Liver-directed therapies for patients with incurable metastatic colorectal cancer
The liver is the most common site for metastases of colorectal cancer. Nearly 50% of mCRC patients will develop liver metastases during the course of their disease, with half having hepatic metastases at the time of primary diagnosis and the other half developing metachronous disease. However, 80-90% of patients with liver metastases are not amenable to surgery at diagnosis, and liver metastases remain the dominant cause of death for patients with mCRC.
Multiple liver-directed therapies have been trialled in an attempt to improve the long-term outcome for patients with non-resectable metastatic colorectal cancer, and to achieve better control of liver metastases. Current technologies may include:
- Embolisation techniques:
- selective internal radiation treatment (SIRT) known as radioembolisation (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia), –which delivers a single, measured targeted radiation dose to liver tumours via injection into the hepatic artery. Yttrium-90 (90Y)–labeled resin microspheres have a median diameter of 32.5 µm, considerably smaller than the particles of other liver-directed therapies such as transarterial chemoembolization, which enables the microspheres to lodge distally within the microvascular plexus of tumors.
- trans-arterial chemoembolization (TACE) (e.g. the use of drug-eluting beads to deliver chemotherapy to the site)that rely on the unique differential blood supply of the liver, in which hepatic metastases are preferentially supplied by the hepatic artery. These techniques are used for more diffuse liver metastases.
- Invasive thermal ablation with distinct size limitations (e.g. radiofrequency ablation, RFA) RFA can be performed with open, laparoscopic, or percutaneous approaches. Some studies have reported that the approach by which RFA is performed has an impact on tumor recurrence rates, with the fewest local recurrences after open RFA, followed by laparoscopy, and finally percutaneous RFA. The best results with RFA are in patients with three or fewer lesions that are each 3 cm or less in diameter and are not located near major vascular structures.
- Hepatic arterial infusion (HAI) of chemotherapy agents. This technique relies on the differential blood supply of the liver. Liver macrometastases (>0.5 cm) derive more than 80 percent of their blood supply from the hepatic arterial circulation, while normal hepatocytes are supplied primarily by the portal circulation. As a result, the administration of chemotherapy into the hepatic artery allows the selective delivery of drug to the tumor with relative sparing of normal hepatocytes. Depending upon a drug's clearance and toxicity profile, a marked increase in the local concentration of drug may be achieved by injection into the hepatic artery. Regional administration of drugs that are rapidly metabolized in the liver by a first-pass effect leads to higher levels of drug exposure and minimizes systemic side effects.
- Conformal radiation treatment techniques (e.g. stereotactic body radiotherapy (SBRT) and high-dose rate brachytherapy). SBRT is a technique that utilizes precisely targeted radiation to a tumor while minimizing radiation to adjacent normal tissue. This targeting allows treatment of small- or moderate-sized tumors in either a single or limited number of dose fractions.
The roles of liver-directed therapies in patients with non-resectable MCRC have not been completely defined. Liver-directed therapies are sometimes utilised after the cancer has progressed on systemic therapy but remains limited to the liver, or in addition to systemic therapy in earlier stages of metastatic disease, aiming to ablate all sites of disease. Whether this rationale is valid remains uncertain. Although some of these methods can provide local control, it is unclear whether the sequential use of regional treatments followed by systemic therapy at the time of progression provides better long-term benefit, in terms of duration of symptom control or survival, than systemic therapy alone. Embolisation techniques rely on the unique differential blood supply of the liver, in which hepatic metastases are preferentially supplied by the hepatic artery. These techniques are used for more diffuse liver metastases.
European Society for Medical Oncology (ESMO) consensus guidelines for the management of patients with colorectal cancer (2016), that patients whose disease is not amenable to surgical resection, but who have a limited number of metastases and involved sites (oligometastatic disease (OMD)), may be considered for local liver ablative treatments as part of a ‘situation-adapted’ treatment strategy following systemic therapy.
The selection of the most appropriate liver-directed therapy for a patient is dependent on a number of factors including:
- the size and localisation of the metastases
- the invasiveness of the procedure
- local expertise regarding the use of a particular ablative technique
- patient preference
- patient co-morbidity, performance status and life expectancy.
Systematic review evidence[edit source]
In patients with incurable metastatic colorectal cancer, what are the effects of liver-directed therapies on survival and quality-of-life outcomes, compared with standard care? (MNG16)
A systematic review was undertaken to evaluate the effects of liver-directed therapies in patients with non-resectable metastatic colorectal cancer.
Seven level II studies were identified that compared liver-directed therapies with systemic therapy alone in colorectal cancer patients with incurable metastatic liver disease.
Seven randomised controlled trials (RCTs) evaluated liver ablative therapies with or without systemic therapy, compared with to systemic therapy alone.
Selective Internal Radiation Therapy (SIRT)
- SIRFLOX was a multicentre Australian phase III RCT of systemic chemotherapy with modified FOLFOX (mFOLFOX6) plus or minus selective internal radiation therapy (SIRT) as first-line treatment of patients with non-resectable liver-only or liver-dominant mCRC. Liver-dominant mCRC was defined as the presence of liver metastases and limited lung (fewer than five nodules of ≤ 1 cm diameter or a single nodule of ≤ 1.7 cm diameter), and/or lymph node involvement (a single anatomic area of < 2 cm diameter). Bevacizumab was allowed, combined with mFOLFOX, at the investigator’s discretionPatients included were WHO performance status 0-1.
- A German open-label phase III RCT compared the combination of SIRT plus intravenous fluorouracil (FU) to FU alone in 44 patients with chemotherapy refractory (5FU, irinotecan and oxaliplatin) liver limited mCRC. Presence of extrahepatic disease was an exclusion factor. Patients enrolled were ECOG 0-2.
- A small Australian phase 2 RCT compared the combination of SIRT (SIR-Spheres) plus systemic fluorouracil/leucovorin chemotherapy (FULV) with FULV alone in 21 patients receiving first line therapy for mCRC with liver metastases +/- extrahepatic disease. Patients were WHO performance status <3.
Radiofrequency Ablation (RFA)
- An RCT by the European Organisation for Research and Treatment of Cancer (EORTC), the Chemotherapy + Local Ablation Versus Chemotherapy (CLOCC) study, compared the combination of radiofrequency ablation (RFA) plus FOLFOX4 with FOLFOX4 alone, and with modified FOLFOX4 with bevacizumab (mFOLFOX4) in 119 patients with non-resectable liver-limited mCRC. Patients with extra hepatic disease were excluded. There had to be <10 liver metastases, with maximum diameter of 4 cm lesions to be treated by RFA. Metastatic involvement of the liver need to be ≤50% and complete treatment of all liver lesions was judged possible, either by RFA alone or by combination with resection of resectable lesions and RFA of the remaining non-resectable liver deposits. A minority of patients (16%) had prior chemotherapy for liver-only metastatic disease. The CLOCC study was initially designed as a phase III study, but transitioned to a phase II study because of slow accrual.
Trans arterial Chemoembolisation (TACE)
- A US phase II multicentre RCT compared the combination of trans arterial chemoembolization (TACE) using irinotecan drug-eluting beads (DEBIRI) plus mFOLFOX plus bevacizumab, with the combination of mFOLFOX plus bevacizumab in 70 patients who were chemotherapy naïve for metastatic disease and had liver-dominant disease (defined as ≥80% of the tumor body burden being confined to the liver) but less than 60% liver replacement by the tumor, and have an Eastern Cooperative Oncology Group performance status score ≤2.
- An Italian multicentre RCT compared DEBIRI with systemic irinotecan, fluorouracil and leucovorin (FOLFIRI) in 74 patients, all were pre-treated, including patients who had received a minimum of 2-3 lines of prior chemotherapy which may have included irinotecan. Patients had liver limited disease occupying up to 50% of the liver with no extrahepatic disease.
Hepatic Arterial Infusion (HAI)
- An RCT by the US Cancer and Leukemia Group B (CALGB 9481) evaluated hepatic arterial infusion (HAI): this US study compared hepatic arterial infusion with systemic bolus FULV in 135 treatment naïve patients. Eligible patients had non-resectable liver-limited (occupying <70% of the liver parenchyma) mCRC with no radiologic evidence of extra-hepatic metastatic disease. Patient included were of performance status 0-2.
There were no RCTs of conformal radiation techniques identified by the systematic review process and thus this form of liver directed therapy is not included in the discussion.
Of these studies, one study had low risk of bias two studies had a moderate risk of bias, and four studies had a high risk of bias overall.
The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Outcomes reported included tumour response, progression-free survival, overall survival, quality of life, adverse events, and subsequent hepatic surgery resection rates.
Liver-directed therapies - Outcomes[edit source]
Tumour response[edit source]
Tumour response outcomes were reported by six of the RCTs.
The small Australian SIRT study reported a significantly improved response (both the first integrated and best confirmed tumour responses at 36 months follow-up) with the addition of SIRT to FULV. Compared with the FULV only group, the SIRT treatment group showed greater complete and partial responses and fewer patients with stable disease (p < 0.001).8 No disease progression was reported in the treatment group.
The SIRFLOX trial reported a nonsignificant improvement in overall tumour response rate in patients who received SIRT plus chemotherapy patients compared with those who received systemic chemotherapy alone (76.4% versus 68.1%; p = 0.113). The improvement in complete response rate approached significance (4.5% versus 1.5%; p = 0.054). However, the SIRT group showed significantly better outcomes than the control group for liver response rate (78.7% versus 68.8%; p = 0.042) and liver complete response (6% versus 1.9%; p = 0.02).
Similarly, the German trial reported that the rate of partial response after a median follow-up of 24.8 months was greater in SIRT group than the non-SIRT group: 10% versus zero; 95% confidence interval (CI) -0.10 to 0.32. The proportion of patients with stable disease was higher in the SIRT group than the non-SIRT group (p = 0.001). Fewer patients in the SIRT group showed progressive disease, but statistical analysis of these data were not reported.
The US DEBIRI study reported that patients who received DEBIRI in addition to systemic chemotherapy showed a significant improvement in overall response rates at follow-up intervals of 2 months (p = 0.01), 4 months (p = 0.03) and 6 months (p = 0.05) using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) instrument. There was also a significantly higher overall response rate in the DEBIRI arm at 2 months (p = 0.01) and at 12 months’ follow-up using Choi’s criteria. However, there was no significant difference in overall response between treatment arms at 4 months (p = 0.09) and 6 months (p = 0.12) using Choi’s Criteria. There was also a significantly higher rate of downsizing to resection in the FOLFOX-DEBIRI group than the FOLFOX/bevacizumab arm (35% versus 16%, p = 0.05). Statistical analysis was not reported for the other outcomes measured in this study.
The Italian DEBIRI study did not report significant differences in outcomes between patients who received DEBIRI alone and those who received to systemic chemotherapy. Although the statistical significance cannot be confirmed as these weren’t reported, the DEBIRI group showed a higher tumour response rate at 50 months’ follow-up, less stable disease and fewer with progressive tumours, compared with the group of patients who did not receive DEBIRI.
The CALGB 9481 study reported a substantial improvement in overall tumour response rate with hepatic arterial infusion, compared with systemic chemotherapy at 6 years’ follow-up (47% versus 24%, p = 0.012). This advantage was observed in the complete and partial response rates. Fewer patients remained with stable disease in the hepatic arterial infusion group than the systemic chemotherapy group, although statistical analysis of these data were not reported.
Tumour response rates associated with RFA were not reported in the CLOCC study.
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Progression-free survival[edit source]
Progression-free survival was reported by all the included RCTs.
The SIRFLOX trial reported similar median progression-free survival rates in the treatment and control groups at 60 months’ follow-up:10.7 months versus 10.2 months, hazard ratio (HR) 0.93 (95% CI 0.77 to 1.12; p = 0.43). In a planned subgroup analysis of patients with liver only metastases there was also no improvement in progression free survival with the addition of SIRT (n=318, HR 0.9 (0.7-1.15)). However, the SIRT group showed a significantly longer median time to liver progression: 20.5 months versus 12.6 months (p = 0.002); HR of 0.69 (95% CI 0.55 to 0.90). Whether this improvement in control of liver metastases will result in improved overall survival is unknown.
The German SIRT trial reported significantly greater median time to progression and time to liver progression at 26 months in the SIRT group compared with the non-SIRT group: HRs 0.51 (95% CI 0.28 to 0.94, p=0.03) and 0.38 (95% CI 0.20 to 0.72, p = 0.003) respectively. This remained the same for the censored median time to liver progression (p = 0.002); HR 0.35 (95% CI 0.18 to 0.69).
The earlier Australian SIRT trial reported significantly longer median time to disease progression at 36 months in the SIRT group than the non-SIRT group (18.6 months versus 3.6 months; p < 0.0005). While the study showed an improvement in progression-free survival with the addition of SIRT to FULV, the small numbers limit interpretation, as does the less conventional chemotherapy comparator.
The CLOCC study reported increased median time to progression in the RFA plus chemotherapy group, compared with the chemotherapy only group (16.8 months versus 9.9 months; p=0.025); HR 0.63 (95% CI 0.42 to 0.95). Progression-free survival at a median follow-up of 4.4 years was significantly higher in the treatment than control group (27.6% versus 10.6%; p = 0.025).
The US DEBIRI study reported that the addition of DEBIRI to systemic chemotherapy achieved a small increase in median time to liver progression at 24 months’ follow-up (17 months versus 12 months; p=0.05). However, between group differences were nonsignificant for median progression free survival in the ‘Liver non-target liver only’ (p = 0.68), median progression free survival for overall extra-hepatic disease and(p = 0.35).median progression-free survival overall (p = 0.18) .
The Italian DEBIRI study reported that, at 50 months’ median follow-up, patients who received DEBIRI had significantly longer progression-free survival than the non-DEBIRI group (7 months versus 5 months; p = 0.006) and longer median time to hepatic progression (7 months versus 4 month, p = 0.006). DEBIRI was also associated with a nonsignificant increase in median time to extra-hepatic progression (p=0.64).
The CALGB 9481 study reported a significant increase in progression-free survival in the hepatic arterial infusion group, compared with the systemic chemotherapy group, at 6 years’ follow-up (24.4 months versus 20 months, p = 0.034). This effect was also seen at 2 years’ follow-up (51% versus 25%), although the statistical significance of this finding was not reported. The CALGB 9481 study reported a significant increase in median time to hepatic progression in the hepatic arterial infusion group, compared with the systemic chemotherapy group, at 3 years’ follow-up (p = 0.034). However, a shorter median time to extra-hepatic progression was also observed in the hepatic arterial infusion group than the systemic chemotherapy group (p = 0.029). A nonsignificant difference in median time to progression, favouring the systemic chemotherapy group, was also observed (p = 0.95).
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Overall survival[edit source]
Overall survival was reported by four of the RCTs.
The Australian SIRT study (n=21) reported significantly greater overall survival in patients who received both SIRT and FULV, compared with those who received FULV only in first line therapy: 29.4 months vs. 12.8 months for patients treated with chemotherapy alone; HR 0.33 (95% CI 0.12 to 0.91; p=0.025). The improvement in survival was not statistically significant and less pronounced for censored data: (HR 0.39 (95% CI 0.14 to 1.13; p = 0.07). While the study showed an improvement in overall survival with the addition of SIRT to FULV, the small numbers limit interpretation, as does the less conventional chemotherapy comparator.
The German SIRT study did not find any significant increase in median overall survival among patients who received SIRT plus 5FU, compared with those who received 5FU only for chemo refractory disease(10 months versus 7.3 months, p = 0.8): HR 0.92 ( 95% CI 0.47 to 1.78).
The CLOCC study reported a small nonsignificant increase in median overall survival at 4.4 years’ median follow-up among patients who received RFA than those who did not (45.3 months versus 40.5 months, p = 0.22): HR 0.74 (95% CI 0.46 to 1.19).
The Italian DEBIRI study reported significantly longer overall median survival at 50 months’ median follow-up in patients who received DEBIRI, compared with those who received systemic chemotherapy: 22 (95% CI 21 to 23) months versus 15 (95% CI 12 to 18) months (p = 0.031). A difference in median survival favouring DEBIRI was reported at 2 years’ follow-up (56% versus 32%) and at 30 months’ follow-up (34% versus 9%) and 50 months’ follow-up (15% versus 0%), although statistical analyses were not reported.
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Resection rate[edit source]
Resection rates were reported by two RCTs.
The SIRFLOX study reported no significant difference in liver resection rates between the SIRT group and the systemic chemotherapy only group (14.2% versus 13.7%, p = 0.857).
The US DEBRI study reported a substantially higher resection rate in patients who received DEBIRI in addition to systemic chemotherapy, compared with those who received non-DEBIRI regimens, which was of borderline statistical significance (35% versus 6%, p = 0.05).
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Adverse events[edit source]
Adverse event rates were reported by all the RCTs.
The SIRFLOX study reported that the total rate of adverse events (≥ Grade 3) was higher among the SIRT group than the non-SIRT group at 60 months’ follow-up, but this difference was not statistically significant (85.4% versus 73.4%, p = 0.516). The SIRT group showed was a significantly higher incidence of neutropenia (p = 0.004), febrile neutropenia (p = 0.02), thrombocytopenia (p < 0.001), fatigue (p = 0.019) and abdominal pain (p = 0.009). There were no significant differences in the rates of other adverse events.
This finding was also seen in the German trial. After 24.8 months’ median follow up, there were more reports of gastrointestinal events, neurological and other toxicities in the SIRT group than the non-SIRT group. In contrast to the SIRFLOX findings, fewer Grade ≥ 3 toxicities were reported among patients who received SIRT than those who did not, but this difference was not statistically significant (5% versus 27%, p = 0.1).
The other Australian SIRT study reported that more Grade 3 and 4 toxicity events occurred in SIRT patients than non-SIRT patients (13 versus 5). There were greater reports of granulocytopenia, anorexia, cirrhosis, mucositis and diarrhoea. One death out of the entire trial was attributed to SIRT. No significance was reported for any of these outcomes.
In the CLOCC study the addition of RFA to systemic chemotherapy was associated with numerically higher incidences of Grade 3–4 toxicity compared to systemic treatment alone, although the impact of this finding cannot be determined as statistical analysis was not reported.
In the US study DEBIRI in addition to systemic chemotherapy was associated with significantly greater incidences of serious adverse events than chemotherapy alone (p = 0.03). The DEBIRI group also showed numerically greater incidences of chemotherapy-related adverse events, but this difference was not statistically significant (p = 0.08). This pattern was seen across total adverse incidence and specific adverse events, but no statistically significant differences were reported. However, there was a consistent trend toward higher incidences of adverse events among patients who received DEBIRI in addition to their standard chemotherapy.
The Italian DEBIRI study reported significantly fewer grade ≥ 3 neutropenia events among patients who received DEBIRI than among those who received FOLFIRI after 50 months’ median follow-up (4% versus 44%, p < 0.0001).
The CALGB 9481 study reported lower rates of adverse events among patients who received hepatic arterial infusion, compared with those who received systemic chemotherapy, including significantly reductions in neutropenia grade ≥ 3 (p < 0.0001) and stomatitis (p = 0.00002), and a nonsignificant reduction in diarrhoea (p = 0.075). However, bilirubin elevation ≥ 3 mg/dL was reported in a higher proportion of the hepatic arterial infusion group than the systemic chemotherapy (p = 0.006).
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'Quality of life[edit source]
Quality-of-life outcomes were reported by four of the RCTs.
The Italian DEBIRI study reported differences in quality-of-life outcomes in favour of DEBIRI compared with FOLFIRI: better physical functioning at 3 months and at 8 months (p = 0.025 for both comparisons) and a longer time from treatment to the beginning of decline in quality of life (8 months versus 3 months, p = 0.0002).
The Australian SIRT study reported no significant differences in patient-rated or clinician-rated quality-of-life scores between patients receiving SIRT in addition to FULV and those receiving FULV only.
The CLOCC study reported no significant differences in quality of life between patients receiving radiofrequency ablation in addition to systemic chemotherapy and those receiving chemotherapy alone.
The CALGB 9481 study assessed quality-of-life (physical functioning domain) using the Rand 26-item Health Status Profile. The hepatic arterial infusion group showed improved quality of life, compared with the systemic chemotherapy group, at 3 months (p = 0.038), 6 months (p = 0.024) and among late dropouts at 12 months (p = 0.001). At 18 months’ follow-up, overall physical functioning was superior among the hepatic arterial infusion group (62% versus 58%), but statistical analysis was not reported.
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Evidence summary and recommendations[edit source]
|Overall, the evidence suggests some benefit to tumour response rate with the use of DEBIRI (TACE), HAI, or the addition of SIRT for colorectal cancer patients with non-resectable liver limited disease, but the clinical relevance of these endpoints remain unclear.||II||, , , , , |
|There is limited evidence that liver directed therapies prolong progression free survival. Some phase II studies suggest benefit for RFA and DEBIRI, and for SIRT in chemotherapy refractory disease, but there are no phase III studies showing improved PFS for liver directed therapies.||II||, |
|Liver directed therapies with RFA and DEBIRI have been shown to improve overall survival in single phase II studies, however there are no phase III studies demonstrating improved overall survival with liver directed therapies.||II||, |
|Overall, liver-directed therapies provide little or no benefit in improving quality of life in metastatic colorectal cancer patients with non-resectable liver limited disease.||II||, , , |
|There is inconclusive evidence to suggest a definitive benefit given by liver directed therapies in improving resection rate in colorectal cancer patients with incurable liver metastases.|
|Liver-directed therapies, in combination with systemic chemotherapy, were generally associated with higher incidences of adverse events in treated patients.||II||, , , , |
All patients with metastatic colorectal cancer should be discussed at a multidisciplinary team meeting with clinicians who have expertise in management of metastatic colorectal cancer.
For patients who could be considered surgical candidates if their metastases were smaller, we suggest initial systemic chemotherapy followed by re-evaluation for surgery.
Wherever possible, patients considering liver-directed therapies should be enrolled into clinical trials examining these treatments in comparison to standard therapies.
Considerations in making these recommendations[edit source]
There is only limited evidence to suggest that liver-directed therapies (selective internal radiation treatment, radiofrequency ablation, hepatic arterial infusion of chemotherapy agents or transarterial chemoembolisation) improve response rates, survival times, resection rates or quality of life in patients with non-resectable liver metastatic colorectal cancer.
Health system implications[edit source]
Clinical practice[edit source]
Liver-directed therapies are highly specialised therapies which are carried out in centres with the requisite expertise. The management these patients requires multidisciplinary team approach whereby the likely interactions between any prior, concurrent or planned biological, chemotherapeutic, local or loco-regional ablative, surgical, external beam radiation treatment, or radiosurgery should be extensively discussed. It is likely that these expert centres are likely to be located in tertiary referral centres. Consideration would need to be given to equitable access particularly for patients from regional/rural areas.
The present recommendations would have little effect on current resourcing because they would only affect referral centres with the necessary expertise and infrastructure required to perform liver ablative therapies. Only highly selected group of mCRC would be suitable for such therapies based on current evidence.
Barriers to implementation[edit source]
No barriers to the implementation of these recommendations are envisaged
Next section: management synchronous primary in metastatic colorectal cancer
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- ↑ Clark ME, Smith RR. Liver-directed therapies in metastatic colorectal cancer. J Gastrointest Oncol 2014 Oct;5(5):374-87 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25276410.
- ↑ Weitz J, Koch M, Debus J, Höhler T, Galle PR, Büchler MW. Colorectal cancer. Lancet 2005 Jan;365(9454):153-65 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15639298.
- ↑ Berber E, Pelley R, Siperstein AE. Predictors of survival after radiofrequency thermal ablation of colorectal cancer metastases to the liver: a prospective study. J Clin Oncol 2005 Mar 1;23(7):1358-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15684312.
- ↑ Rothbarth J, van de Velde CJ. Treatment of liver metastases of colorectal cancer. Ann Oncol 2005;16 Suppl 2:ii144-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15958446.
- ↑ Van Cutsem E, Nordlinger B, Adam R, Köhne CH, Pozzo C, Poston G, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006 Sep;42(14):2212-21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16904315.
- ↑ Abbas S, Lam V, Hollands M. Ten-year survival after liver resection for colorectal metastases: systematic review and meta-analysis. ISRN Oncol 2011;2011:763245 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22091431.
- ↑ Adam R. Developing strategies for liver metastases from colorectal cancer. Semin Oncol 2007 Apr;34(2 Suppl 1):S7-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17449352.
- ↑ Helling TS, Martin M. Cause of death from liver metastases in colorectal cancer. Ann Surg Oncol 2014 Feb;21(2):501-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24081807.
- ↑ Welch JP, Donaldson GA. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg 1979 Apr;189(4):496-502 Available from: http://www.ncbi.nlm.nih.gov/pubmed/443905.
- ↑ Kennedy A, Nag S, Salem R, Murthy R, McEwan AJ, Nutting C, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007 May 1;68(1):13-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17448867.
- ↑ Sangro B, Iñarrairaegui M.. Radioembolization for Hepatocellular Carcinoma: Evidence-Based Answers to Frequently Asked Questions. 2:110 2011;2:1-6. J Nucl Med Radiat Ther 2011;2(1):1-6.
- ↑ 13.0 13.1 BREEDIS C, YOUNG G. The blood supply of neoplasms in the liver. Am J Pathol 1954 Sep;30(5):969-77 Available from: http://www.ncbi.nlm.nih.gov/pubmed/13197542.
- ↑ Amersi FF, McElrath-Garza A, Ahmad A, Zogakis T, Allegra DP, Krasne R, et al. Long-term survival after radiofrequency ablation of complex unresectable liver tumors. Arch Surg 2006 Jun;141(6):581-7; discussion 587-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16785359.
- ↑ Kuvshinoff BW, Ota DM. Radiofrequency ablation of liver tumors: influence of technique and tumor size. Surgery 2002 Oct;132(4):605-11; discussion 611-2 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12407343.
- ↑ Stang A, Fischbach R, Teichmann W, Bokemeyer C, Braumann D. A systematic review on the clinical benefit and role of radiofrequency ablation as treatment of colorectal liver metastases. Eur J Cancer 2009 Jul;45(10):1748-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19356924.
- ↑ Tanis E, Nordlinger B, Mauer M, Sorbye H, van Coevorden F, Gruenberger T, et al. Local recurrence rates after radiofrequency ablation or resection of colorectal liver metastases. Analysis of the European Organisation for Research and Treatment of Cancer #40004 and #40983. Eur J Cancer 2014 Mar;50(5):912-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24411080.
- ↑ Collins JM. Pharmacologic rationale for regional drug delivery. J Clin Oncol 1984 May;2(5):498-504 Available from: http://www.ncbi.nlm.nih.gov/pubmed/6547166.
- ↑ 19.0 19.1 Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016 Aug;27(8):1386-422 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27380959.
- ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 20.11 20.12 20.13 20.14 van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, et al. SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer. J Clin Oncol 2016 May 20;34(15):1723-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26903575.
- ↑ 21.00 21.01 21.02 21.03 21.04 21.05 21.06 21.07 21.08 21.09 21.10 21.11 21.12 21.13 21.14 Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol 2010 Aug 10;28(23):3687-94 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20567019.
- ↑ 22.00 22.01 22.02 22.03 22.04 22.05 22.06 22.07 22.08 22.09 22.10 22.11 22.12 22.13 22.14 22.15 22.16 22.17 22.18 22.19 Van Hazel G, Blackwell A, Anderson J, Price D, Moroz P, Bower G, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol 2004 Nov 1;88(2):78-85 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15499601.
- ↑ 23.00 23.01 23.02 23.03 23.04 23.05 23.06 23.07 23.08 23.09 23.10 23.11 23.12 23.13 23.14 Ruers T, Punt C, Van Coevorden F, Pierie JP, Borel-Rinkes I, Ledermann JA, et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol 2012 Oct;23(10):2619-26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22431703.
- ↑ 24.00 24.01 24.02 24.03 24.04 24.05 24.06 24.07 24.08 24.09 24.10 24.11 24.12 24.13 24.14 24.15 Martin RC 2nd, Scoggins CR, Schreeder M, Rilling WS, Laing CJ, Tatum CM, et al. Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis. Cancer 2015 Oct 15;121(20):3649-58 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26149602.
- ↑ 25.00 25.01 25.02 25.03 25.04 25.05 25.06 25.07 25.08 25.09 25.10 25.11 25.12 25.13 25.14 25.15 25.16 25.17 Fiorentini G, Aliberti C, Tilli M, Mulazzani L, Graziano F, Giordani P, et al. Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. Anticancer Res 2012 Apr;32(4):1387-95 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22493375.
- ↑ 26.00 26.01 26.02 26.03 26.04 26.05 26.06 26.07 26.08 26.09 26.10 26.11 26.12 26.13 26.14 26.15 26.16 Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006 Mar 20;24(9):1395-403 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16505413.