Prophylactic Cranial Irradiation in Extensive Stage Small Cell Lung Cancer Jiraporn Setakornnukul, MD.Division of Radiation Oncology, Department of RadiologyFaculty of Medicine Siriraj Hospital, Mahidol University

Outline

Significance of brain metastases in SCLC

PCI in ED with complete response: evidence from IPD-metaanalyses

Two major RCTs : EORTC & Japanese trials

Worse prognosis in asymptomatic BM ?

Significant neurocognitive toxicity ?

Introduction

Worldwide, lung cancer occurred in approximately 1.8 million patients in 2012 and caused an estimated 1.6 million deaths

95 % of all lung cancers are classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC)

Introduction

SCLC represents about 15% of all lung cancers – Proportion of SCLC/Total lung cancer

NCI Thailand (2011): 21/336 (6.25%) Siriraj Hospital (2009): 29/592 (4.9%)

Nature: rapid doubling time, high growth fraction, and the early development of metastases– 70% Extensive stage – 30% Limited stage

Staging SCLC

Staging SCLC by Veterans' Affairs Lung Study Group (VALSG)

Limited stage: disease confine to one hemithorax or radiotherapy portal field

Extensive stage: tumor beyond the boundaries of limited disease – distant metastases– malignant pericardial/pleural effusions– contralateral supraclavicular and contralateral

hilar involvement

Treatment: ED-SCLC

ED-SCLC is a disseminated disease

Thus systemic chemotherapy is the initial treatment

Background: Treatment outcomes

Response rate after combination CMTComplete response: usually around 10%Partial response: 33-45%

Survival rate after combination CMTMedian survival: 6.9-11.5 mo.1yr-OS: 21-42%2yr-OS: usually less than 5%

Data from 2,580 patient SWOG data base

Kathy S., JCO 1990

Why PCI is the interesting role in SCLC?

Incidence of brain metastasis– At diagnosis: 10-15%– From autopsy: 35-55%

Elliott JA, JCO 1987Bunn PA, Seminars in Oncology 1978

Pattern of failure– Most common failure site: intrathoracic and

CNS

Outline

Significance of brain metastases in SCLC

PCI in ED with complete response: evidence from IPD-metaanalyses

Two major RCTs : EORTC & Japanese trials

Worse prognosis in asymptomatic BM ?

Significant neuocognitive toxicity ?

PCI for complete response ED-SCLC

RR of death: 0.77 (0.54-1.11)

RR of brain met: 0.38 (0.23-0.64)

Cumulative incidence of BM at 3 yr (whole group) 33.3% for PCI and 58.6% for no PCI (Absolute decrease 25.3%)

PCI for any response ED-SCLC

EORTC study from Slotman; Published in NEJM 2007

Published study

Pragmatic study– Inhomogeneous

patients– Clinical follow up

Japanese studyfrom Seto; Presented at ASCO 2014

Abstract only

Efficacy study– Homogeneous

patients– Need MRI brain

follow up

2014

ED-SCLCCombination CMTWith any response

PCI: 20 Gy/5F, 25 Gy/8-10F, 30 Gy/10F

No PCI

Median time between diagnosis and randomization: 4.2 months

Primary end point: the development of symptomatic brain metastases

BM 16.8% (PCI) VS 41.3% (no PCI) Absolute reduction 24.5% Relative reduction 2.46

MS 6.7 mo (PCI) VS 5.4 mo (no PCI)

Primary end point: Overall Survival

BM 32.4% (PCI) VS 58% (no PCI) Absolute reduction 25.6% Relative reduction 1.79

EORTC VS Japanese trialEORTC Japanese study

Population Exclude symptomatic BM Exclude both symptomatic & asymptomatic BM

F/U, CNS Clinical F/USymptomatic BM

MRI F/UMixed symptomatic & asymptomatic BM

BM Absolute reduction 24.5% Absolute reduction 25.6%

PFS 14.7 wk (~3.67 mo) , PCI12 wk (~3 mo), no PCI

2.2 mo, PCI2.4 mo, no PCI

Salvage Rx outside CNS

68% in PCI 45.1% in no PCI

81% in PCI89% in no PCI

MS 6.7 mo in PCI5.4 mo in no PCI

10.1 mo in PCI15.1 mo in no PCI

Asymptomatic brain metastasis

Asymptomatic BM response rate(CMT: cyclophosphamide, doxolubicine, and etoposide)

Response rate: 27%CR rate 2/22 (9%) and PR rate 4/22 (18%)

Median duration to symptomatic BM: 2.3 mo (range, 0.5-5 mo)

Median survival: 8.3 mo (1.3-43.4 mo)

Summary from two studies

PCI can be omitted if patient get a good follow up protocol such as MRI brain every 3 months to early detect asymptomatic BM

Symptomatic BM may cause deteriorate patient performance and cannot receive salvage chemotherapy, so the survival could decrease

Neurocognitive disorder

EORTC trialRole functioning, Cognitive functioning, and

Emotional functioning did not different between PCI and no PCI

Grosshans et al.Persistent declines in cognitive function were not

observed after PCI (25Gy in 10F) in SCLCDo not favor omission PCI due to fears of

neurotoxic effectsGrosshans DR, Cancer 2008

Conclusion (1)

ED-SCLC: Complete response after combination chemotherapy

Should get PCI after CMT Data from Meta-analysis in 1999

– Gain survival benefit 5.4%– Reduce BM 25.3%

Conclusion (2)

ED-SCLC: Any response (Partial response) after combination chemotherapy

Good Prognosis such as single metastasis with complete systemic response– Single metastasis: better prognosis

Foster NR, Cancer 2009

PCI is the standard treatment in both arms in ongoing RCT (EORTC and RTOG)– role of thoracic radiotherapy after

chemotherapy

Conclusion (3)

ED-SCLC: Any response (Partial response) after combination chemotherapy

Moderate to poor prognosis such as multiple metastases and partial response of systemic metastasis

Should receive PCI when patient cannot do regular MRI F/U