CRC Liver Metastases

Concept

Adjuvant HAI after resection of colorectal liver metastases (randomized comparison of HAI + IV vs. IV)

156

Inclusion criteria

R0 resection

Therapy

1. (HAI + IV): IV: 325 mg/m² 5FU d1–5 (bolus) + 200 mg/m² FA (30 min) after 2 weeks HAI: 0.25 mg/kg FUDR 14 days (pump), repeat after 1 week

2. (IV): 6 × 200 mg/m² FA (30 min) + 370 mg/m² 5FU d1–5, every 4 weeks

Results

Median survival: 72.2 mo (HAI + IV) vs. 59.3 mo (IV)

2-year survival: 86 % (HAI + IV) vs. 72 % (IV), p = 0.03

5-year survival: 61 % (HAI + IV) vs. 49 % (IV)

68 % (HAI + IV) vs. 52 % (IV); under exclusion of patients with extrahepatic metastases before recruitment and patients without treatment

Local recurrence within the liver after 2 years: 7/74 patients (HAI + IV) vs. 30/82 (IV)

Recurrence free liver after 2 years: 90 % (HAI + IV) vs. 60 % (IV), p = 0.001

2-year rate progression-free survival: 57 % (HAI) vs. 42 % (IV), p = 0.07

Median PfS: 37.4 mo (HAI + IV) vs. 17.2 mo (IV)

Toxicity

Parameter

HAI + IV

Neutropenia

Diarrhea

Nausea/vomiting

Stomatitis

Conclusions

For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome

mo month, d days

Kemeny et al. (2011) [47]

Concept	Randomized phase II of adjuvant HAI plus systemic chemotherapy with or without bevacizumab (singlecenter study)
N	73
Inclusion criteria	Liver resection
Therapy	HAI (4–5 weeks postsurgery via pump): 0.12 mg × kg × pump volume (30 ml) FUdR + 1 mg/d × 30 ml flow rate dexamethasone
	IV: 85 mg/m² oxaliplatin (oxaliplatin-naive patients) (2 h) or 150 mg/m² irinotecan (oxaliplatin-pretreated patients) + 400 mg/m² FA (2 h concurrently) + 2,000 mg/m² 5-FU (48 h) d15 + 29
	+/− 5 mg/kg bevacizumab d15 + 29
Results	RFS(%) 1 year: 73 vs. 83; 4 years: 37 vs. 46 (beva vs. no beva)
Results	4-year survival (%): 81 vs. 85
Toxicity	Beva vs. no beva (N): abdominal pain: 1 vs. 3, thrombosis: 3 vs. 0, diarrhea: 6 vs. 1, AP and bilirubin (>3): 16 vs. 6
Conclusions	Addition of bevacizumab to HAI plus systemic therapy after liver resection does not increase the RFS or survival but appear to increase toxicity

5.2.2 Palliative Regional Therapies

Lorenz et al. (2000) [48]

Concept	Randomized comparison of HAI (5-FU/FS) with HAI (FUDR) and systemic chemotherapy (5-FU/FS)
N	168
Inclusion criteria	1st-line therapy, tumor load: <75 % of liver volume
Therapy	1. (IA): 1,000 mg/m² 5-FU (24 h) + 200 mg/m² FA (15 min) (d1–5)
	2. (IA): 0.2–0.15 mg/kg/d FUDR (d1–14)
	3. (IV): 1,000 mg/m² 5-FU (24 h) + 200 mg/m² FA (15 min) (d1–5) every 3 weeks
Results	All patients	Tumor load <25 %
	TtP (mo): 9.2: 5.9: 6.6	TtP (mo): 11.6: 6.1: 5.5
	OS (mo): 18.7: 12.7: 17.6	OS (mo): 23.3: 13.4: 21.7
Toxicity (grade III + IV)	Parameter	1	2	3
	Nausea/vomiting	61	23	41
	Stomatitis	76	8	77
	Skin	33	4	49
	Diarrhea	33	11	32
	Abdominal pain	32	26	25
	Increase of liver enzymes value	4	25	15
Conclusions	HAI 5-FU/FS cannot be recommended as a routine therapy. There seems to be an advantage in patients with intrahepatic tumor burden of less than 25 %. An optimization of IA therapies needs further investigations

Gray et al. (2001) [43]

Concept	Combination of SIR-Spheres (SIRT) and HAI vs. HAI alone (randomized phase III study)
N	74
Inclusion criteria	Unresectable liver metastases, chemotherapeutic naive and pretreated patients
Therapy	HAI (port): 0.3 mg/kg/d FUDR (12 days) – 4 weekly intervals
	SIRT: tumor volume <25, 25–50, >50 % of total volume SIRT-equivalent: 2, 2.5, or 3 GBq of ⁹⁰Y
Results	Survival rates per year (%):
		HAI	SIRT + HAI
	1 y	68	72
	2 y	29	39
	3 y	6	17
	5 y	0	3.5
Toxicity	No differences in grade III and IV events
Conclusions	Combination of single SIRT with HAI is more effective than HAI alone

y years

Voigt et al. (2002) [49]

Concept	Chemoembolization of liver metastases
N	11
Inclusion criteria	Inoperability, tumor progress after systemic therapies with 5-FU/FA, 5-FU/FA + CPT-11, 5-FU/FA + oxaliplatin
Therapy	d1, 2 (IA): 5 mg/m² MMC + 4.5 Mio IU IFN α2b + 20 mg dexamethasone + DSM (bolus)
	d1 (IA): 50 mg/m² oxaliplatin (120 min) d1+ 1,500 mg/m² 5-FU (24 h)
	d1 (IV): 500 mg/m² FA (120 min)
	Repetition d 15–22
Results (N = 10)	PR: N = 3, MR: N = 2, SD: N = 4, PD: N = 1
Toxicity	Asthenia (grad I–II): N = 10, neurotoxicity (grade I–II): N = 5, nausea/vomiting (grade II): N = 2
Conclusions	Chemoembolization is an effective therapy in patients with liver metastases after failure of systemic chemotherapies

Pohlen et al. (2004) [50]

Concept	Chemoembolization of nonresectable liver metastases
N	100
Inclusion criteria	Inoperability, tumor load <70 % of liver volume
Therapy	d1–5 (IA): 450 mg DSM + 5 Mio IU IFN α2b (app. 20 min) + 500 mg/m² FS (20 min) + 600 mg/m² 5-FU (120 min) every 3 weeks
Results	RR (%): CR 11, PR 59, SD 14, PD 17
	TtP: 17 mo
	Median survival (total, N = 95): 24 mo
	<25 % tumor load (liver):
	Median survival (N = 30): 39 mo
Toxicity	Parameter	Grad 1–2 (%)	Grad 3–4 (%)
	Nausea/vomiting	55	0
	Diarrhea	58	9
	Mucositis	44	3
	Leukopenia	28	0
	Total	55	12
Conclusions	Chemoembolization is an effective, life-prolonging, and well-tolerated therapy for patients with liver metastases of CRC

Pohlen et al. (2006) [51]

Concept	Comparison of two intra-arterial therapy concepts (chemoembolization vs. HAI)
N	60
Inclusion criteria	Inoperability, tumor load: <70 % of liver volume
Therapy (ART-I vs. ART-II)	ART-I (N = 24): d1–5 (IA-port): 300 mg/m² FA (20 min) + 600 mg/m² 5-FU (120 min) every 3 weeks
Therapy (ART-I vs. ART-II)	ART-II (N = 36): d1–5 (IA-port): 450 mg DSM + 5 Mio IU IFN α2b (app. 20 min) + 500 mg/m² FA (20 min) + 600 mg/m² 5-FU (120 min) every 3 weeks
Results	Parameter	ART-I	ART-II
	RR	50	69
	Median survival	14	26
Toxicity	Parameter (% all grades)	ART-I	ART-II
	Nausea/vomiting	70	55
	Diarrhea	62	64
	Mucositis	45	44
	Leukopenia	25	28
	Port-system infections	12	8
Conclusions	DSM-TACE is superior to HAI with higher response rates and fewer side effects. This combination should be evaluated in larger studies as first- or second-line therapy. The positive effect of the additional embolization is explained as a result of higher drug concentration within tumor tissue after blood-flow reduction by the starch microspheres

Morise et al. (2006) [52]

Concept	Chemoembolization of liver metastases of CRC (4) and stomach carcinoma (1)
N	5
Inclusion criteria	Inoperability
Therapy	d1 (IA): 80 mg CPT-11 + 8 mg MMC + DSM
	DSM – amount: 200–1,200 mg
	d7–14/15 (IA): 1,000 mg 5-FU (24 h) + 100 mg FS (3 h)
	+ (IV) CPT-11, tegafur/uracil, cisplatin (in patients with extrahepatic lesions)
Results	RR (%): 13.1; 55.7; 65.6; 50.0; 0
Toxicity	Abdominal pain, nausea/vomiting, leukopenia
Conclusions	Chemoembolization with DSM and CPT-11 is an effective therapy for patients with advanced tumor disease, especially with liver metastasis. It is recommended as neoadjuvant therapy or after failure of systemic tumor therapies in second line

Fiorentini et al. (2007) [39]

Concept	Chemoembolization with irinotecan-eluting beads (multicenter prospectively)
N	20
Inclusion criteria	Unresectable liver metastases, after systemic chemotherapy failure, tumor burden <75 %
Therapy	DEBIRI: irinotecan 100 mg, 50 % reduction after first cycle (if tox. occurred grade IV) every 3 weeks
Results	RR: 16/20, OS: 15/20 alive by median follow-up of 200 days
Toxicity	Fever (grade 2, 2 days): N = 20, abdominal pain (grade II + III, 12 h): N = 10 + 5, nausea + vomiting (grade II, 11 h): N = 20
Conclusions	TACE with irinotecan-eluting beads is feasible in patients with liver metastases from CRC

Boige et al. (2008) [53]

Concept	Hepatic arterial infusion of oxaliplatin plus intravenous 5-FU/FA (singlecenter prospectively)
N	44
Inclusion criteria	Unresectable liver metastases, after systemic chemotherapy failure
Therapy	HAI (catheter): 100 mg/m² oxaliplatin (2 h) d1
Therapy	IV: 200 mg/m² FA + 400 mg/m² 5-FU (bolus) d1 followed by 2,400 mg/m² 5-FU (over 48 h); every 2 weeks
Results	RR (%): 55, PR: 62 (N = 24), PFS: 7.0 mo, OS: 16 mo
Toxicity	Neutropenia (all grades): N = 21, neuropathy (all grades): N = 40, abdominal pain (all grades): 21, thrombocytopenia (all grades): N = 15, others
Conclusions	HAI oxaliplatin and systemic chemotherapy with 5-FU/FA is feasible, safe with promising results

Idelevich et al. (2009) [54]

Concept	Hepatic arterial infusion of irinotecan, 5-FU/FA plus UFT (singlecenter prospectively)
N	31
Inclusion criteria	Unresectable liver metastases, no prior chemotherapy
Therapy	HAI (port): 120 mg/m² irinotecan (30 min) followed by 20 mg/m² FA (30 min) and 500 mg/m² 5-FU (2 h) d1, 14
Therapy	200 mg/m²/d UFT + 30 mg/d FA d1–22 (two divided daily doses) every 4 weeks
Results	RR (%): 65, PR: N = 20, PD: N = 1; TtP: 12 mo; OS: 36 mo
Toxicity	Hematologic (grade III): N = 5, non-hematologic (grade III + IV): N = 6, catheter dislocation: N = 1
Conclusions	HAI irinotecan with UFT/FA is a feasible and effective treatment for nonresectable CRC liver metastases

Seki et al. (2009) [55]

Concept

Hepatic arterial infusion followed by systemic chemotherapy (singlecenter retrospectively)

Inclusion criteria

Unresectable liver tumor (involvement of all segments or inadequate liver remnant or involvement of all three main veins or unresectability of retrohepatic vena cava or bifurcation of portal vein), no prior chemotherapy with irinotecan or oxaliplatin

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