New perspectives in the management of small cell lung cancer

Table 1 Surgical and survival rates for patients with small cell lung cancer (period time revised 1999-2020) - (dash), lack of information or details

Ref.	Study type & time period. LoE	Inclusion criteria	Number of patients	Neoadjuvant/adjuvant treatments	PCI	Survival data
Jin et al[9], 2018	RS; SEER 2004-2013; 3A	cI-II	n = 2129; S: 387; RT 1032; S + RT: 154; No S or RT: 556		-	5-yr OS T1N0: 46.0% S vs 23.8% RT; 5-yr OS T2N0: 42.6% S vs 24.7% RT; T3N0 or T1-2N1 (stage IIB) patients treated with S did not have higher 5-yr OS rates than those treated with RT
Yang et al[10], 2018	RS; NCDB 2003-2011; Propensity score match S + AC vs CRT; 3A	cT1-2N0M0	S + AC: 501; CRT: 501	S + AC: 501	-	5-yr OS: 47.6% S + AC vs 29.8% CRT (P < 0.01)
Ahmed et al[11], 2017	RS; SEER 2007-2013; 3A	Stage I SCLC	n = 1902; S: 427; S + RT: 115	-	-	MST: 50 mo (S); MST: 60 + mo (S + RT)
Wakeam et al[12], 2017	RS; NCDB 2004-2013; 3A	cT1-2N0M0	n = 5079	-		MST: 25.3 mo
Wakeam et al[13], 2017	RS; NCDB 2004-2013; Stage-specific propensity score match S vs NST; 3A	cI-III	n = 2619	No AD treatment 24% NC or NR 4%; AC 27%; AR 1%; ACR 32%; NC or NR and AC or AR 2%; Other 10%	-	MST cI 38.6 vs 22.9 mo S vs NST; MST cII 23.4 vs 20.7 mo S vs NST; MST cIIIA 21.7 vs 16.0 mo S vs NST
Combs et al[14], 2015	RS; NCDB 1998-2011; 3A	cT1-3N0-2 SCLC	n = 2476; S 841 cIA, 168 cIB	All; S: 68%	-	5-yr OS: 54% (cIA); 36% (cIB)
Ogawa et al[15], 2012	RS; Institutional 1995-2008; 4	cI-III; pI-III SCLC	n = 28 (23 SCLC before S); S 21 cI, 5 cII, 7 cIII2	NC 8; AC 19, ACR 2	-	5-yr OS 47%
Ju et al[16], 2012	RS; Institutional 1990-2009; 4	pI-III	n = 34	NC 3; AC 1, AR 19, 10 CRT	-	5-yr OS 66%
Vallières et al[6], 2009	RS; IASLC 1990-2000; 3A	Resected SCLC	n = 349 (68 pIA, 91 pIB)	-	-	5-yr OS: 53% (pIA); 44% (pIB)
Lim et al[17], 2008	RS; Institutional 1980-2007; 4	cI-cIIIB	n = 59	AC 13; AR 2; ACR 1	-	5-yr OS for all patients 52%; No difference in 5-yr survival across; cT and cN categories; No difference in 5-yr survival across; cI to cIII stages
Wang et al[18], 2007	RS; Institutional; 4	pI-III	n = 122	QT & CRT (not specified)	-	MST 50 mo; 5-yr OS 66%
Veronesi et al[19], 2007	RS; Institutional; 4	cI-IIIA	n = 23	AC all	-	MST 24 mo
Tsuchiya et al[20], 2005	Prospective phase II trial; 1991-1996; 2B	cI-IIIA	n = 62	AC 42 (69%)	-	MST not reached in pI; MST 449 d for pII; MST 712 d for pIIIA; 3-yr OS 61%; 3-yr survival rate cI, cII, cIIIA 68%, 56% and 13% respectively
Brock et al[21], 2005	RS; Institutional 1976-2002; 4	Resected SCLC	n = 82 (24 stage I, S + AC)	AC 55%	23%	5-yr OS: 86% (platinum AC); 42% (non-platinum AC)
Nakamura et al[22], 2004	RS; Institutional; 4	cI-III SCLC	n = 69	S 37, NC 32, AC 41, ACR 7	-	5-yr survival 48.9 % cI, 33.3 % cII, 20.2 % cIIIA, 0 % cIIIB
Badzio et al[23], 2004	Comparative RS; Institutional 1984-1996; 4	cI-III balanced in both, S and NST groups	n = 134	S 67 (all AC); NST 67 (all QT)	34% only S group	MST 22 mo (S); MST 11 mo (NST); 5-yr OS S 27%, NST 4%
Lewiński et al[24], 2001	R; Institutional 1976-2002; 4	cI-IIIA SCLC	n = 75	NC all	If CR to NC	MST N0+1 25 mo; MST N2 14 mo; MST resected 18 mo; 5-yr OS resected 29%
Cataldo et al[25], 2000	RS; Institutional 1982-1992; 4	cI-III SCLC	n = 60	AC 88%; pII AR (11%); pIII AR (21%)	41%	5-yr survival rate 40% pI, 36% pII and 15% pIII
Inoue et al[26], 2000	RS; Institutional 1975-1994; 4	Resected SCLC	n = 91 (32 cIA, 30 cIB)	All 78%	5.5%	MST 53 mo, 5-yr OS 49% (cIA); MST 25 mo, 5-yr OS 47% (cIB)
Kobayashi et al[27], 2000	RS; Institutional 1982-1992; 4	cI-III SCLC	n = 59	NC 71%	-	5-yr survival rate 55% pI, 33% pII, 23% pIII
Eberhardt et al[28], 1999	Prospective phase II trial; Institutional 1991-1995; 2B	cIB-cIIIB	n = 46	IB/IIA had NC + S; IIB/IIIA had NCR + S	-	MST all patients 36 mo; MST R0 patients 68 mo; 5-yr survival rate all patients 46%; 5-yr survival rate R0 patients 63%

ACR: Adjuvant chemoradiotherapy; AD: Adjuvant; AC: Adjuvant chemotherapy; cIA: Clinical stage IA; cIB: Clinical stage IB; CR: Complete response; CRT: Chemoradiotherapy; IASLC: International Association for the Study of Lung Cancer; ISC-LCSG: The Lung Cancer Study Group of the International Society of Chemotherapy; LoE: Level of evidence; MST: Median survival time; NC: Neoadjuvant chemotherapy; NST: Non-surgical treatment; NCDB: National Cancer Data Base; OS: Overall survival; PCI: Prophylactic cranial irradiation; pIA: Pathologic stage IA; pIB: Pathologic stage IB; pII: Pathologic stage II; pIIIA: Pathologic stage IIIA; pIIIB: Pathologic stage IIIB; QT: Chemotherapy; R0: Complete resection; RS: Retrospective study; RT: Radiotherapy; S: Surgery; SCLC: Small cell lung cancer; SEER: Surveillance, Epidemiology, and End Results database.

Table 2 Thoracic radiotherapy and stereotactic body radiotherapy in early-stage small cell lung cancer

Ref.	Sample size	Fractionation	QT	Prophylactic cranial irradiation	Local control	Overall survival	Disease-free survival
Videtic et al[76], 2013	n = 6	60 Gy (3 fx); 50 Gy (5 fx); 30 Gy (1 fx)	4/6	4/6	100% (1 yr)	63% (1 yr)	75% (1 yr)
Shioyama et al[77], 2015	n = 64	48 Gy (4 fx)	36/64	10/64	89% (2 yr)	76% (2 yr)
Stahl et al[79], 2017	n = 285	48-60 Gy (3-5 fx)	130/285		35% (3 yr). 21.5% (5 yr)
Verma et al[75], 2017	n = 74	50 Gy (5 fx)	45/74	17/74	96% (3 yr)
Shioyama et al[78], 2018	n = 43	36-60 Gy (3-10 fx)	8/43	8/43	80.2% (2 yr)	72.3% (2 yr)	44.6% (2 yr)
Verma et al[74], 2019	n = 149	45-60 Gy (3-8 fx)	149/149		83.8% (29.2 mo)
Newman et al[81], 2019	n = 239	BED > 100 Gy (max 8 fx)	84/239		27% (5 yr); 36% (5 yr, with QT)
Singh et al[80], 2019	n = 21	BED 105.6 Gy (3-5 fx)	4/21		100% (1, 2, 3 yr)	73.1% (1 yr); 36.6% (2 yr)	85.7% (1 yr); 42.9% (2 yr)

BED: Biologically equivalent dose; fx: Fraction; QT: Chemotherapy.

Table 3 Combined first-line immunotherapy options for extensive-stage small cell lung cancer

Study	n	Design	Treatment	RR	PFS	OS
NCT01450761	1132	Phase III; Randomized, double-blind; Drug: Ipilimumab	Arm A: PE × 4C + ipilimumab × 4C; Control: PE × 4C + placebo × 4C	PR 62% vs 62%; SD 26% vs 27%; PD 6% vs 9%	4.6 vs 4.4 mo; HR = 0.85, P = 0.0161	11.0 vs 10.9 mo; HR = 0.94, P = 0.3775
Impower 133	403	Phase III. Randomized, double-blind; Drug: Atezolizumab	Arm A: PE + atezolizumab × 4C/atezolizumab; Control: PE + placebo × 4C/placebo	60% vs 64%	5.2 vs 4.3 mo; HR = 0.77, P = 0.02	12.3 vs 10.3 mo; HR = 0.70, P = 0.007
CASPIAN	805	Phase III. Randomized, open-label; Drug: Durvalumab	Arm B (n = 268): Durvalumab + PE × 4C/durvalumab; Control: PE × 4C	68% vs 58%	5.1 vs 5.4 mo; HR = 0.78, P not tested	13.0 vs 10.3 mo; HR = 0.73, P = 0.0047
CASPIAN	805	Phase III. Randomized, open-label; Drug: Durvalumab + tremelimumab	Arm A (n = 268): Durvalumab + tremelimumab + PE × 4C/durvalumab + tremelimumab. Control: PE × 4C	58% both arms	4.9 vs 5.4 mo; HR = 0.84	10.4 vs 10.5 mo; HR = 0.82, P = 0.045
KEYNOTE 604	453	Phase III; Randomized, double-blind; Drug: Pembrolizumab	Arm A: Pembrolizumab + PE; Control: PE + placebo	71% vs 62%	4.5 vs 4.3 mo; HR = 0.75, P = 0.0023	10.8 vs 9.7 mo; HR = 0.80, P = 0.0164
ECOG-ACRIN	160	Phase I. Randomized, open-label; Drug: Nivolumab	Arm A: PE + nivolumab × 4C/nivolumab; Control: PE × 4C	52.29% vs 47.71%	5.5 vs 4.6 mo; HR = 0.65, P = 0.012	11.3 vs 8.5 mo; HR = 0.67, P = 0.038

4C: 4 cycles; OS: Overall survival; PD: Progressive disease; PE: Platinum and etoposide; PFS: Progression free survival; PR: Partial response; RR: Response rate; SD: Stable disease.