Introduction
Materials and methods
Patient cohorts
All patients (n = 106); | HAI/target therapy cohort (N = 44) | Systemic therapy cohort (N = 62) | P value | |||
---|---|---|---|---|---|---|
Age (years) | Median (iqr) | Median | iqr | Median | iqr | n.s |
64 (59–70) | 66.5 | 62.5–71.5 | 62 | 58–69 | ||
Gender | N (%) | N | % | N | % | n.s |
Female | 42 (39.62) | 19 | 43.18 | 23 | 37.10 | |
Male | 64 (60.38) | 25 | 56.82 | 39 | 62.90 | |
Primary tumor site | N | % | N | % | ns | |
Right hemicolon | 27 (25.47) | 10 | 22.73 | 17 | 27.42 | |
Left hemicolon | 53 (50.00) | 27 | 61.36 | 26 | 41.94 | |
Rectum | 26 (24.53) | 7 | 15.91 | 19 | 30.65 | |
Primary tumor pathological grade | N | % | N | % | n.s | |
Well or intermediate | 54 (50.95) | 23 | 52.27 | 31 | 50.00 | |
Poor | 52 (49.05) | 21 | 47.73 | 31 | 50.00 | |
Time to liver metastases | N | % | N | % | n.s | |
Synchronous | 75 (70.75) | 27 | 61.36 | 48 | 77.42 | |
Metachronous | 31 (29.25) | 17 | 38.64 | 14 | 22.58 | |
Bilateral liver involvement | N | % | N | % | n.s | |
Yes | 64 (60.38) | 22 | 50.00 | 42 | 67.64 | |
Not | 42 (39.62) | 22 | 50.00 | 20 | 32.26 | |
At least one metastasis with diameter > 5 cm | N | % | N | % | n.s | |
Yes | 50 (47.17) | 19 | 43.18 | 31 | 50.00 | |
Not | 56 (52.83 | 25 | 56.82 | 31 | 50.00 | |
Extra-hepatic metastasis | N | % | N | % | n.s | |
Absence | 41 (38.68) | 22 | 50.00 | 19 | 30.65 | |
Presence | 65 (61.32) | 22 | 50.00 | 43 | 69.35 | |
Previous systemic chemotherapy for liver metastases | N | % | N | % | ||
First line | 106 | 44 | 100 | 62 | 100 | |
5FU/OX/Leucovorin | 24 | 54.55 | 6 | 9.68 | 0.001 | |
5FU/IRI/Bevacizumab/OX | 6 | 13.64 | 23 | 37.10 | 0.01 | |
5FU | 3 | 6.82 | 1 | 1.61 | n.s | |
5FU/IRI/Leucovorin | 6 | 13.64 | 0 | 0 | 0.04 | |
5FU/IRI/Bevacizumab | 1 | 2.27 | 5 | 8.06 | n.s | |
5FU/OX/Bevacizumab | 1 | 2.27 | 5 | 8.06 | n.s | |
5FU/OX/Cetuximab | 1 | 2.27 | 1 | 1.61 | n.s | |
5FU/OX/IRI/leucovorin | 2 | 4.55 | 3 | 4.84 | n.s | |
Capecitabine | 0 | 0 | 1 | 1.61 | n.s | |
5FU/OX/IRI/cetuximab | 0 | 0 | 10 | 16.13 | 0.005 | |
OX/IRI | 0 | 0 | 1 | 1.61 | n.s | |
OX | 0 | 0 | 2 | 3.22 | n.s | |
OX/IRI/cetuximab | 0 | 0 | 4 | 6.45 | n.s | |
IRI/cetuximab | 0 | 0 | 1 | 1.61 | n.s | |
Second line | 106 | 44 | 100 | 62 | 100 | |
Capecitabine | 20 | 45.45 | 1 | 1.61 | 0.001 | |
5FU/IRI | 15 | 34.09 | 4 | 6.45 | 0.001 | |
Capecitabine/OX | 3 | 6.82 | 1 | 1.61 | n.s | |
Capecitabine/Bevacizumab | 1 | 2.27 | 3 | 4.84 | n.s | |
5FU | 1 | 2.27 | 1 | 1.61 | n.s | |
5FU/IRI/Cetuximab | 1 | 2.27 | 6 | 9.68 | n.s | |
5FU/IRI/Panitumumab | 1 | 2.27 | 0 | 0 | n.s | |
OX/IRI/Cetuximab | 1 | 2.27 | 2 | 3.22 | n.s | |
5FU/Bevacizumab | 0 | 0 | 2 | 3.22 | n.s | |
IRI/Cetuximab | 0 | 0 | 1 | 1.61 | n.s | |
Raltitrexed | 0 | 0 | 3 | 4.84 | n.s | |
5FU/OX/ Panitumumab | 0 | 0 | 1 | 1.61 | n.s | |
5FU/IRI/Aflibercept | 0 | 0 | 5 | 8.06 | n.s | |
OX/IRI/Bevacizumab | 0 | 0 | 3 | 4.84 | n.s | |
IRI | 0 | 0 | 2 | 3.22 | n.s | |
OX/IRI | 1 | 2.27 | 1 | 1.61 | n.s | |
Capecitabine/IRI/Bevacizumab | 0 | 0 | 1 | 1.61 | n.s | |
5FU/IRI/Bevacizumab | 0 | 0 | 3 | 4.84 | n.s | |
5FU/OX/Bevacizumab | 0 | 0 | 3 | 4.84 | n.s | |
5FU/OX/IRI/Bevacizumab | 0 | 0 | 10 | 16.13 | 0.005 | |
5FU/OX/IRI/Cetuximab | 0 | 0 | 6 | 9.68 | n.s | |
OX/Cetuximab | 0 | 0 | 1 | 1.61 | n.s | |
IRI/Bevacizumab | 0 | 0 | 3 | 4.84 | n.s | |
Eastern Cooperative Oncology Group (ECOG) | N | % | N | % | 0.001 | |
2 | 29 (27.36) | 20 | 45.45 | 9 | 14.52 | |
1 | 43 (40.57 | 24 | 54.55 | 19 | 30.65 | |
0 | 34 (32.07) | 0 | 0 | 34 | 54.84 | |
KRAS, NRAS, BRAF genotype status | n = 106 (%) | N | % | N | % | n.s |
No mutations | 68 (64.15) | 30 | 68.18 | 38 | 61.29 | |
Mutations | 38 (35.85) | 14 | 31.82 | 24 | 38.71 | |
KRAS exon 2 codon 12 | − 11 | – (78.6%) | 18 | – (75%) | ||
KRAS exon 2 codon 13 | − 0 | – (0%) | 3 | – (12.5%) | ||
KRAS exon 3 codon 61 | − 0 | – (0%) | 1 | – (4.17%) | ||
NRAS exon 3 codon 61 | − 2 | – (14.3%) | 0 | – (0%) | ||
NRAS exon 2 codon 12 | − 0 | – (0%) | 3 | – (12.5%) |
HAI with chemo-filtration
Liquid biopsy precision, chemosensitivity, and tumor gene expression assays
Drug regimens
Part-A | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Pt | IV-CTCs | 5-FU | Oxaliplatin | Irinotecan | Mitomycin | Doxorubicin | Cisplatin | Alkeran | Carboplatin | Raltitrexed | TC based on CST | |||||||
1 | 9.8/ml | S = 58% | S = 62% | S = 80% | S = 86% | S = 20% | S = 70% | S = 25% | S = 45% | S = 20% | MMC (30 mg/m2) | |||||||
2 | 16.8/ml | S = 81% | S = 80% (A) | S = 20% | S = 82% | S = 26% | S = 81% | S = 25% | S = 75% | S = 60% | MMC (30 mg/m2) | |||||||
3 | 14.8/ml | S = 70% | S = 75% | S = 70% | S = 82% | S = 19% | S = 80% | S = 25% | S = 70% | S = 60% | MMC (30 mg/m2) | |||||||
4 | 8.9/ml | S = 65% | S = 70% | S = 82% | S = 82% | S = 24% | S = 65% | S = 24% | S = 80% | S = 70% | MMC (30 mg/m2), IRI (200 mg/m2) | |||||||
5 | 15.3/ml | S = 65% | S = 70% | S = 60% | S = 81% | S = 22% | S = 65% | S = 23% | S = 60% | S = 45% | MMC (30 mg/m2), OX (150 mg/m2) | |||||||
6 | 9.8/ml | S = 25% | S = 45% | S = 75% | S = 85% | S = 24% | S = 40% | S = 20% | S = 42% | S = 20% | MMC (30 mg/m2), IRI (200 mg/m2) | |||||||
7 | 8.9/ml | S = 70% | S = 80% | S = 55% | S = 82% | S = 22% | S = 75% | S = 24% | S = 65% | S = 70% | MMC (30 mg/m2) | |||||||
8 | 12.2/ml | S = 48% | S = 61% | S = 48% | S = 82% | S = 23% | S = 70% | S = 23% | S = 47% | S = 28% | MMC (30 mg/m2) | |||||||
9 | 16.2/ml | S = 60% | S = 72% | S = 42% | S = 45% | S = 20% | S = 62% | S = 56% | S = 57% | S = 60% | 5-FU (600 mg/m2), OX (150 mg/m2) | |||||||
10 | 9.8/ml | S = 70% | S = 70% | S = 70% | S = 46% | S = 25% | S = 65% | S = 24% | S = 55% | S = 25% | 5-FU (600 mg/m2), OX (150 mg/m2) | |||||||
11 | 9.4/ml | S = 25% | S = 55% | S = 75% | S = 60% | S = 30% | S = 50% | S = 35% | S = 45% | S = 60% | MMC (30 mg/m2), IRI (200 mg/m2) | |||||||
12 | 7.5/ml | S = 62% | S = 75% | S = 85% | S = 58% | S = 22% | S = 55% | S = 20% | S = 70% | S = 38% | OX (150 mg/m2), IRI (200 mg/m2) | |||||||
13 | 8.9/ml | S = 70% | S = 80% | S = 85% | S = 25% | S = 24% | S = 70% | S = 40% | S = 60% | S = 25% | 5-FU (600 mg/m2), OX (150 mg/m2), IRI (200 mg/m2) | |||||||
14 | 9.3/ml | S = 35% | S = 50% | S = 80% | S = 30% | S = 35% | S = 45% | S = 30% | S = 54% | S = 50% | IRI (200 mg/m2) | |||||||
15 | 15.1/ml | S = 40% | S = 55% | S = 80% | S = 60% | S = 30% | S = 45% | S = 75% | S = 55% | S = 25% | IRI (200 mg/m2) | |||||||
16 | 16.3/ml | S = 50% | S = 60% | S = 80% | S = 25% | S = 20% | S = 45% | S = 75% | S = 60% | S = 10% | IRI (200 mg/m2) | |||||||
17 | 8.7/ml | S = 55% | S = 70% | S = 40% | S = 75% | S = 24% | S = 65% | S = 24% | S = 55% | S = 20% | MMC (30 mg/m2), OX (150 mg/m2) | |||||||
18 | 14.1/ml | S = 75% | S = 75% | S = 75% | S = 30% | S = 30% | S = 60% | S = 40% | S = 60% | S = 25% | 5-FU (600 mg/m2), OX (150 mg/m2), IRI (200 mg/m2) | |||||||
19 | 8.8/ml | S = 50% | S = 70% | S = 25% | S = 75% | S = 35% | S = 65% | S = 20% | S = 55% | S = 28% | MMC (30 mg/m2), OX (150 mg/m2) | |||||||
20 | 12.2/ml | S = 50% | S = 70% | S = 30% | S = 75% | S = 24% | S = 60% | S = 24% | S = 55% | S = 25% | MMC (30 mg/m2), OX (150 mg/m2) | |||||||
21 | 9.8/ml | S = 48% | S = 60% | S = 85% | S = 80% | S = 60% | S = 45% | S = 50% | S = 35% | S = 28% | IRI (200 mg/m2) | |||||||
22 | 10/ml | S = 50% | S = 60% | S = 90% | S = 80% | S = 60% | S = 85% | S = 25% | S = 65% | S = 65% | IRI (200 mg/m2) | |||||||
23 | 7.5/ml | S = 75% | S = 80% | S = 25% | S = 25% | S = 25% | S = 55% | S = 40% | S = 60% | S = 50% | 5-FU (600 mg/m2), OX (150 mg/m2) | |||||||
24 | 9.3/ml | S = 50% | S = 81% | S = 90% | S = 85% | S = 20% | S = 61% | S = 21% | S = 62% | S = 40% | IRI (200 mg/m2) | |||||||
25 | 16.2/ml | S = 60% | S = 65% | S = 80% | S = 65% | S = 72% | S = 60% | S = 20% | S = 48% | S = 65% | IRI (200 mg/m2) | |||||||
26 | 7.5/ml | S = 55% | S = 50% | S = 50% | S = 81% | S = 45% | S = 65% | S = 70% | S = 50% | S = 30% | MMC (30 mg/m2) | |||||||
27 | 12.2/ml | S = 25% | S = 70% | S = 60% | S = 70% | S = 55% | S = 70% | S = 40% | S = 55% | S = 65% | MMC (30 mg/m2), OX (150 mg/m2) | |||||||
28 | 15.1/ml | S = 45% | S = 85% | S = 30% | S = 90% | S = 31% | S = 35% | S = 44% | S = 45% | S = 75% | MMC (30 mg/m2), OX (150 mg/m2) | |||||||
29 | 7.5/ml | S = 50% | S = 55% | S = 80% | S = 70% | S = 20% | S = 60% | S = 70% | S = 62% | S = 27% | IRI (200 mg/m2) | |||||||
30 | 9.8/ml | S = 37% | S = 85 | S = 42% | S = 65% | S = 65 | S = 60% | S = 49% | S = 50% | S = 25% | OX (150 mg/m2) | |||||||
31 | 8.9/ml | S = 45% | S = 70% | S = 20% | S = 25% | S = 20% | S = 60% | S = 30% | S = 60% | S = 10% | OX (150 mg/m2) | |||||||
32 | 9/ml | S = 53% | S = 55% | S = 35% | S = 85% | S = 35% | S = 55% | S = 23% | S = 45% | S = 20% | MMC (30 mg/m2) | |||||||
33 | 15.1/ml | S = 55% | S = 83% | S = 70% | S = 20% | S = 25% | S = 60% | S = 20% | S = 62% | S = 50% | OX (150 mg/m2) | |||||||
34 | 8.3/ml | S = 55% | S = 60% | S = 45% | S = 80% | S = 24% | S = 50% | S = 40% | S = 50% | S = 20% | MMC (30 mg/m2) | |||||||
35 | 8.4/ml | S = 40% | S = 85% | S = 50% | S = 20% | S = 20% | S = 50% | S = 22% | S = 55% | S = 75% | OX (150 mg/m2) | |||||||
36 | 8.3/ml | S = 50% | S = 80% | S = 65% | S = 60% | S = 40% | S = 70% | S = 20% | S = 55% | S = 20% | OX (150 mg/m2) | |||||||
37 | 8.4/ml | S = 70% | S = 75% | S = 60% | S = 81% | S = 24% | S = 75% | S = 24% | S = 65% | S = 60% | MMC (30 mg/m2) | |||||||
38 | 15.2/ml | S = 60% | S = 60% | S = 40% | S = 85% | S = 20% | S = 60% | S = 45% | S = 50% | S = 20% | MMC (30 mg/m2) | |||||||
39 | 9.8/ml | S = 38% | S = 35% | S = 41% | S = 91% | S = 30% | S = 60% | S = 49% | S = 50% | S = 10% | MMC (30 mg/m2) | |||||||
40 | 6.9/ml | S = 55% | S = 65% | S = 40% | S = 85% | S = 24% | S = 55% | S = 24% | S = 60% | S = 25% | MMC (30 mg/m2) | |||||||
41 | 9.7/ml | S = 70% | S = 82% | S = 75% | S = 83% | S = 65% | S = 80% | S = 22% | S = 75% | S = 70% | MMC (30 mg/m2) | |||||||
42 | 6.9/ml | S = 35% | S = 42% | S = 50% | S = 80% | S = 35% | S = 55% | S = 65% | S = 48% | S = 40% | MMC (30 mg/m2) | |||||||
43 | 9.8/ml | S = 60% | S = 72% | S = 42% | S = 70% | S = 23% | S = 60% | S = 65% | S = 70% | S = 28% | MMC (30 mg/m2) | |||||||
44 | 9.9/ml | S = 50% | S = 70% | S = 40% | S = 75 | S = 20% | S = 50% | S = 50% | S = 60% | S020% | MMC (30 mg/m2), OX (150 mg/m2) |
Part B | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Pt | EGFR | VEGFR | KRAS | NRAS | BRAF | MDR1 | TYMS | DHFR | SHMT1 | ERCC1 | GST | Target therapy | ||||||
1 | OE = 40% | OE = 45% | NM | NM | NM | OE = 80% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
2 | OE = 45% | OE = 45% | NM | NM | NM | OE = 65% | OE = 0% | OE = 25% | OE = 0% | OE = 0% | OE = 25% | |||||||
3 | OE = 35% | OE = 45% | NM | NM | NM | OE = 65% | OE = 0% | OE = 0% | OE = 0% | OE = 15% | OE = 20% | |||||||
4 | OE = 50% | OE = 50% | MT12e2 | NM | NM | OE = 60% | OE = 10% | OE = 0% | OE = 0% | OE = 20% | OE = 20% | |||||||
5 | OE = 35% | OE = 45% | MT12e2 | NM | NM | OE = 55% | OE = 0% | OE = 0% | OE = 0% | OE = 25% | OE = 20% | |||||||
6 | OE = 25% | OE = 40% | MT12e2 | NM | NM | OE = 80% | OE = 10% | OE = 0% | OE = 0% | OE = 20% | OE = 20% | |||||||
7 | OE = 50% | OE = 35% | NM | NM | NM | OE = 65% | OE = 5% | OE = 25% | OE = 10% | OE = 0% | OE = 15% | |||||||
8 | OE = 65% | OE = 70% | NM | NM | NM | OE = 80% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 18% | Bevacizumab (5 mg/kg) | ||||||
9 | OE = 55% | OE = 70% | NM | NM | NM | OE = 80% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Bevacizumab (5 mg/kg) | ||||||
10 | OE = 35% | OE = 40% | NM | NM | NM | OE = 40% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 5% | |||||||
11 | OE = 35% | OE = 45% | NM | NM | NM | OE = 62% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
12 | OE = 60% | OE = 85% | NM | NM | NM | OE = 70% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Bevacizumab (5 mg/kg) | ||||||
13 | OE = 36% | OE = 40% | NM | NM | NM | OE = 30% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | |||||||
14 | OE = 20% | OE = 20% | NM | NM | NM | OE = 80% | OE = 10% | OE = 0% | OE = 0% | OE = 25% | OE = 20% | |||||||
15 | OE = 50% | OE = 20% | MT12e2 | NM | NM | OE = 60% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
16 | OE = 50% | OE = 25% | MT12e2 | NM | NM | OE = 65% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
17 | OE = 30% | OE = 20% | NM | NM | NM | OE = 60% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 5% | |||||||
18 | OE = 25% | OE = 25% | NM | NM | NM | OE = 30% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
19 | OE = 20% | OE = 30% | MT12e2 | NM | NM | OE = 65% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
20 | OE = 25% | OE = 35% | NM | MT61e3 | NM | OE = 70% | OE = 10% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
21 | OE = 80% | OE = 60% | NM | NM | NM | OE = 61% | OE = 0% | OE = 0% | OE = 45% | OE = 0% | OE = 10% | Cetuximab (250 mg/m2) | ||||||
22 | OE = 65% | OE = 80% | MT12e2 | NM | NM | OE = 83% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Bevacizumab (5 mg/kg) | ||||||
23 | OE = 30% | OE = 30% | NM | NM | NM | OE = 50% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 5% | |||||||
24 | OE = 45% | OE = 45% | NM | NM | NM | OE = 80% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
25 | OE = 50% | OE = 80% | NM | NM | NM | OE = 60% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 8% | Bevacizumab (5 mg/kg) | ||||||
26 | OE = 60% | OE = 90% | NM | NM | NM | OE = 70% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Bevacizumab (5 mg/kg) | ||||||
27 | OE = 20% | OE = 45% | NM | NM | NM | OE = 58% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
28 | OE = 20% | OE = 45% | MT12e2 | NM | NM | OE = 60% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
29 | OE = 60% | OE = 40% | NM | NM | NM | OE = 78% | OE = 0% | OE = 0% | OE = 45% | OE = 0% | OE = 10% | Cetuximab (250 mg/m2) | ||||||
30 | OE = 20% | OE = 45% | MT12e2 | NM | NM | OE = 62% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
31 | OE = 45% | OE = 30% | NM | NM | NM | OE = 65% | OE = 10% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
32 | OE = 60% | OE = 55% | NM | NM | NM | OE = 60% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Cetuximab (250 mg/m2) | ||||||
33 | OE = 10% | OE = 45% | NM | NM | NM | OE = 42% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
34 | OE = 20% | OE = 20% | NM | NM | NM | OE = 70% | OE = 10% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
35 | OE = 70% | OE = 55% | NM | NM | NM | OE = 58% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 12% | Cetuximab (250 mg/m2) | ||||||
36 | OE = 40% | OE = 45% | NM | NM | NM | OE = 70% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
37 | OE = 50% | OE = 50% | NM | MT61e3 | NM | OE = 65% | OE = 0% | OE = 0% | OE = 0% | OE = 5% | OE = 25% | |||||||
38 | OE = 20% | OE = 30% | NM | NM | NM | OE = 70% | OE = 5% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
39 | OE = 20% | OE = 20% | MT12e2 | NM | NM | OE = 75% | OE = 15% | OE = 0% | OE = 0% | OE = 0% | OE = 25% | |||||||
40 | OE = 30% | OE = 30% | NM | NM | NM | OE = 80% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | |||||||
41 | OE = 10% | OE = 45% | NM | NM | NM | OE = 65% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 20% | |||||||
42 | OE = 50% | OE = 80% | MT12e2 | NM | NM | OE = 70% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Bevacizumab (5 mg/kg) | ||||||
43 | OE = 60% | OE = 30% | NM | NM | NM | OE = 70% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Cetuximab (250 mg/m2) | ||||||
44 | OE = 45% | OE = 55% | MT12e2 | NM | NM | OE = 70% | OE = 0% | OE = 0% | OE = 0% | OE = 0% | OE = 10% | Bevacizumab (5 mg/kg) |
Response assessment
Statistical analysis
Results
Tumor response in the two cohorts
Adverse events
Adverse events | HAI/target therapy cohort (n = 44) | Systemic therapy cohort (n = 62) | χ2 | P value | ||||
---|---|---|---|---|---|---|---|---|
Grade | n | % | Grade | n | % | |||
Bone marrow hypocellularity | − 1/2 | 6 | 13.64 | − 1/2 | 5 | 8.06 | 0.86 | 0.35 |
− 3/4 | 1 | 2.27 | − 3/4 | 8 | 12.90 | 3.74 | 0.06 | |
Liver function | ||||||||
AST and ALT increased | − 1/2 | 3 | 6.82 | − 1/2 | 6 | 9.68 | 0.27 | 0.60 |
− 3/4 | 1 | 2.27 | − 3/4 | 3 | 4.83 | 0.47 | 0.49 | |
Total bilirubin increased | − 1/2 | 2 | 4.55 | − 1/2 | 5 | 8.06 | 0.52 | 0.47 |
− 3/4 | 0 | 0 | − 3/4 | 1 | 1.61 | n.a | ||
Ascites/itch | − 1/2 | 0 | 0 | − 1/2 | 3 | 4.83 | n.a | |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Gastrointestinal symptoms | ||||||||
Nausea/vomiting | − 1/2 | 7 | 15.90 | − 1/2 | 29 | 46.77 | 10.93 | 0.001 |
− 3/4 | 3 | 6.82 | − 3/4 | 1 | 1.61 | 1.92 | 0.17 | |
Diarrhea | − 1/2 | 3 | 6.82 | − 1/2 | 41 | 66.13 | 37.29 | 0.001 |
− 3/4 | 0 | 0 | − 3/4 | 4 | 6.45 | n.a | ||
Constipation | − 1/2 | 0 | 0 | − 1/2 | 4 | 6.45 | n.a | |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Anorexia | − 1/2 | 0 | 0 | − 1/2 | 16 | 25.80 | 13.37 | 0.001 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Dysgeusia | − 1/2 | 0 | 0 | − 1/2 | 2 | 3.28 | n.a | |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Other | ||||||||
Abdominal pain | − 1/2 | 2 | 4.55 | − 1/2 | 1 | 1.61 | 0.80 | 0.37 |
− 3/4 | 0 | 0 | − 3/4 | 2 | 3.23 | n.a | ||
Non-infectious fever | − 1/2 | 18 | 40.90 | − 1/2 | 3 | 4.83 | 21.08 | 0.001 |
− 3/4 | 2 | 4.55 | − 3/4 | 1 | 1.61 | 0.80 | 0.37 | |
Multiple hepatic abscesses | − 1/2 | 0 | 0 | − 1/2 | 0 | 0 | n.a | |
− 3/4 | 1 | 2.27 | − 3/4 | 0 | 0 | n.a | ||
Neuropathy | − 1/2 | 1 | 2.27 | − 1/2 | 4 | 6.45 | 1.00 | 0.32 |
− 3/4 | 0 | 0 | − 3/4 | 1 | 1.61 | n.a | ||
Oxaliplatin allergy | − 1/2 | 1 | 2.27 | − 1/2 | 0 | 0 | n.a | |
− 3/4 | 0 | 0 | − 3/4 | 1 | 1.61 | n.a | ||
Alopecia | − 1/2 | 1 | 2.27 | − 1/2 | 2 | 3.23 | 0.08 | 0.77 |
− 3/4 | 3 | 6.82 | − 3/4 | 0 | 0 | n.a | ||
Fatigue | − 1/2 | 3 | 6.82 | − 1/2 | 39 | 62.90 | 33.84 | 0.001 |
− 3/4 | 0 | 0 | − 3/4 | 2 | 3.23 | n.a | ||
Mucositis | − 1/2 | 5 | 0 | − 1/2 | 27 | 43.54 | 12.65 | 0.001 |
− 3/4 | 0 | 0 | − 3/4 | 2 | 3.23 | n.a | ||
Hand–Foot Syndrome | − 1/2 | 0 | 0 | − 1/2 | 11 | 17.74 | 8.71 | 0.003 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Rash | − 1/2 | 5 | 0 | − 1/2 | 8 | 12.90 | 0.06 | 0.81 |
− 3/4 | 0 | 0 | − 3/4 | 2 | 3.23 | n.a | ||
Rhinitis/epistaxis | − 1/2 | 7 | 15.90 | − 1/2 | 16 | 25.80 | 1.48 | 0.22 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Paronychia | − 1/2 | 0 | 0 | − 1/2 | 5 | 8.06 | 3.72 | 0.06 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Deep vein thrombosis | − 1/2 | 0 | 0 | − 1/2 | 2 | 3.23 | n.a | |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Conjunctivitis | − 1/2 | 0 | 0 | − 1/2 | 5 | 8.06 | 3.72 | 0.06 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Kidney failure | − 1/2 | 0 | 0 | − 1/2 | 2 | 3.23 | n.a | |
− 3/4 | 0 | 0 | − 3/4 | 2 | 3.23 | n.a | ||
Arterial hypertension | − 1/2 | 0 | 0 | − 1/2 | 14 | 22.58 | 11.45 | 0.001 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a | ||
Dysphonia | − 1/2 | 0 | 0 | − 1/2 | 5 | 8.06 | 3.72 | 0.06 |
− 3/4 | 0 | 0 | − 3/4 | 0 | 0 | n.a |
Quality of life in the two cohorts
Patient cohort survival times
Part A | ||||||
---|---|---|---|---|---|---|
Variables | HAI/target therapy cohort (n = 44) | Systemic therapy cohort (n = 62) | ||||
PFS (months) [n.pts] | Log-rank χ2 (P value) | Cox HR, (95%CI) | PFS (months) [n.pts] | Log-rank χ2 (P value) | Cox HR, (95%CI) | |
Age | ||||||
< 66 years | 5 [n = 21] | 0.50 | 3 [n = 41] | 0.01 | ||
- ≥ 66 years | 5 [n = 23] | (0.48) | 3 [n = 21] | (0.93) | ||
Gender | ||||||
Females | 6 [n = 19] | 1.90 | 3 [n = 23] | 0.60 | ||
Males | 5 [n = 25] | (0.17) | 3 [n = 39] | (0.44) | ||
Primary tumor site | ||||||
Right hemicolon | 5 [n = 10] | 3 [n = 17] | ||||
Left hemicolon | 5 [n = 27] | 0.60 | 2.5 [n = 26] | 1.14 | ||
Rectum | 5 [n = 7] | (0.74) | 3 [n = 19] | (0.56) | ||
Primary tumor pathological grade | ||||||
Well or intermediate | 5 [n = 23] | 3.14 | 3 [n = 31] | 0.05 | ||
Poor | 5 [n = 21] | (0.08) | 3 [n = 31] | (0.83) | ||
Time to liver metastases | ||||||
Synchronous | 5 [n = 27] | 0.10 | 3 [n = 48] | 0.03 | ||
Metachronous | 5 [n = 17] | (0.75) | 3 [n = 14] | (0.87) | ||
Bilateral liver involvement | ||||||
Yes | 5.5 [n = 22] | 0.31 | 3 [n = 42] | 5.97 | 1.78 | |
Not | 5 [n = 22] | (0.57) | 6 [n = 20] | (0.01) | (1.02–3.09) | |
Presence of at least one metastasis with diameter > 5 cm | ||||||
Yes | 5 [n = 19] | 5.97 | 1.94 | 3 [n = 31] | 1.13 | |
Not | 6 [n = 25] | (0.01) | (1.04–3.64) | 3 [n = 31] | (0.29) | |
Presence of extra-hepatic metastasis | ||||||
Yes | 5 [n = 22] | 3.52 | 3 [n = 43] | 6.29 | 1.87 | |
Not | 6.5 [n = 22] | (0.06) | 5 [n = 19] | (0.01) | (1.04–3.37) | |
ECOG classification | ||||||
0 | 3 [n = 34] | |||||
1 | 6.5 [n = 24] | 5.21 | 1.86 | 5 [n = 19] | 6.85 | 2.27 |
2 | 5 [n = 20] | (0.02) | (0.99–3.46) | 2 [n = 9] | (0.03) | (1.04–4.98) |
KRAS, NRAS, and BRAF status | ||||||
No mutations | 5.5 [n = 30] | 2.25 | 3 [n = 38] | 0.49 | ||
Mutations | 5 [n = 14] | (0.13) | 3 [n = 24] | (0.48) |
Part B | ||||||
---|---|---|---|---|---|---|
Variables | HAI/target therapy cohort (n = 44) | Systemic therapy cohort (n = 62) | ||||
Survival/3rd line (months) [n.pts] | Log-rank χ2 (P value) | Cox HR, (95%CI) | Survival/3rd line (months) [n.pts] | Log-Rank χ2 (P value) | Cox HR, (95%CI) | |
Age | ||||||
< 66 years | 9 [n = 21] | 2.17 | 8 [n = 41] | 0.28 | ||
≥ 66 years | 14 [n = 23] | (0.14) | 9 [n = 21] | (0.60) | ||
Gender | ||||||
Female | 14 [n = 19] | 1.25 | 8 [n = 23] | 0.02 | ||
Male | 10 [n = 25] | (0.26) | 9 [n = 39] | (0.88) | ||
Primary tumor site | ||||||
Right hemicolon | 11 [n = 10] | 11 [n = 17] | ||||
Left hemicolon | 14 [n = 27] | 4.12 | 6.5 [n = 26] | 1.84 | ||
Rectum | 15 [n = 7] | (0.13) | 9 [n = 19] | (0.40) | ||
Primary tumor pathological grade | ||||||
Well or intermediate | 15 [n = 23] | 5.50 | 1.96 | 10 [n = 31] | 0.16 | |
poor | 9 [n = 21] | (0.02) | (1.04–3.69) | 8 [n = 31] | (0.69) | |
Time to liver metastases | ||||||
Synchronous | 9.5 [n = 27] | 0.21 | 8.5 [n = 48] | 0.16 | ||
Metachronous | 14 [n = 17] | (0.65) | 9 [n = 14] | (0.69) | ||
Bilateral liver involvement | ||||||
Yes | 13.5 [n = 22] | 0.01 | 7 [n = 42] | 6.41 | 2.06 | |
Not | 14 [n = 22] | (0.92) | 15.5 [n = 20] | (0.01) | (1.14–3.70) | |
Presence of at least one metastasis with diameter > 5 cm | ||||||
Yes | 9 [n = 19] | 10.08 | 2.46 | 6 [n = 31] | 5.61 | 1.86 |
Not | 15 [n = 25] | (0.001) | (1.31–4.63) | 13 [n = 31] | (0.02) | (1.09–3.20) |
Presence of extra-hepatic metastasis | ||||||
Yes | 9 [n = 22] | 1.89 | 7 [n = 43] | 5.63 | 2.02 | |
Not | 14 [n = 22] | (0.17) | 12 [n = 19] | (0.02) | (1.10–3.72) | |
ECOG classification | ||||||
0 | 10 [n = 34] | |||||
1 | 15 [n = 24] | 11.4 | 2.59 | 11 [n = 19] | 8.38 | 1.47 |
2 | 9 [n = 20] | (0.001) | (1.38–4.88) | 5 [n = 9] | (0.01) | (0.99–2.20) |
KRAS, NRAS, and BRAF genotype status | ||||||
No mutations | 14 [n = 30] | 1.72 | 11 [n = 38] | 2.15 | ||
Mutations | 9 [n = 14] | (0.19) | 7 [n = 24] | (0.14) |