Colorectal hepatic metastasis: Evolving therapies

Abstract

The approach for colorectal hepatic metastasis has advanced tremendously over the past decade. Multidrug chemotherapy regimens have been successfully introduced with improved outcomes. Concurrently, adjunct multimodal therapies have improved survival rates, and increased the number of patients eligible for curative liver resection. Herein, we described major advancements of surgical and oncologic management of such lesions, thereby discussing modern chemotherapeutic regimens, adjunct therapies and surgical aspects of liver resection.

Key Words: Colorectal cancer, Hepatic metastasis, Hepatectomy, Survival, Chemotherapy, 5-fluorouracil leucovorin and oxaliplatin

Core tip: The management of colorectal hepatic metastasis is complex, and should involve a multidisciplinary tumor board involving specialized medical and surgical oncologists. Although liver resection still remains as the key step in the management of liver metastasis, the introduction of new chemotherapeutic regimens and recent adjunct therapies, including radiofrequency ablation, cryotherapy and radioembolization improved patient care, and prolonged survival in patients with unresectable disease.

INTRODUCTION

Colon cancer is the third most common malignancy in the United States, and comprising around 10% of all cancer-related mortality[1]. Most disease-related mortality is associated with metastatic disease. Approximately 25% of patients is diagnosed with metastases at initial presentation, and around 50% will present metastases during the clinical management of the disease[2,3]. The survival for untreated colorectal hepatic metastasis (CHM) are dismal with medial survival estimated in only 6 to 9 mo[4].

Although liver resection still remains as the most important modality in the treatment of CHM, the introduction of recent adjunct therapies, including radiofrequency ablation (RFA), cryotherapy and radioembolization improved patient care, and prolonged survival in patients with unresectable disease. Concurrently, the evolution of chemotherapy with the introduction of multidrug therapy optimized response rates, and expanded the number of surgical candidates for curative liver resection. Herein, we describe the current management of CHM, thereby discussing major advancements in chemotherapeutic regimens, adjunct therapies and surgical technique, and describe paradigm changes in resectability and outcomes.

DETERMINATION OF STRATEGY

The management of CHM is complex, and should involve a multidisciplinary tumor board including oncologists, radiologists, colorectal and hepatobiliary surgeons. Clinical and laboratory suspicion of metastasis should be routinely confirmed by radiological imaging. Options available include computed tomography (CT), ultrasound, fluorodeoxyglucose-positron emission tomography (PET), and magnetic resonance imaging (MRI). Multi-detector CT is widely available, and is routinely used for detection of CHM[5]. MRI is being used more commonly, and provides better visualization of liver lesions as compared to CT by some experts[6]. PET scan is usually associated with CT (PET-CT), and is superior to CT or MRI for identification of equivocal lesions, metastases, and local recurrence, prior to resection of metastatic disease[7-10].

Several prognostic factors should be considered during definition of therapeutic strategy, including: staging of the primary tumor, interval diagnosis between the primary and metastatic lesions, number and size of metastases, presence of surgical margins and extrahepatic recurrence, and elevated biochemical markers such as carcinoembrionic antigen, alkaline phosphatase, and albumin[11-15]. The most important decision for definition of the therapeutic plan is defined based on resectability of metastatic disease. Patients should be stratified as suitable for resection, potentially resectable after chemotherapy and/or adjunct therapies, and those with unresectable disease.

MANAGEMENT OF RESECTABLE DISEASE

Liver resection continues to be the most crucial step in the management of CHM, potentially offering definitive treatment to a subset of patients. The use of chemotherapy is used as an adjunct therapy, thereby enhancing the 5-year survival at approximately 37%-58%[16,17]. Assessment of resectability is based on the volume of future remnant liver with adequate vascular inflow and outflow and biliary drainage[18]. For patients with normal liver function, 20% of remnant tissue is required, whereas in the presence of steatosis and cirrhosis, 30% and 40% of residual liver is necessary, respectively. Negative margins of 1-cm is associated with improved outcomes, and is currently recommended by most experts[19,20]. Contraindications to resection include uncontrollable extrahepatic disease, extensive lymph node involvement, including retroperitoneal or mediastinal nodes, bone or central nervous system metastases[21]. Local predictors of unresectability are determined by hepatic vascular involvement, and bilaterally, that would leave an inadequate functional liver remnant. Perioperative combination with chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen given 3 mo prior and 3 mo following resection of metastases enhances survival by 8% at 3 years[22]. Neoadjuvant chemotherapy for patients with resectable liver metastases is still under investigation, and currently, remains controversial. Another topic of major debate is regarding the timing of the colectomy relative to the hepatectomy in cases of synchronous CHM. Typically, the primary colorectal cancer (CRC) is resected first, however in select cases where the liver disease is marginally resectable and primary CRC is small, the liver resection may be considered as initial approach to avoid progression of CHM. Combined resections are associated with shorter hospital stay and less morbidity, with similar 5-year survival and technically more challenging[23].

MANAGEMENT OF POTENTIALLY RESECTABLE DISEASE

Initially unresectable liver metastases can become resectable after being downsized by neoadjuvant chemotherapy, and, in such cases, resection may be advocated. Bismuth et al[24] reported the first experience with downstaging of unresectable lesions to resectable. They found similar outcomes to those patients with initially resectable lesions[25]. Nuzzo et al[26] found similar operative complications, and 3-year overall survival between initially resectable patients and those with initially unresectable but downstaged lesions. Subsequent reports showed conversion rates between 30%-50% with the combination of hepatic artery infusional fluoxuridine with systemic chemotherapy[27,28]. In these patients, response to initial chemotherapy appears to be a predictor of outcome[29].

Initial experience with addition of a vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) target agent (bevacizumab or cetuximab, respectively) is associated with higher resection rates in patients with initially unresectable disease. Resection is usually performed 5-8 wk after the last chemotherapy cycle with cetuximab or bevacizumab, respectively. The decision for resectability in these patients is often challenging, and involves a multidisciplinary team, depending on the experience of hepatobiliary surgeon and assessment for sufficient remnant liver. Many surgeons and oncologists would offer resection as soon as the lesion has become resectable, whereas others usually continue chemotherapy for 4 to 9 mo regardless of the response[30].

Several techniques have been recently introduced aiming at downsizing metastatic disease and improving resectability, including radioembolization, intra-arterial chemotherapy, and local ablation techniques, especially radiofrequency ablation. These adjunct modalities will be discussed separately.

MANAGEMENT OF UNRESECTABLE DISEASE

The majority of patients with CRC and concurrent metastasis has unresectable disease. However, due advances in systemic therapy, the survival of these patients is progressively improving[31]. The median survival is improved, estimated in up to 24 mo.

The approach for unresectable metastatic disease with synchronous CRC is still controversial. Resection of the bowel cancer initially is associated with precise definition of nodal and peritoneal status, prevention of local complications, the theoretical advantage of reduced total-body tumor load as well as psychological benefits for the patient[11]. However, the chemotherapy-first approach is considered better by other experts due to the avoidance of postoperative morbidity and mortality, potential downstaging of unresectable CHM to resectability, and data showing equivalent survival benefits[11].

Monoclonal therapy against VEGF and EGFR should be considered especially in refractory cases, and will be further discussed in this review. For non-curative therapy of CHM, in addition to using the standard FOLFOX or FOLFIRI chemotherapy regimens, single agent strategies have been used with survival benefits as evidenced by the MRC FOCUS (using 5-FU-LV) and CAIRO (using capecitabine) trials[32-34].

TREATMENT MODALITIES

Resection

Surgery is the key step in the management of patients with CHM and represents the only chance for cure. Resection of CHM is considered a relatively safe operation with an operative mortality less than 5% by most recent series[30,35,36]. In high volume centers, median hospital stay ranges between 5 and 10 d for minor and major resections[36,37]. With increased outcomes, hepatectomies are now safely performed in elderly patients[38].

In cases of multiple, bilateral CHM, surgical options include: parenchyma-sparing approaches, and two-stage hepatectomy. In a two-stage operation, a portion of the liver disease is removed, and the contralateral portal vein is occluded, followed by 1 to 3 mo interval to allow for hypertrophy of the remaining liver and a curative-intent, second-stage hepatectomy. In such cases, the portal vein is occluded intraoperatively or subsequently by percutaneous embolization. Most experts perform minor segment resection first followed by resection of major liver. The minor-first approach spares the patient with progressive disease to undergo a major hepatectomy.

Within 2 years, most patients developed a recurrence[11,39]. Approximately 40% of them are eligible to undergo reoperation. The 5-year survival after first and second hepatectomies was 47% and 32%, respectively[40].

The experience with laparoscopic resection of CHM is yet minimal. Buell et al[41] and Mala et al[42] demonstrated tumor clearance, feasibility and safety of laparoscopic liver resection in 31 and 42 patients with CHM, respectively[41,42]. Long-term outcomes compared to open approach remains unknown.

CHEMOTHERAPY

Although chemotherapy plays a vital role in managing resectable and unresectable CHM, the timing of delivery is still controversial. For resectable disease, delivery of chemotherapy may be offered before colon resection (pre-operative), after colon resection but before liver resection (peri-operative) or after both resections (post-operative).

Pre- and peri-operative chemotherapy for resectable disease

For patients with potentially resectable CHM, response to chemotherapy has become an important adjunct in deciding whether to proceed with surgery. Typically, most tumors either reduce in size or remain unchanged following chemotherapy[22,43-46].

The recommended approach of delivering neoadjuvant chemotherapy to patients with resectable CHM consists of a 2-3 mo course of FOLFOX in order to limit chemotherapy-induced liver injury[46]. Chemotherapy application is considered safe to be used in patients with intact colorectal tumors[47]. In order to avoid difficulties locating both colorectal tumors and CHM that respond well to systemic chemotherapy, it would be prudent to mark the lesions before initiation of therapy, typically done using India ink tattoo or metallic coils placed by interventional radiology[48]. The disadvantages of pre-operative chemotherapy application include the development of new extrahepatic lesions[49] as well as a possible increased incidence of post-operative sequelae[22].

Adjuvant chemotherapy

The application of 5-FU-based chemotherapy post-CHM resection is established in most clinical practice despite prospective data limited to only two studies[50-52]. Pooled analysis of these two trials demonstrated a trend towards longer disease-free survival but no difference in median progression-free survival or overall survival. At present, there is no role for irinotecan-containing chemotherapy regimen (FOLFIRI) following hepatic resection with no benefit demonstrated when compared to 5-FU based regimens[53].

The application of systemic chemotherapy for CHM is associated with hepatotoxicity, a sequelae that has been recognized to increase the risk of peri- and post-operative mortality for CHM resection candidates. Amongst these hepatotoxic sequelae are hepatic steatosis seen in 30%-47% of patients on 5-FU[17], non-alcoholic steatohepatitis (NASH) in 12%-25% of patients on irinotecan[18] and sinusoidal dilation in 78% of patient on oxaliplatin[37]. The impact of these hepatotoxic effects is somewhat varied, although it is clear that the irinotecan-associated NASH appears to be the most significant with established evidence of increased post-operative mortality due to liver failure. Although previously the recognition of these adverse reactions was the domain of oncologists, the significant impact on post-operative outcomes has made it imperative for surgeons to be mindful of them too before considering operative intervention.

MOLECULAR TARGETED THERAPIES

Monoclonal antibodies against VEGF and EGFR have added an additional therapeutic option for treatment in select patients when used in combination with chemotherapy. Evidence of the therapeutic benefit of this treatment modality was initially found using the anti-VEGF monoclonal antibody, bevacizumab, with findings of improved survival when used in combination with therapy of IFL (irinotecan, 5-FU and leucovorin)[54]. Additional studies have demonstrated similar benefits in response rate, disease-free progression and overall survival of using bevacizumab in combination with 5-FU/LV alone and FOLFOX in the first-line and second-line settings respectively[29]. Bevacizumab has, however, been associated with a number of complications, most notably gastrointestinal perforation, risk of bleeding and wound healing problems. As a result, the use of this modality requires careful monitoring, with treatment withheld for 6-8 wk prior to resection[55,56].

Panitumumab and cetuximab are EGFR inhibitors that have also demonstrated benefits in treating patients with metastatic CRC. Benefits have particularly been found using cetuximab in chemorefractory patients, improving survival compared to standard therapies[57]. Indeed, similar to bevacizumab, cetuximab appears to have superior effects when used in combination with[29]. It also appears that EGFR inhibitors are most effective for non-mutated (wild-type) K-ras colorectal tumors[55]. The side-effect profile for anti-EGFR antibodies is less extensive, limited to acneiform rash and hypomagnesemia and allergic reactions with cetuximab only[29] and no significant hepatotoxic effects seen thus far.

ADJUNCT THERAPIES

With the role of surgical resection for CHM widely accepted, the roles of non-operative liver directed therapies continue to evolve. With numerous new adjunctive therapies coming to the fore in recent years producing encouraging outcomes (including downstaging of CHM and increasing survival), the decision to integrate these options into current practice is challenging. Broadly speaking, there are three non-operative, liver directed therapies in use; intra-arterial therapies, ablative therapies, and radiotherapies.

INTRA-ARTERIAL THERAPIES

The role of intra-arterial therapies continues to evolve. The delivery of intra-arterial therapies uses the principal that hepatic metastases deriving their blood supply from hepatic arteries[58,59]. Therefore, intra-arterial therapy enhances drug delivery to hepatic tumors, maximizing local tumor therapy and limiting systemic therapy with its side-effects.

Hepatic arterial infusion chemotherapy

The hepatic arterial infusion (HAI) modality delivers chemotherapy directly to the liver via intra-abdominal catheters or infusion pumps cannulating the gastroduodenal artery[60,61]. An intimate understanding of hepatobiliary anatomy by surgeons is required to avoid placement of these catheters within aberrant anatomy leading to organ underperfusion with associated peptic ulceration, pancreatitis or biliary sclerosis[62]. The complex technical skills for correct placement of these infusion pumps requires experience often attainable at high volume centers. The delivery of HAI may be initiated as soon as the first post-operative week provided the patient has recovered well. In the United States, the chemotherapeutic agent most commonly used for HAI is fluoxuridine (FUDR) due to its high uptake by the liver limiting systemic toxic effects[63], although the low toxicity benefit may be lost by concomitant systemic chemotherapy use[64]. Dexamethasone has been delivered in conjunction with FUDR HAI-therapy, reducing biliary sclerosis, increasing tumor response rate and patient survival[65]. In Europe, 5-FU based HAI chemotherapy has also been used with some success.

HAI in unresectable disease

The role of HAI chemotherapy in unresectable disease is yet to be defined. This is largely due to inconclusive evidence from trials regarding patient outcomes[66]. On one hand, HAI has been found to produce higher tumor response rates than systemic therapy alone, but on the other no significant survival advantage has been found via the numerous randomized trials performed so far[67]. The application of combination therapy of HAI and systemic chemotherapy as second-line therapy following failed conventional chemotherapy[68] or to downstage initially unresectable CHM[28] have been suggested roles for HAI.

HAI as adjuvant therapy

The evidence supporting adjuvant HAI-therapy is even less established. To date, there has only been evidence from a single RCT that demonstrated a significant survival advantage applying HAI chemotherapy over systemic chemotherapy in the adjuvant setting[69]. This subject is therefore under ongoing scrutiny in current studies assessing HAI chemotherapy vs modern chemotherapy regimens.

Radioembolization

Radioembolization (or selective internal radiation therapy; SIRT) delivers high-energy beta-emitting radiation locally to CHM, delivering its effects specifically on tumor vasculature and minimizing collateral hepatic damage[70]. At present, this modality is delivered via two forms; Yttrium-90 (⁹⁰Y)-labeled resin microspheres (SIR-Spheres^®; Sirtex Medical, Sydney, Australia) and ⁹⁰Y-labeled glass microspheres (Therasphere^®; MDS Nordion, Ottawa, Canada). Radioembolization therapy is performed by injecting radioactive microspheres designed to embolize into small vessels around the metastases via branches of the hepatic artery, usually using a percutaneous femoral approach and fluoroscopic monitoring[71].

The current benefits with radioembolization using ⁹⁰Y microspheres have been reduced tumor load of unresectable CHM particularly if refractory to conventional chemotherapy. Indeed, combing radioembolization with chemotherapy has produced longer tumor suppression compared to chemotherapy alone[72]. The results of the recently ended SIRFLOX trial evaluating the efficacy of first-line therapy of FOLFOX6 combined with SIR-Spheres^®vs FOLFOX6 alone will hopefully provide additional evidence in favor of this treatment strategy in patients with unresectable CHM[73,74].

Further, trials have also demonstrated similar benefits of ⁹⁰Y microspheres used in combination with other treatment modalities like HAI therapy, demonstrating a superior time to progression compared to HAI alone[73,74].

The evidence supporting the use of ⁹⁰Y glass microspheres in CHM is less extensive with limited research demonstrating CHM tumor regression in upto 88% of patients with chemo-refractory tumors treated with ⁹⁰Y glass microspheres[75]. The further assessment of ⁹⁰Y-glass microspheres as salvage therapy continues to be evaluated with an ongoing phase III multicenter randomized trial (EPOCH trial) which will hopefully provide corroborative evidence in support of this modality[17]. The long-term toxicity effects of radioembolization techniques are yet to elucidated.

Chemoembolization

Chemoembolization [or transcatheter arterial chemoembolization (TACE)] is a form of transarterial therapy that also utilizes the principal of liver tumors’ predominantly arterial supply, allowing for regional therapy to the tumors. Similar to HAI, TACE is delivered using selective angiographic techniques by injection of chemotherapeutic drug combined with embolic material resulting in selective ischemic and chemotherapeutic effects on the CHM[76].

At present, there is no standard approach to delivering TACE therapy, although the application of a newer approach, drug-eluting beads composed of irinotecan (DEBIRI^®; Biocompatibles United Kingdom Ltd, Farnham, United Kingdom) is gaining wider acceptance through ongoing clinical trials[77-79]. Irinotecan is preferentially used in this modality due to its properties allowing for application to the beads. Administration of DEBIRI^® occurs via a selective arterial catheter, depositing the beads adjacent to the CHM tumors. This allows for slow release of irinotecan locally to the tumors.

Although DEBIRI^® is presently not approved by the United States Food and Drug Administration, there are promising early results on its efficacy and safety. Available clinical trials suggest that DEBIRI^® treatment may be associated with a median survival time of 15-25 mo, which is broadly equivalent to the outcomes achieved for unresectable CHM with the use of best-practice systemic chemotherapy[76]. In addition, the majority of patients that had responded to TACE treatment had failed first-line chemotherapy regimens[76]. Further evidence from additional trials[78,80-82] have also found successful downstaging of unresectable CHM to resectable status with most trials describing minimal toxicity effects[76].

It must be mentioned that the majority of the available trials to date have methodological flaws, and their conclusions must be interpreted with caution. To address the lack of high-quality randomized comparative trials assessing DEBIRI^® use, there is ongoing research to evaluate its benefits when used in combination with systemic chemotherapy.

ABLATION TECHNIQUES

Ablation techniques aim to induce local destruction of the CHM. At present, the exact role of ablative techniques in the treatment of CHM is unclear, although there have been suggestions that its roles may include to reduce tumor size minimizing the extent of liver resection required, adjunctive therapy for patients either unfit for surgery or with unresectable disease. Ablative approaches can be subdivided into cryoablation, RFA and microwave ablation.

Cryoablation

Cryoablation was the first thermal ablative modality attempted to treat unresectable hepatic malignancies[83]. Cryoablation (or cryosurgery) is induced by local delivery of liquid nitrogen or argon on a probe tip to the CHM, resulting in tumor destruction by intracellular ice crystals that form from the rapid cooling. The “iceball” that forms around the tip of the probe can be measured by real-time intraoperative ultrasound although there has been some suggestion that the tissue furthest away from the tip may not be cooled sufficiently to cause tissue destruction[17].

Cryotherapy applications

Cryoablation application appears to vary between institutions. In general, its primary use has been for the ablation of unresectable CHM. Despite initial thoughts that cryoablation could be used in patients with resectable CHM, high tumor recurrence following cryosurgery has tempered this enthusiasm. So far, previous research has demonstrated a modest 5 year survival of 26% but also low mortality rates of less than 5% following cryotherapy for CHM[84]. Cryoablation used in combination with surgery has also been shown to produce similar survival benefits to surgery alone in patients with initially unresectable CHM[85].

The application of cryotherapy to the remnant liver resection margins (edge cryotherapy) remains undecided. Although some authors have reported the decreased application of edge cryotherapy due to report higher complication rates than hepatic resection alone[17], other institutions have reported positive outcomes with this approach, finding potential cure of up to 13% of advanced unresectable CHM compared with resection alone.

Additional benefits of cryosurgery include its facility in treating bilobar CHM or recurrent hepatic tumors following resection in addition to evidence from animal models that shows decreased secretion of factors that stimulate growth of occult micrometastases following cryotherapy compared to post-surgical resection[86]. One of the shortcomings of cryoablation is its poor ability to destroy tumors next to larger blood vessels due to the “heat-sinking” effect[87], resulting in recurrence rates as high as 44%. Another disadvantage of this modality is that for unclear physiologic reasons, patients may suffer from a systematic inflammatory response (cryoshock phenomenon)[82,88,89] associated with periprocedural deaths[88,89].

RFA

By far, the most extensively evaluated ablative approach is RFA. RFA is the most widely applied ablative modality due to ease and safety of application and inexpense of equipment[17]. This modality is applied by placing needles within and adjacent to CHM through which alternating electrical current is delivered at radiofrequency range generating heat to desiccate the tumors[90,91].

Application

Although RFA is in widespread use across many institutions internationally, a paucity of randomized controlled trials up to now has prevented the development of a consistent approach to its use. Indeed, to date, there are no RCTs comparing surgical resection with RFA in resectable CHM, a study that at present seems inconceivable and unethical considering established survival data from surgical resection. At present, most evidence from the retrospective studies available comparing RFA and resection has demonstrated the inferiority of RFA compared to surgical resection with increased local recurrence rates (16%-60% vs 0%-24%) and worse long-term survival[91,92].

At present, RFA is being used to treat unresectable CHM only, with no extrahepatic metastatic disease[93]. Tumors amenable to successful treatment with RFA have typically been solitary CHM or a few which are not close to large hepatic vessels[93]. Tumor size in particular has been limited to 3-cm due to the circumferential rim of ablation currently delivered by ablation probes being approximately 4-cm in diameter, a limitation that may be addressed with advancement of the technology. Overlapping ablations can be used to treat larger tumors although this has been associated with less successful complete ablation[94]. The presence of large blood vessels limits RFA efficacy because their high blood flow acts a “heat sink”, protecting adjacent cells from thermal ablation[17].

RFA is delivered via open, laparoscopic or percutaneous approaches[93]. The application of ultrasound, CT and MRI are particularly important to guide the needle in the percutaneous approach while intraoperative ultrasound is an additional adjunct used to directly visualize the tumor in the operative approaches. It appears at present that RFA via laparotomy is associated with the lowest recurrence rate followed by laparoscopy, and finally by percutaneous approach. The trade-off of using the least invasive percutaneous approach must be weighed up against poor tumor visualization increasing the potential for recurrence. The surgical approaches are typically applied at the time of primary or hepatic metastasis tumor resection.

In addition to the aforementioned advantages of RFA, it has a relatively lower morbidity profile of < 10% independent of the approach used for delivery being surgical or percutaneous[95]. Amongst the complications that have been seen, thermal injury (bowel and biliary injury), mechanical (biliary and vessel injury) and septic (abscess and peritonitis) have been the most widely reported. A more infrequent presentation of post-ablative syndrome where patients suffer from self-limiting constitutional upset including malaise, febrile episodes, myalgia, nausea and vomiting has also been reported[93].

Microwave ablation

Microwave ablation (MWA) is a more recently developed technique used for CHM. MWA is applied via a microwave probe delivered into the tumor via image-guided percutaneous, or ultrasound guided surgical approaches. Via these probes, microwave radiation between 900 MHz and 2.4 GHz is delivered that causes polarized water molecules within the tissue to oscillate generating friction that produces heat that destroys tissue by coagulative necrosis[96].

MWA application

As this modality is relatively new, the evidence of its efficacy is limited and has included too many different liver tumor types particularly hepatocellular carcinoma. The exact application of MWA for CHM is therefore still unclear. Although reported local recurrence rates have been extremely variable ranging from 3% to 50%, encouraging evidence from the largest series reported rates as low as 3% and 6%[97,98]. Further research would therefore provide the evidence to define its role as an ablative therapy in CHM management.

The purported advantages of MWA have been the more extensive nature of tissue destruction created by the heating mechanism generated by this technique. This mechanism also appears to be less prone to the “heat-sink” effect seen with RFA therapy[99]. There has also been suggestion that intra-operative hepatic inflow occlusion (Pringle maneuver) increases the size of ablated lesions[100]. Further, there appears to be reduced occurrence of charring using MWA and it creates larger ablation zones up to 6 cm away more rapidly than RFA[96]. Interestingly, there is now growing interest over a further method of cell death induced by microwaves characterized by normal-looking but non-viable cells. If indeed this is correct, this would have important implications in the post-procedure observation of the ablated tumors, requiring likely routine histopathology to differentiate seemingly viable tumor from completely ablated ones.

The complication rates from MWA range from 6% to 30%, most often associated with cases where laparotomy and additional procedures had been performed[90,97,98].There are at present concerns of potential inadvertent injury to surrounding organs due to the higher energy generated by this modality.

STEREOTACTIC BODY RADIOTHERAPY

Stereotactic body radiotherapy (SBRT) is another newer technology that has generated growing interest for use in ablating CHM[101]. Unlike external beam radiation therapy (EBRT) which had previously been abandoned for use in liver tumors due to the narrow therapeutic window between tumoricidial and hepatoxic effects, SBRT uses more modern technology that allows for safe treatment delivery in lung and liver with hypofractionation[101].

Application

SBRT is based on techniques used in stereotactic radiosurgery for brain tumors[101]. In this modality, the tumor location is identified using four-dimensional imaging that maps the target area accounting for patient movements during breathing. Gold seeds called fiducials are then placed within the tumor, which guide treatment. Using the predetermined tumor coordinates, high-dose radiation is delivered over a relatively shorter duration compared to conventional EBRT.

Although encouraging evidence of tumor local control rates as high as > 90% have been demonstrated in lung tumors using SBRT[102,103], its application in liver tumors specifically CHM is still under scrutiny with few well-designed studies presently available in current literature. The optimum radiation dosage is also undetermined, although it appears that a higher dose of up to 60 Gy is most effective, eliminating high local progression rates seen at lower doses[104], maximizing tumor response rate (up to 90%) and 2-year local control rate of 100%.

Although the treatment is focused, it does not eliminate surrounding toxicity. Specifically, acute gastrointestinal and liver toxicity in addition to chest wall pain have been reported side effects of the therapy. In addition, and more importantly, although there is some early evidence of local tumor control with SBRT, it is not yet been demonstrated to significantly impact survival.

However, the encouraging early results have lead to the assertion that SBRT be considered as an option in patients not offered surgery after chemotherapy to locally ablate their CHM[101].

CONCLUSION

The management of CHM is complex, and should involve a multidisciplinary tumor board involving specialized medical and surgical oncologists. Although overall survival has increased tremendously over the last 5 years with the introduction of adjunct therapies, more efficient chemotherapeutic regimens still need to be discovered. Concurrently, the criteria for resection is much more liberal and should be based on functional remnant liver volume. Even in situations where multiple, bilobar liver metastases are present, resection may be a considered option. Both basic studies and prospective trials are necessary to further understand the molecular aspects of colorectal hepatic metastasis, and therefore improve outcomes.