GOECP/SEOR radiotherapy guidelines for small-cell lung cancer

Table 1 Chronological changes in the combined treatment of small cell lung cancer

Chronological changes in SCLC treatment
Ref.	Stage (LS or ES)	Phase	Treatment	Median survival	5-yr survival	P value	Level of evidence
Miller et al[4] 1969	LS	III	RT	28.5 wk; 43 wk	1%; 5%	0.04	A I
Bergsagel et al[8] 1972	LS	III	RT; RT + Ch	21 wk; 42 wk	NR	< 0.05	A I
Einhorn et al[13] 1976	LS	II	RT + PCT	12 mo	10%		C III
Bunn et al[18] 1987	LS	III	PCT; PCT + RT	12 mo; 15 mo	10%; 15%	< 0.05	A I
Turrisi et al[27] 1988	LS	II	Early AHF-RT + CE	23 mo	30% at 3 yr		C III
Murray et al[26] 1993	LS	III	Early RT + CE; late RT + CE	21 mo; 19 mo	20%; 13%	< 0.05	A I
Pignon et al[21] 1992	LS	Meta-analysis	PCT (no CE); PCT (no CE) + TRT	< 14% mortality	> 5% at 3 yr	0.001	A I
Jeremic et al[29] 1997	LS	III	Early AHF-RT + CE; late AHF-RT + CE	36 mo; 34 mo	30%; 15%	0.0027	A I
Turrisi et al[31] 1999	LS	III	Early AHF-RT + CE; early NFRT + CE	23 mo; 19 mo	26%; 16%	0.04	A I
Jeremic et al[41] 1999	ES	III	PCT + RT + PCI; PCT + PCI	17 mo; 11 mo	9.1%; 3.7%	0.0041	A I
Aupérin et al[33] 1999	LS	Meta-analysis	PCI; no PCI	> 6% at 3 yr			A I
Takada et al[30] 2002	LS	III	Early AHF-RT + CE; late AHF-RT + CE	31.3 mo; 20.8 mo	24%; 18%	< 0.05	A I
Slotman et al[38] 2007	ES	III	CE + PCI; CE		27% at 1 yr; 13% at 1 yr	< 0.001	A I
Slotman et al[42] 2015	ES	III	CE + PCI; CE + TRT + PCI		3% at 3 yr; 13% at 3 yr	< 0.03	A I
Faivre-Finn et al[43] 2017	LS	III	CE + AHF-RT 45 Gy; CE + NFRT 66 Gy	29 mo; 19 mo	34%; 31%	NS	A I

LS: Limited-stage; ES: Extensive-stage; TRT: Thoracic radiotherapy; AHF-RT: Accelerated hyperfractionated radiotherapy; NFRT: Normofractionated radiotherapy; Ch: Chemotherapy; PCT: Polychemotherapy; PCI: Prophylactic cranial irradiation; CE: Cisplatin + etoposide; NS: Not significant.

Table 2 Diagnostic staging recommendations for small cell lung cancer

Diagnosis of small cell lung carcinoma
Staging with combined VALSG and TNM AJCC 8th edition (I, A)
Baseline study
Age, tobacco use, comorbidities, complete physical examination, and ECOG PS
Complete blood analysis: Blood count, biochemistry, liver and kidney function, alkaline phosphatase, LDH
Cardiology study: Electrocardiogram +/- echocardiogram
Respiratory function testing in patients expected to receive locoregional treatment
CT with intravenous contrast (unless medically contraindicated)
Upper thoracoabdominal CT with intravenous contrast; include pelvis in advanced stages
Intravenous contrast improves the definition of central tumours and lymph node involvement (III, A)
18F-FDG PET/CT
18F-FDG PET/CT recommended in patients expected to undergo locoregional treatment (III, A)
Images are acquired with the patient in the radiotherapy treatment position according to consensus protocol between Nuclear Medicine and Radiation Oncology departments (IV, A)
Not recommended for restaging after chemotherapy in sequential treatment
Brain staging
Brain MRI is preferable
Brain CT with IV contrast (without contrast is inadequate)
Bone scintigraphy
Only indicated if PET/CT is not available
Abdominal MRI
Only indicated to assess uncertain liver or adrenal lesions (V, C)
Histological confirmation
Invasive tests used as appropriate according to tumour location
Follow WHO criteria for cell typing. Immunohistochemistry for differential diagnosis

VALSG: Veterans Administration Lung Study Group; TNM: Tumor-node-metastasis; AJCC: American Joint Committee on Cancer; PS: Performance status; LDH: Lactate dehydrogenase; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography; FDG: Fluorodeoxyglucose; MRI: Magnetic resonance imaging; WHO: World Health Organization.

Table 3 Tumor-node-metastasis American Joint Committee on Cancer 8^th edition lung cancer

TNM AJCC 8th edition lung cancer
T: Primary tumour
Tx	Not evaluable by imaging or malignant cells in sputum or bronchial lavage
T0	No evidence of primary tumour
Tis	Carcinoma in situ
T1	≤ 3 cm surrounded by lung or visceral pleura, or lobar bronchus
T1a (mi)	Minimally invasive
T1a	≤ 1 cm
T1b	> 1 cm to ≤ 2 cm
T1c	> 2 cm to ≤ 3 cm
T2	> 3 cm to ≤ 5 cm, or involving main bronchus without affecting the carina, visceral pleura, or atelectasis or obstructive pneumonitis extending to the hilar region, affecting part or all of the lung
T2a	> 3 cm to ≤ 4 cm
T2b	> 4 cm to ≤ 5 cm
T3	> 5 cm to ≤ 7 cm, or tumour nodules in the same lobe, or invasion of the chest wall (parietal pleura), phrenic nerve, parietal pericardium
T4	> 7 cm, or nodules in a different ipsilateral lobe or invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina
N: Regional lymph node involvement
Nx	Not evaluable
N0	No node involvement
N1	Ipsilateral peribronchial and/or hilar and intrapulmonary nodes
N2	Ipsilateral mediastinal nodes and/or subcarinal
N3	Contralateral mediastinal or contralateral hilar nodes, or any scalene or supraclavicular nodes
M: Distant metastasis
M0	No metastasis
M1	Distant metastasis
M1a	Nodules in contralateral lobe; pleural or pericardial or pleural or pericardial effusion
M1b	Single extrathoracic metastasis (including non-regional lymph node)
M1c	Multiple extrathoracic metastases

TNM: Tumor-node-metastasis; AJCC: American Joint Committee on Cancer.

Table 4 Grouping by tumor-node-metastasis stage: American Joint Committee on Cancer 8^th edition lung cancer

TNM AJCC 8th edition lung cancer grouping by stage
Occult carcinoma	Tx	N0	M0
Stage 0	Tis	N0	M0
Stage IA1	T1a (mi)-T1a	N0	M0
Stage IA2	T1b	N0	M0
Stage IA3	T1c	N0	M0
Stage IB	T2a	N0	M0
Stage IIA	T2b	N0	M0
Stage IIB	T1-2	N1	M0
	T3	N0	M0
Stage IIIA	T1-2	N2	M0
	T3	N1	M0
	T4	N0-1	M0
Stage IIIB	T1-2	N3	M0
	T3-4	N2	M0
Stage IIIC	T3-4	N3	M0
Stage IVA	Any T	Any N	M1a-b
Stage IVB	Any T	Any N	M1c

TNM: Tumor-node-metastasis; AJCC: American Joint Committee on Cancer.

Table 5 Planning volumes in the principal studies of concurrent chemoradiotherapy in small cell lung cancer

Ref.	Study	Volume
Jeremic et al[41] 1999	Prospective, randomised	GTV + hilum + 2 cm; entire mediastinum + both supraclavicular fossae + 1 cm
Zhu et al[116] 2011	Retrospective	Primary GTV + GTVn > 1 cm short axis
Yee et al[117] 2012	Prospective, phase II	GTVp + GTVn visible on planning CT
Slotman et al[44] 2015	Phase III, randomised	GTVp post-CT + 15 mm + ipsilateral hilum + nodes involved pre-CT
Luan et al[119] 2015	Retrospective	CR post-CT: Primary GTV bed and GTVn involved pre-CT; SD post-CT: GTVp + GTVn; PD post-CT: New GTVp + GTVn + GTV
Qin et al[118] 2016	Retrospective	GTV: Thoracic, mediastinal, and supraclavicular fossae
Gore et al[47] 2017	Phase II, randomised	Post-CT volume including the primary tumour and nodal areas involved at diagnosis
Luo et al[120] 2017	Retrospective	Post-CT GTVp + pre-CT primary tumour bed + GTVn of nodes involved pre-CT
Zhang et al[121] 2017	Literature review	CR: Mediastinum initially involved; PR: Residual pulmonary lesions + initially involved lymph nodes

GTV: Gross tumour volume; GTVn: Lymph node gross tumour volume; GTVp: Primary gross tumour volume; CT: Computed tomography; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease.

Table 6 Summary of the main studies of prophylactic cranial irradiation in small cell lung cancer

PCI in SCLC
Ref.	Stage (LS or ES)	Phase	Treatment	Survival	P value	Incidence of BM	P value	Level of evidence
Arriagada et al[144] 2002	LS	III	PCI; no PCI	18% at 5 yr; 15% at 5 yr	0.06	20% at 5 yr; 37% at 5 yr	< 0.001	A I
Aupérin et al[33] 1999	LS	Meta-analysis	PCI; no PCI	20.7%; 15.3%	0.01	0.38; 0.57	0.001	A I
Warde et al[20] 1992	LS	Meta-analysis	PCI; no PCI	HR 0.82		HR 0.48		A I
Takahashi et al[122] 2017	ES	III	PCI; MRI + no PCI	13.6 mo; 11.6 mo		48%; 69%		A I
Rusthoven et al[81] 2020		III	WBRT; SRS			5.2 mo; 6.5 mo	0.003	A I
Yin et al[145] 2019		Meta-analysis	PCI; observation	HR 0.81	< 0.001	HR 0.45	< 0.001	A II
De Ruysscher et al[146] 2018		III	PCI; observation	24.2 mo; 21.9 mo	0.56	7%; 27.2%	0.001	A I
Slotman et al[38] 2007	ES	III	PCI; no PCI	6.7 mo; 5.4 mo		15% at 1 yr; 40% at 1 yr	< 0.001	A I
Le Péchoux et al[154] 2009	LS	III	Standard dose PCI; high dose PCI	42%; 37%	0.05	29% at 2 yr; 23% at 2 yr	0.18	A I
Ref.	Stage (LS or ES)	Phase	Treatment	Median Survival	P value	Incidence of neurological deficit	P value	Level of evidence
Yang et al[157] 2018	LS	Meta-analysis	PCI; no PCI	HR 0.52		RR 0.5		A I
Viani et al[148] 2012	LS-ES	Meta-analysis	PCI; no PCI	OR 0.73	0.01
Ge et al[149] 2018	ES	Meta-analysis	PCI; no PCI	HR 0.57	< 0.001	RR 0.47	< 0.01	A I
Brown et al[164] 2020		III	HA + WBRT + Memantine; WBRT + Memantine			Learning 11.5%, memory 16.4%; learning 24.7%, memory 33.3%	0.049; 0.02	AI
van Meerbeeck et al[165] 2019		III	PCI; PCI + HA			HVLT-R 28%; 29%	> 0.05	A I
De Dios et al[167] 2019	LS-ES	III	PCI; PCI + HA			FCSRT 21.7%, 32.6%, and 18.5% at 3, 6 and 12 mo; FCSRT 5.1%, 7.3% and 3.8% at 3, 6 and 12 mo	< 0.05	AI

LS: Limited-stage; ES: Extensive-stage; PCI: Prophylactic cranial irradiation; SCLC: Small cell lung cancer; WBRT: Whole brain radiotherapy; SRS: Stereotactic radiosurgery; HR: Hazard ratio; RR: Relative risk; OR: Odds ratio; MRI: Magnetic resonance imaging; HA: Hippocampal avoidance; BM: Brain metastasis; HVLT-R: Hopkins Revised Verbal Learning Test; FCSRT: Free and cued selective reminding test.