Embolization Therapy: Principles and Clinical Applications, 1 Ed.

Colorectal Liver Disease

C. T. Sofocleous • P. Sideras • Elena N. Petre

Intra-arterial therapies directed to the liver take advantage of the dual hepatic blood supply and specifically the fact that liver tumors are fed by the hepatic artery, whereas the normal liver parenchyma gets its supply primarily from the portal vein.1 Surgery confers the best treatment option for colorectal liver metastases (CLM) but, unfortunately, only 20% of patients are eligible. Even more unfortunate is the 70% rate of patients developing new liver metastases after resection.1 There is, therefore, a tremendous need for nonsurgical therapies targeting liver metastases in patients with colorectal cancer. When using intra-arterial therapies in the setting of liver metastases, a drug (or radiation) injected in the hepatic artery will preferentially reach the tumor. Intra-arterial therapies to the liver include radioembolization or selective internal radiation therapy (SIRT), hepatic arterial chemotherapy (HAC), and transarterial chemoembolization (TACE) with oil or drug-eluting beads (DEB-TACE).2 Such treatments have been used as salvage therapies to manage progression after systemic therapies or other local or locoregional therapies.35 Intra-arterial therapies have also been used earlier in the course of the disease to achieve maximal response aiming to convert a candidate from nonsurgical to surgical. HAC with different chemotherapeutic agents allows 90% response rates and conversion to surgery up to 40% to 50% of initially inoperable patients.6 TACE and, in particular, DEB-TACE with irinotecan-loaded beads (DEBIRI) have been used for CLM with promising response rates and oncologic outcomes.79 Radioembolization or SIRT is a unique way of delivering a high tumoricidal dose of radiation to the tumor via the arterial pathway while minimizing toxicity to uninvolved liver. This therapy received original U.S. Food and Drug Administration approval when the use of resin microspheres in combination with HAC proved superior in terms of response and liver tumor control when compared to HAC alone.10 Subsequent results of SIRT were promising enough and led to further randomized control trials in the salvage setting as well as an ongoing trial with the use of SIRT with first-line chemotherapy (SIRFLOX).1114 With these new techniques, as well as the much better established percutaneous thermal ablation, interventional oncology has emerged as an integral part of the colon cancer patient management in a multidisciplinary and tailored manner along with radiation, surgical, and medical oncology. Such tailored and multidisciplinary approach can achieve the best possible oncologic outcomes and specifically improve disease progression-free and patient overall survivals. In this chapter, we will discuss the indications for and the use of arterially directed liver therapies and we will review the literature with their respective expected outcomes.

INDICATIONS

Arterially directed liver therapies (ATs) are local or regional treatments that are most often used in patients suffering from colon cancer liver metastases without or with limited and controlled extrahepatic disease. Such therapies have been used as salvage treatments after failure of intravenous (IV) standard of care chemotherapy. Interestingly, the response rates were improved even in cases where the AT was administered with a drug that previously failed.12Candidates for intra-arterial therapies are generally patients with a life expectancy of more than 3 months, ideally with Eastern Cooperative Oncology Group (ECOG) status of 2 or better and with a sufficient functional liver reserve. There is no uniform agreement on what is considered sufficient liver function, but a bilirubin level of greater than 3 mg/dL, an albumin level of less than 3 g/dL, and an international normalized ratio of 1.6 or higher are often deemed contraindications for any AT. Biliary obstruction should be corrected before any AT to prevent biliary necrosis and rapid deterioration of liver function, which can be fatal. Furthermore, patients with insufficient sphincter of Oddi are at increased risk of hepatic abscess formation, and in these cases, preprocedural and postprocedural biliary excreted antibiotic coverage is mandatory.15

Whenever such therapies are used as first-line treatments, also called induction treatments, their goal is to obtain the highest response as early as possible in the disease to convert a nonsurgical to a surgical candidate. Indeed, it has been shown that there is a linear correlation between the response rate and the resection rate when ATs were used as induction therapies.16 It is necessary to indicate that ATs are commonly used in patients who cannot undergo surgery or ablation. As such, most patients will have more than three tumors in the liver or larger tumors that cannot be resected or ablated with clear margins.17

HEPATIC ARTERIAL CHEMOTHERAPY

Intra-arterial hepatic chemotherapy has the goal of increasing drug concentrations in the metastatic deposits resulting in significant increase in response rates. The advantage of this route is proportional to the first-pass extraction of the drug by the liver and inversely proportional to body clearance. One drug that has been extensively used is floxuridine (FUDR), having a 95% liver extraction with liver exposures ranging from 100 to 300 times higher than with systemic administration.2 Also, the advantage of HAC applied with other chemotherapeutic agents was that exposure was several-fold increased by this method rather than IV perfusion alone. This allows intermittent administration with repeated course of chemotherapy over few weeks through the peripheral arterial access where a permanent subcutaneous port is linked to the intra-arterial catheter. This affords a better quality of life.

HAC requires placement of permanent intra-arterial catheter linked to a port usually placed surgically,1,18,19 although percutaneous placement is also feasible.20,21 During placement, the surgeon skeletonizes the hepatic arteries around the tip of the catheter that is placed in the gastroduodenal artery. This is done to prevent any extrahepatic delivery of the chemotherapeutic agent in the gastrointestinal tract. Often, the placement of the hepatic arterial infusion pump (HAIP) is performed while the patient is under general anesthesia for resection of the primary and/or a liver metastasis. At the same type, cholecystectomy is routinely performed.1 When no resection is anticipated, the HAIP can be placed through minimal invasive techniques, replacing largely the need for open surgery or repeated catheterizations.21 Similarly to the surgical ligation of arterial branches during intra-arterial hepatic pump placement, interventional radiologists ensure remodeling of flow before the insertion of the indwelling catheter so that there is only hepatopetal flow from the catheter’s tip where chemotherapy is released in a distribution that covers all the intrahepatic metastases, preventing the extrahepatic delivery of cytotoxic agents. First, any arterial branches that may cause delivery of the chemotherapy outside the liver should be occluded with coil percutaneously.22 Arteries that do not feed the liver such as right gastric and gastroduodenal are routinely coil-embolized to avoid gastrointestinal toxicity of extrahepatic drug perfusion resulting in gastroduodenal ulceration due to perfusion of chemotherapy in an extrahepatic vessel that remains patent beyond the tip.23 This can still occur when a small branch was not detected or recanalized after surgical ligation or coil embolization. A Tc-99m macroalbumin aggregate (MAA) study after pump placement is routinely performed to indicate that there is only hepatopetal flow without extrahepatic accumulation of tracer. In the event of extrahepatic accumulation of tracer, angiographic embolization may still be needed to correct the flow and salvage the intra-arterial pump/catheter for safe chemotherapy administration.24,25 Historically when combination of 5-fluorouracil (5-FU) and folinic acid was the standard regimen for IV chemotherapy in CLM, all clinical trials using 5-FU or FUDR demonstrated a better response rate for HAC than for IV treatments alone, with a few trials demonstrating survival benefit.26,27 In a more recent study, intra-arterial oxaliplatin combined with IV 5-FU demonstrated an overall response rate of 62% among the 39 assessable patients, including 17, 12, and 12 patients who had failed to respond to prior systemic chemotherapy with FOLFIRI, FOLFOX, or both, respectively.28 Of note, in the same report, an R0 surgical resection was performed afterward in 18% of initially nonresectable patients and ablation with clear margins (A0) in 2%. More combined chemotherapy schemes including a single intra-arterial agent such as FUDR plus two IV agents such as oxaliplatin and irinotecan allowed as high as 90% tumor response rates.29 In another study involving 36 patients with extensive nonresectable liver metastases (i.e., ≥4 metastases in 86% and bilobar disease in 91% of patients), HAC was used with oxaliplatin (100 mg/m2 in 2 hours) plus IV 5-FU and leucovorin (leucovorin 400 mg/m2 in 2 hours; 5-FU 400 mg/m2 bolus then 2,500 mg/m2 in 46 hours) and cetuximab (400 mg/m2 then 250 mg/m2/week or 500 mg/m2every 2 weeks) as first-line treatment. Overall response rate (ORR) was 90% and disease control rate was 100%. Forty-eight percent of patients were downstaged enough to undergo an R0 resection and/or ablation.2

TRANSARTERIAL CHEMOEMBOLIZATION AND DRUG-ELUTING BEADS

There are several different techniques under the acronym TACE. The most common procedure is the intra-arterial injection of chemotherapy emulsified with Lipiodol Ultra-Fluide (LUF; Guerbet, Aulnay-sous-Bois, France) followed by injection of embolic material.3034 Lipiodol was first injected into the hepatic arteries in the early 1980s because of its capacity to target and remain fixed in tumors; LUF was first used as a diagnostic tool for the evaluation of disseminated hepatocellular carcinoma30 and then emulsified with various drugs for the treatment of liver tumors.31 The emulsion produces oil drops in the arterial flow, and these drops have a propensity to go through the largest arteries (which are the tumor feeders) without entering the small ones due to the surfactant properties of the oil drops.32 With Lipiodol-TACE, ratio of drug concentration in the tumor compared to the healthy liver and to peripheral blood levels can be as high as 10 and 1,000 times, respectively.33 Embolization after chemo-Lipiodol increases the efficacy of treatment by prolonging contact of chemotherapy to the tumor cells and by adding ischemia to the highly hypervascularized tumor usually targeted with this treatment. Such embolization has been reported to induce failure of the transmembrane pump, thus increasing drug retention inside of cells.34

Regimens used to deliver TACE included (1) cisplatin, doxorubicin, mitomycin C, Ethiodol, and polyvinyl alcohol that had shown an ORR of 43% in one study35; median survivals of 33 months from initial diagnosis, 27 months from the time of liver metastases, and 9 months from the start of chemoembolization were documented, suggesting a possible improvement over reported survival time for systemic therapies alone35; and (2) mitomycin C alone (52.5%), mitomycin C with gemcitabine (33%), or mitomycin C and irinotecan (14.5%) showing an ORR of 63%.9

In 2006, the development of DEB loaded with irinotecan (DEBIRI) came for the first time in clinical practice for the management of CLM.36 DEBIRI loaded with irinotecan had a 75% reduced systemic plasma level compared with intra-arterial irinotecan alone.37

In a randomized study of two courses of DEBIRI (36 patients) compared with eight courses of IV irinotecan, 5-FU, and leucovorin (FOLFIRI; 38 patients) used to treat 74 patients who failed at least two lines of chemotherapy, the DEBIRI arm was met with statistically significant improvement of all oncologic outcomes including patient survival.38 Specifically, the response rates were 69% for the DEBIRI group compared with 30% for the systemic FOLFIRI group. Similarly, the 2-year overall survival (OS) was 56% compared with 32%, and the median OS was 22 months compared with 15 months for DEBIRI versus FOLFIRI groups.

Improvement in quality of life was of longer duration for the DEBIRI group (8 months) compared to the FOLFIRI group (3 months, P = .0002). Finally, overall cost was lower for the DEBIRI treatment arm.

In a multicenter, single-arm study of 55 patients who underwent DEBIRI after failing systemic chemotherapy, response rates were 66% at 6 months and 75% at 12 months, with an OS of 19 months and a progression-free survival of 11 months.5

A recent comparison study of DEBIRI versus radioembolization for salvage therapy for liver-dominant CLM including series of 36 patients reported similar survival for both treatments as salvage therapy, with median survival times of 7.7 months for the DEBIRI group and 6.9 months for the radioembolization (SIRT) group. The 1-, 2- and 5-year survival rates were 43%, 10%, and 0%, respectively, in the DEBIRI group and 34%, 18%, and 0%, respectively, in the SIRT group.4

Around 30% of TACE sessions are associated with adverse events during or after the treatment. The factors predictive of adverse events and significantly greater hospital length of stay are lack of pretreatment with hepatic arterial lidocaine (P = .005), more than three treatments (P = .05), achievement of complete stasis (P = .04), treatment with greater than 100 mg DEBIRI in one session (P = .03), and bilirubin greater than 2.0 µg/dL with more than 50% liver replaced by tumor (P = .05).39 Table 41.1 displays results of studies using TACE for the treatment of CLM.

RADIOEMBOLIZATION/SELECTIVE INTERNAL RADIATION THERAPY

Traditional external beam radiation therapy in patients with diffuse hepatic malignancy does not improve overall survival40 because liver tolerance for developing radiation-induced injury is low compared with the doses required for tumoricidal effect.41 The usual dose of normal liver tissue tolerance to radiation is 30 Gy, whereas the dose required to induce a tumoricidal effect of a solid tumor is 70 Gy or higher.42 These facts resulted in the idea of selective internal transarterial radiation with the delivery of radiotherapy yttrium 90 (Y90)–impregnated microspheres. Currently, two different Y90 microsphere products with a mean diameter of 20 to 35 µm are available: TheraSpheres (Nordion, Ottawa, Ontario, Canada), which are glass microspheres, and SIR-Spheres (SIRTeX Medical Limited, New South Wales, Australia), which are resin microspheres.

Radioembolization delivers targeted radiation therapy to unresectable liver metastases by the injection of β-emitting isotope Y90, which is bound to nondegradable microspheres into the arterial supply of the liver. These microspheres are unable to pass through the vasculature of the liver due to their relatively large size in comparison to the capillaries and are therefore trapped in the tumor capillaries.

The physical properties of this radioactive isotope are a half-life of 64 hours and no γ-energy emission, thus allowing immediate release of the patient after treatment. The average range of radiation penetration in tissues is 2.5 mm to 1 cm. This allows delivery of high dose of ionizing radiation to the tumor with minimal radiation to surrounding tissue and thus causing considerably less toxicity to the normal liver.43Criteria for radioembolization include patients with unresectable (and noneligible for ablation) CLM, patients with liver-only or liver-dominant disease, life expectancy of at least 3 months, and acceptable liver reserve. As a matter of fact, in a recent phase I trial, we demonstrated that SIRT can be safely used as a salvage therapy in heavily pretreated patients who progressed after multiple lines of systemic chemotherapy and HAC as well as resection (Fig. 41.1). Provided that the bilirubin level is low (≤1.5 mg/dL), the risk of radiation-induced liver failure is extremely low even in the most heavily pretreated population.44

Once the patient is selected for radioembolization, pretreatment angiography (mapping) is performed. Considering the highly variable hepatic arterial anatomy and the potential hazardous effects of a nontarget delivery of radioactive microspheres into extrahepatic sites, one has to ensure that there is no hepatofugal flow from the point of sphere injection. Preparation before radioembolization, similarly to the previously described preparation for HAIP placement, requires either embolization of vessels such as the gastroduodenal, right gastric, falciform, and pancreaticoduodenal arteries or placement of an infusion catheter distal enough to all vessels with potential hepatofugal flow and nontarget sphere delivery.45 Another particular feature of tumor vessels is arteriovenous shunting. Because the highest tolerable dose to the lung is around 30 Gy for a single application, one has to assess the fraction of the lung shunting before radioembolization by means of lung scanning after the intra-arterial infusion of 200 to 400 MBq (4 to 10 mCi) Tc-99m MAA (Fig. 41.2). The lung shunting fraction is defined as the percent shunt fraction of microspheres from liver to lung. The dose of radioactive microspheres should be adapted according to the lung shunting fraction. It is also important to correlate the Tc-99m MAA scan with angiographic findings by using single-photon emission computed tomography (SPECT) or even SPECT/CT to identify potential extrahepatic accumulations.46 Y90 delivery should aim to treat all the lesions with as selective approach as possible, allowing more precise tumor targeting while minimizing the radiation exposure to healthy uninvolved hepatic parenchyma. At the same time, this selective approach eliminates the need of prophylactic embolization of vessels that will no longer be a source of extrahepatic delivery of radioactive spheres due to reflux. For patients with bilobar disease, the lobe with the most lesions should be treated first, and administration to the contralateral lobe should be performed in a separate session 4 to 6 weeks later. New developments now allow the safe delivery of Y90 spheres without the need for coil embolization. These include recent unpublished expertise indicating that it is safe to mix resin microspheres with iodinated contrast. This allows immediate visualization and very early detection of reflux that further increases the safety of Y90 administration. Finally, the use of antireflux catheters also allows the delivery of the entire dose without the need of coil embolization.

Radioembolization has initially had large application in chemorefractory disease. Overall response of 17% to 35% and stable disease rates of 24% to 61% have been described.47,48 Median survival after radioembolization has been from 6.7 to 17 months.49 Table 41.2 represents overall patient survival after SIRT treatment.

Modest effects of radioembolization were seen when it was used as a salvage monotherapy after complete chemotherapy failure. Radioembolization alone in this setting showed an overall response of 24%, a progression-free survival of 3.7 months, and 1- and 2-year OS rates of 50.4% and 19.6%, respectively.50

The major contribution of radioembolization were documented when it was used together with systemic chemotherapy.12,51 The concept behind this combined treatment was that tumors were sensitized by one treatment for the other and thus a synergistic effect of SIRT with chemotherapy was seen with better response rates.52

As a matter of fact, in a randomized controlled trial,12 it was shown that the combination of SIRT with protracted 5-FU had a significantly better progression-free survival when compared to protracted 5-FU alone in patients who had previously failed 5-FU–containing regimens. Table 41.3 represents median overall patient survival with combination chemotherapy and SIRT.

TIPS AND TRICKS

Tips

• Use CT angiography or cone-beam CT to optimally delineate segmental anatomy and arterial tumor supply.

• Selective Y90 infusion (sectoral or segmental) allows more precise tumor targeting while minimizing the radiation exposure to healthy uninvolved liver tissue and eliminates the need of prophylactic embolization of vessels that will no longer be a source of extrahepatic delivery of radioactive spheres due to reflux.

• Follow-up imaging with PET/CT might be a more sensitive indicator of early tumor response (PET response criteria in solid tumors; PERCIST) compared to dynamic CT.

Tricks

• Prophylactic transcatheter embolization of the right gastric artery (RGA) in preparation forradioembolization/HAC can be more easily achieved in retrograde approach via left gastric artery (LGA).

• Consider using iodinated contrast material when pushing resin microspheres and 5% dextrose for flushing the catheter in between administrations.

• Consider using iodinated contrast material when pushing resin microspheres and 5% dextrose for flushing the catheter in between administrations.

DISCUSSION

In the last 30 years, the natural history of colorectal cancer has been significantly improved due to the development of several chemotherapeutic agents.53 As described in a review in the mid-1980s, solitary CLM, if left untreated, had survival rates of about 70% and 45% at 1 and 2 years, respectively.54 Thirty years later, in 2011, survival rates have dramatically improved to more than 60% at 2 years and 35% at 5 years. This improvement is attributed to the availability of new chemotherapeutic agents along with improved imaging for early tumor detection as well as aggressive surgical debulking and locoregional therapies including AT.

Although the National Comprehensive Cancer Network (NCCN) guidelines53 support the value of systemic chemotherapy in the management of CLM, they do not support the widespread use of intra-arterial locoregional therapies largely because of their lower level of evidence (mostly level 3, small numbers of level 2, and sparse numbers of level 1 evidence). Despite the relative lack of endorsement by the NCCN guidelines regarding the use of intra-arterial therapies (mostly attributed to the small number of randomized controlled trials), these methods show improved progression-free survivals and provide a very promising research ground especially in combination with different chemotherapeutic agents.

Tumor control and decrease in tumor load in metastatic disease is achieved with systemic treatment. Although the mainstay of treatment of CLM is by IV administration of oxaliplatin and irinotecan, targeted chemotherapies with administration through the hepatic artery achieve higher response rates than does IV therapy.27,28

Transarterial therapies have the advantage of preferentially reaching metastases because their vascularization is nearly 100% arterial, whereas the vascularization of liver parenchyma is 30% arterial and 70% portal. In addition, if the drug injected in the hepatic artery is selectively retained in the liver during embolization, systemic passage and therefore systemic toxicity of the drug will be reduced as well.

TACE and radioembolization are two techniques commonly used for treating liver metastases from different tumor entities. Intra-arterial–directed therapies such as HAC, TACE, DEB-TACE, and SIRT have shown high response rates and can now be used as an adjunct to the initial chemotherapy agent that failed12 or as induction chemotherapy to downsize unresectable liver metastases to resection.35,55

Particularly, HAC and SIRT have reported a fraction of treated patients being downsized to resection. Both HAC and SIRT have also been associated with best oncologic outcomes when combined with earlier lines of systemic chemotherapy.10

Earlier series of TACE with several chemotherapeutic agents indicated that chemoembolization might offer some benefit in the control of CLM, particularly for those patients who progressed through prior lines of systemic chemotherapy.35,36

The recent development of DEBIRI shows initial promise. A very recent randomized controlled trial by Fiorentini et al.38 demonstrated that DEBIRI in combination with FOLFIRI offered a statistically significant prolongation of the progression-free survival and, more importantly, the overall survival of patients with CLM. This study sets the stage for more and larger similarly designed trials to prove the value of arterially directed therapies for patients with nonresectable CLMs.

SIRT with Y90-impregnated beads is another new therapy that essentially delivers very high doses of radiation directly in the tumor via the arterial tree. Several series have shown the safety and efficacy of this treatment even in the most heavily and compromised patients with colon cancer hepatic metastases.44 SIRT is now accepted in the salvage setting when systemic chemotherapy has failed to control CLM.50,60

Similarly to DEBIRI, several series have indicated that SIRT in combination with different systemic chemotherapy regimens prolongs the progression-free survival and may prolong overall survival.13,51

These data show that currently, there are several intra-arterial therapies for the patient with CLM who cannot undergo resection or ablation. The selection of the best therapy for each patient certainly requires multidisciplinary discussion and cooperation. SIRT has the advantage of a limited recovery time, allowing the patient to be discharged the same day. It carries a risk, however, for radiation-induced liver disease that has been reported as late as 4 months after therapy.11 To prevent this risk, a careful selection of even heavily pretreated patients is required for effective and safe treatment.44

In addition, SIRT requires a preparatory arteriogram for hepatic arterial flow evaluation and redistribution, lung shunt, and detailed dose calculation. On the other hand, TACE with or without DEBIRI is associated with postembolization syndrome, requiring a short stay in the hospital for supportive care. One point that should be kept in mind is that one type of therapy does not preclude the use of another treatment. Therefore, if local progression is documented at short time interval after one arterially directed therapy, one might consider the use of a different arterially directed treatment.

This chapter was undertaken with the intention to give an overview of the interventional arterial therapies available for the treatment of hepatic metastases. As such, we performed a relatively concise description and discussions of the most commonly used image-guided intra-arterial interventional embolotherapies and have provided most of the relevant references. We would like to close by stating that we, like many others in the field, aspire that interventional oncology may have reached the point to be considered the fourth pillar in oncology along with medical, surgical, and radiation oncology. This is in particular the case when it comes to the management of hepatic metastases and in those originating from colorectal cancer.

REFERENCES

 1. Cohen AD, Kemeny NE. An update on hepatic arterial infusion chemotherapy for colorectal cancer. Oncologist. 2003;8:553–566.

 2. de Baere T, Deschamps F. Arterial therapies of colorectal cancer metastases to the liver. Abdom Imaging. 2011;36:661–670.

 3. Evans KA, Richardson MG, Pavlakis N, et al. Survival outcomes of a salvage patient population after radioembolization of hepatic metastases with yttrium-90 microspheres. J Vasc Interv Radiol. 2010;21:1521–1526.

 4. Hong K, McBride JD, Georgiades CS, et al. Salvage therapy for liver-dominant colorectal metastatic adenocarcinoma: comparison between transcatheter arterial chemoembolization versus yttrium-90 radioembolization. J Vasc Interv Radiol. 2009;20:360–367.

 5. Martin RC, Joshi J, Robbins K, et al. Hepatic intra-arterial injection of drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver metastases refractory to systemic chemotherapy: results of multi-institutional study. Ann Surg Oncol. 2011;18:192–198.

 6. Kemeny NE, Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27:3465–3471.

 7. Martin RC, Joshi J, Robbins K, et al. Transarterial chemoembolization of metastatic colorectal carcinoma with drug-eluting beads, irinotecan (DEBIRI): multi-institutional registry. J Oncol. 2009;2009:539795.

 8. Pohlen U, Mansmann U, Berger G, et al. Multicenter pilot study of 5-fluorouracil, folinic acid, interferon alpha-2b and degradable starch microspheres via hepatic arterial infusion in patients with nonresectable colorectal liver metastases. Anticancer Res. 2004;24:3275–3282.

 9. Vogl TJ, Gruber T, Balzer JO, et al. Repeated transarterial chemoembolization in the treatment of liver metastases of colorectal cancer: prospective study. Radiology. 2009;250:281–289.

10. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12:1711–1720.

11. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres—safety, efficacy, and survival. Radiology. 2008;247:507–515.

12. Hendlisz A, Van den Eynde M, Peeters M, 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;28:3687–3694.

13. Kosmider S, Tan TH, Yip D, et al. Radioembolization in combination with systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer. J Vasc Interv Radiol. 2011;22:780–786.

14. Sharma RA, Van Hazel GA, Morgan B, et al. Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. J Clin Oncol. 2007;25:1099–1106.

15. Geschwind JF, Kaushik S, Ramsey DE, et al. Influence of a new prophylactic antibiotic therapy on the incidence of liver abscesses after chemoembolization treatment of liver tumors. J Vasc Interv Radiol. 2002;13:1163–1166.

16. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16:1311–1319.

17. Wang X, Sofocleous CT, Erinjeri JP, et al. Margin size is an independent predictor of local tumor progression after ablation of colon cancer liver metastases. Cardiovasc Intervent Radiol. 2013;36:166–175.

18. Kemeny M. Hepatic artery infusion of chemotherapy as a treatment for hepatic metastases from colorectal cancer. Cancer J. 2002;8(suppl 1):S82–S88.

19. Kemeny MM. The surgical aspects of the totally implantable hepatic artery infusion pump. Arch Surg. 2001;136:348–352.

20. Tanaka T, Arai Y, Inaba Y, et al. Radiologic placement of side-hole catheter with tip fixation for hepatic arterial infusion chemotherapy. J Vasc Interv Radiol. 2003;14:63–68.

21. Arai Y, Takeuchi Y, Inaba Y, et al. Percutaneous catheter placement for hepatic arterial infusion chemotherapy. Tech Vasc Interv Radiol. 2007;10:30–37.

22. Sofocleous CT, Petre EN, Gonen M, et al. CT-guided radiofrequency ablation as a salvage treatment of colorectal cancer hepatic metastases developing after hepatectomy. J Vasc Interv Radiol. 2011;22:755–761.

23. Deschamps F, Elias D, Goere D, et al. Intra-arterial hepatic chemotherapy: a comparison of percutaneous versus surgical implantation of port-catheters. Cardiovasc Intervent Radiol. 2011;34:973–979.

24. Sofocleous CT, Schubert J, Kemeny N, et al. Arterial embolization for salvage of hepatic artery infusion pumps. J Vasc Interv Radiol. 2006;17:801–806.

25. Bloom AI, Gordon RL, Ahl KH, et al. Transcatheter embolization for the treatment of misperfusion after hepatic artery chemoinfusion pump implantation. Ann Surg Oncol. 1999;6:350–358.

26. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst. 1996;88:252–258.

27. Kemeny NE, Niedzwiecki D, Hollis DR, 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;24:1395–1403.

28. Boige V, Malka D, Elias D, et al. Hepatic arterial infusion of oxaliplatin and intravenous LV5FU2 in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure. Ann Surg Oncol. 2008;15:219–226.

29. Kemeny N, Jarnagin W, Paty P, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol. 2005;23:4888–4896.

30. Nakakuma K, Tashiro S, Hiraoka T, et al. Hepatocellular carcinoma and metastatic cancer detected by iodized oil. Radiology. 1985;154:15–17.

31. Konno T, Maeda H, Iwai K, et al. Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium. Cancer. 1984;54:2367–2374.

32. de Baere T, Dufaux J, Roche A, et al. Circulatory alterations induced by intra-arterial injection of iodized oil and emulsions of iodized oil and doxorubicin: experimental study. Radiology. 1995;194:165–170.

33. Egawa H, Maki A, Mori K, et al. Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats. J Surg Oncol. 1990;44:109–114.

34. Kruskal JB, Hlatky L, Hahnfeldt P, et al. In vivo and in vitro analysis of the effectiveness of doxorubicin combined with temporary arterial occlusion in liver tumors. J Vasc Interv Radiol. 1993;4:741–747.

35. Albert M, Kiefer MV, Sun W, et al. Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol. Cancer. 2011;117:343–352.

36. Aliberti C, Tilli M, Benea G, et al. Trans-arterial chemoembolization (TACE) of liver metastases from colorectal cancer using irinotecan-eluting beads: preliminary results. Anticancer Res. 2006;26:3793–3795.

37. Taylor RR, Tang Y, Gonzalez MV, et al. Irinotecan drug eluting beads for use in chemoembolization: in vitro and in vivo evaluation of drug release properties. Eur J Pharm Sci. 2007;30:7–14.

38. Fiorentini G, Aliberti C, Tilli M, 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;32:1387–1395.

39. Martin RC, Howard J, Tomalty D, et al. Toxicity of irinotecan-eluting beads in the treatment of hepatic malignancies: results of a multi-institutional registry. Cardiovasc Intervent Radiol. 2010;33:960–966.

40. Russell AH, Clyde C, Wasserman TH, et al. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Phys. 1993;27:117–123.

41. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122.

42. Dawson LA, McGinn CJ, Normolle D, et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2000;18:2210–2218.

43. Kennedy AS, Nutting C, Coldwell D, et al. Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers. Int J Radiat Oncol Biol Phys. 2004;60:1552–1563.

44. Sofocleous CT, Garcia AR, Pandit-Taskar N, et al. Phase I trial of selective internal radiation therapy for chemorefractory colorectal cancer liver metastases progressing after hepatic arterial pump and systemic chemotherapy. Clin Colorectal Cancer. 2014;13:27–36.

45. Liu DM, Salem R, Bui JT, et al. Angiographic considerations in patients undergoing liver-directed therapy. J Vasc Interv Radiol. 2005;16:911–935.

46. Ahmadzadehfar H, Sabet A, Biermann K, et al. The significance of 99mTc-MAA SPECT/CT liver perfusion imaging in treatment planning for 90Y-microsphere selective internal radiation treatment. J Nucl Med. 2010;51:1206–1212.

47. Kennedy AS, Coldwell D, Nutting C, et al. Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience. Int J Radiat Oncol Biol Phys. 2006;65:412–425.

48. Jakobs TF, Hoffmann RT, Dehm K, et al. Hepatic yttrium-90 radioembolization of chemotherapy-refractory colorectal cancer liver metastases. J Vasc Interv Radiol. 2008;19:1187–1195.

49. Vente MA, Wondergem M, van der Tweel, I et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol. 2009;19:951–959.

50. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer. 2010;103:324–331.

51. Van Hazel G, Blackwell A, Anderson J, 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;88:78–85.

52. Nicolay NH, Berry DP, Sharma RA. Liver metastases from colorectal cancer: radioembolization with systemic therapy. Nat Rev Clin Oncol. 2009;6:687–697.

53. Benson AB III, Bekaii-Saab T, Chan E, et al. Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2013;11:141–152; quiz 152.

54. Wagner JS, Adson MA, Van Heerden, JA et al. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg. 1984;199:502–508.

55. Goere D, Deshaies I, de Baere T, et al. Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg. 2010;251:686–691.

56. Aliberti C, Fiorentini G, Muzzio PC, et al. Trans-arterial chemoembolization of metastatic colorectal carcinoma to the liver adopting DC Bead(R), drug-eluting bead loaded with irinotecan: results of a phase II clinical study. Anticancer Res. 2011;31:4581–4587.

57. Tellez C, Benson AB III, Lyster MT, et al. Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature. Cancer. 1998;82:1250–1259.

58. Wasser K, Giebel F, Fischbach R, et al. Transarterial chemoembolization of liver metastases of colorectal carcinoma using degradable starch microspheres (Spherex): personal investigations and review of the literature [in German]. Radiologe. 2005;45:633–643.

59. Salman HS, Cynamon J, Jagust M, et al. Randomized phase II trial of embolization therapy versus chemoembolization therapy in previously treated patients with colorectal carcinoma metastatic to the liver. Clin Colorectal Cancer. 2002;2:173–179.

60. Lewandowski RJ, Thurston KG, Goin JE, et al. 90Y microsphere (TheraSphere) treatment for unresectable colorectal cancer metastases of the liver: response to treatment at targeted doses of 135-150 Gy as measured by [18F]fluorodeoxyglucose positron emission tomography and computed tomographic imaging. J Vasc Interv Radiol. 2005;16:1641–1651.

61. Mulcahy MF, Lewandowski RJ, Ibrahim SM, et al. Radioembolization of colorectal hepatic metastases using yttrium-90 microspheres. Cancer. 2009;115:1849–1858.

62. Cianni R, Urigo C, Notarianni E, et al. Radioembolisation using yttrium 90 (Y-90) in patients affected by unresectable hepatic metastases. Radiol Med. 2010;115:619–633.

63. Hendlisz A, Van den Eynde M, Peeters M, 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;28:3687–3694.

64. van Hazel GA, Pavlakis N, Goldstein D, et al. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J Clin Oncol. 2009;27:4089–4095.