Version July 2025
INTRODUCTION —
Surgical resection is the treatment of choice for patients with isolated colorectal cancer (CRC) liver metastases when feasible, and many of these patients are potentially cured. However, even with liver-limited disease, most patients are not surgical candidates because of tumor location, multifocality, or inadequate hepatic reserve.
There are several nonsurgical treatment options for patients with liver-isolated CRC metastases who are not candidates for potentially curative resection. These include systemic chemotherapy, as well as liver-directed therapies such as:
●Tumor ablation (radiofrequency or microwave coagulation, cryoablation, irreversible electroporation [IRE], histotripsy)
●Radiation therapy, which includes conventional fractionation external beam radiation therapy and stereotactic body radiation therapy (SBRT)
●Regional chemotherapy via the hepatic artery
●Radioembolization using Yttrium-90 (Y-90) labeled resin or glass microspheres
●Transarterial chemoembolization (TACE)
Some of these techniques may also be useful for patients with metastatic CRC and isolated or predominant liver metastases that are refractory to systemic therapy.
This topic review will cover indications and techniques for nonsurgical liver-directed methods for local tumor treatment. Resection and the use of preresection (induction) chemotherapy, as well as systemic treatment strategies for metastatic CRC, are discussed separately.
●(See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)
●(See "General principles of systemic therapy for metastatic colorectal cancer".)
●(See "Initial systemic therapy for metastatic colorectal cancer".)
SYSTEMIC THERAPY-NAÏVE DISEASE
Resectable disease
Surgery — Surgical resection is the treatment of choice for most patients with isolated (ie, no extrahepatic metastases) and resectable CRC liver metastases. If a margin-negative resection can be accomplished, surgical therapy in patients with liver-isolated disease is associated with a substantial long-term overall survival (OS) benefit relative to no surgery. These data are discussed separately. (See "Hepatic resection for colorectal cancer liver metastasis", section on 'Oncologic'.)
Prior to surgical resection, some patients may be offered initial (neoadjuvant) systemic therapy. In the setting of synchronous metastatic disease, a major advantage of this approach is that it allows an understanding of the natural history of the metastatic disease before subjecting the patient to surgery that might not be curative. Multidisciplinary evaluation is necessary, with input from medical oncology, surgical oncology, interventional radiology, and radiation oncology. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Potentially resectable disease'.)
What is the role of thermal ablation? — For patients with a limited number of isolated, resectable CRC liver metastases ≤3 cm, surgical resection is the treatment of choice. Liver-directed thermal ablation (either radiofrequency ablation [RFA] or microwave ablation [MWA]) may provide similar OS and reduce complications compared with surgery, based on observational studies [1-5] and a phase III trial (COLLISION) [6]. However, in our view, while the COLLISION trial suggests that thermal ablation results in noninferior OS compared with surgery in this population, the results are not definitive since patient enrollment was stopped early for benefit. Stopping the trial early also makes it difficult to determine whether some patients might have benefitted more from surgical resection than thermal ablation. The decision to use surgery, ablation, or both is also complex and best discussed in a multidisciplinary conference since the selection of therapy is based on many factors aside from tumor size (eg, patient performance status and comorbidities, tumor location, and proximity to liver capsules, biliary structures, and major vessels). In addition, patients who need multiple thermal ablations are best treated at centers of excellence for the management of CRC since such procedures require special proficiency. We await long-term follow-up of OS (to confirm curative intent) in the COLLISION trial prior to exclusively using thermal ablation to treat this population.
Studies have compared local thermal ablation techniques (ie, RFA and MWA) to surgical resection [7-9]. In a systematic review and meta-analysis of mainly observational studies and two randomized trials of patients with CRC liver metastases, either RFA or MWA were compared to partial hepatectomy [7]. Relative to partial hepatectomy, RFA alone was associated with inferior OS (10 observational comparative studies, hazard ratio [HR] for death 1.78, 95% CI 1.35-2.33) but fewer complications (HR 0.47, 95% CI 0.28-0.78). However, interpretation of these OS results, which included mostly retrospective studies, was limited by selection bias since thermal ablation was only used to treat patients with unresectable liver metastases. OS was similar for resection and MWA based upon one randomized trial, with serious concerns about the risk of bias [10]. As local thermal ablation techniques have improved (larger ablation margins, better imaging guidance, and imaging confirmation of successful therapy), subsequent observational studies have demonstrated similar OS outcomes between thermal ablation (RFA or MWA) and hepatic resection [1-5].
Based on these initial data, a noninferiority, single-blind phase III study (COLLISION) was conducted to compare RFA to hepatic resection [6]. In this study, 296 patients with resectable CRC metastases isolated to the liver were randomly assigned to either hepatic resection or surgical or percutaneous thermal ablation. All patients had good Eastern Cooperative Oncology Group performance status (0 to 2) (table 1), no extrahepatic metastases, no more than 10 resectable liver metastases, and one or more liver metastases that were ≤3 cm and amenable to both resection and ablation.
Most patients had low-tumor burden disease (62 percent), followed by intermediate- (31 percent), and high-tumor burden groups (7 percent). The latter two groups were randomly assigned to treatment while in the operating room. Most patients had also not received prior systemic therapy (78 percent). The median number of liver metastases (two) and the mean size of the target liver metastases (13 to 14 mm) were similar between the two treatment arms. Approximately half the patients had synchronous metastases and the other half had metachronous metastases. The study also allowed additional resections for tumors >3 cm and additional ablations for unresectable liver metastases. Using these criteria, among those randomly assigned to surgery, the proportion treated with resection alone or resection plus ablation was 61 and 35 percent, respectively. Among those randomly assigned to ablation, the proportion treated with ablation alone or resection plus ablation was 80 and 18 percent, respectively.
At a median follow-up of 29 months, relative to surgery, ablation had similar OS (HR 1.05, 95% CI 0.69-1.58), similar distant progression-free survival (HR 1.03, 95% CI 0.78-1.37), and similar per-patient local control (HR 0.13, 95% CI 0.02-1.06) but higher per-tumor local control (HR 0.09, 95% CI 0.01-0.74) [6]. Ablation was also associated with lower morbidity and mortality relative to surgery including lower treatment-related mortality (0 versus 2 percent), lower all-cause 90-day mortality (1 versus 2 percent), less grade ≥3 toxicity (7 versus 20 percent), and shorter hospital stays (median 4 versus 1 day[s]). The trial was stopped early for benefit.
Potentially resectable disease — Patients with isolated CRC liver metastases that are potentially resectable may be offered initial systemic therapy to reduce tumor burden and render them surgical candidates. Further details are discussed separately. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases' and "Hepatic resection for colorectal cancer liver metastasis", section on 'Patient selection'.)
Not suitable for resection
Approach to therapy — Patients with isolated liver metastases and a limited number of small lesions may be deemed unsuitable for resection because of tumor location, impaired general health status, or an insufficient future liver remnant to resect all lesions. For such patients, locoregional liver-directed treatment is an acceptable option for initial therapy. Examples of locoregional liver-directed therapy include thermal ablation (ie, RFA or MWA), nonthermal ablation (eg, irreversible electroporation [IRE], histotripsy), stereotactic body radiotherapy (SBRT), Yttrium-90 (Y-90) radioembolization, and transarterial chemoembolization (TACE). The choice of the specific locoregional treatment depends on local expertise, the number, size, and location of lesions, as well as patient preference. One advantage of locoregional liver-directed therapy for appropriately selected patients is the deferral of systemic therapy-related toxicity. (See 'Options for liver-directed therapy' below.)
Initial systemic therapy is another option. One commonly employed strategy is to start with systemic therapy; for patients whose disease remains liver-limited, systemic therapy can be followed by consolidation therapy with locoregional liver-directed therapy such as thermal ablation (RFA, MWA) or SBRT. (See 'Liver-directed therapy plus systemic therapy' below.)
Patients who are ineligible for locoregional therapy because of disease extent, or poor underlying liver function, or if locoregional therapy is not available, are treated with initial systemic therapy. Specific recommendations are provided separately. (See "Initial systemic therapy for metastatic colorectal cancer" and "Management of metastatic colorectal cancer in older adults and those with a poor performance status".)
The relative benefit of locoregional liver-directed therapies over modern palliative combination systemic therapy alone for patients who are unsuitable for resection is uncertain. There are no randomized trials in which patients with systemic therapy-naïve liver isolated hepatic metastases who were unsuitable for resection were randomly assigned to any form of liver-directed therapy versus initial systemic therapy. Furthermore, most of the studies examining the different forms of locoregional liver-directed therapy were conducted at a time before the introduction of oxaliplatin, irinotecan, and biologic agents such as bevacizumab and agents targeting the epidermal growth factor receptor. Long-term survival for patients with metastatic CRC has clearly improved with the availability of more active anticancer agents. As an example, in a report of pooled data from North Center Cancer Treatment Group trials conducted in the fluorouracil (FU) plus leucovorin (LV) era, only 1.1 percent of patients were alive at five years [11]. By contrast, in a report from the phase III FIRE-3 trial (first-line irinotecan with short-term infusional FU plus LV [FOLFIRI] plus either bevacizumab or cetuximab), the five-year survival rate for patients with RAS wild-type tumors treated with FOLFIRI plus cetuximab was approximately 20 percent [12]. An important point is that although many of the survival gains are attributable to advances in systemic therapy, more aggressive use of surgical resection of metastatic disease has also contributed. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Systemic therapy versus supportive care'.)
In general, these benefits are obtained with sequential use of all active agents, and it is still not established whether there is any survival benefit to initiating systemic therapy early, at the time metastatic disease is diagnosed, versus deferring therapy until patients become symptomatic. This subject is discussed separately. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Timing of systemic therapy'.)
A different question is whether the addition of locoregional liver-directed ablation (RFA, MWA, or SBRT) to systemic therapy improves outcomes. This is addressed below. (See 'Liver-directed therapy plus systemic therapy' below.)
We do not suggest adding concurrent radioembolization to initial systemic therapy, as this approach does not improve OS and worsens toxicity. (See 'Radioembolization plus systemic therapy (systemic therapy-naïve disease)' below.)
Options for liver-directed therapy — The options for locoregional liver-directed therapy include thermal (RFA, MWA) and nonthermal (IRE, histotripsy) tumor ablation, SBRT, Y-90 radioembolization, and TACE. The choice of the specific locoregional treatment depends on local expertise, the number, size, and location of lesions, as well as patient and clinician preference.
●The best results with thermal ablation (RFA or MWA) are seen in patients with three or fewer lesions that are each less than 3 cm in diameter and are not located near structures such as major bile ducts, gallbladder, stomach or bowel, diaphragm or major vessels. While both techniques are reasonable, we generally favor MWA. (See 'Choice of thermal ablation technique' below.)
●Nonthermal techniques, such as IRE or histotripsy, may be employed for lesions that are not in a suitable location for thermal ablation. Due to lack of energy penetration outside of liver tissue bracketed by probes, IRE may be a reasonable alternative to thermal ablation when there is concern for injury to adjacent organs, major bile ducts, or major vessels. Histotripsy is another emerging technique that could provide tumor control for sonographically visible lesions generally <3 cm in diameter. (See 'Irreversible electroporation' below and 'Histotripsy' below.)
●Y-90 radiation segmentectomy technique that involves delivery of an ablative dose of beta radiation to a small sector of liver tissue may be a reasonable alternative for lesions not in a suitable location or too large for ablation. (See 'Yttrium-90 radiation segmentectomy' below.)
●Multifocal uni- or bilobar disease could be palliated using Y-90 radioembolization or TACE. TACE regimens may include conventional preparation with mitomycin C, gemcitabine, and irinotecan or drug-eluting bead (DEB) platforms loaded with irinotecan.
●The benefit of SBRT relative to tumor ablation is unclear, and the choice usually depends on local expertise and patient preference. (See 'Stereotactic body radiotherapy' below.)
●Hepatic intra-arterial chemotherapy delivered via implanted pump is a therapeutic option for patients with isolated liver metastases that are not amenable to surgical resection or other forms of local ablation, but it is not widely used and its place in the therapeutic armamentarium for liver-isolated metastatic CRC is not established. If it is used, this approach should be restricted to centers with expertise in the technical aspects of regional chemotherapy. (See 'Hepatic intra-arterial chemotherapy' below.)
Tumor ablation — Tumor ablation is an option for patients with isolated liver metastases from CRC who are not suitable for potentially curative resection because of tumor location, impaired general health status, or an insufficient future liver remnant to resect all lesions. (See "Initial systemic therapy for metastatic colorectal cancer".)
Choice of thermal ablation technique — Hyperthermic (ie, thermal) ablation (using radiofrequency waves or microwaves) has largely become the ablation method of choice based on its safety profile and results, particularly in patients with three or fewer metastases with none greater than 5 cm in diameter.
RFA and MWA can be administered as an outpatient procedure and may be considered a less morbid alternative to surgical resection in patients who are at high risk for, or otherwise not candidates for, surgery [13]. Hyperthermic ablation using RFA or MWA is limited by the difficulty in determining the true lesion margin, which often extends beyond the leading edge, and the lack of specificity of tissue damage. The risk of local recurrence after ablation is increased in lesions larger than 3.5 to 4 cm. Ablation margins extending at least 1 cm beyond visible liver edge by imaging are recommended to prevent local recurrences.
Whether MWA is more effective or safer than RFA is not certain; there are no published randomized trials. Some retrospective comparative series have concluded that RFA might be preferable for peribiliary lesions, while others suggest that MWA may be a better choice for perivascular tumors [14,15].
A systematic review of 75 studies on thermal ablation for CRC liver metastases, most studies (36) reported results for RFA, with local recurrence rates ranging from 10 to 31 percent, whereas studies reporting on outcomes after MWA (n = 13) had a much lower local recurrence rate (5 to 13 percent) [16].
A later meta-analysis of observational studies comparing MWA versus RFA for a variety of hepatic lesions (16 studies involving 2062 patients) concluded that while MWA was associated with a better six-year OS, this was based on only a few series [17]. Other outcomes (one- and five-year OS, local recurrence rate, adverse effects) were similar.
There are numerous methods to achieve tumor ablation, and this clinical problem has drawn much interest from the biomedical technology world.
Radiofrequency ablation — RFA has been widely applied to patients with primary hepatocellular cancer (HCC) and metastatic liver tumors, though differences in surrounding liver (eg, cirrhosis) and tumor physical characteristics should preclude extrapolation of results from one tumor type to the other. RFA can be performed using 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 [18-21]. However, local tumor recurrence rates overlap broadly with each technique, and clinician experience (as well as the type of RFA equipment) is also inversely related to local recurrence rates [22,23]. An expert panel convened by the American Society of Clinical Oncology (ASCO) to review the evidence on RFA for CRC liver metastases concluded that there is insufficient evidence to resolve the issue of optimal approach [8].
Several factors limit the success rate of RFA, including lesion size, location, and lesion number:
●Lesion size and RFA success – The highest ablation success rates are achieved in patients with a solitary metastasis or a few metastases that are all less than 3 cm in size [24-27]. The relationship between size and local recurrence rate is likely related to the size of the thermal injury that can be created by modern RFA devices [28]. Because the objective of thermal ablation is to induce coagulative necrosis of the targeted tumor as well as a rim of normal hepatic parenchyma (ideally 10 mm), the best results are obtained when the tumor is smaller than the size of the coagulative necrosis produced by a single ablation probe (approximately 4 cm). In most (but not all [29]) series, local failure rates increase dramatically when tumor size increases, especially beyond 3.5 to 4 cm [16,30-34]. As an example, in one study, local tumor progression rates after RFA for lesions ≤3 cm versus >3 to 5 cm were 15 and 61 percent, respectively [34]. In another observational study of patients with lesions <3 cm versus 3 to 5 cm, there was no difference between the groups for OS (HR 1.339; 95% CI 0.824-2.176). Local tumor progression-free survival (HR 3.388) and local control (HR 3.744) were superior in the group with smaller tumors. The same study found that >5 mm margin could be achieved for 94.2 percent of lesions <3 cm versus 58.5 percent of lesions 3 to 5 cm [35].
●Impact of tumor location and number – The location of the tumors within the liver also impacts on the success of RFA:
•Lesions that are located near large (≥1 cm) blood vessels may be inadequately treated because rapidly flowing blood cools the area being heated (a phenomenon called heat sink effect) [30,36,37].
•Percutaneous RFA may sometimes be avoided for treatment of lesions that are located in the dome or along the inferior liver edge for fear of diaphragmatic injury [38] or adjacent to the intestine, stomach, heart, gallbladder, or major bile duct due to concern for thermal damage. However, these lesions can be successfully treated with the use of protective techniques such as hydrodissection (administration of water or normal saline between target liver lobe and adjacent structure), pneumodissection (administration of carbon dioxide between target liver lobe and adjacent structure), and laparoscopic or open laparotomy approaches [39].
•Ablation of solitary metastases is associated with very high rates of local tumor control and survival (5-year survival >50 percent in two separate series [40,41]).
●Long-term outcomes – The vast majority of published data on efficacy of RFA for CRC liver metastases come from retrospective series, many of which have limited follow-up (20 months or less); there are few published randomized trials [18,42-47]. A systematic review of the literature on RFA for CRC liver metastases reported a wide range of five-year survival (14 to 55 percent) and local recurrence rates (3.6 to 60 percent) [8]. However, both the retrospective series and limited number of prospective trials consist of a variable mix of patients with potentially resectable liver-isolated disease and unresectable liver metastases with or without extrahepatic disease involvement.
Among appropriately selected patients with potentially resectable liver metastases [48-54], at least three systematic reviews and meta-analyses have been conducted [7-9], with all three concluding that particularly in the absence of extrahepatic disease, there is not enough evidence to support the use of RFA over resection in patients with potentially resectable CRC liver metastases. (See 'Resectable disease' above.)
●Complications – RFA is a relatively well-tolerated technique; however, severe and potentially fatal complications can arise. In the ASCO systematic review, the reported mortality rate was 0 to 2 percent, and the major complication rate was between 6 and 9 percent in most studies [8]. Postablation syndrome, which is characterized by low-grade fever, malaise, chills, delayed pain, and nausea and vomiting, occurs in 30 to 40 percent of patients, and appears, on average, three days after ablation and lasts five days [55]. It is usually self-limiting and resolves within ten days. Opioids are rarely needed.
Other postprocedure complications may be more serious, and not self-limiting. One series that addressed other potentially more serious complications included 312 patients with hepatic tumors (predominantly colorectal metastases) who underwent 350 procedures (226 percutaneous and the remainder intraoperative) [56]. Five deaths were attributed to treatment (one each from liver failure and colon perforation, three from portal vein thrombosis). Portal vein thrombosis was significantly more common in cirrhotic (2 of 5) compared with noncirrhotic livers (0 of 54) after intraoperative RFA performed during a Pringle maneuver. There were 37 nonfatal serious complications (incidence 10.6 percent), which included:
•Liver abscess in seven, which developed in all three patients with a bilioenteric anastomosis compared with less than 2 percent of the others
•Pleural effusion and skin burns in five patients each
•Hypoxemia during treatment in four patients
•Pneumothorax in three patients
•Subcapsular hematoma in two patients
•Acute kidney insufficiency, hemoperitoneum, and needle tract seeding in one patient each
Microwave ablation — Microwave systems use an electromagnetic signal to generate heat by vigorous agitation of water molecules in tissues, resulting in cellular death by coagulation necrosis [10,57].
Although best studied for treatment of small HCCs, MWA has gained acceptance as a favorable alternative to RFA, and in some cases, preferred over RFA, for thermal ablation of metastatic liver tumors [14,15,58-60]. There are several advantages of MWA over RFA, such as higher intratumoral temperatures, incorporation of multiple applicators simultaneously, allowing treatment of multiple lesions, and less procedural pain [61,62]. Because the electromagnetic waves produce thermal necrosis by molecular friction, the heat sink effect is less of an issue with MWA than with RFA. Although MWA can be performed intraoperatively [63], at most institutions, MWA is performed percutaneously by interventional radiologists [59,64].
●MWA versus resection – In one of the only randomized trials directly comparing local nonsurgical ablation versus resection, 30 patients with potentially resectable hepatic metastases from CRC were randomly assigned to laparotomy with ultrasonographically-guided MWA or surgical resection [10]. Both approaches were associated with similar two-year (56 and 57 percent) and three-year (14 and 23 percent) survival rates, as well as similar median survival (27 and 25 months, respectively). Notably, this trial was downgraded for quality because of serious concerns about risk of bias in one meta-analysis [7]. (See 'Resectable disease' above.)
Additional information is available from a propensity score analysis derived from a population-based Swedish registry of all patients undergoing liver resection or MWA as a first intervention for CRC liver metastases measuring ≤3 cm between 2013 and 2016 [1]. The characteristics of the unmatched cohort of 82 MWA patients and 645 resected patients differed significantly as to age, comorbidity, tumor location, number of metastases, and prior systemic therapy, and OS favored resection (three-year OS 76 versus 69 percent). However, a difference was no longer evident in cohorts with propensity score matching (70 MWA and 201 resected, three-year OS 76 versus 76 percent).
Long-term outcomes with MWA for CRC liver metastases are further supported by several retrospective series [65,66].
●Complications – Reported complications of percutaneous MWA are similar to those reported for RFA, and are typically mild, including pain, fever and transaminase elevation; the risk of liver abscess, bile leak/biloma, ascites/pleural effusion, diaphragm injury, and needle track seeding are all low [59,65].
Interstitial laser ablation — Published experience with interstitial laser thermotherapy is limited to a few institutions [64,67-69]. One series consisted of 603 patients who underwent MRI-guided laser thermotherapy of 1801 CRC liver metastases; details of additional oncologic therapy were not provided [69]. Clinically relevant complications included pleural effusion (1.1 percent), liver abscess (0.4 percent), and intra-abdominal bleeding, pneumothorax, bile duct injury, bronchobiliary fistula, and death within 30 days in 0.1 percent each. At six months postprocedure, 95 percent of the lesions were controlled locally, and none recurred thereafter with up to 7.6 years of follow-up; median follow-up duration was not stated. Five-year survival was 37 percent.
Irreversible electroporation — IRE is a nonthermal ablation technique that involves delivery of strong electrical pulses between paired electrodes inserted in parallel configuration to bracket a target lesion, such as the NanoKnife System [70] or via a single monopolar electrode, such as the Aliya System [71]. Electrical pulses cause pores to form in cell membranes leading to cell death. A systematic review included eight studies (five prospective phase II studies and three retrospective case cohorts) that included 162 patients with 283 CRC liver metastases <3 cm in size treated with IRE. Procedures were performed under general anesthesia with cardiac cycle synchronization and with the use of either CT or ultrasound for lesion localization. Probe spacing was less than 3.2 cm for all ablations. Nonfatal cardiac arrhythmia occurred in nine (5.6 percent) patients. Six bile leaks and one late biliary stricture were reported. There were two procedure-related deaths. Procedure-related hemorrhage occurred in seven patients, with one patient requiring laparotomy to control bleeding. There were no reports of procedure-related liver failure. Local control lasted between zero months for patients with residual disease after IRE to up to 10 months. Progression-free survival ranged from 4 to 12 months. OS at 24 months was 61 to 62 percent for two of the studies and a third study reported a median OS of 2.7 years [72].
Histotripsy — Histotripsy is a nonthermal ablation technique that involves delivery of ultrasound wave bursts that last microseconds. These energy bursts result in cavitation from gas in tissues. Cavitation is generation, oscillation, and collapse of gas microbubbles activated by ultrasound. Microbubbles expand rapidly from 2 to 5 nm to 100 nm and subsequently collapse causing cells to fracture [73]. Published outcomes of histotripsy have been limited to two human studies of 8 and 44 patients [74,75]. A total of 15 patients with CRC liver metastases were included. Both studies met technical endpoint of producing a successful ablation in 95 to 100 percent of patients. Severe adverse events were encountered in three patients and included sepsis in a patient with a biliary stent, pleuritic chest pain that required hospitalization, and liver failure due to extensive liver parenchyma replacement by metastases. Other clinical outcomes were not reported.
Yttrium-90 radiation segmentectomy — Y-90 radiation segmentectomy involves delivery of an ablative dose (>200 Gy) of Y-90 glass or resin microspheres to a small sector of liver via a branch of the hepatic artery, typically to a single segment or less. This technique may be an alternative to ablation for lesions that are not safely accessible for thermal ablation or IRE probe placement. Y-90 radiation segmentectomy was evaluated in two retrospective studies [76,77] that included 13 patients with metastatic CRC metastases out of 46 patients that were included between the two studies. Local tumor progression rate was 28 to 33 percent. Severe adverse events were rare and included biloma in one patient (2 percent), and abscesses in three patients (7 percent).
Response assessment — The efficacy of percutaneous ablation therapy is typically assessed by periodic contrast-enhanced dynamic CT or MRI starting one month after therapy. Standard methods to assess treatment response to anticancer therapies (eg, unidimensional Response Evaluation Criteria in Solid Tumours [RECIST] criteria (table 2) [78], bidimensional perpendicular measurement using World Health Organization criteria [79]) involve measurement of tumor dimensions before and after treatment, and categorize the degree of response according to the degree of shrinkage. However, methods such as these disregard the extent of necrosis, which is the end result of locoregional ablative therapies, and may underestimate the disease response posttreatment.
In patients with HCC, the degree of contrast enhancement within tumor masses is an indicator of viable tumor, and methods to assess response to local ablation are based on the persistence or growing areas of contrast enhancement on cross-sectional imaging rather than changes in tumor size. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer".)
However, for patients with CRC liver metastases, contrast enhancement is typically absent, and there is no consensus on appropriate endpoints to define clinical benefit from locoregional therapies. Treated tumors characteristically show low density on posttreatment CT scans. These regions, which are often interpreted as tumor necrosis, may even be larger than the area of the original tumor. However, this appearance is nonspecific and should not be considered to represent an "objective response," and these response categories should not be used. The most important indicator of benefit from these therapies is the time to disease progression as detected by periodic cross-sectional imaging. Disease progression may be manifest by growth of tumor at the treated site, progression in other parts of the liver, or in extrahepatic sites.
Some patients have elevated levels of serum tumor markers such as carcinoembryonic antigen (CEA). While a reduction in serum CEA levels may not be accompanied by objective tumor shrinkage in patients treated with percutaneous ablation therapy, at least some data suggest a correlation between the magnitude of CEA decline and survival following ablation [80]. As with patients treated with systemic therapy, a rising CEA in a patient treated with local ablation may precede radiographic tumor progression. Treatment decisions should not be based on rising tumor markers levels alone, but progressive rising tumor markers should prompt repeat radiographic reevaluation. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Assessing treatment response'.)
Stereotactic body radiotherapy — There are no randomized trials comparing SBRT with other forms of liver-directed nonsurgical therapy, and its role in the therapeutic armamentarium for unresectable liver metastases, particularly in patients who are eligible for thermal ablation (RFA, MWA), is not well defined. Nevertheless, SBRT is an effective and safe alternative to thermal ablation, with durable local control. In practice, the choice of SBRT over hyperthermic ablation using RFA or MWA generally depends on local expertise and patient preference. One issue is that RFA or MWA can often be carried out in one treatment session, while SBRT often requires several sessions. SBRT may also be preferred over thermal ablation for lesions that abut a large blood vessel, gallbladder, stomach, bowel, or the diaphragm.
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. Early experience with SBRT for liver metastases suggests that this technique is safe and associated with sustained local control, although the reported range of long-term local control is broad (59 to 91 percent at two to three years) [81-88]. Post SBRT local control is generally defined as disappearance of, decrease in, or no increase in the size of the treated lesion(s). (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)
As examples:
●As noted above, in a systematic review of 18 retrospective series encompassing 656 patients treated with SBRT for CRC liver oligometastases (most studies specified no more than two liver metastases, and most patients had received at least one or two lines of systemic therapy), the pooled local control rates at one and two years (available from 13 studies), were 67 and 59 percent, respectively [85]. Pooled rates of grade 1 to 2 and 3 to 4 acute liver toxicity were 30.7 and 8.7 percent, respectively. (See 'Approach to therapy' above.)
●Comparable results were noted in a phase II trial of SBRT for unresectable liver metastases in 61 patients, of whom 29 had a CRC primary [86]. In this group, the local control rate at three years was 75 percent, and results were not significantly different for lesions smaller or larger than 3 cm (77 versus 81.9 percent, respectively).
●In a registry-based analysis (RSSearch Patient Registry), 427 patients with 568 liver metastases were treated with SBRT [88]. In preliminary results from a subgroup analysis of the 217 patients with 233 CRC liver metastases, one- and two-year local control rates with SBRT were 75 and 55 percent, respectively [87].
ASCO guidelines for managing CRC liver metastases recommend consideration of SBRT following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection [89]. (See 'Tumor ablation plus systemic therapy' below.)
Hepatic intra-arterial chemotherapy — Despite a multitude of trials, the relative benefit of regional (hepatic arterial infusional chemotherapy [HAIC]) over systemically-administered chemotherapy for patients with hepatic metastases from CRC remains unclear, particularly within the context of newer systemic therapies that include oxaliplatin, irinotecan, and the biologic agents (bevacizumab, anti-epidermal growth factor strategies). Regional chemotherapy through the hepatic artery remains a therapeutic option for patients with isolated liver metastases that are not amenable to surgical resection or local ablation, but it is not widely used, and its place in the therapeutic armamentarium for metastatic CRC is not established. If it is used, this approach should be restricted to centers with expertise in the technical aspects of regional chemotherapy.
HAIC is based upon the following principles:
●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 [90]. 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 [91].
●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 [91]. 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.
Extensive clinical investigation of HAIC began in the 1970s and 1980s, initially via percutaneously placed catheters and then by a totally implantable pump system. In several prospective trials, enrolling over 400 previously untreated patients with metastatic CRC, randomly assigned patients to systemic fluoropyrimidine chemotherapy or to HAIC with FUDR (floxuridine) delivered via an implanted pump [92-96],the response rate to HAIC was consistently superior but this did not translate into a significant survival improvement in any study or in two separate meta-analyses [97,98]. Subsequent improvements in HAIC technique led to a resurgence of interest in the use of this therapy.
●Technique and complications of pump placement – The goal of intrahepatic artery catheter placement is to enable bilobar hepatic perfusion of chemotherapy and prevent administration to the stomach or duodenum (misperfusion).
A preoperative CT angiogram defines the arterial supply of the liver [99]. If suitable for placement of a hepatic artery catheter, and no extrahepatic tumor, a total devascularization of the distal stomach and proximal duodenum is performed in order to minimize the risk of misperfusion [100]. Any variations in the hepatic lobar arterial supply, including a replaced or accessory left or right hepatic artery, require ligation of that vessel [101].
In nearly all cases, the gastroduodenal artery is chosen for cannulation. Once the catheter is situated, the pump itself is placed in a subcutaneous pocket and it is loaded with heparinized water. Dissection of the lymphatics at the porta hepatis is performed to make room for the pump. Finally [99], 5 mL of fluorescein or methylene blue are injected into the pump side port, and the liver, stomach, and duodenum examined to verify bilobar liver perfusion and to exclude misperfusion to the stomach or duodenum.
Postoperatively, before initiating HAIC, a Tc-99m macro-aggregated albumin scan is necessary to ensure the absence of misperfusion and to assess the adequacy of whole liver perfusion [102,103].
Early postoperative complications consist of arterial injury leading to hepatic artery thrombosis, incomplete perfusion of the entire liver due to missed recognition of an accessory hepatic artery, misperfusion to the stomach or duodenum, or pump pocket hematoma. If the above steps are followed rigorously, these complications should occur in fewer than 5 percent of patients.
Late complications include biliary injury, inflammation or ulceration of the stomach or duodenum, pump pocket infection, or catheter thrombosis. The development of antral or duodenal ulceration should prompt endoscopic examination of the stomach and duodenum with concomitant injection of methylene blue through the pump side-port [104]. Immediate deep blue staining of the ulcerated site warrants an angiographic search for a vessel responsible for the misperfusion. Once identified, the offending vessel can often be embolized using interventional radiologic techniques.
When the infusion pump is no longer being used the infusion device needs to be either operatively removed or regularly flushed to prevent thrombosis.
●Optimizing chemotherapy – The dose of fluorodeoxyuridine (FUDR) employed in early phase III trials of HAIC (0.3 mg/kg per day for 14 of 28 days) induced severe biliary toxicity [105]. A number of strategies were explored to maximize the safety and efficacy of HAIC.
•Dexamethasone and leucovorin – In an attempt to ameliorate any inflammatory aspect of the biliary toxicity, FUDR (0.3 mg/kg per day for 14 days) was administered with and without dexamethasone in a randomized phase II trial [106]. While the addition of dexamethasone did not lessen biliary toxicity, both the response rate and median survival were superior to FUDR alone.
A subsequent series of studies tested FUDR modulated by intra-arterial LV (which enhances the activity of FU by promoting the formation of a stable ternary complex with thymidylate synthetase) plus dexamethasone [107]. The response rate in previously untreated patients was 78 percent, and the median survival was 25 months [108]. A strict paradigm for dose-reduction reduced the incidence of biliary sclerosis to 3 percent, although dose adjustment or temporary treatment delay was necessary in nearly every patient.
•Oxaliplatin and irinotecan – Oxaliplatin and irinotecan are two highly active agents in metastatic CRC. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Chemotherapy backbone'.)
Both can be safely delivered to the liver via the hepatic artery [109-111]. In one report, 28 previously untreated patients with liver isolated metastatic CRC received intra-arterial oxaliplatin (100 mg/m2 over two hours) followed by IV FU and LV administered according to the de Gramont regimen (LV 200 mg/m2 over two hours, followed by FU 400 mg/m2 bolus, and then a 22-hour infusion of FU 600 mg/m2), with repeated courses every two weeks [109]. The objective response rate was 64 percent, and the median OS was 27 months. Grade 3 or 4 neutropenia complicated therapy in 10 patients, and there were two treatment-related deaths, one in the setting of febrile neutropenia. Whether these results are better than could be achieved by systemic administration of oxaliplatin, FU, and LV (eg, the FOLFOX regimen) is unclear.
●HAIC plus systemic therapy – It was postulated that the combined use of intra-arterial plus systemic therapy might improve outcomes by addressing concerns about extrahepatic tumor progression during HAIC while achieving maximal therapeutic effect in the liver. At least three trials have directly compared HAIC versus systemic therapy, but all used inferior chemotherapy by modern standards in the control group (ie, intravenously LV-modulated FU alone) [112-114]. A meta-analysis of these three trials combined with seven earlier randomized trials in which the control arm was systemic therapy or best supportive care concluded that response rates were higher with HAIC but this did not translate into better survival [115]. None of the trials included irinotecan or oxaliplatin in the control arm.
The only available data, from a retrospective analysis of a cohort of individuals treated with HAIC plus modern systemic therapy over a 10-year period within a single health care system, suggest that the combined approach of HAIC plus modern combination systemic therapy might be associated with an approximate doubling of median OS relative to systemic therapy alone (33 versus 15 months); this was not a randomized trial, and the OS in the control group was low by modern standards [116]. Furthermore, the patients in the control group received therapy at affiliated community cancer centers, while all those receiving HAIC had been referred to and managed at the flagship oncologic hospital. It remains unknown whether any HAIC approach will improve upon or even match the results from contemporary modern systemic combination therapy.
Liver-directed therapy plus systemic therapy
Tumor ablation plus systemic therapy — The benefit of thermal ablation (RFA, MWA) or SBRT for the locoregional treatment of liver metastases who are undergoing initial systemic therapy for metastatic CRC remains unproven. However, it is an option for patients with a limited burden of liver-limited disease following initial systemic therapy, as studies suggest that selected patients may benefit.
Local tumor ablation is often used for unresectable CRC liver metastases concurrent with systemic therapy [63], but it has not been clear whether any form of nonsurgical local therapy contributes to better survival, and few, if any, studies have utilized modern systemic combination therapy as the control arm.
There have been no phase III randomized trials of thermal ablation plus systemic therapy versus systemic therapy alone. In the only randomized phase II trial addressing the benefit of combined therapy versus systemic therapy alone, 119 patients with initially unresectable CRC liver metastases and no extrahepatic disease were randomly assigned to systemic treatment alone (oxaliplatin plus LV and short-term infusional FU with or without bevacizumab) or with aggressive local treatment, which was defined as RFA with or without resection [46,117]. Eligibility was limited to patients with fewer than 10 lesions that could all be treated with RFA alone or with combined treatment, which included resection of resectable lesions and RFA of nonresectable lesions.
In the latest analysis, patients randomly assigned to RFA plus resection in conjunction with systemic therapy had a significantly longer median survival (45.6 versus 40.5 months), and eight-year OS (36 versus 9 percent; HR 0.58, 95% CI 0.33-0.88) [117]. Patients receiving RFA plus resection in conjunction with systemic therapy had fewer liver recurrences (65 versus 82 percent), but a higher extrahepatic recurrence rate (35 versus 14 percent). At the RFA sites only 11 of 170 lesions recurred (6.5 percent) in nine patients (15 percent of the total). Although posttreatment salvage systemic therapy details were not provided, the cause of death was progressive disease in significantly fewer patients who underwent local ablative treatment (57 versus 81 percent).
While this randomized study suggests that combining local ablative and/or surgical resection with systemic therapy improves survival in patients with liver-limited metastatic CRC, one must interpret the results cautiously. The study was closed early due to poor accrual and was conducted prior to the use of modern systemic therapy for metastatic CRC. Furthermore, in the RFA arm, 27 of the 50 patients also underwent hepatic resection. Finally, the OS exceeded 40 months in both arms, suggesting extremely unusual patient selection leading to a group of patients with remarkable prognoses.
Radioembolization plus systemic therapy (systemic therapy-naïve disease) — We do not suggest adding concurrent radioembolization to initial systemic therapy. Numerous randomized trials suggest this approach does not improve OS compared with systemic therapy alone and is associated with more adverse events. Additional study is needed to define whether there is a subpopulation of patients with liver-isolated or liver-predominant metastatic CRC that might benefit from combined therapy.
A means of delivering focal radiation to the liver employs radioactive isotopes (eg, 131-labeled lipiodol or Y-90 tagged glass or resin microspheres) that are delivered selectively to the tumor via the hepatic artery (radioembolization, also called selective internal radiotherapy). Radioembolization is most often used for patients with systemic therapy-refractory disease. (See 'Radioembolization' below.)
Data from initial studies suggested the potential benefit of combining Y-90 resin microspheres with initial intravenous fluoropyrimidine-based chemotherapy in patients with CRC liver metastases [118,119]. This led to the conduct of several phase III trials (SIRFLOX, FOXFIRE, and FOXFIRE-Global), in which systemic therapy-naïve patients with CRC liver metastases not amenable to potentially curative resection or ablation were randomly assigned to oxaliplatin-based chemotherapy (with or without an investigator-chosen biologic agent) alone or with a single treatment of radioembolization concurrent with cycle 1 or 2 of chemotherapy [120,121]. In the combined analysis of all three trials (1103 patients, 549 receiving chemotherapy alone and 554 receiving chemotherapy plus radioembolization), at a median follow-up of 43 months, the addition of Y-90 radioembolization to chemotherapy improved the objective response rate (72 versus 63 percent), but this did not translate into improved OS (median 22.6 versus 23.3 months, HR 1.04, 95% CI 0.9-1.19) or progression-free survival (median 11 versus 10.3 months, HR 0.90, 95% CI 0.79-1.02), or a greater likelihood of subsequent liver resection [122]. Furthermore, combined treatment caused more grade 3 or 4 adverse events (especially hematologic toxicity). Of the 11 patients with treatment-related deaths, eight deaths were in the chemotherapy plus radioembolization group, three of which were attributed to radiation-induced liver disease.
SYSTEMIC THERAPY-REFRACTORY DISEASE
Choice of approach — A nonsurgical locoregional liver-directed treatment approach is a reasonable option for patients with CRC and isolated liver (or liver predominant) metastases who progress on several systemic therapies; such an approach may improve symptoms and prolong overall survival (OS). (See "Second- and later-line systemic therapy for metastatic colorectal cancer".)
In most cases, the extent of disease will preclude tumor ablation or stereotactic body radiotherapy (SBRT). Therefore, appropriate options include transarterial chemoembolization (TACE) or Yttrium-90 (Y-90) radioembolization (the latter possibly in combination with fluorouracil [FU], capecitabine, or trifluridine and tipiracil). The choice is usually based on local expertise, patient preference, and disease/patient characteristics. (See 'Transarterial (chemo)embolization' below and 'Radioembolization' below.)
Transarterial (chemo)embolization — Transarterial embolization without and with chemotherapy (TACE) has been investigated in patients with chemorefractory CRC liver metastases using both conventional techniques and drug eluting beads. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'TACE and bland particle embolization'.)
Data from mainly retrospective experience suggests that TACE can achieve disease stabilization in 40 to 60 percent of treated patients, including those with chemorefractory liver-predominant metastatic CRC, with survival durations that may approach a year or more [123-135]. Outcomes seem to be better than can be achieved with continued systemic therapy. As examples:
●Data are available from a single center experience of TACE with 564 patients with isolated liver metastases from CRC who were repeatedly treated with TACE (mean six sessions per patient); 84 were treated in the neoadjuvant setting, the remainder with palliative intent [126]. The median survival after the first TACE procedure was 14.3 months, and one-, two-, and three-year survival rates were 62, 28, and 7 percent, respectively. Notably, survival was significantly better when TACE was performed after first- or second-line systemic therapy (1 to 12 months) than after third- to forth-line therapies (six months). Evaluation of local tumor control demonstrated a partial response in 17 percent and stable disease in 48 percent.
●The only data to directly compare TACE versus systemic palliative systemic therapy come from a phase III trial in which 74 patients with isolated hepatic metastases from CRC were randomly assigned to two monthly infusions of hepatic intra-arterial irinotecan drug-eluting beads (DEBIRI) or four months of intravenous (IV) therapy with irinotecan plus short-term infusional FU and leucovorin (LV; FOLFIRI) [124]. All patients had received at least two or three lines of prior systemic therapy, none in the three months prior to enrollment. Of note, 13 patients (36 percent) treated with DEBIRI and 14 patients (37 percent) treated with FOLFIRI had prior systemic treatment with irinotecan as a part of IFL regimen. Compared with FOLFIRI, DEBIRI improved objective response rate (69 versus 20 percent), OS (56 versus 32 percent at two years, median 22 versus 15 months), and progression-free survival (seven versus four months). While the median time to hepatic progression was significantly longer in the group treated with DEBIRI (seven versus four months), the median time to extrahepatic progression was also inexplicably longer in this group (median 13 versus 9 months).
Radioembolization
Patient selection — Patients with CRC liver metastases who are unsuitable for resection may benefit from radioembolization (also called selective internal radiotherapy). However, given the risks of toxicity and the potential for extrahepatic disease progression while patients are treated with liver-directed therapy, it is difficult to know how to incorporate Y-90 radioembolization into the treatment scheme for patients with unresectable hepatic metastases from CRC. We tend to reserve this approach for patients with chemorefractory disease who have a liver-predominant tumor burden and no other therapeutic options.
Based on a consensus panel from the Radioembolization Brachytherapy Oncology Consortium, radioembolization is limited to patients who meet the following criteria [136]:
●Unresectable metastatic hepatic disease with liver-dominant tumor burden, and a life expectancy >3 months.
●An absolute contraindication to Y-90 microsphere treatment is a pretreatment 99mTc macroaggregated albumin scan that demonstrates the potential for ≥30 Gy radiation exposure to the lung lungs over a single treatment (or >50 Gy radiation exposure to the lungs over the patient's lifetime) or flow to the gastrointestinal tract that cannot be corrected by catheter techniques.
●Relative contraindications include limited hepatic reserve, irreversibly elevated serum bilirubin levels, compromised portal vein (unless selective or superselective radioembolization can be performed), and prior radiotherapy involving the liver [137].
Radioembolization alone — By contrast to approaches in which the radiation source is external to the patient (ie, external beam radiation therapy, SBRT), alternative means of delivering focal radiation to the liver employ radioactive isotopes (eg, 131-labeled lipiodol or Y-90 tagged glass or resin microspheres) that are delivered selectively to the tumor via the hepatic artery (radioembolization, also called selective internal radiotherapy). After injection into the branch of the hepatic artery that perfuses the region of the liver with the metastasis, the microspheres become preferentially lodged in the arteriolar vasculature surrounding the tumor, delivering high doses of radiation to the area. Maximum tissue penetration for the pure beta-emitter Y-90 is 1.1 cm, so most normal liver parenchyma is spared.
SIR-Sphere, a product consisting of Y-90-labeled biocompatible resin microspheres (20 to 40 micrometers in diameter), is available in North America and approved in the United States (concurrent with hepatic intraarterial injection of fluorodeoxyuridine [FUDR]) for the treatment of unresectable liver metastases from primary CRC. Approval was based upon results from a single controlled trial, in which 74 patients with liver-isolated CRC metastases (60 systemic therapy-naïve) were randomly assigned to hepatic intra-arterial chemotherapy with FUDR alone or in conjunction with a single intrahepatic artery administration of SIR-Spheres [138]. Combined therapy was associated with a significantly better objective complete response rate (44 versus 18 percent) and median time to progression (16 versus 10 months), and similar grade 3 and 4 toxicity. Although the one-, two-, three-, and five-year survival rates for patients receiving SIR-Spheres (72, 39, 17, and 4 percent, respectively) did not differ significantly from those of patients in the control arm (68, 29, 7, and 0 percent, respectively), Cox regression analysis suggested a survival benefit for patients who lived longer than 15 months. Notably, at least three adequately powered phase III trials have failed to demonstrate a benefit for radioembolization plus systemic therapy over systemic therapy alone for systemic therapy-naïve disease, and this is generally not considered a standard approach. (See 'Radioembolization plus systemic therapy (systemic therapy-naïve disease)' above.)
Several studies note benefit from Y-90 radioembolization alone in patients with chemorefractory liver-predominant metastatic CRC [139-146]. A systematic review of 20 studies comprising 979 patients found that rates of complete radiologic response, partial response, and stable disease were 0 (range 0 to 6), 31 (range 0 to 73), and 40.5 (range 17 to 78) percent, respectively [147]. Approximately 57 percent had a serologic response (reduction in serum carcinoembryonic antigen). The median time to intrahepatic disease progression was nine months, median time to disease progression overall was 4.9 months, and the median OS was 12 months. Overall, acute toxicity developed in 11 to 100 percent (median 41 percent), most of which was mild (grade 1 or 2). However, the wide range of delivered radioactivity, different treatment volume (ie, lobar versus whole liver) and method/timing of posttreatment evaluation, and variable percentages of patients with extrahepatic disease and concurrent use of systemic therapy in some studies compromise the ability to interpret the results.
Radioembolization plus systemic therapy (systemic therapy refractory-disease) — Radioembolization has also been studied in combination with radiosensitizing agents such as infusional FU, capecitabine, and trifluridine and tipiracil in patients with CRC liver-dominant metastases who progressed on or were intolerant of oxaliplatin and irinotecan-based therapy regimens. Data are as follows:
●In a phase III trial (EPOCH), 428 patients with metastatic CRC who progressed after initial oxaliplatin-based (64 percent) or irinotecan-containing (36 percent) systemic therapy were randomly assigned to second-line systemic therapy (either oxaliplatin- or irinotecan-based, depending of what regimen was used first-line) with or without a single Y-90 radioembolization treatment to all radiographically demonstrable disease in one or both liver lobes [148]. The addition of radioembolization to systemic therapy improved objective response rate (34 versus 21 percent), and progression-free survival (median 8 versus 7.2 months, HR 0.69, 95% CI 0.54-0.88). However, OS was similar between the treatment arms (14 versus 14.4 months, HR 1.07, 95% CI 0.86-1.32), and combination therapy causes more grade 3 toxicity (68 versus 49 percent).
●In a phase III trial, 44 patients with systemic therapy-refractory CRC and liver-dominant metastases were randomly assigned to receive single-session radioembolization with Y-90 resin microspheres to all radiographically visible liver disease in combination with FU (225 mg/m2 for 14 days followed by 300 mg/m2 until disease progression) or FU (300 mg/m2 for 14 days) alone [119]. Compared to systemic therapy alone, radioembolization plus systemic therapy increased the median time to liver progression (5.5 versus 2.1 months, HR 0.38; 95% CI 0.20-0.72). Of the 44 patients, 25 patients received further treatment after progression, including 10 patients in the systemic therapy alone arm who received radioembolization. OS was similar between the two treatment arms (median 10 versus 7.3 months, HR 0.92, 95% CI 0.47-1.78). Grade 3 or 4 toxicities were recorded in six patients in FU monotherapy group and in one patient after radioembolization plus FU treatment.
●A phase I dose escalation trial evaluated radioembolization combined with capecitabine in 24 patients with advanced unresectable, systemic therapy-refractory liver-dominant cancers, 17 of whom had CRC [149]. Patients received capecitabine at doses of 375 to 1000mg/m2 for 14 days in combination with sequential lobar Y-90 radioembolization with resin microspheres on day 2 of cycles 1 and 3. Partial responses, as determined by RECIST v1.0 criteria, were seen in four patients (17 percent) and stable disease in 17 patients (71 percent). Median time to progression was 6.4 months (range 1.5 to 29.9 months) and median OS was 8.1 months (range 3.9 to 43.3 months). Most grade 3 to 4 adverse events were hematologic. There were no instances of radioembolization-induced liver disease noted.
●The rationale for combining Y-90 radioembolization with trifluridine and tipiracil for patients who have not been exposed to this drug is for possible extrahepatic disease control. This combination was evaluated in a phase I trial of 21 patients with systemic therapy-refractory CRC and liver-dominant disease [150]. No dose-limiting toxicities were reported with trifluridine and tipiracil up to the maximum recommended dose of 35 mg/m2 (80mg maximum dose). Partial response, as determined by RECIST v1.0 criteria were seen in four patients (19 percent) and stable disease in 12 patients (57 percent). Liver disease control rate in the treated liver lobes was 100 percent, and overall (hepatic and extrahepatic) disease control rate was 75 percent. Median progression-free survival was 3.8 months (range 0.7 to 21.2 months), and median OS was 6.4 months (range 3 to 30.6 months). Majority of grade 3 to adverse events were hematologic, however, two patients (9.5 percent) patients developed radioembolization-induced liver disease approximately five months after radioembolization that resulted in death 2 and 26 months after manifestation of liver dysfunction symptoms.
Radioembolization treatment-related toxicity is not trivial. Among the hepatic parenchymal changes that are described in response to radioembolization are transient transaminase elevation and hyperbilirubinemia, ipsilateral hepatic lobar volume decrease with contralateral lobar hypertrophy induction of liver fibrosis, and portal hypertension. The frequency and risk factors for development of these adverse effects and their influence on liver insufficiency are not well characterized. Complications of radioembolization are discussed in more detail separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Complications'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Colon and rectal cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Treatment of metastatic colorectal cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Systemic therapy-naïve disease
•Resectable disease
-Surgery – For patients with isolated (ie, no extrahepatic metastases) and resectable colorectal cancer (CRC) liver metastases, surgical resection is the treatment of choice if a margin-negative resection can be accomplished. (See 'Resectable disease' above and "Hepatic resection for colorectal cancer liver metastasis", section on 'Oncologic'.)
Prior to surgical resection, some patients may be offered initial (neoadjuvant) systemic therapy. In the setting of synchronous metastatic disease, a major advantage of this approach is that it allows an understanding of the natural history of the metastatic disease before subjecting the patient to surgery that might not be curative. Multidisciplinary evaluation is necessary. (See "General principles of systemic therapy for metastatic colorectal cancer", section on 'Potentially resectable disease'.)
-What is the role of thermal ablation? – For patients with a limited number of isolated, resectable CRC liver metastases ≤3 cm and no extrahepatic metastases, surgical resection is the treatment of choice. Liver-directed thermal ablation (either radiofrequency ablation [RFA] or microwave ablation [MWA]) may provide similar overall survival (OS) and reduce complications compared with surgery, based on a randomized trial (COLLISION). However, the decision to use surgery, thermal ablation, or both is complex and best discussed in a multidisciplinary conference. We await long-term follow-up of OS (to confirm cure) in the COLLISION trial prior to exclusively using thermal ablation to treat this population. (See 'What is the role of thermal ablation?' above.)
•Potentially resectable disease – Patients with isolated CRC liver metastases that are potentially resectable may be offered initial systemic therapy to reduce tumor burden and render them surgical candidates. Further details are discussed separately. (See 'Potentially resectable disease' above and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Patients with initially unresectable metastases' and "Hepatic resection for colorectal cancer liver metastasis", section on 'Patient selection'.)
•Not suitable for resection – Patients with isolated liver metastases and a limited number of small lesions may be deemed unsuitable for resection because of tumor location, impaired general health status, or an insufficient future liver remnant to resect all lesions. (See 'Not suitable for resection' above.)
-Treatment options – For such patients, locoregional liver-directed treatment is an acceptable option for initial therapy. Examples of locoregional liver-directed therapies include thermal ablation (ie, RFA or MWA), nonthermal ablation (eg, irreversible electroporation (IRE), histotripsy), stereotactic body radiotherapy (SBRT), Yttrium-90 (Y-90) radioembolization, and transarterial chemoembolization (TACE). The choice of the specific locoregional treatment depends on local expertise, the number, size, and location of lesions, as well as patient and clinician preference. One advantage of this approach for appropriately selected patients is the deferral of systemic therapy-related toxicity. (See 'Approach to therapy' above and 'Options for liver-directed therapy' above.)
Initial systemic therapy is another option. One commonly employed strategy is to start with systemic therapy; for patients whose disease remains liver-limited, systemic therapy can be followed by consolidation therapy with locoregional liver-directed therapy such as thermal ablation (RFA, MWA) or SBRT. (See 'Approach to therapy' above and "Initial systemic therapy for metastatic colorectal cancer" and 'Tumor ablation plus systemic therapy' above.)
-No role for concurrent radioembolization and initial systemic therapy – We do not suggest adding concurrent radioembolization to initial systemic therapy as this approach does not improve OS and worsens toxicity (Grade 2B). (See 'Radioembolization plus systemic therapy (systemic therapy-naïve disease)' above.)
-Ineligible for locoregional therapy – Patients who are ineligible for locoregional therapy because of disease extent, or poor underlying liver function, or if locoregional therapy is not available, are treated with initial systemic therapy. Specific recommendations are provided separately. (See "Initial systemic therapy for metastatic colorectal cancer" and "Management of metastatic colorectal cancer in older adults and those with a poor performance status".)
●Systemic therapy-refractory disease – For patients with CRC and isolated liver (or liver-predominant) metastases and adequate underlying liver function who progress on several systemic therapies, a nonsurgical locoregional liver-directed treatment approach is a reasonable option. (See 'Systemic therapy-refractory disease' above.)
In most cases, the extent of disease will preclude tumor ablation or SBRT. Therefore, appropriate options include TACE or Y-90 radioembolization (the latter possibly in combination with FU, capecitabine, or trifluridine and tipiracil). The choice is usually based on local expertise, patient preference, and patient/tumor characteristics. (See 'Transarterial (chemo)embolization' above and 'Radioembolization' above.)
