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Purpose: This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment., Methods: Twenty patients were enrolled. None had prior adjuvant chemotherapy. Cetuximab was added to a FOLFOX7 backbone and administered at 500 mg/m 2 every 14 days with dose reductions to 400 and 300 mg/m 2 in the event of toxicity. In the absence of toxicity, dose-escalations to 600, 700, and 800 mg/m 2 were allowed. The mean dose of cetuximab (mg/m 2 /week) throughout the study was 289 mg/m 2 . Paired samples were collected for correlative studies, where feasible., Results: We assessed the conversion rates from unresectable to resectable in hepatic-only, KRAS exon 2 WT mCRC. Seventeen of 20 patients undergoing chemotherapy were considered resectable by imaging criteria; R0 resection was achieved in 15/20 patients. Molecular profiling revealed heterogeneity between patients at the gene-expression, pathway signaling, and immune-profile levels., Conclusions: Although 15/20 (75%) converted to R0 resection, by 2 years, 10/15 R0 resections had recurred. Therefore, chemotherapy plus cetuximab is of limited long-term benefit in this setting. ctDNA analysis may guide additional therapy including immunotherapy., (© 2022 Wiley Periodicals LLC.)

Hepatic resection for colorectal metastases, limited to the liver, has become the standard of care, and currently remains the only potentially curative therapy. Numerous single institutional reports have demonstrated long-term survival and there are no other treatment options that have shown a survival plateau. However, curative resection is possible in less than 25% of those patients with disease limited to the liver, which translates into only 5-10% of the original group developing colorectal cancer. To increase the number of patients who could benefit from hepatic resection, the last decade has seen considerable effort being directed towards novel approaches to permit curative hepatic resection such as: neoadjuvant systemic and regional chemotherapy, pre-operative portal vein embolization for hypertrophy of future liver remnant, staged hepatic resection and radio frequency ablation combined with resection for addressing multiple bilobar metastases. This article reviews development of these innovative multidisciplinary modalities and the aggressive surgical approach that has been adopted to extend the frontiers of surgical therapy for colorectal hepatic metastases.

Hepatic resection for colorectal metastases, limited to the liver, has become the standard of care, and currently remains the only potentially curative therapy. Numerous single institutional reports have demonstrated long-term survival, and there are no other treatment options that have shown a survival plateau. However, curative resection is possible in less than 25% of patients with disease limited to the liver, which consequently translates into only 5% to 10% of the original group developing colorectal cancer. To increase the number of patients who could benefit from hepatic resection, the last decade has seen considerable effort directed towards the following areas, (1) refining prognostic factors that would improve patient selection, (2) advancements in surgical technique such as, use of intraoperative ultrasonography, controlling hemorrhage through use of vascular clamping techniques supplemented with low central venous pressure anesthesia, availability of novel devices for parenchymal transection, and controlled anatomic hepatectomy with Glissonian technique, and (3) novel approaches to permit curative hepatic resection such as, preoperative portal vein embolization for hypertrophy of future liver remnant and staged hepatic resection. This article reviews development of these innovative multidisciplinary modalities and the aggressive surgical approach that has been adopted to extend the frontiers of surgical therapy for colorectal hepatic metastases.

Background: The relationship between volume and outcome has been established in the literature for several complex surgical procedures. Improved outcome has been suggested at high-volume hospitals or with high-volume surgeons., Methods: The objective of this study was to evaluate the experience of a low-volume hospital with major liver resections. The setting of the study was a community-based teaching hospital with a surgical residency training program., Results: A total of 46 major liver resections were performed between January 1992 and December 2002. Procedures performed were hepatic lobectomies (n = 15; right, n = 11; left, n = 4), trisegmentectomies (n = 5; right, n = 3; left, n = 2), segmentectomies (n = 16; left lateral, n = 12; right posterior, n = 4), and wedge resections (n = 10). Operations were performed by 14 different surgeons; however, 23 operations were performed by 1 surgeon. Sixteen patients (34%) developed 23 complications. The average length of hospital stay was 9.7 days. There were no 30-day postoperative mortalities. Out of 46 patients who underwent major liver resection over the last 10 years, 13 patients are still alive. Overall survival ranged from 3 to 84 months, with a median survival of 30.6 months. The actual 5-year survival was 36% (8 of 22) for all patients operated on >5 years ago, and the actual 2-year survival was 61% (20 of 33)., Conclusions: Major liver resection can be performed safely with low rates of morbidity and operative mortality with careful selection of patients at a low-volume community-based teaching hospital.

Surgical resection for selected patients with hepatic metastases from colorectal cancer can cure approximately one-fourth of these patients. The addition of regional chemotherapy as an attempt to improve this statistic has been extensively investigated in clinical trials. As part of a multidisciplinary educational program, a series of debates on various topics in oncology are held at the Roswell Park Cancer Institute, Buffalo, New York, involving the medical, surgical, and radiation oncology departments. One such debate focused on the use of regional chemotherapy after potentially curative resection of hepatic metastases from colorectal cancer. The representative medical and surgical oncology fellows (N.I.K. and B.P.M.), with guidance from their respective mentors (C.G.L., J.F.G., and N.J.P.), presented concise reviews from the literature arguing for and against the use of regional chemotherapy in this setting. They appear as Parts 1 and 2 in this article. This exercise is purely educational and does not in any way reflect the opinion or the clinical practice of the authors. ., (Copyright 2002 Wiley-Liss, Inc.)

The survival of patients undergoing liver resection for colorectal metastases is poor in the presence of extrahepatic disease. Therefore identification of periportal and celiac lymph node metastases is central to proper patient selection. In this study we examined the technique of intraoperative hepatic lymphatic mapping with isosulfan blue dye in humans. Intrahepatic dye injection was performed in patients undergoing surgical exploration for colorectal liver metastases. The location of all blue-stained lymphatics and lymph nodes was recorded. All stained and unstained lymph nodes were biopsied for pathologic examination. Thirteen intraoperative lymphatic mapping procedures were performed in 11 patients. A blue-stained lymphatic was visualized in 11 of 13 injections (85%). A blue lymph node was visualized in seven of 13 injections (54%). Three of the seven blue nodes (43%) were not detected by the surgeon before the mapping procedure. There were no complications associated with the intrahepatic dye injections. All biopsied lymph nodes were negative for metastatic tumor. We conclude that intraoperative hepatic lymphatic mapping with isosulfan blue dye is a simple, rapid, and safe technique in humans. It may serve as an adjunct to random lymph node biopsy for the identification of periportal and celiac nodal metastases before liver resection in patients with metastatic colorectal carcinoma.

The status of the porta hepatis lymph nodes in patients with hepatic metastases from colorectal cancer affects their prognosis and management. Lymphatic mapping with isosulfan blue dye is well established in breast cancer and melanoma. An animal model consisting of three dogs receiving general anesthesia was utilized. Each dog underwent a laparotomy and increasing doses of isosulfan blue dye were injected into the right medial segment of the liver. Intraoperatively, the presence of blue dye in the porta hepatis region was determined and the lymph node identified. Continuous physiological monitoring was performed. Serum determination of liver function tests, amylase levels, and white blood cell count were performed preoperatively and on postoperative days 1, 2, 4, and 7. The animals were sacrificed on day 7. A portal lymph node was identified in each case and there was no perioperative morbidity or mortality. There were no significant alterations in blood pressure or heart rate in the animals. There was a dose-responsive decrease in the O2 saturation as measured by transcutaneous monitoring, but arterial blood gas analysis showed that pO2 levels remained stable. There were no significant changes in the liver function tests, amylase levels, or white blood cell counts. There was a small increase in alkaline phosphatase, which normalized by postoperative day 7. Hepatic injection of isosulfan blue dye appears to be safe and effective in identifying porta hepatis lymph nodes in the animal model and sets the basis for further study in human subjects.

Background: The proximity of a hepatic tumor to major vessels and bile ducts limits the use of cryotherapy because of the potential damage to these structures. However, the effects of cryotherapy on major hepatic vessels and bile ducts are not well understood., Methods: Nine pigs underwent laparotomy and intraoperative ultrasound to identify hepatic vessels larger than 5.0 mm. Cryotherapy consisting of two freeze-thaw cycles was performed, incorporating the identified vessel. In four pigs the Pringle maneuver was performed to determine the effects of partial vascular occlusion on the hepatic parenchyma and structures undergoing cryotherapy. The animals were sacrificed 30 days postoperatively, and the livers were processed for histologic examination., Results: Eight of the nine livers had vessels larger than 5.0 mm incorporated into the iceball, with all vessels having evidence of infarction but remaining patent. All the livers had major bile ducts incorporated in the iceball, with eight having evidence of infarction. The Pringle maneuver had no real effect on the degree of vessel and bile duct infarction. There was no incidence of hepatic bleeding, liver fracture, bile leak, or hemobilia., Conclusions: Cryotherapy results in the infarction of major hepatic vessels and bile ducts but can be safely performed in the porcine model. Proximity of tumors to major vascular and biliary structures may not be a contraindication to the use of cryotherapy. Further studies are necessary to determine whether cryotherapy can be used in humans.

Background: Intrahepatic and extrahepatic factors are utilized by the surgeon in the decision-making process for the performance of hepatic resection for patients with colorectal metastases. Accurate preoperative and intraoperative staging are mandatory to avoid unnecessary surgery. In this report the intraoperative determinants of hepatic unresectability were evaluated., Methods: This was a retrospective review of medical records from January 1985 to March 1996 of 62 patients with colorectal hepatic metastases who at the time of exploratory laparotomy were deemed to have unresectable disease based on intrahepatic or extrahepatic factors. The stage of the primary tumor, disease free interval, preoperative carcinoembryonic antigen, computed tomography portography, intraoperative ultrasound, and assessment of intrahepatic and extrahepatic tumor extension were evaluated., Results: Intraoperative determination of the extent of required hepatic resection, including trisegmentectomy (9 patients; 15%) and total hepatectomy (10 patients; 16%), accounted for the majority of unresectable patients. Patients with > 4 metastases (8 patients; 13%) and satellitosis (6 patients; 10%) accounted for 23% of unresectable patients. Four patients had extensive nonmalignant hepatic parenchymal disease precluding resection. Thorough abdominal exploration revealed extrahepatic disease in 13 of 62 patients (21%). Routine periportal/celiac lymph node biopsies revealed metastases in an additional 12 patients (19%), 7 of whom (11%) had only periportal/celiac lymph node metastases., Conclusions: A meticulous abdominal exploration prior to hepatic resection for patients with colorectal metastases is essential to identify those patients with extrahepatic disease. Periportal and celiac lymph nodes commonly are involved by tumor. Therefore, routine periportal/celiac lymph node biopsies should be performed in the absence of other extrahepatic disease.

Cryosurgery of hepatic metastases from colorectal carcinoma is a form of local therapy for unresectable disease. After curative resection, failures occur in the liver, and at extrahepatic sites. This pilot study evaluated the toxicity and tolerance to cryotherapy and intraoperative chemotherapy for unresectable hepatic metastases from colorectal cancer. If after exploratory celiotomy for potential curative resection of hepatic metastases the patient was deemed unresectable because of location and/or number of lesions, cryosurgery and intraoperative chemotherapy with systemic 5-fluorouracil 600 mg/m2 and leucovorin 500 mg/m2 was performed. Four patients were treated with cryochemotherapy. All patients developed toxicity. Two patients developed grade II leukopenia on Postoperative Days 2 and 12, and grades II and III diarrhea on Postoperative Days 5 and 7, respectively. Grade III hyperbilirubinemia and thrombocytopenia occurred in one patient on Postoperative Days 3 and 7. Acute respiratory distress syndrome, postoperative ileus, and grade II mucositis occurred in one patient each. All patients had delays and dose reductions on their subsequent chemotherapy treatments secondary to toxicity. Two patients had disease progression, one had stable disease. and one is "disease free." Combining the tumoricidal effects of chemotherapy and cryosurgery is in theory a good concept. However, the toxicity of 5-FU and leucovorin is enhanced by this approach.

A major stumbling block in the study of human colorectal cancer metastasis has been the lack of an effective in vivo model producing liver metastasis on a consistent basis. In this study surgical specimens of colorectal carcinoma were implanted in scid mice and studied for engraftment, growth, and the capacity to produce hepatic metastases. Human colorectal cancers would engraft and propagate in the subcutis and intraperitoneally. Sporadic metastasis to the liver occurred in 3 of 54 (6%) animals with cancer implanted subcutaneously. Liver metastasis occurred in 24 of 25 (96%) mice with cancer implanted in the gonad fat pad. Tumor growth to extremely large volumes subcutaneously did not enhance metastatic potential, and neither did longer term growth in the subcutaneous space. Tumor placed in the gonad fat required no special manipulation and in most cases a single piece of solid tumor was implanted. In situ hybridization confirmed the persistence of the human tissue in these metastasizing tumors. Our model will allow for the study of the processes involved in metastasis of solid tumors, characterization of differences between the primary tumor and the metastatic one, and evaluation of possible therapeutic modalities.

Purpose: It is commonly believed that the right lobe of the liver is the most frequent site of colorectal liver metastases. However, direct evidence for this is lacking in the literature. This study was designed to document and evaluate the pattern of liver metastases according to liver segments., Methods: A retrospective medical records review of 270 patients with hepatic metastases from colorectal adenocarcinoma was performed to determine the pattern of metastases according to Couinaud's segments. There was operative confirmation of liver metastases in 202 patients (75 percent). A total of 1,166 segments were involved with liver metastases and were used in this analysis. Segment I was excluded from calculations because of its dual blood supply. When groups contained different numbers of Couinaud's segments an appropriate correction was made in the statistical comparison., Results: There were 736 (63 percent) right lobe segments (V, VI, VII, VIII) and 430 (37 percent) left lobe segments (II, III, IV) involved with metastases (P < 0.001). Of 430 left lobe segments, 298 (69 percent) involved the left lateral segment (II, III) and 132 (31 percent) involved the medial segment (IV) of the left lobe (P = 0.25). When evaluating patients with 4 or less segments involved, there were 258 right lobe segments (75 percent) and 88 left lobe segments (25 percent) involved with metastases (P < 0.0001). Of 88 left lobe segments with 4 or less segments involved, there were 68 segments (77 percent) involving the left lateral segment and 20 segments (23 percent) involving the medial segment of the left lobe (P = 0.035). All of these relationships were statistically independent of the primary tumor site., Conclusions: We have documented an overall predominance of right hepatic lobe metastases independent of site of the primary colorectal carcinoma. However, when metastases occurred in the left lobe, the left lateral segment (II, III) was more commonly affected than the medial segment (IV), but this difference was statistically significant only when there were four or less segments involved with liver metastases.

From April 1975 to January 1982, 97 patients with greater than or equal to 50% of the liver involved with metastasis from colorectal carcinoma underwent hepatic artery ligation. The purpose was to evaluate median survival times in relation to performance status, synchronous intraabdominal metastasis, pulmonary metastasis, liver function tests (alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), total bilirubin, and Dukes' staging. Results reveal that for performance status 0 to 1 (normal or symptoms, but ambulatory), median survival time was 12.3 months; status 2 to 3 (in bed less than or greater than 50% of time), 8.3 months; status 4 (100% bedridden), 2.6 months, (P less than 0.01). Median survival time in patients with only intrahepatic metastasis was 10 months versus 7 months for synchronous intraabdominal metastasis (P less than 0.01). For 20 patients with pulmonary metastasis undergoing hepatic artery ligation, the median survival time was 8.8 months (P less than 0.05). The median survival time in patients whose alkaline phosphatase was 2 times normal was 12.4 months, whereas, if alkaline phosphatase was 2 times to 4 times or greater than 4 times normal, median survival times were 7.1 and 6.9 months, respectively (P less than 0.01). Factors that adversely affect survival for hepatic artery ligation are extrahepatic metastasis, poor performance status, and elevated liver function tests (alkaline phosphatase 2 times normal). The overall median survival time in this study is 9.5 months with certain subgroups achieving 12.4 months' survival.

After an explanation of alternative treatment modalities, 30 patients with unresectable liver metastases from colorectal adenocarcinoma chose to have no treatment. Fourteen patients (47 percent) had synchronous liver metastases and 16 (53 percent) had metachronous lesions. Thirteen of the 30 patients (43 percent) had histologic documentation of liver metastases, with the remaining 17 patients diagnosed by liver scan, ultrasonography, or computerized axial tomography. Twenty-four of 30 patients (80%) had less than 25 percent liver involvement (Stage I), 23 of 24 patients had alkaline phosphatase levels less than twice normal, and 20 of 24 patients were asymptomatic from their liver metastases. The remaining six patients had liver stages II or III at the time of diagnosis. Overall mean survival of the 30 reported patients with untreated metastatic colorectal cancer to liver is 16 months (range, 2 to 58 months; median survival, 12 months).

Surgical results were analyzed in 36 patients who had undergone hepatic resection for metastases from colorectal carcinoma. Survival was not altered by the type of surgical resection nor in the presence of solitary compared with multiple lesions. No difference in survival from the time of liver resection was noted in patients staged as Dukes' B and Dukes' C (metachronous liver metastasis) in comparison to patients who presented with synchronous liver metastases. Overall median survival was 22 months with no 5 year survivors to date. There is a tendency for recurrence to occur in extrahepatic sites, which emphasizes the need for an effective chemotherapeutic agent.

A retrospective review was undertaken to determine the influence of preoperative alkaline phosphatase levels on the prognosis of patients who had undergone resection of liver metastasis from colorectal adenocarcinoma at Roswell Park Memorial Institute. From March 1967 to March 1985, 26 patients underwent laparotomy who were thought to have solitary liver metastasis. Twenty of these patients were divided into two groups: group A consisted of seven patients who survived at least 24 months without any evidence of disease and were free of disease at the time of this report. Group B consisted of 13 patients who recurred or died from metastases following liver resection. The preoperative levels of alkaline phosphatase clearly showed that an elevated level before surgery was associated with a poor prognosis in the majority of cases. In group A only one of seven patients had an elevated level where seven of 13 patients in group B had elevated preoperative alkaline phosphatase levels. In conclusion, preoperative alkaline phosphatase levels may be helpful in determining the prognosis of patients considered for curative resection of solitary liver metastasis from colorectal carcinoma.

A proposed classification system for liver metastasis from colorectal carcinoma is presented. This proposed system utilizes the prognostic factors of the extent of hepatic involvement by metastasis at the time of laparotomy, performance status, preoperative serum alkaline phosphatase level, and the presence or absence of extrahepatic intraabdominal disease at the time of laparotomy. Because of the several different modes of treatment for liver metastasis from colorectal carcinoma, it is necessary that a liver classification system be adopted so that different treatment groups will be comparable. The proposed system utilizes the extent of hepatic involvement by metastasis at laparotomy with a division into three subsets of patients described by a Roman numeral. Roman numeral I represents less than or equal to 25 per cent involvement of the liver by metastasis; Roman numeral II represents greater than 25 per cent but less than or equal to 50 per cent involvement by liver metastasis, and Roman numeral III represents greater than 50 per cent involvement by liver metastasis. An Arabic subscript number is used to describe the patients' performance status. Alkaline phosphatase levels are described by a subscript letter with a representing less than two times normal alkaline phosphatase, b representing greater than two times, but less than four times normal levels, and c representing greater than four times normal levels. At the time of laparotomy extrahepatic intra-abdominal disease is represented by the superscript letter E.