gastrointestinal tract and abdomen management of hepatic ... · gastrointestinal tract and abdomen...

Scientific American Surgery DOI 10.2310/7800.2269

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© 2015 Decker Intellectual Properties Inc

gastrointestinal tract and abdomen

M A N A G E M E N T O F H E P A T I C M E T A S T A S E S F R O M C O L O R E C T A L C A N C E R

Rory Smoot, MD, and David M. Nagorney, MD, FACS

The management of patients with hepatic metastases from colorectal cancer has emerged as a major focus of oncologic treatment worldwide. Colorectal cancer ranks as the third most frequent cancer in men and women. Metastatic involve-ment of the liver will affect nearly 50% of patients with col-orectal cancer during their lifetime. Historically, hepatic resection of colorectal metastases alone provided long-term progression-free survival in selected patients. This outcome, which has been confirmed repeatedly, coupled with techni-cal advances in hepatic resection and, importantly, effective systemic chemotherapy, has pushed resection of metastatic colorectal cancer as key in the multimodality management of these patients. In fact, hepatic resection is the cornerstone for the long-term survival of patients with stage IV colorec-tal cancer. This review discusses the surgical management of patients with hepatic metastases from colorectal cancer.

Presentation and Imaging

Hepatic metastases from colorectal cancer can present either syn-chronously or metachro-nously with the primary cancer. Although the clinical presentation has implications for the sequencing of multimodal management strategies, the initial workup for metastatic colorectal cancer requires complete staging. Most typically, clinical staging is accomplished with contrast-enhanced computed tomogra-phy (CT) of the chest, abdomen, and pelvis. Other imaging studies, such as magnetic resonance imaging (MRI) and pos-itron emission tomography (PET), are used selectively to resolve indeterminate dimensional imaging findings. Defini-tion of the extent of extrahepatic disease is necessary before hepatic resection is incorporated into an overall multimodal management strategy. In general, other distant metastatic cancer precludes hepatic resection. However, in selected patients with limited extrahepatic distant metastases in whom all sites of metastatic disease are resectable, particu-larly limited pulmonary metastases, hepatic resection should be employed.1–4 The sequence of multimodal therapies for patients with extrahepatic disease is discussed below. Hepatic imaging should fully address resectability. Resect-ability is defined anatomically as complete resection or ablation of all identified hepatic metastases (R0) and preser-vation of an adequately functioning hepatic remnant. In practice, an adequate remnant implies 20% or greater hepatic volume (≥ one section) in patients without underly-ing hepatic disease,5 with an afferent and efferent hepatic vasculature and biliary system that is maintainable with or without reconstruction. Moreover, resectability implies that

dimensional imaging provides the capability of accurately measuring total and partial hepatic volumes, which is inte-gral to defining an adequate hepatic remnant. Inadequate or marginal remnant volumes per se do not preclude hepatic resection. Such findings should prompt strategies to increase remnant volume, such as portal vein embolization (PVE) or various types of staged hepatic resections. Accurate definition of the number, distribution, and site of hepatic metastases is paramount in defining anatomic resectability. Finally, resectability also implies that the clinical functional status of the patient and the tumor biology are permissive of hepatic resection. In general, a clinical performance status of 50% or greater of normal and either responsiveness or lack of progression with neoadjuvant chemotherapy are required for hepatic resection.

ultrasonography

Ultrasonography (US) has limited preoperative utility for defining resectability because it is operator dependent. More-over, despite the real-time capture of images, its dimensional display of anatomic relationships within the liver is limited and not global. US lacks the axial cross-sectional imaging that provides reproducible, user-independent information regarding spatial relationships within the liver for pre-operative planning. US is useful for further assessing small (< 1 cm) indeterminate lesions on CT as cysts or hemangio-mas preoperatively. US is routinely used to confirm intra operatively the extent of hepatic disease identified pre-operatively to ensure an R0 resection and to identify occult metastases. US can be undertaken either at laparotomy or laparoscopically. The echogenicity of metastases in relation to that of the surrounding liver affects the sensitivity, speci-ficity, and accuracy of US.6 The potential effects of modern neoadjuvant chemotherapy on the underlying liver can impact US findings. Concordance of preoperative and intra-operative imaged hepatic metastases is essential for R0 resection. When intraoperative US fails to identify all meta-stases seen preoperatively, intraoperative US contrast agents can be used to identify such occult metastases to complete the R0 resection, although such agents are not widely avail-able in the United States.7–10

positron emission tomography

The use of PET for assessing resectability is limited to determining the overall extent of disease and to identifying occult extrahepatic metastases. PET is not used routinely because of cost and overall accuracy. Because PET is typi-cally fused with noncontrast CT, its value as the primary imaging modality for surgical decision making is limited.11 PET is most useful when concern for occult metastatic dis-ease is significant, such as in patients whose poor clinical performance status is incongruous with the extent of disease identified by dimensional imaging; in patients whose

Scientific American Surgery

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gastro management of hepatic metastases from colorectal cancer — 2

Optimized

Approach to the Patient with Hepatic Metastases from Colorectal Cancer

AnatomyUnilobarFuture liver remnant (FLR)

adequateNo vascular issues

BiologyMetachronous (> 12 months)≤ 3 lesions

ConditionEastern Cooperative Oncology

Group (ECOG) ≤ 1

Resectable

AnatomyPortal vein embolization for

inadequate FLR sizeStrategy for extended resection

Two stageIn situ perfusionAssociating liver partition

with portal vein ligationBiology

Systemic therapy withstability/response

ConditionECOG ≤ 1Nutrition/comorbidities optimized

Optimization

AnatomyBilobarFLR size inadequateFLR outflow involvement

BiologySynchronous (< 12 months)4 or more lesions

ConditionECOG > 1 (optimization

possible)

Borderline resectable

Anatomy< 2 contiguous segments

uninvolvedUnreconstructable vascular

involvementBiology

Progression on systemictherapy

ConditionECOG ≥ 2 (optimization not

possible)

Unresectable

Adjuvant systemic therapy

Resection

Palliation

Optimization unsuccessful

imaged disease is disparate from concurrent serum tumor markers; or in patients requiring further definition of an indeterminate lesion. PET is limited by poor spatial resolu-tion and even when combined with fused CT often does not provide enough spatial and size resolution and anatomic detail to allow operative planning. Moreover, there are significant false positive findings in patients with recent resections of the primary colorectal cancer or concurrent inflammatory conditions and false negative findings in patients undergoing systemic chemotherapy. Small lesions (< 1 cm) are often not visualized, and secondary issues, including cost and availability, further limit the application of this imaging modality.

computed tomography

Contrast-enhanced CT is used most often for clinical stag-ing and assessment of resectability. Hepatic metastases from colorectal cancer are relatively avascular and often appear hypodense during portal venous phases of imaging. These characteristics allow a clear assessment of the number, size, and location of the metastases and their relationship to the intrahepatic vasculature and biliary system [see Figure 1]. Additionally, contrast-enhanced CT provides information regarding the hepatic anatomy, parenchyma, remnant

volume, and regional lymph node status. Variations in vascular anatomy are clearly depicted by contrast-enhanced CT, allowing concise preoperative planning. CT depicts gross characteristics of the liver, such as contour, nodularity, lobar atrophy, steatosis, and splenomegaly, which can affect operative planning. Specifically, CT provides evidence of parenchymal response to modern systemic chemotherapy (chemotherapy-associated liver disease [CALD]), that is, steatohepatitis and the sinusoidal obstruction syndrome, which affects operative risk relevant to preoperative coun-seling of patients. CT provides reliable measurement of overall and subtotal hepatic volume, which is essential for accurately defining remnant volume and consequently resectability with or without intervention to affect remnant growth. Finally, CT can demonstrate objectively metastatic response to chemotherapy, whether by size or morphology, which affects multimodality therapy, including resection.12,13

magnetic resonance imaging

MRI of the liver defines accurately the extent and distri-bution of hepatic metastases from colorectal cancer and is at least as equivalent as CT.14 MRI is useful particularly in identifying hepatic metastases in patients previously treated with chemotherapy and steatosis [see Figure 2]. For small


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Figure 1 Computed tomographic image demonstrating the relation-ship of vascular structures to liver metastasis.

lesions, less than 1 cm specifically, MRI is associated with higher sensitivity and specificity than contrast-enhanced CT.15 With the introduction of liver-specific MRI contrast agents, the accuracy of lesion identification has been further increased.16 Similar to CT, the underlying liver health, anatomy, and remnant volume can be assessed with MRI. Additionally, magnetic resonance cholangiography (MRC) best defines the biliary system when relevant to hepatic resection, providing details for central hepatic resections or other resections close to the biliary confluence. How-ever, MRI lacks the accuracy of contrast-enhanced CT extrahepatically.

Figure 2 Magnetic resonance image demonstrating multiple small liver metastases (arrows).

Liver-Directed Therapy

Surgical resection and various ablative techniques (radio-frequency ablation [RFA] and microwave ablation) are applicable for the treatment of hepatic metastases from col-orectal cancer. The choice of technique and/or the combina-tion of techniques is determined by the size, number, and location of metastases within the liver and local institutional expertise. In general, undertaking liver-directed therapy implies that the primary and regional extent of the colorectal cancer has been fully addressed in patients presenting with metachronous hepatic metastases or is considered resectable in patients presenting with metastases synchronous with the primary cancer. Preoperative imaging should evaluate the site of origin of the primary colorectal cancer to exclude locoregional recurrence in patients with metachronous hepatic metastases. Resectable locoregional recurrence dic-tates resection, which can be undertaken either concurrently with the hepatic resection or as a staged procedure. Simi-larly, in patients with synchronous presentation of the pri-mary colorectal cancer and hepatic metastases, resection of the primary cancer and hepatic metastases may be addressed either concurrently or separately. Management of patients with synchronous presentation of the primary cancer and hepatic metastases is complex. Operative strategy is influenced by the site of the primary colorectal cancer, the extent of hepatic metastases, and the institutional operative risks. Options included resection of the primary cancer first, con-current resection of the primary cancer and hepatic metasta-ses, and resection of the hepatic metastases first. Resection of the primary cancer first is seldom undertaken currently because the risk of complications related to the primary can-cer is low. Hemorrhage is rarely life threatening, and obstruction can be palliated by endoscopic luminal stenting. Moreover, primary colorectal cancers are as responsive to current neoadjuvant chemotherapy as the metastases. Con-current resections reduce the duration of hospitalization and overall risks in selected patients. In general, resection of the primary cancer with minor hepatic resections is accepted widely, whereas staged resections are undertaken for patients requiring major hepatic resections.17 The extent of hepatic metastases that require major hepatic resection or staged hepatic resection to fully address hepatic metastases should prompt consideration of resection of the hepatic dis-ease first because hepatic tumor burden poses greater risk to life than the primary cancer. Neoadjuvant chemotherapy usually precedes hepatic resection in such patients to assess cancer responsiveness and to downsize metastases to resectability.

Hepatic Resection

Hepatic resection is the treatment of choice for selected patients with metastatic colorec-tal cancer. Selection is predicated on maintain-ing a sufficient func-tional hepatic remnant and resection of all iden-tified metastases. The expected 5-year overall survival for


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patients undergoing hepatic resection for metastatic colorec-tal cancer ranges from 30 to 60%.18–22 The type of hepatic resection, whether anatomic or nonanatomic, has not cor-related with outcome.23,24 R0 resection is essential for pro-longed survival. Although negative margins of resection correlate strongly with survival, the actual measured mar-gin, in fact, is influenced by transection techniques that dis-rupt adjacent parenchyma by variable degrees. Although, traditionally, a margin of 1 cm or greater was recommended, current evidence suggests that smaller margins are associ-ated with similar overall survival provided that the metas-tases are not disrupted intraoperatively.25 The efficacy of modern chemotherapy, whether neoadjuvant or adjuvant, likely affects the outcome in patients with small margin R0 resection and R1 resections. Specifically, confirmed morpho-logic and pathologic response correlates with decreased local recurrence.26 Regardless of factors that affect margins, pathologically negative margins are recommended. Numer-ous clinicopathologic factors in patients with hepatic metas-tases from colorectal cancer have been correlated with survival. Consequently, multiple clinicopathologic scoring systems have been developed to identify prognostic factors following hepatic resection of metastatic colorectal cancer. The Memorial Sloan-Kettering Cancer Center (MSKCC) risk score is used most commonly.20 This scoring system is based on five factors, with 1 point given for each [see Table 1]. The prognostic value of this scoring system has been validated in several patient populations.27,28 Although scoring systems stratify survival risk and possibly identify patients who should not undergo hepatic resection, in practice, they have had limited impact on subsequent cancer therapy.

Extended Resections

The extent of hepatic metastases affects opera-tive approaches to the liver. Metastases limited to one lobe or less are addressed by lobar or lesser resections to spare nonmetastatic liver and optimize functional remnant volume. Hepatic resection in patients with bilobar, multiple metastases is more problem-atic. Frequently, these patients require staged hepatic resec-tions. Although multiple parenchymal-sparing resections are preferred if technically feasible, R0 resection often requires lobar or extended lobar resection and segmental or subsegmental resections of the contralobar remnant. The

primary strategy in such patients is identifying the future hepatic remnant and ensuring optimal functional volume. Hepatic volumetry is performed and correlated to the patient’s body surface area.29 Current recommendations for minimal functional remnant volume for patients after hepatic resection are provided here [see Table 2].30,31 If mini-mal remnant volume is not present, PVE of the nonremnant liver is the standard strategy to induce remnant hypertrophy [see Figure 3]. Liver hypertrophy is expected approximately 3 to 4 weeks after PVE [see Figure 4]. Repeat volumetry is performed to confirm remnant growth and to restage met-astatic disease to exclude progression. The rate of hypertro-phy or the “kinetic growth rate” may more accurately predict outcome after resection than remnant volume.32 In patients with multiple, bilobar metastases, PVE may precede extended resection during a one-stage approach or follow resection of metastases in the hepatic remnant during a staged approach. Staged resection for hepatic metastases is employed when limited metastases are present in a small projected remnant. Usually, metastases are removed by nonanatomic resection. Subsequently, PVE of the nonrem-nant liver follows, and staged resection of the embolized liver is performed after confirmation of hypertrophy for final clearance of metastatic disease [see Figure 5 and Figure 6]. Alternatively, portal vein ligation of the nonremnant liver during the initial hepatic resection can be performed.

Recently, an innovative staged resection was introduced, termed associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) [see Figure 7].33 This tech-nique similarly involves clearance of the remnant during the initial stage of resection. Additionally, the liver is divided along the planned plane of transection for the extended resection and the portal vein to the nonremnant liver is divided. The hepatic artery, hepatic vein, and the bile duct of the nonremnant or deportalized liver are left intact. Rapid hypertrophy, typically in 1 to 2 weeks, has been demon-strated, which facilitates the second operation for resection of the deportalized segment. Experience with this technique is limited, and patient selection is unclear. Current morbidity and mortality suggest application in only high-volume spe-cialty centers. Whether ALPPS will provide specific survival benefits or affect overall treatment strategies for patients with metastatic colorectal cancer to the liver is unknown.

Ablation Techniques

Various thermal ablative techniques have been employed for the treatment of hepatic metastases from colorectal cancer.34 Techniques for ablation include heat (RFA and

Table 1 Memorial Sloan-Kettering Cancer Center Risk Score Factors

Node-positive primary tumorMore than one tumorTumor > 5 cmInterval from primary tumor to metastasis of < 12 monthsCarcinoembryonic antigen (CEA) levels > 200 ng/mL

One point given for each.

Table 2 Recommendations for Minimal Functional Remnant Volume for Patients after

Hepatic Resection30,31

Patient Type Percentage

Patient with a normal liver 20

Patient after neoadjuvant chemotherapy or with noncirrhotic hepatic disease

30

Patient with cirrhosis 40


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microwave ablation) and cold (cryoablation; infrequently used currently). Chemical ablation with alcohol has been limited because diffusion of the agent is inconsistent and unpredictable. Thermal methods have been employed percutaneously and intraoperatively (both laparoscopically guided and with an open approach). Ablation has been used for treatment of lesions alone or in combination with resec-tion. RFA is the most common ablative technique currently employed.

Resection versus Ablation

No randomized, controlled, prospective trial has com-pared RFA with resection. A recent large meta-analysis has shown resection to be superior in terms of progression-free and overall survival at 3 and 5 years.35 These findings persisted regardless of whether the metastases were solitary, less than 3 cm, or approached percutaneously, laparoscopi-cally, or at laparotomy. Morbidity was greater for resection than for RFA, although mortality was equivalent. These data support resection as the standard for treatment of hepatic metastases from colorectal cancer. Factors that support the use of ablative techniques either alone or in combination with resection include impaired patient functional status and parenchymal sparing of the hepatic remnant.

Sequence of Therapy

perioperative chemotherapy

Systemic chemotherapy is an essential compon-ent in the multimodal treatment of metastatic colorectal cancer.36 Cur-rent evidence suggests that perioperative systemic chemotherapy and hepatic resection are associated with greater survival than resection alone. The role of perioperative chemotherapy in the treat-ment of patients with resectable colorectal liver metastases has been evaluated in a multinational, randomized, controlled phase III trial; the European Organisation for Research and Treatment of Cancer (EORTC) Intergroup trial 40983 compared an oxaliplatin-based chemotherapy regimen (FOLFOX4) perioperatively as six cycles pre- and posthepatic resection versus hepatic resection alone.37 A statistically sig-nificant increase in progression-free survival at 3 years favored patients who had undergone perioperative chemo-therapy and hepatic resection, although overall survival was not increased. These results were confirmed at the long-term follow-up.38

neoadjuvant chemotherapy

Although increased survival after neoadjuvant chemo-therapy in patients with resectable colorectal metastases has not been confirmed by a randomized clinical trial to date, neoadjuvant systemic chemotherapy has been shown to increase resectability in patients in whom hepatic metastases were considered initially unresectable. Long-term survival has been equivalent in patients whose metastases were successfully downsized to resectability compared with patients whose metastases were resectable initially.39–44

a

b

c

Figure 3 (a) Right portal vein embolization. (b) Venogram of portal venous system followed by (c) right portal vein embolization.


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adjuvant chemotherapy

The role of adjuvant systemic chemotherapy has been established for patients with resectable primary colorectal cancer by large, randomized, controlled phase III trials.45,46 However, the role of adjuvant chemotherapy for patients with resectable hepatic metastases has not been established. Trials addressing this question are insufficiently powered to address disease-free and overall survival.47,48 Pooled analysis of two trials did demonstrate adjuvant chemotherapy as predictive of overall and disease-free survival by multivari-ate analysis but not by Kaplan-Meier analysis.49

perioperative versus adjuvant chemotherapy

The timing of chemotherapy in the treatment of patients with resectable hepatic metastases from colorectal cancer is unestablished by randomized trials. Retrospective analy-sis of patient cohorts undergoing perioperative versus adju-vant chemotherapy has demonstrated similar results for disease-free and overall survival.50 Although perioperative chemotherapy has the potential advantages of assessing chemotherapy responsiveness and downsizing of metastases preoperatively to potentially improve margins, chemotherapy-associated toxicity on nonmalignant liver has the potential to increase operative risk and may offset such advantages. The recognition of chemotherapy-associated hepatic toxicity is duration dependent and consequently dic-tates that hepatic resection precede completion of a full course of chemotherapy. Currently, up-front resection of

clearly resectable metastases followed by adjuvant systemic chemotherapy is acceptable. In contrast, patients who have marginally resectable metastases based on number or size, patients presenting with synchronous metastases, or patients with metachronous metastases after a short pro-gression-free interval (< 12 months) should undergo periop-erative systemic chemotherapy with subsequent restaging before hepatic resection.

primary versus metastatic disease

For patients with synchronous disease, there are three options for sequencing the surgical therapy:

1. Resection of the colorectal primary tumor first 2. Resection of the liver metastases first3. Synchronous resection of the colorectal primary and liver

metastases

In the setting of synchronous disease, the patient is often treated with perioperative chemotherapy, and in the setting of rectal primary tumors, chemoradiation is traditionally added to the treatment regimen prior to resection of the tumor. The traditional approach has been to treat with neoadjuvant chemotherapy and then address the primary disease, followed by adjuvant chemotherapy and then liver resection. Proponents of this approach note the ability to monitor for development of the additional disease in the liver during the interval between operations and assess the chemosensitivity of the metastatic disease.

a b

Figure 4 Liver atrophy and hypertrophy occur after right portal vein embolization. Shown are images of the liver (a) at baseline and (b) 6 weeks after portal vein embolization. The right hemiliver is outlined in white.


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The alternative approach of addressing the liver metasta-ses first has been shown to be feasible.51–53 The advantages of the “liver-first” approach are as follows: hepatic metasta-ses, which are the primary cause of death, are addressed initially before progression to unresectability; the risk of disappearing metastases is reduced; and the mortality and morbidity related to resection of the primary colorectal cancer are avoided. Moreover, in patients with rectal cancer requiring irradiation, the hepatic resection can be completed during the expected postirradiation rest interval. The liver- first approach arose to address patients primarily with com-plex bilobar hepatic metastases or patients with advanced rectal cancers requiring multimodality pelvic treatment or complex rectal resections. Although the liver-first approach can be used in patients with less extensive hepatic meta-stases, there is no clinical advantage of this approach for

patients requiring minor (≤ 3 segments) hepatic resections to address the metastases. Our approach to resectable synchro-nous disease has been neoadjuvant chemotherapy followed by concurrent resection. For patients with bilobar metastases requiring a two-stage approach, the projected remnant is cleared of metastases and the primary tumor is resected concurrently at the first stage. The patient then undergoes PVE postoperatively, or alternatively a portal vein ligation is performed at the first stage, and an extended hepatic resection is completed as a second stage after appropriate hypertrophy has been achieved.

Disappearing Metastases

Improved response to systemic chemotherapy has resulted in a complete radiologic resolution or response in some patients. Such metastases have been termed “disappearing

Tumorectomies

Hypertrophyof the LeftHemiliver

Atrophy ofRight Hemiliver

Right Hepatectomy

Right Portal VeinEmbolization

Multiple LiverTumors


a

b

c

d

Figure 5 Staged hepatic resection with interval portal vein embolization. (a) Future liver remnant is cleared of metastases. (b) Right portal vein embolization. (c) Interval imaging. (d) Extended hepatectomy.


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a b

c d

Figure 6 (a, b) Computed tomography demonstrating multiple bilobar colorectal metastases. (c) Pathology specimen from segment 2 resection (first stage). (d) Intraoperative photograph after extended right hepatectomy (second stage).


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metastases.” Most radiographically disappearing metastases are found intraoperatively by inspection, palpation, or intraoperative US. Most sites of disappearing metastases occurring after systemic chemotherapy that are resected harbor residual disease. Complete pathologic response in disappearing metastases based on long-term follow-up of unresected sites or the absence of cancer in resected sites is less than 40%. Consequently, the recommended strategy for resection of hepatic metastases in these patients remains addressing all sites of metastases identified initially, pro-vided that these sites can be resected or ablated without

jeopardizing the remnant.30,54 The only initial imaging factor correlating with disappearance is the size of the metastasis (< 2 cm). The potential for disappearing metastases necessi-tates involvement of a hepatic surgeon early in the overall treatment plan, particularly in patients receiving neoadju-vant chemotherapy. Importantly, preoperative chemotherapy should be limited to a short course (< 6 cycles) to minimize hepatotoxicity and disappearing metastases. Moreover, placement of fiducials radiologically adjacent to small metastases can guide identification of sites of disappearing metastases for resection.



DividedPortal Vein

Tumorectomies

Hypertrophyof the LeftHemiliver

Right Hepatectomy

Atrophy ofRight Hemiliver

a

b

c

d

Figure 7 Associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) procedure. (a) Multiple bilobar liver metastases. (b) The liver parenchyma is divided. The portal vein to the side to be resected is divided, and the arterial and biliary structures are maintained. (c) Interval imaging. (d) The hepatic artery, bile duct, and hepatic vein to the deportalized liver are divided and the specimen is removed.


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15. Kulemann V, Schima W, Tamandl D, et al. Preoperative detection of colorectal liver metastases in fatty liver: MDCT or MRI? Eur J Radiol 2011;79:e1–6.

16. Zech CJ, Korpraphong P, Huppertz A, et al. Randomized multicentre trial of gadoxetic acid-enhanced MRI versus conventional MRI or CT in the staging of colorectal cancer liver metastases. Br J Surg 2014;101:613–21.

17. Yin Z, Liu C, Chen Y, et al. Timing of hepatectomy in resect-able synchronous colorectal liver metastases (SCRLM): simultaneous or delayed? Hepatology 2013;57:2346–57.

18. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency abla-tion, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004;239:818–25; discussion 25–7.

19. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235:759–66.

20. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309–18; discussion 18–21.

21. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008;247:125–35.

22. Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Ann Surg 2007;246:183–91.

23. Inoue Y, Hayashi M, Komeda K, et al. Resection margin with anatomic or nonanatomic hepatectomy for liver metastasis from colorectal cancer. J Gastrointest Surg 2012; 16:1171–80.

24. Lalmahomed ZS, Ayez N, van der Pool AE, et al. Anatomi-cal versus nonanatomical resection of colorectal liver metas-tases: is there a difference in surgical and oncological outcome? World J Surg 2011;35:656–61.

25. de Haas RJ, Wicherts DA, Flores E, et al. R1 resection by necessity for colorectal liver metastases: is it still a contrain-dication to surgery? Ann Surg 2008;248:626–37.

26. Andreou A, Aloia TA, Brouquet A, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg 2013;257:1079–88.

27. Reissfelder C, Rahbari NN, Koch M, et al. Validation of prognostic scoring systems for patients undergoing resec-tion of colorectal cancer liver metastases. Ann Surg Oncol 2009;16:3279–88.

28. Takakura Y, Okajima M, Kanemitsu Y, et al. External vali-dation of two nomograms for predicting patient survival after hepatic resection for metastatic colorectal cancer. World J Surg 2011;35:2275–82.

29. Vauthey JN, Chaoui A, Do KA, et al. Standardized mea-surement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 2000;127:512–9.

30. Adams RB, Aloia TA, Loyer E, et al. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford) 2013;15:91–103.

31. Shindoh J, Tzeng CW, Aloia TA, et al. Optimal future liver remnant in patients treated with extensive preoperative chemotherapy for colorectal liver metastases. Ann Surg Oncol 2013;20:2493–500.

Financial Disclosures: Rory Smoot, MD, and David M. Nagorney, MD, FACS, have no relevant financial relationships to disclose.

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Acknowledgment

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