 Sx 103 12mo 11%

Billing 2001 Sx 28 24mo 21%

Hu 2006 Either 84 SI 26mo

SIII 9mo

7.6%

Flannery TW et al. Int J Rad Oncol Biol Phys 2008;72:19-23

Bonnette P et al. Chest 2001;119:1469

Billing PS et al. J Thorac Cardiovasc Surg 2001;122:548-53

Hu C et al. Cancer 2006;106:1998-2004

Outcome depends on primary disease stage and treatment

60 – 80% died of non-neurological causes

42 patients, diagnosed 1993 – 2006 (i.e. < 4 pa)

Most important prognostic factor was management of thoracic disease (and KPS)

Definitive thoracic therapy (26/42):◦ Median Survival 26 months◦ 5 yrs survival 34%

Non-definitive thoracic therapy (16/42):◦ Median Survival 13months, ◦ 5 yrs survival 0%

Flannery TW et al. Int J Rad Oncol Biol Phys 2008;72:19-23

We now take the superior outcomes of driver-mutated disease for granted!◦ 2nd generation agents

◦ Better CNS penetrance

◦ More pro-active approach from neuro-oncology teams

The questions are about sequencing and treatment combinations.

Many patients are now on a ‘brain mets journey’ with different treatments at different times

Neuro-surgeons Clinical Nurse SpecialistsNeuro-oncologists Physio / OTNeuro-radiologists MDT Co-ordinatorsNeurologists Data Manager

Surgery Confirms histology

Larger lesion Risk of neurological

decline Faster resolution of

symptoms

Complications usually immediate (6%)

Faster tapering of dex Relies on fitness for

GA

SRS Known histology

Smaller lesion <3cm, no mass effect

Possible in eloquent regions

Out-patient treatment; possible in older, less fit patients

Complications usuallydelayed

Risk of radiation necrosis

Longer use of steroids

Motor cortex Speech areas

Specialist confirmation of imaging diagnosis

Simultaneous assessment of whether surgery or SRS

is the most appropriate modality

Panel of opinion – 5 surgeons, 4 clinical oncologists

Clinical oncology input to help guide surgical

decision-making with respect to prognosis / future

treatment options

Swift, smooth patient pathway; optimal

communication

No delays (hopefully!)

Number of metastases able to treat with SRS

Evidence that volume is more important than number

UK Guidelines:

Total mets vol ≤ 20cc

WBRT still has a role

11cc 8.5cc

NICE evidence review Jan 2018:

RCTs used 3 or 4 metastases, but there is no clear biological rationale for that number

There is no clear survival difference between incremental increases in the number of metastases so it is difficult to set an arbitrary maximum

Some centres are able to treat > 10 metastases safely and with good outcomes

There committee therefore decided not to make a recommendation regarding the maximum number of metastases to be treated with SRS

Brain tumours (primary) and brain metastases in adults

NICE guidance: Draft for consultation Jan 2018; Evidence Review C

Yamamoto et al Lancet Oncol 2014; 15(4):387-95

• Prospective observational study from 23 facilities in Japan • 1 to 10 newly diagnosed brain metastases • Karnofsky PS≥ 70 or higher• Largest tumour <10 mL in volume, <3 cm in longest diameter• Total cumulative volume ≤15 mL

Observation

Adjuvant WBRT

Cavity SRS

Trials:◦ adjuvant WBRT vs observation

◦ cavity SRS vs observation

◦ adjuvant WBRT vs SRS

359 patients

SRS: 199 Surgery: 160

81 WBRT100 Obs 99 WBRT 79 Obs

Almost all patients received their randomised treatment

99% surgical resections considered “complete”

Randomised Randomised

Kocher M et al J Clin Oncol 2011:29; 134-141

WBRT reduces relapse at

initial site

Impact of adjuvant WBRT on intracranial disease control / recurrence

WBRT reduces relapse at

other sites in the brain

• No difference in OS or

functional independence

• Extracranial disease and PS ≥

2 were prognostic

Kocher M et al J Clin Oncol 2011:29; 134-141

Mahajan, A et al. Lancet Oncology 2017;18:1040-1048

• 132 patients randomised

• Resection cavity < 4cm

• No difference in Overall Survival

12 month freedom

from local recurrence

72% SRS arm

43% observation arm

• 194 patients randomised: adjuvant post-op WBRT vs SRS cavity boost

Results:

• Overall survival - no difference

• Cognitive deterioration free survival - favoured SRS

• QoL at 6 months - favoured SRS

• Functional independence - SRS better at 3mths, same at 6mths

• median favoured SRS (> 17.6 vs 14.0 mo)

• Intracranial control favoured WBRT:

• at 12 months, surgical cavity control 80.6% vs 60.5%

• distant brain control (no new mets) 89.2% vs 64.7%

Brown PD et al. Lancet Oncology 2017;18:1049-1060

Both WBRT and cavity SRS reduced local recurrence following resection of a brain met ◦ (from approx. 60-70%% to 20-30%)

Neither improved OS

WBRT results in reduced relapse elsewhere in the brain

SRS results in better QOL, longer functional independence, longer time until cognitive deterioration

Recent change in thinking: Active surveillance or cavity boost

• (Clinical challenges: Difficulty defining cavity, margin of normal tissue, dose especially for larger cavities)

• Possible with modern radiotherapy techniques

• Single arm US study reported improved neurocognitive outcomes

compared to historic data on WBRT

• UK multicentre HIPPO Phase II RCT of WBRT vs HS-WBRT post-

op or post-SRS – closed early due to failure to recruit

The benefit of SRS or surgery in selected subgroups of NSCLC patients is well-established

Management strategies for oncogene-addicted NSCLC are developing rapidly

Control / treatment of extra-cranial disease and performance status dictate prognosis

If extra-cranial disease is controlled and prognosis good, a more aggressive approach in the brain is beneficial and justifiable

➢ Management of brain metastases must be individualised

➢ Patients may have different treatments at different times – a ‘brain mets journey’

➢ If omitting adjuvant post-op XRT, 3-monthly MR brain follow-up is required

➢ Many questions remain regarding sequencing and combining treatments

Klinik für Radioonkologie

UniversitätsSpital Zürich

Nicolaus Andratschke

Early Versus dElayed on demand Radiosurgery

(EVER) for newly diagnosed measurable brain

metastases in driver mutated non-small cell lung

cancer (NSCLC) - A phase 2 randomized multi-

center study

// 28. März 2018Advanced Photon Radiotherapy - Matthias Guckenberger 52

A well-constituted neuro-oncology multi-disciplinary team enhances patients’ care and treatment pathways

Good communication is vital in optimising care

Suggested reading:Metastatic Brain Disease from NSCLC – Getting Back to the Drawing Board

A Greystoke and P MulvennaClinical Oncology 2018; 30;137-143

Thank you