Few Mets in the Brain - academia.cat€¦ · Lancet 2009 . SRS, exactrac Conventional arctherapy with asymmetric isocenter . In favor of WBI • Less progression in the brain (Aoyama

Few Mets in the Brain

Salvador Villà

ICO HUGTIP Badalona

IOT Barcelona Acadèmia, desembre 2014

Patient...

Age: 56 yo Middle Favorable

Performance status: KPS 90 (or less...?) (and after

corticosteroids!) Favorable!

Extracranial disease: No. Favorable!

Activity of primary tumor: No. Favorable!

Number of mets: 1, Size 13mm Favorable!

Histology (primary tumor): Lung ca,

Adenocarcinoma. Unfavorable!

KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 100 Normal no complaints; no evidence of disease.

90 Able to carry on normal activity; minor signs or symptoms of

disease.

80 Normal activity with effort; some signs or symptoms of disease.

70 Cares for self; unable to carry on normal activity or to do active

work.

60 Requires occasional assistance, but is able to care for most of his

personal needs.

50 Requires considerable assistance and frequent medical care.

40 Disabled; requires special care and assistance.

30 Severely disabled; hospital admission is indicated although death

not imminent.

20 Very sick; hospital admission necessary; active supportive

treatment necessary.

10 Moribund; fatal processes progressing rapidly.

0 Dead

Karnofsky Performance Status

Memory

loss?

MRI better than

CT

Neurocognitive

evaluation?

Dexamethasone and mets Vecht et al, Neurology 94

• Convencional dosage 16 mg/d

• 2 double blind trials: 4 mg vs. 8 mg and 4

mg vs. 16 mg

• Kf > 80, 96 p recuited

• Improvement of KPS: no changes

• Side effects: dosis dependent

Sarin (Lancet Neurol 2003)

• 1. Starting total dose with 4mg/24h

• 2. If after 72h clinical improvement is not observed, adding 8mg/24h

• 3. If after next 72h clinical improvement is not observed, it was advised to increase doses 4 mg every 6h till to reach 24mg/24h.

• 4. If stabilization or improvement of symptoms and signs were observed, decreasing of 4 mg every 72 h was recommended.

• 5. In case of getting worse, starting as scheduled above.

• 6. If high endocranial pressure or consciousness were altered, starting with 24 mg/24h of dexamethasone and manitol.

• Taking of pills could be done at the morning 2/3 of total doses, and at the evening 1/3 of total dose.

Treat the patient!

Do not treat the image!

Tom Nikkelsen et al, J of Neurooncol 2010

Forsyth et al 2003

Variables RPA Rotterdam SIR BSBM GPA Rades1-2 DS-GPA

PS KPS ECOG KPS KPS KPS KPS KPS

Age <65 NA <50, 51-59 >59 NA <50, 51-59, >59 <70 <50, 51-59, >59

ECM No vs yesLimited

activityNo vs yes No vs yes No vs yes No vs yes No vs yes

Control

PTNo vs yes

Limited

activityPD vs no PD NA NA NA NA

Steroids NAType of

responseNA NA NA NA NA

N of BM NA NA 1,2-3,>3 NA 1, 2-3, >3 1, 2-3, >3 1, 2-3, >3

Vol of BM NA NA Yes NA NA NA NA

Interval

to BMNA NA NA NA NA <8m vs >8m NA

Histology NA NA NA NA NA NA Yes

Sperduto et al, 2008

GPA: 3.5, MST 11 months

(Prospectively validated, Villà et al 2011)

Sperduto et al, 2011

MST 14.8

For RPA class 1: 7.1 m

There are limitations in the ability

of physicians to accurately predict

patient survival (Tsao et al,

ASTRO 2012)

Kondziolka et al , J Neurosurg 2014

All p

A-B

C- lung

D- breast

• Large oedema in single BM: best prognostic prognostic (Spanberger

13)

• Central necrosis and patterns of enhancement: negative factor

(2001, Xu 2012). Hypofractionated RT, better (Tomas-Dasu 14)

• Cystic BM: similar LC compared to noncystic BM (Ebinu 2013)

• High DWI and low ADC indicated poor OS (Berghoff 13)

• Total tumour volume of BM: factor (Baschnagel 2013, Hartford

2013)

• No differences between supratentorial lobes and infratentorial region

(EORTC 22952)

• Radiation necrosis: spectroscopy MRI, PET MET, surgery

Imaging factors

PF and histology, Lung Ca

• NSCLC: Adenoca and large-cell ca had a higher chance of BM (Shi

2006)

• Radio-resistant tumor (NSCLC) and poor response to WBI alone vs.

S and WBI (Mintz 1996).

• Focused RT dose and EGR mutation influence outcome (Lee 12)

• NSCLC with unique mets: 3 different situations and many

interpretations in the literature

• NSCLC: high Ki-67 expression and low p53 expression predicted

poor OS and correlation with BM

• NSCLC: Ki67 index, microvascular density and hypoxia-inducible

factor 1 alpha as promising prognostic value (Berghoff 14)

• ALK gene (anaplastic lymphoma kinase) translocations and

amplifications: constant incidence between PTs and BM (Preusser

13)

In favor of (focal) Stereotactic RT

• Same survival (Aoyama 07, Chang 09, Kocher 11)

• Better QoL (Soffietti 13)

• Better cognitive outcome (Chang 09)

• New focal treatments possible (Aoyama 07, Kocher 11)

• Less leukoencephalopathy

Soussain et al

Lancet 2009

SRS, exactrac

Conventional arctherapy with

asymmetric isocenter

In favor of WBI

• Less progression in the brain (Aoyama 07, Kocher 11)

• Drugs to prevention cognitive damage (RTOG trial,

memantine, Brown 13)

• New techniques to reduce dose in whole brain areas

• New techniques to protect hipocampus

Phase 2 RTOG trial 0933,

Gondi et al JCO 2014

Dose distribution for the higher dose regions

using WBRT+SIB

WBRT with conventional SRT

where the combined dose is not taken into account

Baumert et al 2013 Figure 1: WBRT /SIB: low (green) and high dose (red) levels delivered synchronously

Surgery for BM

• Accessible, no eloquent area?

• In posterior fossa

• More than one mets?

• No evidence that Surgery is better than

SRT

Well-demarcated

NSCLC

Vascular co-option

Melanoma

Diffuse invasion

SCLC

Influenced by expression of alfa v integrins complexes

Neuro-Oncol 2013

Conclusions

• To be careful with corticosteroids

• Try to avoid Whole Brain Irradiation

• Focal treatment!

• Close Follow-Up

• MRIs needed

• Prophylaxis in NSCLC?

Subclassification Class 2 (Yamamoto 2012)

• 4 factors:

KPS: 90 to 100 vs. 70 to 80

Number of BM: 1 vs. multiple

ECM: yes vs. no

PT status: controlled vs. not controlled

Class IIa, IIb, IIc (3753 GKRS patients)

Niwinska et al, 2012. Breast ca

Nomogram (Barnholtz-Sloan et al, 2012)

Nomogram from Rotterdam after SRS (Rodrigues 2014)

(PF related to TX) German group have added PT and ECM (Huttenlocher 2014)

Nieder et al Cancer 2011

Comparison of median survival in 7 studies using the recursive

partitioning analyses (RPA) classes (treatment was WBRT with or

without local measures, none of the studies is limited to one

particular cancer type).

Nieder and Mehta 2009

Carsten and Mehta 2009

Rades 2: scoring systems for irradiated patients,

Rades et al 2011

Marko et al, 2012. Breast cancer

Nomogram from Rotterdam after SRS (PF related

to TX) (Rodrigues 2014)

Table 7: Advantages and Disadvantages of Brain Metastases Prognostic Indices

Prognostic Index Statistical Validation Advantages Disadvantages

RTOG RPA large prospectively collected RTOG clinical trial primary

dataset, multiple validation investigations

well-known and described classification

system, frequently utilized in clinical care

and clinical trials moderate OC with low PPG PPV, some validation

studies suggest high PPG MMR

ROTTERDAM large primary dataset, no validation investigations*

good OR for both PPG and GPG

classifications, high PPG PPV, low PPG

MMR small GPG (<10%) in primary validation, use of

subjective steroid response, moderate GPG PPV

SIR very small primary dataset, large validation dataset confirming

OC derived from whole brain plus SRS

population small GPG (10%) in primary validation, moderate

OC with very low PPG PPV

BS-BM small primary dataset, validation datasets do not confirm high

OC seen in primary report derived from various SRS populations,

simple scoring system small (3%) PPG group with low PPV, high GPG

MMR

GPA very large prospective RTOG clinical trial primary dataset,

moderate sized validation cohorts derived from WBRT and SRS patient

populations, good GPG OC small GPG cohorts in primary and validation

datasets, low PPG PPV, high GPG MMR

RADES I large primary dataset, no validation investigations*

balanced proportions of patients in each of

four groups, overall good OC and PPG

MMR low PPG PPV

GGS moderate size primary dataset, no validation investigations* straightforward index construction, overall

good OC small (3%) PPG group with low PPV, high PPG

MMR

DS-GPA large primary dataset, no validation investigations*

disease-specific scoring integrated into

index, balanced proportions of patients in

each of four groups complex index construction, OC could not be

calculated from published reports

RADES II large primary dataset, no validation investigations* good OC, well balanced groups patient population not well reported in manuscript

* no validation studies that meet systematic review eligibility criteria (see methods section)

PPV = Positive Predictive Value; PPG = Poor Prognostic Group; GPG = Good Prognostic Group; OR = Operating Characteristics; SRS =

Stereotactic Radiosurgery; MMR = Major Misclassification Rate

Systemic review of scores Rodrigues et al 2013

Nieder et al Cancer 2011

Nieder et al Cancer 2011

Review Nieder et al Cancer 2011-1

• Mets USA: 170,000 per year

• Cost of care: 43,955 euros

• Management approaches: supportive

care, surgery, RT

• TX alghoritmes: based on patients’

prognosis and aim (palliation, prolongation

of survival, or both)

Review Nieder et al Cancer 2011-2

• Retrospective study

• 2 equally sized groups of patients

• 1- contemporary: 2005-2009 (103 p)

• 2- historical: 1983-1989 (103 p)

• Matching: diff in sex, colorectal ca (more in contemporary), no extracranial mets (less in contemporary group), single brain (less contemporary group), syncrhonous (less historical), interval (shorter in historical), RPA class (poorer in historical), and GPA score 0-1 (poorer in contemporary)

Nieder et al Cancer 2011

Nieder et al Cancer 2011

Review: Nieder et al, Cancer 2011

Diagnosis-specific GPA

Nieder et al, Cancer 2011

Villà et al, 2011

1-4 BM, max diameter 30 mm Aoyama 2006

An EORTC Phase III trial of Adjuvant Whole

Brain Radiotherapy Versus Observation in

patient with 1 to 3 Brain Metastases From

Solid Tumor After Surgical Resection or

Radiosurgery: Quality-of-Life analysis

R. Soffietti1, M. Kocher2, M. U. Abacioglu3, S. Villa4, F. Fauchon5,

B. G. Baumert6, L. Fariselli7, T. Tzuk-Shina8,R-D Kortmann9, C.

Carrie10, M. Ben Hassel11, M.Kouri12, E.Valeinis13, D. van den

Berge14, R. P. Mueller2, G. Tridello15,16, L. Collette16, A.

Bottomley8 on behalf of EORTC Radiation Oncology and Brain

Tumor Groups

Soffietti et al, 2011 (submitted)

Conclusion Adjuvant WBRT after surgery or radiosurgery of

a limited number of brain metastases from solid

tumors may negatively impact some aspects of

HRQOL, even if these effects are transitory.

Consequently, observation with close monitoring

with MRI (as done in the EORTC trial) is not

detrimental for HRQOL.

Soffietti et al, 2011 (submitted)

Lung cancer 1993.Solitary Brain mets Surgery + WBI 1996

MRI scan

4/2011

Figure 1: WBRT /SIB: low (green) and high dose (red) levels delivered synchronously

Hypocampus identification with image fusion

SRS for brain mets

Sperduto et al, 2008

Conventional arctherapy with asymmetric isocenter

Brain mets