Role of radiotherapy in oligometastatic breast cancer: Review of the literature

Table 1 Prospective randomized phase III trials investigating the role of locoregional treatment in de novo metastatic breast cancer

Ref.	n	Treatment	Patients	Median follow-up (mo)	Outcomes
Khan et al[21] (ECOG-ACRIN E2108)	256	Primary systemic therapy: LRT (n = 125); No LRT (n = 131)	NR	59	3-yr OS: 68.4% vs 67.9%, P = 0.63
					3-yr locoregional recurrence/progression: 10.2% vs 25.6%, P = 0.003
Fitzal et al[18] (ABCSG-28 POSYTIVE)	90	Arm A: Primary surgery + systemic therapy (n = 45)	Arm A: More cT3 and cN2 tumors	37.5	Stopped early
					Median OS (mo): 34.6 vs 54.8, P = 0.267
					Time to distant progression (mo): 13.9 vs 29.0, P = 0.0668
		Arm B: Primary systemic therapy (n = 45)
Soran et al[20] (MF07-01)	274	LRT + systemic therapy (n = 138)	LRT arm: More ER/PR (+), less triple negative tumors	54.5 vs 55	Median OS (mo): 46 vs 37, P = 0.005
		Systemic therapy (n = 136)			Unplanned subgroup analysis: Improvement in survival: ER/PR (+), HER2 (-), < 55 yr, solitary bone-only metastasis
Badwe et al[19] (NCT00193778)	350	Primary systemic therapy: LRT (n = 173); No LRT (n = 177)	Similar patient and tumor characteristics	23	Median OS (mo): 19.2 vs 20.5, P = 0.79
					Median LR-PFS (mo): not attained vs 18.2, P < 0.0001
					Median distant-PFS (mo): 11.3 vs 19.8, P = 0.012

NR: Not reported; LRT: Locoregional treatment; c: Clinic; T: Tumor; N: Node; ER: Estrogen receptor; PR: Progesterone receptor; OS: Overall survival; HER2: Human epidermal growth factor receptor 2; LR: Locoregional; PFS: Progression-free survival.

Table 2 Retrospective studies published within the last decade investigating the impact of locoregional treatment to the primary tumor site in de novo metastatic breast cancer

Ref.	n	Treatment	Patient	Median follow-up (mo)	Outcomes
Ma et al[35]	987	Surgery (n = 463)	Surgery arm: More T1-2, HR-positive, solitary metastasis, bone only metastasis	NR	Median survival (mo): 45 vs 28, P < 0.001
		No surgery (n = 524)
					Better survival in surgery after systemic therapy than primary surgery
					Triple negative, brain metastases: No benefit of surgery
Lane et al[16] (NCDB)	24015	Systemic therapy alone (n = 13505)	Surgery after systemic therapy arm: Younger, more T3-4 and HR-negative	NR	Median OS (mo): 37.5 vs 49.4 vs 52.8, P < 0.001
		Surgery before systemic therapy (n = 4552)			RT: No impact on OS
		Systemic therapy before surgery (n = 5958)
Li et al[36] (SEER database)	20870	Surgery (n = 5779)	Surgery arm: Younger, more T1-3, N+, Gr III, and less HR+	NR	Surgery arm (± RT): Improved BCSS and OS (P < 0.001)
		No surgery (n = 15091)
			More chemo and RT received
Pons-Tostivint et al[37]	4276	LRT (n = 1706): Surgery, RT or both	LRT arm: Younger, more solitary or bone-only metastases	45.3	Median OS (mo): HR-positive, HER2- negative: 61.6 vs 45.9, P < 0.001
		No LRT (n = 2570)			HR-positive, HER2-positive: 77.2 vs 52.6, P = 0.008
					Triple negative: 19 vs 18.6, P = 0.54
					Bone only metastases: 70.4 vs 62, P < 0.001
					Visceral metastases: 83 vs 52.7, P < 0.001
Choi et al[38]	245	LRT (n = 82): Surgery, RT or both	LRT arm: < T4, no liver or brain metastasis, and < 5 metastatic sites	40	5-yr LRFS: 62% vs 20%, P < 0.001
					5-yr OS:73% vs 45%, P = 0.02
		No LRT (n = 163)
Gultekin et al[7]	227	LRT (n = 188): Surgery, RT or both	LRT arm: Less T3-4 and more solitary metastases	35	5-yr OS: 56% vs 24%, P < 0.001
					5-yr PFS: 27% vs 7%, P < 0.0001
		No LRT (n = 39)
Nguyen et al[39]	733	LRT (n = 378): Surgery, RT or both	LRT arm: Younger, more T1-2, N0-1, limited M1 disease	21	5-yr OS: 21% vs 14%, P < 0.001
					5-yr PFS 72% vs 46%, P < 0.001
		No LRT (n = 355)
Neuman et al[25]	186	Surgery (n = 69): 13% RT	Surgery arm: More HER2-negative, smaller tumors, more solitary metastasis	52	No difference in OS (P = 0.10)
		No surgery (n = 117)

NCDB: National Cancer Database; SEER: Surveillance, Epidemiology, and End Results, RT: Radiotherapy; LRT: Locoregional treatment; T: Tumor; HR: Hormone receptor; HER2: Human epidermal growth factor receptor 2; N: Node, Gr: Grade; M: Metastasis; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; BCSS: Breast cancer-specific survival; LRFS: Local recurrence-free survival.

Table 3 Retrospective studies investigating the role of radiotherapy as a local treatment of metastases in oligometastatic disease

Ref.	n	Treatment	Patients	Median follow-up (mo)	Outcomes
Weykamp et al[28]	46	SBRT: Bone, lung, liver, adrenal gland	Inclusion criteria: breast cancer, oligometastatic (≤ 3) or oligoprogressive (1) disease	21	2-yr LC, DC, PFS and OS: 89%, 44%, 17%, and 62%, respectively
		Median 3 frx (1-10)/28 Gy (24-60 Gy)
					Solitary metastasis: Poor prognostic factor for DC and PFS
			58 lesions
					Higher age: Poor prognostic factor for OS
Kobayashi et al[29]	75	Primary systemic chemotherapy: CR/PR	Inclusion criteria: breast cancer, ≤ 2 metastatic organs, < 5 metastases, < 5 cm lesions	103	10-yr and 20-yr OS: 59.2% and 34.1%, respectively
		Surgery or RT			10-yr and 20-yr RFS: 27.4%
					Single organ metastasis, local treatment and shorter DFI: Better RFS
Hong et al[4]	361	SBRT	Extracranial oligometastases (≤ 5)	26.2	3-yr OS, PFS and TMC were 56%, 24%, and 72%, respectively
		10 frx/50-60 Gy or 3 frx/24-48 Gy
			Breast cancer (16%)
					Primary tumor type, interval to metastasis, number of treated metastasis, and mediastinal/hilar LN, liver, or adrenal metastases: Associated with OS
					All breast cancer patients: RPA class 1 (3-yr OS 75%)
Cha et al[40]	49	Endocrine therapy plus LRT (n = 33)	Inclusion criteria: HR-positive, HER2-negative	101.6 vs 105.6	Median OS (mo): 72.3 vs 91, P = 0.272
		82% RT: Bone, LN
		Endocrine therapy alone (n = 16)
					Median PFS (mo): 30 vs 18, P = 0.049
			Similar patient and tumor characteristics

SBRT: Stereotactic body radiation therapy; frx: Fraction, Gy: Gray, CR: Complete response; PR: Partial response; RT: Radiotherapy; LN: Lymph node; LRT: Locoregional treatment; HR: Hormone receptor; HER2: Human epidermal growth factor receptor 2; LC: Local control; DC: Distant control; OS: Overall survival; PFS: Progression-free survival; DFI: Disease-free interval; TMC: Treated metastasis control; RPA: Recursive partitioning analysis.

Table 4 Prospective studies exploring the role of radiotherapy to metastatic sites in oligometastatic disease including primary breast cancer

Ref.	n	Treatment	Patients	Median follow-up (mo)	Outcomes
Palma et al[5] (SABR-COMET)	99	Palliative RT ± systemic therapy (n = 33)	Inclusion criteria: 1-5 metastases, life expectancy ≥ 6 mo, controlled primary tumor	51	5-yr OS: 17.7% vs 42.3%, P = 0.006
					4-yr PFS 3.2% vs 21.6%, P = 0.001
		1 frx/8 Gy or 10 frx/30 Gy
					LC 46% vs 63%, P = 0.039
		SABR ± systemic therapy (n = 66)
					≥ Gr 2 toxicity: 9% vs 29%, P = 0.026
			Primary breast cancer (n): 5 vs 13
		Different regimens according to tumor size and location			SABR: Gr 5 toxicity (n = 3)
Milano et al[9]	48	HSRT: ≥ 50 Gy in 10 frx	Inclusion criteria: breast cancer, 1-5 extracranial metastases, primary controlled	52	5- and 10-yr OS:
					Bone-only oligometastases: 83% and 75%
					Non-bone-only oligometastases: 31% and 17% (P = 0.002)
					GTV > 25 cc: Poor prognostic factor for LC
Trovo et al[6]	54	SBRT: 3 frx/30-45 Gy (n = 44)	Inclusion criteria: breast cancer, ≤ 5 extracranial metastases, primary controlled	30	2-y LC: 97%
					2-y OS: 95%
		IMRT: 25 frx/60 Gy (n = 10)			1- and 2-yr PFS: 75% and 53%, respectively
					No ≥ Gr 3 toxicity
			92 lesions
Salama et al[26]	61	SBRT: Lung, LN, liver, bone, adrenal, soft tissue, pancreas	Inclusion criteria: 1-5 metastatic sites, life expectancy > 3 mo	20.9	1-yr and 2-yr OS: 81.5% and 56.7%, respectively
					1-yr and 2-yr PFS: 33.3% and 22.0%, respectively
		3 frx/24-48 Gy	Breast cancer (11.3%)
Scorsetti et al[31]	33	SBRT: 3-4 frx/48-75 Gy	Inclusion criteria: breast cancer, < 5 lung or liver metastases, other metastatic sites stable or responding after chemotherapy	24	1- and 2-yr LC: 98% and 90%, respectively
					1- and 2-yr OS: 93% and 66%, respectively
					1- and 2-yr PFS: 48% and 27%, respectively
					No grade 3-4 toxicities
			43 lesions
Milano et al[30]	40	SBRT doses and fractionation was not mentioned	Inclusion criteria: breast cancer, ≤ 5 metastases	NR	4-yr OS: 59%
					4-yr PFS: 38%
					4-yr LC: 89%
					Favorable prognosis: Solitary metastasis, smaller tumor volume, bone-only disease, and stable or regressing lesions

RT: Radiotherapy; frx: Fraction; Gy: Gray; SBRT: Stereotactic body radiation therapy; HSRT: Hypofractionated stereotactic radiotherapy; IMRT: Intensity-modulated radiation therapy; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; LC: Local control; LN: Lymph node; Gr: Grade; GTV: Gross tumor volume.