Management of oligometastatic non-small cell lung cancer patients: Current controversies and future directions

Table 1 Prospective trials of local treatment in oligometastatic disease

Author	n	Primary site, n	Treatment groups	Type of treatment	Endpoints	Toxicity
Rusthoven et al[7], 2009	47	CRC: 15; Lung: 10; breast: 4; other: 10	SBRT	Phase I: 36-60 Gy in 3 fx; Phase II: 60 Gy in 3 fx.	LC 2 yr: 92%; OS 2 yr: 30%	G3: 2%; No RILD
Salama et al[29], 2011	61	NSCLC: 11; SCLC: 5; H&N: 5. Other: 40	SBRT	3 fx: 8 Gy 3 fx: 20 Gy	MFu: 20.9 mo; PFS 2 yr: 22%; OS 2 yr: 56.7%	G3 (n = 2)
Iyengar et al[88], 2014	24	NSCLC	SBRT: 1 fx: 19-24 Gy; 3 fx: 27-33 Gy; 5 fx: 35-40 Gy	SBRT + erlotinib	MFU: 11.6 mo; PFS: 14.7 mo;; OS: 20.4 mo	G3 (n = 2); G4 (n = 1); G5 (n = 1) (after SBRT to three sites)
Collen et al[104], 2014	26	NSCLC	SBRT after primary treatment	50 Gy in 10 fx	MFu: 16.4 mo; PFS 1 yr: 45%, median 11.2 mo; OS 1 yr: 67%	G2: 15% G3: 8% (n = 2)
Gomez et al[33], 2018	49	NSCLC	LCT (CRT/Surgery of all lesions) vs maintenance therapy/obs.	SBRT n = 5; Surgery n = 3; pemetrexed n = 16, erlotinib n = 2; afatinib n = 1, bevacizumab	Median PFS: 14.2 mo/4.4 mo (P < 0.05) Median OS: 41.2 mo/17.0 mo (P < 0.05)	Similar, G3
Iyengar et al[31], 2018	29	NSCLC	Maintenance Ct alone vs SBRT followed by maintenance Ct	Ct: carboplatin + pemetrexed; SBRT: 1, 3 and 5 fractions with 21-27 Gy, 26.5-33 GY and 30-37.5 Gy respectively	MFu: 9.6 mo Median PFS: -Ct: 3.5 mo -SBRT: 9.7 mo (P < 0.05); Median OS: - no difference	G3 n: 4 vs 2; G4 n: 1 (ct only); G5 n: 3 vs 6. No grade 3 or higher toxicity attributable to SBRT
De Ruysscher et al[30], 2018	40	NSCLC	Primary: RT or CRT, LCT (surgery, SBRT)	SBRT: 54 Gy of bone metastases. CNS: 1 fx: 8-20 Gy single or 24 Gy × 3 fx. PORT: 60 Gy	Median OS: 13.5 mo; 2-6 yr OS: 23.3%-10.3% Median PFS: 12.1 mo; 2-6 yr PFS: 51.3%-2.5%	G3 esophagitis: 15%; > G4: 0%

CRC: Colorectal cancer; NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; CNS: Central nervous system; ECOG: Eastern Cooperative Oncology Group; PORT: Postoperative radiotherapy; PFS: Progression-free survival; MFU: Median follow up; OS: Overall survival; LCT: Local consolidative therapy; Ct: Chemotherapy; RT: Radiotherapy; fx: Fraction; CRT: Chemoradiotherapy; SBRT: Stereotactic body radiotherapy; LC: Local control; RILD: Radiation-induced liver disease; H&N: Head and neck.

Table 2 Publishes results for stereotactic body radiation therapy-treated liver metastases

Study	Number of lesions	Patients, n	Primary tumor	Dose/fractions	Toxicity	Mean follow-up, mo	Control, local	Survival
Blomgren et al[74]	Variable	31	Various	8-66 Gy/1-4	2 Hemorrhagic gastritis	1.5-3.8	80%	Not reported
Hoyer et al[75]	1-6 (< 6 cm)	44	Various	45 Gy/3	1 liver failure 2 severe GI toxicity	52	2-yr: 86%	1-yr: 67% 2-yr: 38%
Mendez Romero et al[76]	1-3 (< 7 cm)	25	Various	37.5 Gy/3	4 acute grade ≥ 3 1 late grade 3	12.9	2-yr: 86%	1-yr: 85% 2-yr: 62%
Rusthoven et al[7]	1-3 (< 6 cm)	47	Various	60 Gy/3	< 2% late	16	2-yr: 92% < 3 cm: 100%	mean, 17.6 mo
Lee et al[77]	Variable	68	Various	28-60 Gy/3	Acute: 8 GIII, 1 GIV	10.8	1-yr: 71%	18 m: 47%
Ambrosino et al[78]	1-3 (< 6 cm)	27	Various	25-60 Gy/3	Not reported	13	74%	Not reported
Goodman et al[79]	1-5 (< 5 cm)	26	Various	18-30 Gy/1	Late: 4 GII	17.3	1-yr: 77%	1-yr: 62% 2-yr: 49%
Rule et al[80]	1-5	27	Various	30 Gy/3 50-60 Gy/5	No ≥ G2	20	30 Gy: 56% 50 Gy: 89%60 Gy: 100%	30 Gy: 56% at 2-yr 50 Gy: 67% at 2-yr 60 Gy: 50% at 2-yr
Scorsetti et al[81]	1-3 (< 6 cm)	61	Various	52.5-75/3	No ≥ G3	24	91%	1-yr: 80%2-yr: 70%
Mahadevan et al[70]	Variable	427	Various	45 (12-60) / 3 (1-5)	Not reported	14 (1-91)	Median: 52 mo 1-yr: 84%2-yr: 72%	Mean: 22 mo 1-yr: 74% 2-yr: 49%

GI: Gastrointestinal.

Table 3 Clinical trials in patients with oligometastatic non-small cell lung cancer

Clinical trial identifier	Title	Objective
NCT01185639	Stereotactic Body Radiation Therapy (SBRT) in Metastatic Non-Small Cell Lung Cancer	To evaluate the efficacy of SBRT in oligometastatic NSCLC patients who achieve partial response or stable disease after 4 cycles of ChT. The hypothesis is that SBRT after 4 cycles of ChT is feasible, safe, with good local control, and improves time to progression
NCT 02314364	A Trial of Integrating SBRT With Targeted Therapy in Stage IV Oncogene-driven NSCLC	To evaluate SBRT in patients with stage 4 NSCLC and EGFR, ALK, or ROS1 mutations who have been treated with erlotinib, gefitinib, or other targeted drugs
NCT03275597	Phase Ib Study of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Non-small Lung Cancer (NSCLC) With Dual Immune Checkpoint Inhibition	To evaluate the safety and tolerability of SBRT combined with durvalumab and tremelimumab for oligometastatic NSCLC
NCT02975609	Phase II Trial of SBRT Compared With Conventional Radiotherapy for Oligometastatic Non-Small Cell Lung Cancer	To compare the efficacy and safety of SBRT vs conventional radiotherapy after response to 4-6 cycles of chemotherapy. Outcome measures for both groups include PFS, OS, and adverse effects
NCT03808337	Investigating the Effectiveness of Stereotactic Body Radiotherapy (SBRT) in Addition to Standard of Care Treatment for Cancer That Has Spread Beyond the Original Site of Disease	To determine if SBRT to all oligometastatic lesions can extend time to progression
NCT02417662	Stereotactic Ablative Radiotherapy for Oligometastatic Non-small Cell Lung Cancer (SARON)	Phase III study of efficacy and safety in oligometastatic NSCLC patients comparing conventional ChT alone to ChT plus conventional radiotherapy to the primary tumor and SBRT to the metastases

SBRT: Stereotactic body radiation therapy; NSCLC: Non-small cell lung cancer; ChT: Chemotherapy; PFS: Progression-free survival; OS: Overall survival.