Patient selection for hepatic resection for metastatic colorectal cancer

Introduction

The most common site of hematogenous metastasis from colorectal cancer is the liver. Approximately one half of patients with colorectal cancer develop liver metastasis during the course of their disease (1). Hepatic resection for liver metastasis remains the only potentially curative therapy, with 5 year survival rates of approximately 50% (2) and an actual 10-year cure rate approaching 20% (3). Additionally, effective systemic and regional chemotherapy combined with resection can result in long-term survival without cure (4). Therefore, the goals and indications for hepatic resection include both the possibility of cure and prolongation of life. This report focuses on factors which we feel are important for properly selecting patients to undergo surgical therapy. The initial patient consultation focuses on 3 areas: I. the patient’s ability to tolerate the operation, II. determining technical resectability and III. predicting whether removal of liver disease will improve long-term survival.

Operative morbidity and patient selection

Operative mortality for liver resections performed for metastatic colorectal cancer has decreased substantially over the past 3 decades to <5% in most series and is approximately 1% in high volume centers (2,5-15). Reported major complication rates are greater than 20% in most series and are therefore an important issue (16-20). Patient selection plays a critical role in minimizing mortality and morbidity following hepatic resection. Pre-existing comorbidities contribute substantially to surgical morbidity and mortality. Therefore, one goal of the preoperative evaluation should be to exclude patients with prohibitive operative risks and to identify patients with manageable conditions that can be medically optimized before operation.

Advanced age is not a contraindication to hepatic resection which is now routinely performed in elderly patients with acceptable morbidity and mortality (21,22). Some centers have demonstrated that the American Society of Anesthesiology (ASA) and Acute Physiology and Chronic Health Evaluation (APACHE) scores can be useful in predicting complications (23,24). Although such surrogates of physiological conditions can help predict complications in this patient population, they fail to provide guidelines for managing co-morbid conditions in the perioperative setting. Performance status and frailty are very important predictors of perioperative outcome (25,26) and are routinely evaluated at the preoperative visit. Patients are evaluated for their co-morbid conditions by appropriate sub-specialty services and risk stratified. Patients must be fit for a major laparotomy (in most cases), the metabolic consequences of a hepatic resection and the attendant substantial physical recovery.

All patients being considered for a hepatic resection should be assessed for preoperative liver dysfunction. Although most patients with colorectal cancer do not have underlying chronic liver disease, exposure to chronic chemotherapy can result in hepatic steatosis, steatohepatitis, sinusoidal obstruction syndrome and even portal hypertension (27-31). Steatosis and steatohepatitis also frequently occur in the general population but are likely exacerbated with chemotherapy treatment. Chemotherapy associated steatohepatitis (CASH) results from chronic liver damage which can make surgical resection risky due to higher rates of postoperative liver dysfunction. There is evidence that CASH increases the risk of postoperative complications after hepatic resection for metastatic colorectal cancer (28-30). The assessment of liver function can be complex and unfortunately, blood tests are not reliable predictors of liver function. Nonetheless, all patients should have liver chemistries, a complete blood count and a prothrombin time measured prior to surgery. These laboratory values combined with a clinical evaluation are used to calculate a Child-Pugh classification (32). We routinely perform hepatic resections on Child-Pugh class A patients with acceptable morbidity and mortality, but generally consider class B and C patients as prohibitively high operative risk. A more critical assessment is to assess the patient for portal hypertension. Patients with significant portal hypertension have a very high risk of mortality associated with hepatic resection and are generally not considered candidates (33). Splenomegaly, thrombocytopenia (<100 K/mcl) and varices on endoscopy or on CT scan are all indicative of portal hypertension. If there is doubt about the presence of portal hypertension, a more direct measurement of portal pressures can be obtained with a hepatic vein wedge pressure (34). Cross-sectional imaging should be reviewed carefully for signs of steatosis, cirrhosis and portal hypertension. MRI is effective for determining the degree of steatosis by decomposing the liver signal into its fat and water components (35). CT is effective at identifying varices and splenomegaly which are indicative of portal hypertension (36). No single test can reliably predict which patients have adequate hepatic reserve to tolerate a resection. However, with a comprehensive investigation of chemotherapy history, liver function tests, platelet count, Child-Pugh score, and imaging findings in conjunction with the extent of resection required the operative risk can be reasonably estimated. In patients with evidence of liver dysfunction related to chronic chemotherapy, morbidity can be minimized by decreasing the volume of resected liver with parenchymal sparing resection techniques or by increasing the volume of the future liver remnant (FLR) utilizing portal vein embolization (PVE). (see below)

Preoperative cross sectional imaging and role of positron emission tomography (PET)

Every patient evaluated for hepatic resection for colorectal cancer should undergo cross-sectional imaging to evaluate the extent of both intra- and extrahepatic disease. We routinely obtain contrast-enhanced multidetector helical computed tomography (CT) imaging of the chest, abdomen and pelvis on patients being evaluated for hepatic resection. Although somewhat controversial, we obtain chest CT scans to rule out pulmonary metastasis because of its high degree of sensitivity (37) and potential to change management. However, a potential weakness of routinely obtaining chest CT scans is its lack of specificity and false positive rate of identifying non-specific small pulmonary nodules. These small pulmonary nodules are frequently under the resolution for PET scans, may be nearly impossible to biopsy percutaneously, and probably do not justify a thoracotomy or thoracoscopic procedure. Forty-three percent of patients selected for liver resection for colorectal metastases at our institution have subcentimeter pulmonary nodules of which one third ultimately proved to be metastatic disease (38). However, the presence of limited subcentimeter pulmonary nodules did not significantly impact 3-year DSS and should not necessarily preclude liver resection (38). The goal of hepatic imaging is to define the number, location, distribution and relation of the hepatic tumors to vascular and biliary structures. The standard CT scan to evaluate for liver metastasis is a triphasic scan with 2.5-5 mm slices. The arterial phase is useful to define arterial anatomy and identify co-existing benign lesions. However, colorectal metastases are not very vascular and therefore are best seen on the portal venous phase where they appear hypodense. The sensitivity of identifying liver metastasis with contrast enhanced multidetector CT scans approaches 80-90% (39-41). Superior image resolution of CT provides excellent vascular and anatomic detail which is useful in preoperative planning. However, CT lacks the sensitivity and ability to characterize lesions less than 1cm.

Contrast enhanced magnetic resonance imaging (MRI) is another useful imaging modality for assessing the extent of liver disease with an accuracy of 80-90% (42-44). MRI is most useful for evaluating equivocal lesions and differentiating metastasis from benign lesions. It may also be beneficial in defining relationships to the biliary tree with MRI cholangiopancreatography. We selectively use contrast enhanced MRI in order to characterize indeterminate liver lesions and for patients with steatosis from obesity, diabetes and previous chemotherapy. MRI is particularly useful in identifying ‘disappearing’ tumors while on chemotherapy since many of these tumors are not visible due to the development of hepatic steatosis (45). The strength of MRI is the ability to characterize small liver lesions using liver specific contrast agents such as EOVIST (gadolinium-EOB-DTPA) (46,47), but the low sensitivity for detecting extrahepatic disease limits our use as a first-line imaging modality.

Some centers have advocated for the routine use of positron emission tomography (PET). PET most frequently uses fludeoxyglucose (FDG), a glucose analogue which accumulates in glucose-avid rapidly metabolizing cancer cells and inflammatory cells. When comparing preoperative CT alone to combined PET and CT, Strasberg et al. reported an improved resectability rate from 86% to 95% with the addition of PET (48). These data are encouraging because PET-CT may identify otherwise radiologically occult extrahepatic disease and may improve long term survival by selection. However, it is important to note that all of these patients had high quality CT scans as well, so the utility of PET-CT alone for evaluating liver metastasis is limited because the sensitivity of PET in the liver for small lesions is poor. PET-CT is also limited by the non-specificity of positive lesions. A recent meta-analysis suggested PET-CT may be slightly more sensitive (91-100% versus 78-94%) and specific (75-100% versus 25-98%) than CT alone for hepatic colorectal metastases (49), but these results were based on only 5 studies. It is possible that expert radiologic review of high quality CT scans may abrogate the purported benefit of PET-CT. We currently use PET-CT selectively for patients at high risk of extrahepatic disease or indeterminate extrahepatic lesions, realizing that subcentimeter lesions may fall below the diagnostic threshold of detection.

Determining technical resectability

A negative resection margin is associated with a lower local recurrence rate and improved long-term survival (50). Scheele et al. demonstrated that patients who undergo an R0 resection have a three-fold increase in median survival compared to R1 or R2 resections (51). Similarly, another more recent study by Pawlik et al. demonstrated a significantly higher risk of liver recurrence and decreased overall survival with positive margins (50). The optimal resection margin is still debatable. One study reported a resection margin of ≥1 cm being associated with improved disease-free survival, but other studies have demonstrated that the width of resection margin is not independently associated with improved oncologic outcome as long as the margin is microscopically negative (50,52). We studied 1019 patients undergoing hepatic resection for colorectal metastases and found that obtaining a >1cm margin was independently associated with improved outcome but subcentimeter resections are also associated with favorable outcomes (53). Therefore, a negative margin should be attainable for a patient to be deemed resectable and aiming for 1cm margins should be encouraged when possible. We speculate that obtaining a negative margin can be both a technical and biologic issue. Some tumors that appear to be resected with narrow gross margins are found to have pathologically negative margins, while other resections which appear to have wide gross margins are found to have microscopically positive margins. Although no data exist to support this, we believe this dilemma may be indicative of underlying tumor biology.

Determining technical resectability should focus on preserved structures rather than those which require resection. This is a critical issue because the risk of hepatic resection is directly related to the relative volume of hepatic parenchyma resected. Hepatic metastases are considered technically resectable when a negative resection margin is anticipated, all hepatic disease can be resected and/or ablated, two adjacent liver segments can be spared, vascular inflow, outflow and biliary drainage can be preserved, and a sufficient liver remnant (FLR) will remain (>20% of the total estimated liver volume) (54-57).

For non-diseased livers >20% of normal total liver appears to be a safe FLR (58,59). However, greater FLRs of 30-40% are probably necessary for patients on chronic chemotherapy or for diseased livers with significant steatosis (60). CT and MRI can accurately determine the volume of the FLR and both are utilized at our institution selectively, particularly for patients with small FLRs, underlying steatosis and those treated with long-term chemotherapy. One often underappreciated strategy for such patients is the use of parenchymal sparing resection techniques. The use of segmental and sub-segmental resections and intraoperative thermal ablation can often spare a patient an unnecessary large volume resection. For patients that require a major hepatic resection with an inadequate FLR volume based on cross-sectional imaging, pre-operative portal vein embolization (PVE) contralateral to the FLR is performed, followed by repeat volume measurements. Our goal for PVE is to achieve an approximately 10% increase in FLR. Failure to induce hypertrophy is either indicative of a technical failure and requiring repeat PVE, or represents a diseased liver without regenerative capacity for which resection has a high likelihood of postoperative liver failure. It has been suggested that the existence of bilobar disease is a relative contraindication to PVE because of potential contralateral tumor growth. Some feel that this situation is best approached with a 2-stage hepatectomy with PVE after the first stage of resection (61,62). However, PVE appears safe and effective in combination with concomitant chemotherapy (63) and we currently perform PVE while patients remain on chemotherapy.

Predicting oncologic outcome

The ultimate decision on whether to resect colorectal liver metastasis assumes technical resectability, but must take into account the predicted oncologic outcome and potential clinical benefit. The presence of liver metastases defines the patient as stage IV by the American Joint Committee on Cancer staging system. However, cure is still achievable because the liver is frequently the only site of metastatic disease. The benefit of hepatic resection for metastatic colorectal cancer has never been tested in a randomized trial. However, 5-year survival for patients with colorectal liver metastasis treated with systemic chemotherapy alone is rare and cure essentially does not occur. Five-year survival after hepatic resection is 41-58% (2,8,11,15) and 10 year disease-free cure rates approach 20%. Therefore, a regional approach to liver disease is clearly indicated and improves survival. However, predicting which patients will benefit based on diverse clinical and pathological features can be difficult.

The ideal predictive scoring system would use preoperatively available factors to predict which patients derive no benefit from surgical resection and should be treated with systemic chemotherapy alone. Unfortunately, such an ideal predictor has been elusive. Fong et al. developed an effective clinical risk score (CRS) based on a retrospective multivariable analysis that identified 5 preoperatively available variables to predict outcome following hepatic resection. One point each was assigned for node positive disease, disease-free interval <12 months, number of tumors >1, preoperative CEA level >200 ng/dL, and size of tumor >5 cm (7). CRS is useful in predicting survival as well as the likelihood of disseminated disease and resectability (64). However, patients with a high CRS have a predicted 5-year survival of approximately 20% and documented 10 year cures. Patients with one or multiple negative prognostic factors still benefit from hepatic resection (65) as evidenced by documented long-term survival and cure (3).

Patients with ≥4 liver metastases, or evidence of extrahepatic disease were not offered hepatic resection in the past. However, the number of metastasis is no longer a contraindication to liver resection (52,66,67). Many of the early studies failed to perform multivariate analysis and thus confounding variables were not considered. We believe that although recurrence rates are very high after resection of ≥4 metastases, the associated long-term survival and small potential for cure (5-10%) justify surgical resection in selected patients. Several recent studies indicate that although the presence of extrahepatic disease portends a worse survival, complete resection of both the hepatic and extrahepatic metastases can result in long-term survival. Although highly selected patients with limited and completely resected extrahepatic disease experience long-term survival, recurrence rates in this group of patients approach 100%. We therefore, feel that patients with extrahepatic disease must be carefully selected with the use of neoadjuvant chemotherapy, extensive imaging and should be extensively counseled about the nearly universal recurrence rates after operation (68-71). In general, these patients should have a single site of resectable disease, limited hepatic disease and stable or responsive disease on systemic chemotherapy before considering resection.

We generally view liver resections for metastatic colorectal cancer as either potentially curative or operations with very high or nearly universal recurrence where controlling liver disease may prolong survival. Patients without evidence of extrahepatic disease, <4 metastases and in whom a negative resection margin is achievable are resected with curative intent. In patients with ≥4 metastases the operation is still considered potentially curative but recurrence rates are high. If technically resectable, these patients are offered resection but we are more likely to treat with a brief course of chemotherapy prior to resection. Patients with resectable extrahepatic disease, and those in which a margin is likely to be positive on final pathology have a nearly universal rate of recurrence but may still benefit from resection. Unfortunately, margin status is not completely predictable based on preoperative imaging and therefore this issue cannot reliably be used to exclude patients from resection. Nonetheless, if the margin is very likely to be involved due to tumor abutment of vascular structures that must be preserved we feel it is reasonable to treat with systemic and/or regional chemotherapy prior to resection in hope of achieving response and decreasing the chance of a positive margin. Concurrent resection of all extrahepatic disease in well selected patients is associated with the possibility of long-term survival at our institution but patients are highly selected. Currently, we restrict such resections to patients with limited, resectable single sites of extrahepatic disease who have stable or responsive disease on chemotherapy (71).

There are numerous reasons to justify the use of preoperative systemic chemotherapy. Preoperative chemotherapy may increase the R0 resection rate while preserving remnant liver parenchyma, treat unrecognized microscopic disease and be used as a test of chemoresponsiveness. Modern chemotherapy with fluorouracil (FU), leucovorin and oxaliplatin or irinotecan have improved response rates over the last decade and offer the possibility of converting unresectable to resectable disease. Studies have demonstrated meaningful conversion rates between 14-41% with systemic chemotherapy alone (9,72). Our institution offers hepatic artery infusional (HAI) therapy with floxuridine and dexamethasone combined with systemic chemotherapy for patients with extensive liver disease not amenable to resection. When systemic chemotherapy is combined with HAI, 47% of initially deemed unresectable patients were eventually converted to resectable at our institution with promising long-term outcomes (73).

Using neoadjuvant chemotherapy for resectable disease (<4 metastases, no extrahepatic disease and technically resectable with clear margins) is debatable. Many argue that progression on chemotherapy portends a poor prognosis after resection and neoadjuvant chemotherapy is a strategy to identify such patients. Adam et al. retrospectively reviewed 131 patients treated with neoadjuvant chemotherapy who underwent liver resection and found that 5-year survival was significantly worse in the group of patients that progressed on chemotherapy versus responders (8% vs. 37%) (74). However 24% of patients had extrahepatic disease, all had 4 or more hepatic metastases and 25% were on 2^nd or 3^rd line chemotherapy. These data simply do not apply to patients with straightforward resectable disease. We recently reviewed 111 patients with synchronous colorectal liver metastases who were all initially deemed resectable and received neoadjuvant chemotherapy and found that response to therapy did not correlate with overall survival (75). Given the low rates of progression on modern chemotherapy (5-10%), the associated hepatotoxicity and the fact that progression does not necessarily translate into poor outcome we do not favor neoadjuvant chemotherapy for resectable disease.

Conclusion

Proper selection of patients for hepatic resection metastatic colorectal cancer demands a multidisciplinary approach in order to identify patients with prohibitive risks and medically optimize comorbidities prior to surgery. Cross-sectional imaging is crucial to determine technical resectability and identify extrahepatic disease. The definition of resectability has evolved over the past 3 decades to include multiple hepatic tumors, <1 cm margins, limited extrahepatic disease and should now focus on complete extirpation of disease with preservation of anatomic structures. Currently, hepatic disease is deemed resectable when 2 contiguous liver segments with adequate inflow, outflow and biliary drainage can be preserved and adequate liver remnant volume will remain. The presence of limited and resectable extrahepatic disease no longer precludes surgical resection. We favor upfront hepatic resection in patients presenting with potentially curative and resectable disease (<4 metastases, no extrahepatic disease and technically resectable with clear margins) and reserve neoadjuvant chemotherapy for patients with a high likelihood of recurrence as defined above. When experienced surgeons properly select patients, hepatic resections can be performed safely and effectively in this diverse patient population.

Footnote

No potential conflict of interest.

References

1. Steele G Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989;210:127-138. [PubMed]
2. House MG, Ito H, Gönen M, Fong Y, Allen PJ, DeMatteo RP, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg 2010;210:744-52, 752-5.
3. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007;25:4575-4580. [PubMed]
4. Ito K, Govindarajan A, Ito H, Fong Y. Surgical treatment of hepatic colorectal metastasis: evolving role in the setting of improving systemic therapies and ablative treatments in the 21st century. Cancer J 2010;16:103-110. [PubMed]
5. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995;19:59-71. [PubMed]
6. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 1996;77:1254-1262. [PubMed]
7. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309-318, discussion 318-321. [PubMed]
8. Fernandez FG, Drebin JA, Linehan DC, Dehdashti F, Siegel BA, Strasberg SM. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004;240:438-447, discussion 447-450. [PubMed]
9. Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001;8:347-353. [PubMed]
10. Kato T, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum 2003;46:S22-S31. [PubMed]
11. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235:759-766. [PubMed]
12. Minagawa M, Makuuchi M, Torzilli G, et al. Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 2000;231:487-499. [PubMed]
13. Jamison RL, Donohue JH, Nagorney DM, Rosen CB, Harmsen WS, Ilstrup DM. Hepatic resection for metastatic colorectal cancer results in cure for some patients. Arch Surg 1997;132:505-510, discussion 511. [PubMed]
14. Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Ann Surg 2007;246:183-191. [PubMed]
15. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004;239:818-825, discussion 825-827. [PubMed]
16. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236:397-406, discussion 406-407. [PubMed]
17. Coelho JC, Claus CM, Machuca TN, Sobottka WH, Gonçalves CG. Liver resection: 10-year experience from a single institution. Arq Gastroenterol 2004;41:229-233. [PubMed]
18. Mala T, Bøhler G, Mathisen Ø, Bergan A, Søreide O. Hepatic resection for colorectal metastases: can preoperative scoring predict patient outcome? World J Surg 2002;26:1348-1353. [PubMed]
19. Doci R, Gennari L, Bignami P, Montalto F, Morabito A, Bozzetti F. One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg 1991;78:797-801. [PubMed]
20. Cady B, Jenkins RL, Steele GD Jr, et al. Surgical margin in hepatic resection for colorectal metastasis: a critical and improvable determinant of outcome. Ann Surg 1998;227:566-571. [PubMed]
21. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resection for malignancy is safe and effective for the elderly. Ann Surg 1995;222:426-434, discussion 434-437. [PubMed]
22. Mentha G, Huber O, Robert J, Klopfenstein C, Egeli R, Rohner A. Elective hepatic resection in the elderly. Br J Surg 1992;79:557-559. [PubMed]
23. Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000;191:38-46. [PubMed]
24. Gagner M, Franco D, Vons C, Smadja C, Rossi RL, Braasch JW. Analysis of morbidity and mortality rates in right hepatectomy with the preoperative APACHE II score. Surgery 1991;110:487-492. [PubMed]
25. Brown NA, Zenilman ME. The impact of frailty in the elderly on the outcome of surgery in the aged. Adv Surg 2010;44:229-249. [PubMed]
26. Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg 2010;210:901-908. [PubMed]
27. Rubbia-Brandt L. Sinusoidal obstruction syndrome. Clin Liver Dis 2010;14:651-668. [PubMed]
28. Khan AZ, Morris-Stiff G, Makuuchi M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J Hepatobiliary Pancreat Surg 2009;16:137-144. [PubMed]
29. Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 2003;7:1034-1044. [PubMed]
30. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065-2072. [PubMed]
31. Fong Y, Bentrem DJ. CASH (Chemotherapy-Associated Steatohepatitis) costs. Ann Surg 2006;243:8-9. [PubMed]
32. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649. [PubMed]
33. Llovet JM, Fuster J, Bruix JBarcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004;10:S115-S120. [PubMed]
34. Thalheimer U, Leandro G, Samonakis DN, Triantos CK, Patch D, Burroughs AK. Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients. Dig Liver Dis 2005;37:601-608. [PubMed]
35. Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative Assessment of Liver Fat with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging 2011;34. :spcone.
36. Yu NC, Margolis D, Hsu M, Raman SS, Lu DS. Detection and grading of esophageal varices on liver CT: comparison of standard and thin-section multiplanar reconstructions in diagnostic accuracy. AJR Am J Roentgenol 2011;197:643-649. [PubMed]
37. Davis SD. CT evaluation for pulmonary metastases in patients with extrathoracic malignancy. Radiology 1991;180:1-12. [PubMed]
38. Maithel SK, Ginsberg MS, D’Amico F, et al. Natural history of patients with subcentimeter pulmonary nodules undergoing hepatic resection for metastatic colorectal cancer. J Am Coll Surg 2010;210:31-38. [PubMed]
39. Bhattacharjya S, Bhattacharjya T, Baber S, Tibballs JM, Watkinson AF, Davidson BR. Prospective study of contrast-enhanced computed tomography, computed tomography during arterioportography, and magnetic resonance imaging for staging colorectal liver metastases for liver resection. Br J Surg 2004;91:1361-1369. [PubMed]
40. Kuszyk BS, Bluemke DA, Urban BA, et al. Portal-phase contrast-enhanced helical CT for the detection of malignant hepatic tumors: sensitivity based on comparison with intraoperative and pathologic findings. AJR Am J Roentgenol 1996;166:91-95. [PubMed]
41. Kondo H, Kanematsu M, Hoshi H, et al. Preoperative detection of malignant hepatic tumors: comparison of combined methods of MR imaging with combined methods of CT. AJR Am J Roentgenol 2000;174:947-954. [PubMed]
42. Oudkerk M, van den Heuvel AG, Wielopolski PA, Schmitz PI, Borel Rinkes IH, Wiggers T. Hepatic lesions: detection with ferumoxide-enhanced T1-weighted MR imaging. Radiology 1997;203:449-456. [PubMed]
43. van Etten B, van der Sijp J, Kruyt R, Oudkerk M, van der Holt B, Wiggers T. Ferumoxide-enhanced magnetic resonance imaging techniques in pre-operative assessment for colorectal liver metastases. Eur J Surg Oncol 2002;28:645-651. [PubMed]
44. Peterson MS, Baron RL, Murakami T. Hepatic malignancies: usefulness of acquisition of multiple arterial and portal venous phase images at dynamic gadolinium-enhanced MR imaging. Radiology 1996;201:337-345. [PubMed]
45. Auer RC, White RR, Kemeny NE, et al. Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy. Cancer 2010;116:1502-1509. [PubMed]
46. Reimer P, Tombach B, Daldrup H, et al. New MR contrast media in liver diagnosis. Initial clinical results with hepatobiliary Eovist (gadolinium-EOB-DTPA) and RES-specific Resovist (SH U 555 A). Radiologe 1996;36:124-133. [PubMed]
47. Mintorovitch J, Shamsi K. Eovist Injection and Resovist Injection: two new liver-specific contrast agents for MRI. Oncology 2000;14:37-40. Williston Park. [PubMed]
48. Strasberg SM, Dehdashti F, Siegel BA, Drebin JA, Linehan D. Survival of patients evaluated by FDG-PET before hepatic resection for metastatic colorectal carcinoma: a prospective database study. Ann Surg 2001;233:293-299. [PubMed]
49. Patel S, McCall M, Ohinmaa A, Bigam D, Dryden DM. Positron emission tomography/computed tomographic scans compared to computed tomographic scans for detecting colorectal liver metastases: a systematic review. Ann Surg 2011;253:666-671. [PubMed]
50. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241:715-722, discussion 722-724. [PubMed]
51. Scheele J, Altendorf-Hofmann A, Grube T, Hohenberger W, Stangl R, Schmidt K. Resection of colorectal liver metastases. What prognostic factors determine patient selection? Chirurg 2001;72:547-560. [PubMed]
52. Altendorf-Hofmann A, Scheele J. A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma. Surg Oncol Clin N Am 2003;12:165-192. xi.. [PubMed]
53. Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after hepatic resection for colorectal metastasis. Ann Surg 2007;246:295-300. [PubMed]
54. Vauthey JN, Pawlik TM, Abdalla EK, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 2004;239:722-730, discussion 730-732. [PubMed]
55. Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 2002;137:675-680, discussion 680-681. [PubMed]
56. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg 2007;11:1057-1077. [PubMed]
57. Charnsangavej C, Clary B, Fong Y, Grothey A, Pawlik TM, Choti MA. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1261-1268. [PubMed]
58. Shoup M, Gonen M, D’Angelica M, et al. Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg 2003;7:325-330. [PubMed]
59. Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg 2009;250:540-548. [PubMed]
60. Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274-286. [PubMed]
61. Elias D, De Baere T, Roche A. Mducreux, Leclere J, Lasser P. During liver regeneration following right portal embolization the growth rate of liver metastases is more rapid than that of the liver parenchyma. Br J Surg 1999;86:784-788. [PubMed]
62. Chun YS, Vauthey JN, Ribero D, et al. Systemic chemotherapy and two-stage hepatectomy for extensive bilateral colorectal liver metastases: perioperative safety and survival. J Gastrointest Surg 2007;11:1498-1504, discussion 1504-1505. [PubMed]
63. Covey AM, Brown KT, Jarnagin WR, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 2008;247:451-455. [PubMed]
64. Jarnagin WR, Conlon K, Bodniewicz J, et al. A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases. Cancer 2001;91:1121-1128. [PubMed]
65. Dômont J, Pawlik TM, Boige V, et al. Catalytic subunit of human telomerase reverse transcriptase is an independent predictor of survival in patients undergoing curative resection of hepatic colorectal metastases: a multicenter analysis. J Clin Oncol 2005;23:3086-3093. [PubMed]
66. Kokudo N, Imamura H, Sugawara Y, et al. Surgery for multiple hepatic colorectal metastases. J Hepatobiliary Pancreat Surg 2004;11:84-91. [PubMed]
67. Weber SM, Jarnagin WR, DeMatteo RP, Blumgart LH, Fong Y. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 2000;7:643-650. [PubMed]
68. Headrick JR, Miller DL, Nagorney DM, et al. Surgical treatment of hepatic and pulmonary metastases from colon cancer. Ann Thorac Surg 2001;71:975-979, discussion 979-980. [PubMed]
69. Regnard JF, Grunenwald D, Spaggiari L, et al. Surgical treatment of hepatic and pulmonary metastases from colorectal cancers. Ann Thorac Surg 1998;66:214-218, discussion 218-219. [PubMed]
70. Elias D, Sideris L, Pocard M, et al. Results of R0 resection for colorectal liver metastases associated with extrahepatic disease. Ann Surg Oncol 2004;11:274-280. [PubMed]
71. Carpizo DR, Are C, Jarnagin W, et al. Liver resection for metastatic colorectal cancer in patients with concurrent extrahepatic disease: results in 127 patients treated at a single center. Ann Surg Oncol 2009;16:2138-2146. [PubMed]
72. Giacchetti S, Itzhaki M, Gruia G, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 1999;10:663-669. [PubMed]
73. Kemeny NE, Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2009;27:3465-3471. [PubMed]
74. Adam R, Pascal G, Castaing D, et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg 2004;240:1052-1061, discussion 1061-1064. [PubMed]
75. Gallagher DJ, Zheng J, Capanu M, et al. Response to neoadjuvant chemotherapy does not predict overall survival for patients with synchronous colorectal hepatic metastases. Ann Surg Oncol 2009;16:1844-1851. [PubMed]