Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases

Table 1 Chemotherapy for advanced or metastatic disease (NCCN and ESMO guidelines)

Options for	Options for therapy	Options for therapy
Initial therapy	After first progression	After second progression
FOLFOX +/- bmab or cetux/pmab1	Irinotecan +/- bmab or aflib or cmab/pmab1	Irinotecan + cmab or pmab1
CAPOX +/- bmab or cmab/pmab1	FOLFIRI +/- bmab or aflib or cmab/pmab1	Regorafenib
		Clinical trial
		Best supportive care
FOLFIRI +/- bmab or cmab/pmab1	FOLFOX +/- bmab	CAPOX
	CAPOX +/- bmab	FOLFOX
	Irinotecan + cmab/pmab1	Irinotecan + cmab/pmab1
		Regorafenib
		Clinical trial
		Best supportive care
Bmab + 5-FU/LV or Cape or FOLFOXIRI	Bmab + FOLFOX/FOLFIRI/Irinotecan/CAPOX	Irinotecan + cmab/pmab1
	Bmab + Irinotecan + Oxaliplatin	FOLFOX
	Aflib + FOLFIRI/Irinotecan	CAPOX
	Irinotecan + cmab/pmab1	Regorafenib
	Regorafenib

¹(KRAS/NRAS WT gene only). Bmab: Bevacizumab; Cape: Capecitabine; Cmab: Cetuximab; Pmab: Panitumumab; Aflib: Aflibercept.

Table 2 Highlights of ongoing clinical trials (National Cancer Institute) regarding systemic treatment for metastatic colorectal cancer

Protocol ID	Principle investigator	Phase, purpose, and relevance
NCT02149108	Boehringer Ingelheim	Phase III study of salvage nindetanib
NCT02305758	AbbVie	Phase IIstudy of first-line veliparib (PARP inhibitor) added to FOLFIRI +/- bmab
NCT02060188	Bristol-Myers Squibb	Phase II study of nivolumab (anti-PD1 antibody) +/- Ipilimumab in recurrent and microsatellite high (MSI-H) colon cancer
NCT02119676	Incyte	Phase II study of salvage ruxolitinib (a JAK1 and JAK2 inhibitor) in combination with regorafenib
NCT02260440	University of Pittsburgh	Phase II study of salvage pembrolizumab (anti-PD1) in combination with azacitidine
NCT01661972	Duke University Medical Center	Phase I/II study of capecitabine plus aflibercept (“X-TRAP study”)
NCT02168777	Bayer	Phase I/II study of remafetinib with regorafenib
NCT02079740	National Cancer Institute, United States	Phase Ib/II study of trametinib (a MEK inhibitor) and navitoclax (BCL-2 Family Inhibitor) in KRAS mutant advanced tumors
NCT00940316	Genentech, OSI Pharmaceuticals, Amgen	Phase I/II study of dual epidermal growth factor receptor inhibition With Erlotinib and Panitumumab with or without chemotherapy
NCT01985763	Mt. Sinai School of Medicine, New York City	Phase I/II study of first line genistein (a soy derivative that interrupts Wnt signaling) in addition to standard regimens
NCT01471353	University of Florida	Phase II study of salvage sorafenib plus capecitabine (SorCape)
NCT01750918	GlaxoSmithKline	Phase I/II study of trametinib and dabrafenib in combination with panitumumab in BRAF-mutation V600E colorectal cancer and in patients with resistance to prior anti-EGFR therapy

Table 3 Highlights of radiofrequency ablation literature for colorectal liver metastases

Ref.	Level of evidence	Year	Study details	1 yr OS%	3 yr OS%	5 yr OS%	7 yr OS%	10 yr OS%	Median OS (mo)	Procedure-related complications
1Gillams et al[53]	II-2	2004	Prospective, 167 patients	91	28	25			38	< 1% (1/167)
			Percutaneous (ValleyLab)
			Mean 4 lesions
			Mean 4 cm max diameter
Hildebrand et al[108]	II-2	2006	Prospective, 88 pts/420 lesions	92	42				28	3.4% (3/88)
			Percutaneous (RITA/ValleyLab)
			Mean 3.5 lesions
			Median 2.7 cm max diameter
Siperstein et al[109]	II-2	2007	Prospective, 234 patients		20.2	18.4			24	Not reported
			Laparoscopic
			Mean 3 lesions
			Median 4 cm max diameter
Berber et al[110]	II-2	2008	Prospective, 68 pts/68 lesions		20.6	30			20.5	2.9% (2/68)
			Laparoscopic
			All solitary lesions
			Median 3.7 cm max diameter
Veltri et al[111]	II-2	2008	Retrospective, 122 pts/199 lesions	79	38	22			31.5	1% (2/199)
			Percutaneous (RITA/ValleyLab /LeVeen)
			Mean 1.6 lesions
			Median 3 cm max diameter
Gleisner et al[112]	II-2	2008	Prospective, 66 patients	92.3	51.1	28.3			38.1	Not reported
			Intraoperative (RITA)
			Median 2 lesions
			Median 3 cm max diameter
1Gillams and Lees[113]	II-2	2009	Prospective, 309 pts/617 lesions		49	24			36	3.7% (23/617)
			Percutaneous (Covidien/RITA)
			Mean 4 lesions
			Median 2.3 cm max diameter
Sofocleous et al[114]	II-2	2011	Prospective, 56 pts/71 lesions	91	41				31	4% (2/56)
			Percutaneous (LeVeen/Valleylab/RITA)
			Mean 1.4 lesions
			Median 1.9 cm max diameter
Solbiati et al[115]	II-2	2012	Retrospective, 99 pts/202 lesions	98	69.3	47.8	25	18	53.2	1.3% (2/156)
			Percutaneous (Covidien)
			Mean 2 lesions
			Mean 2.1 cm diameter +/- 0.75 cm std deviation
Bale et al[52]	II-2	2012	Retrospective, 63 pts/189 lesions	87	44	27			27 mo for unresectable patients,	17% (17/98)
			Percutaneous (Covidien) with Treon Navigation						58 mo for resectable patients
			Mean 2 lesions						(P = 0.002)
			Mean 2 cm diameter
Hamada et al[116]	II-2	2012	Retrospective 84 pts/141 lesions	90.6	44.9	20.8			34.9	2.2% (3/138)
			Percutaneous (Valleylab)
			Mean 1.7 lesions
			Mean 2.3 cm max diameter +/- 1.4 cm

¹Partially redundant series. Level of Evidence based on the United States Agency of Healthcare Research and Quality Classification of Levels of Evidence. OS: Overall survival.

Table 4 Highlights of cryoablation literature for colorectal liver metastases

Ref.	Level of evidence	Year	Study details	1 yr OS%	3 yr OS%	5 yr OS%	Median OS (mo)	Procedure-related Complications
Rivoire et al[117]	II-2	2002	Retrospective, 24 patients, 69 lesions	92	58		39	21% (5/24) had iceball fracture, successfully treated with suture (all cryoablation performed at laparotomy)
			Laparotomy (Erbokryo CS-6)
			10-15 min freeze, 5 min thaw, 5-10 min freeze, occasionally with Pringle maneuver
			Mean 3 lesions
			Mean 4.5 cm max diameter
Yan et al[118]	II-2	2003	Prospective, 172 pts/420 lesions Laparotomy (L.C.S. 3000/Erbe) 1 cm margin, freeze-partial thaw-freeze Mean 4 lesions	89	41	19	28	28% (48/172) (all cryoablation performed at laparotomy, not percutaneously)
			Median 3.6 cm max diameter					Gelfoam packed into every tract
Brooks et al[119]	II-2	2005	Prospective, 93 patients	85	43	19	33	Cryoablation-related complications not specifically reported
			Laparotomy (L.C.S. 3000/Erbe)
			Median 2 lesions
Niu et al[120]	II-2	2007	Prospective, 124 pts/124 lesions	84	43	24	29	Not reported
			Laparotomy (L.C.S. 3000/Erbe)					Gelfoam was packed into every tract
			1 cm margin, freeze-partial thaw-freeze
			For lesions > 3 cm, two probes always used
			Mean 4 lesions
			Mean 4 cm max diameter
Paganini et al[121]	II-2	2007	Retrospective, 49 pts	87	43	23	31	22% (11/49)
			Laparotomy (CMS AccuProbe/Erbe)
			Mean 5 lesions
			Median 3 cm max diameter
Ng et al[122]	II-2	2012	Retrospective, 211 pts	87	21	12	27	Cryoablation-related complications not specifically reported
(Part 1)			Laparotomy (L.C.S. 3000/Erbe)
			Single-freeze thaw performed except for “smaller” lesions where partial double freeze-thaw performed
			Mean 4.4 lesions
	II-2	2012	Mean size 4 cm	87	31	17	34	Cryoablation-related complications not specifically reported
Ng et al[122]			Retrospective, 93 pts
(Part 2)			Laparotomy-assisted cryoablation of inadequate resection margins as determined by operator; (L.C.S. 3000/Erbe)
Shyn et al[123]	II-2	2014	Mean 2.2 lesions	Local progression at a mean interval of 30.3 mo (range 13-72 mo) was seen in 14/54 patients (26%). Survival not reported				Not reported
			Mean lesion size 5.7 cm
			Retrospective, 39 patients, 54 lesions
			Percutaneous (Galil)
			Median 4 probes (range 1-7) each 17 Gauge, 15 min freeze, 10 min passive thaw, 15 min freeze cycle
			Mean 1.4 lesions
			Mean lesion size 3 cm

Level of Evidence based on the United States Agency of Healthcare Research and Quality Classification of Levels of Evidence.

Table 5 Highlights of microwave ablation literature for colorectal liver metastases

Ref.	Level of evidence	Year	Study details	1 yr OS%	3 yr OS%	5 yr OS%	Median OS (mo)	Procedure-related complications
Shibata et al[59]	II-1	2000	Prospective, randomized, 14 pts, 58 lesions	71	14		27	14% (2/14) - one biliary fistula and one hepatic abscess
			Laparotomy (Azwell HSD-20M)
			Mean 4 lesions
			Mean 2.7 cm
Liang et al[124]	II-2	2003	Retrospective, 74 patients, 149 lesions	91.4	46.4	29	20.5	4% (3/74) skin burns (in patients with tumors with extracapsular extension)
			Laparotomy (Microtaze AZM-520)
			Mean 2 lesions
			Mean 0.8 cm max diameter
Tanaka et al[125]	II-2	2006	Retrospective, 16 patients, 35 lesions	80	51	17	28	19% (3/16) Bleeding, biliary fistula, wound infection. (all patients underwent MWA via laparotomy, none percutaneous)
			Laparotomy (Microtaze AZM-520)
			Mean 2 lesions
			Mean 0.8 cm max diameter

Table 6 Highlights of chemoembolization literature for colorectal liver metastases

Ref.	Level of evidence	Year	Study details	Response rate (SD, CR, PR)	PFS/TTP (mo)	1 yr OS	2 yr OS	Median OS (mo)
Lang and Brown[126]	II-2	1993	TACE, Doxorubicin	63		65%	22%
			Prospective cohort, 46 patients
Hong et al[127]	II-2	2009	TACE, cisplatin + doxorubicin + mitomycin C			43%	10%	7.7
			Retrospective cohort, 21 patients
Vogl et al[82]	II-2	2009	TACE, mitomycin C alone or with gemcitabine vs irinotecan	63		62%	28%	14
			Prospective cohort, 463 patients
Albert et al[77]	II-2	2011	TACE, cisplatin, doxorubicin, mitomycin C	43	3	36%	13%	9
			Retrospective cohort, 121 patients
Martin et al[128]	II-2	2011	DEB-TACE (DEBIRI)			75%		19
			Prospective cohort, 55 patients
Fiorentini et al[79]	I	2012	DEB-TACE (DEBIRI)	80	7		56%	15
			Randomized Controlled Trial, 74 patients, DEBIRI vs FOLFIRI
Narayanan et al[129]	II-2	2013	DEB-TACE (DEBIRI)	68.6	3			13.3
			Retrospective cohort, 28 patients
Iezzi et al[83]	II-1	2015	DEB-TACE (DEBIRI) + Capecitabine	60	4			7.3
			Prospective Phase II Trial, 20 patients

OS: Overall survival; TACE: Transcatheter arterial chemoembolization; TTP: Time to progression.

Table 7 Highlights of yttrium-90 radioembolization literature for colorectal liver metastases

Ref.	Level of evidence	Year	Study details	Median OS	Median PFS
				(mo)	(mo)
Kennedy et al[86]	II-2	2006	Phase II Prospective study	10.5
			208 patients
Sharma et al[130]	II-2	2007	Phase I, 20 patients		9.3
			No prior chemotherapy SIRT + FOLFOX4		(14.2 if had only liver-confined disease)
			SIR-Spheres only
Benson et al[131]	II-2	2013	Phase II Prospective study	8.8	2.9
			151 patients (61 colorectal)
			Theraspheres only
Lewandowski et al[132]	II-2	2014	Phase II Prospective study	10.6
			214 patients
			Theraspheres only
Sofocleous et al[133]	II-2	2014	Phase I, 19 patients	14.9	5.2
			Prior hepatic arterial and peripheral chemotherapy
			SIR-Spheres only
Gray et al[87]	I	2001	Phase III Randomized controlled trial	17 vs 15.9	15.9 vs 9.7
			74 patients	(P = 0.18)	(P = 0.001)
			First-line SIRT +/- Regional chemotherapy		Liver PFS
			46 patients
Van Hazel et al[90]	I	2004	Phase II Randomized Controlled trial	29.4 vs 11.8	11.5 vs 4.6
			21 patients	(P = 0.008)	(P < 0.004)
			First-line SIRT +/- 5-FU/LV
Hendlisz et al[134]	I	2010	Phase III Randomized controlled trial	10 vs 7.3	5.5 vs 2.1 (P = 0.001)
			First-Line SIRT +/- 5-FU	(P = 0.8)
SIRFLOX[135]	I	Ongoing	Phase III Randomized controlled trial
			Primary Endpoint: Progression free survival
			Size: 532 patients
FOXFIRE[136]	I	Ongoing	Phase III Randomized controlled trial
			Primary Endpoint: Overall survival
			Size: 490 patients
EPOCH[137]	I	Ongoing	Phase III Randomized controlled trial
			Primary Endpoint: Progression free survival