Therapeutic management options for stage III non-small cell lung cancer

Table 1 Prospective trials of multi-modality therapy for resectable stage III non-small-cell lung cancer

Ref.	Phase	Study design	Chemo regimen	RT	Number of patients	Stage	Median f/u (mo)	OS	Median OS (mo)	PFS	Median PFS (mo)	Response rate
Pless et al[35] (2015)		Induction chemoRT + surgery vs induction chemo + surgery	Cisplatin/docetaxel	44 Gy in 2 Gy fxns over 3 wk	232	IIIA (N2)	52.4		37.1 vs 26.2		12.8 vs 11.6 (P = 0.67)	ORR: 61% vs 44%
Thomas et al[36] (2008)	3	Induction chemo + induction chemoRT + surgery vs induction chemo + surgery	Induction: Cisplatin/etoposide ChemoRT: Carboplatin/vinorelbine	45 Gy in 1.5 Gy fxns (twice daily)	524	III A/B (N2/3)		5-yr, 21% vs 18% (P = 0.97)	15.7 mo vs 17.6 mo	5-yr, 16% vs 14% (P = 0.87)	9.5 vs 10	CR: 60% vs 20% (P < 0.0001) Mediastinal downstaging: 46% vs 29% (P < 0.02)
EORTC 08941 Van Meerbeeck et al[37] (2007)	3	Induction chemo + surgery vs chemoRT	Platinum-based	60-62.5 Gy in 1.95-2.05 Gy daily fxns	332	IIIA (N2)	> 72	5-yr, 15.7% vs 14% (P = 0.6)	16.4 vs 17.5 (P = 0.6)	2-yr, 27% vs 24% (P = 0.6)	9 vs 11.3 (P = 0.6)
INT 0139 Albain et al[38] (2009)	3	Induction chemoRT + surgery vs chemoRT	Cisplatin/etoposide	45 Gy boost to 61 Gy if definitive chemoRT	396	IIIA (N2)	22.5	5-yr, 27.2% vs 20.3% (P = 0.10)	23.6 vs 22.2 (P = 0.24)	5-yr, 22.4% vs 11.1% (P = 0.017)	12.8 vs 10.5 (P = 0.017)
RTOG 0229 Suntharalingam et al[39] (2010)	2	Induction chemoRT + surgery	Carboplatin/paclitaxel	50.4 Gy + 10.8 Gy to gross disease	60	III A/B (N2/3)		1-yr, 77%	26.6	1-yr, 52%	13.1	Improved mediastinal sterilization 50% to 70% met
ESPATUE Eberhardt et al[40] (2015)	3	Induction chemotherapy + induction chemoRT + RT boost vs Induction chemotherapy + induction chemoRT + surgery	Induction chemo: Cisplatin/paclitaxel Induction chemoRT: Cisplatin/vinorelbine	45 Gy in 1.5 Gy twice daily fxns Definitive chemoRT: Boost to 65-71 Gy	246	III A/B (N2/N3)	78	5-yr, 40% vs 44% (P = 0.34)		5-yr PFS, 35% vs 32% (P = 0.75)
Eberhardt et al[40] (2015)	3	Induction chemo + induction chemoRT + surgery vs induction chemo + definitive chemoRT	Induction: Cisplatin/paclitaxel ChemoRT: cisplatin/vinorelbine	45 Gy in 1.5 Gy fxns (twice daily)	246	IIIA (N2), select IIIB (N3)	78	5-yr, 40% vs 44%		5-yr, 35% vs 32%

CR: Complete response; ORR: Overall response rate; OS: Overall survival; RT: Radiotherapy; PFS: Progression free survival.

Table 2 Chemotherapy agents for non-small-cell lung cancer by generation

Generation	Agents	Effect on survival for stages II-III
First	Methotrexate Cyclophosphamide Vincristine Doxorubicin	No effect
Second	Cisplatin, cisplatin-based combinations Ifosfamide Mitomycin Vindesine Vinblastine Etoposide	Combination with radiation superior to radiation alone Concurrent superior than sequential chemotherapy and radiation
Third	Paclitaxel, paclitaxel-based combinations Docetaxel Gemcitabine Vinorelbine Irinotecan Topotecan	Expected to be superior to second generation agents given with radiation

Table 3 Prospective trials for hyperfractionated radiation schedules for non-small-cell lung cancer treatment

Ref.	Phase	Study design	Chemo regimen	RT	No. of patients	Stage	Median f/u (mo)	OS	Median OS (mo)	Response rate	Toxicity
RTOG 83-11 Cox et al[106] (1990)	1 and 2	Randomized 1 of 5 dose groups: 60, 64.8, 69.6, 74.4, 79.2 Gy	None	Dose delivered in 1.2 Gy twice daily fxns	848	III	N/A	2-yr, 29% (69.6 Gy arm)	13 (69.6 Gy arm)		Risk for severe/ life-threatening pneumonitis- 2.6% (60 Gy), 5.7% (64.8 Gy), 5.7% (69.6 Gy), 8.1% (74.4 Gy)
RTOG 8808/ ECOG 4588 Sause et al[107] (2000)	3	Conv. RT + chemo vs hyperFRT vs conv. RT	Cisplatin/ vinblastin	Conv RT: 60 Gy in 2 Gy daily fxns HyperFRT: 69.6 Gy in 1.2 Gy twice daily fxns	458	II-IIIB, unresectable	> 60	5-yr, 8%, 6%, 5%	13.2, 12, 11.4		6 G4+ RT-related toxic events-4 of them in hyperFRT arm
RTOG 9410 Curran et al[51] (2010)	3	Sequential chemoRT (conv., arm 1) vs concurrent chemoRT (conv., arm 2) vs concurrent chemoRT (hyperFRT, arm 3)	Cisplatin/vinblastine (arms 1 and 2) Cisplatin/etoposide (arm 3)	Conv: 63 Gy in 1.8 daily fxns HyperFRT: 69.6 Gy in 1.2 Gy twice daily fxns	610	II-III, inoperable	132	5-yr, 10%, 16%, 13%)	14.6, 17, 15.6	ORR- 61%, 70%, 65%	G3+ acute esophagitis- 4%, 22%, 45% No difference in G5 toxicities
Saunders et al[112] (1999)		CHART vs conv. RT	None	Conv RT: 60 Gy in 2 Gy daily fxns HyperFRT: 54 Gy in 1.5, 3 x daily fxns, for consecutive days	563	III	> 48	2-yr, 29% vs 20% (P = 0.004) 2-yr, 33% vs 19% if SCC			Severe dysphagia, 19% vs 3%
ARO 97-1 Baumann et al[113] (2011)		CHARTWEL vs conv. RT	None	Conv RT: 66 Gy in 2 Gy fxns for 6.5 wk CHARTWEL: 60 Gy in 1.5, 3 x daily fxns for 2.5 wk	460	I-IIIB	40.8	2-yr, 31% vs 32% 3-yr, 22% vs 18% 5-yr, 11% vs 7%			Higher incidence of acute dysphagia with CHARTWEL
INCH trial Hatton et al[114] (2011)		Induction chemo + CHART vs CHART alone	Cisplatin/vinorelbine	54 Gy in 1.5 Gy fxns (3 x daily) for 12 consecutive days	46	I-III, inoperable	33		25 vs 17		G3/4 adverse effects 65% vs 57%
ECOG 2597 Belani et al[115] (2005)	3	Induction chemo + conv. RT vs induction chemo + CHART	Carboplatin/paclitaxel	Conventional RT: 64 Gy in2 Gy fxns (daily) 57.6 Gy in 1.6 Gy fxns (3 x daily) for 15 d	141	IIIA/B, inoperable	> 36	2-yr, 24% vs 44% 3-yr, 14% vs 34%	14.9 vs 20.3	ORR, 22% vs 25%	Acute esophagitis 16% vs 25% G3/4 acute pulmonary toxicity observed in conventional RT arm
Hatton et al[100] (2016)	1	Randomized 1 of 4 dose groups: 54, 57.6, 61.2, 64.8 Gy	None	Each dose group delivered in 1.8 Gy, 2-6 fxns daily	18	IIIA/B	21	2-yr, 49% (entire cohort)	24 (entire cohort)	ORR, 61% (entire cohort) CR, 28% (entire cohort)	G3/4 adverse effects in 6 of 18 patients No dose-limiting toxicities

SCC: Squamous cell carcinoma; OS: Overall survival; RT: Radiotherapy.

Table 4 Prospective trials for hypofractionation radiation schedules for non-small-cell lung cancer treatment

Ref.	Phase	Study design	Chemo regimen	RT	No. of patients	Stage	Median f/u (mo)	OS	Median OS (mo)	Response rate	Toxicity
RTOG 8312 Graham et al[116] (1995)	Pilot	HypoFRT	None	75 Gy in 2.68 fxns daily for 5.5 wk	59	IIIA/B		1-yr, 41% 2-yr, 25% 3-yr, 18% 5-yr, 4%	10		Most common was G1/2 pulmonary fibrosis and pneumonitits
Slawson et al[117] (1990)		Conv. RT vs HypoFRT		Conv. RT: 60 Gy in 2 Gy fxns (daily) HypoFRT: 60 Gy in 5Gy fxn (weekly)	150	Locally advanced, unresectable	36	1-yr, 49% vs 59% 2-yr, 23% vs 29%		CR, 17% vs 26%	No difference for later reactions
EORTC 08972-22973 Belderbos et al[61] (2007)	3	Sequential vs concurrent chemo + hypoFRT	Gemcitabine/cisplatin	66 Gy in 2.75 Gy fxns in 32 d	158	I-IIIB, Inoperable	39	2-yr, 34% vs 39% 3-yr, 22% vs 34%	16.2 vs 16.5		G3 hematological toxicity higher in sequential arm (30% vs 6%) Esophagitis more common in concurrent arm (5% vs 14%)
SOCCAR Maguire et al[101] (2014)	2	Sequential vs concurrent chemo + hypoFRT	Cisplatin/vinorelbine	55 Gy in 2.75 Gy fxns over 4 wk	130	III, inoperable	N/A	2-yr, 46% vs 50%	18.3 vs 24.3		G3+ esophagitis 8.5% vs 8.8% Tx-related mortality, 1.7% vs 2.9%
Liu et al[126] (2013)		Concurrent chemo + HypoFRT dose escalation	Carboplatin/vinorelbine	60-75 Gy in 3 Gy fxns for 5 wk	26	IIIA/B, unresectable	11.5	1-yr, 60.9%	13	CR, 26.9% Partial, 53.8% Stable, 19.2% ORR, 80.8%	Acute esophagitis, 88.5% (G3 = 15.4%) Pneumonitits, 42.3% (G3 = 77%)
Lin et al[127] (2013)	1	Concurrent chemo + hypoFRT dose escalation	Carboplatin/vinorelbine	60-72 Gy in 3Gy fxns for 5 wk	13	IIIA/B, unresectable	10			CR, 23.1% Partial, 15.4% Stable, 15.4% ORR, 84.6%	4 instances dose-limiting toxicities, all occurring in 72 Gy arm
Kim et al[128] (2013)		Concurrent chemo + hypoFRT IMRT dose escalation	Cisplatin/vinorelbine	48 Gy in 2.4 Gy fxns with boosts of 16.8 Gy/7, 20 Gy/7, or 22.7 Gy/7	12	II-IIIB, unresectable	22	1-yr, 58.3%	12.7	CR, 75% Partial, 33% Stable, 25%	No G3 acute or late radiation-toxicities

HypoFRT: Hypofractionation; IMRT: Intensity-modulated radiotherapy; CR: Complete response.