Liver resection for colorectal cancer metastases

Questions

1. Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)?
2. What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy (“conversion”)?
3. What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy?

Perspectives

Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%–10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required.

Methodology

Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline.

Practice Guideline

These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent.

• 1(a). Patients with liver and lung metastases should be seen in consultation with a thoracic surgeon. Combined or staged metastasectomy is recommended when, taking into account anatomic and physiologic considerations, the assessment is that all pulmonary metastases can also be completely removed. Furthermore, liver resection may be indicated in patients who have had a prior lung resection, and vice versa.
• 1(b). Routine liver resection is not recommended in patients with portal nodal disease. This group includes patients with radiologically suspicious portal nodes or malignant portal nodes found preoperatively or intraoperatively. Liver plus nodal resection, together with perioperative systemic therapy, may be an option—after a full discussion with the patient—in cases with limited nodal involvement and with metastases that can be completely resected.
• 1(c). Routine liver resection is not recommended in patients with nonpulmonary ehms. Liver plus extrahepatic resection, together with perioperative systemic therapy, may be an option—after a full discussion with the patient—for metastases that can be completely resected.
• 2(a). Perioperative chemotherapy, either before and after resection, or after resection, is recommended in patients with resectable liver metastatic disease. This recommendation extends to patients with ehms that can be completely resected (R0). Risks and potential benefits of perioperative chemotherapy should be discussed for patients with resectable liver metastases. The data on whether patients with previous oxaliplatin-based chemotherapy or a short interval from completion of adjuvant therapy for primary crc might benefit from perioperative chemotherapy are limited.
• 2(b). Liver resection is recommended in patients with initially unresectable metastatic liver disease who have a sufficient downstaging response to conversion chemotherapy. If complete resection has been achieved, postoperative chemotherapy should be considered.
• 3. Surgical resection of all lesions, including lesions with rcr, is recommended when technically feasible and when adequate functional liver can be left as a remnant. When a lesion with rcr is present in a portion of the liver that cannot be resected, surgery may still be a reasonable therapeutic strategy if all other visible disease can be resected. Postoperative chemotherapy might be considered in those patients. Close follow-up of the lesion with rcr is warranted to allow localized treatment or further resection for an in situ recurrence.

     

Lymphatic dissemination of hepatic metastases. Implications for the follow-up and treatment of patients with colorectal cancer

Hepatic spread of colorectal cancer is a prominent cause of treatment failure, but selected patients with liver metastases may attain long-term palliation or cure with liver resection. A review of the records of 81 patients seen at the National Cancer Institute for treatment of colorectal hepatic metastases revealed 7 instances of metastases discovered at operation within the hepatic lymphatic drainage in the absence of other extrahepatic tumor. These patients were studied with reference to location and stage of the primary colon cancer and location of metastases at the time of planned liver resection. All seven patients had their extrahepatic lymphatic disease limited to nodes draining the liver, implicating lymphatic dissemination from hepatic metastases as the mechanism of tumor spread. This pattern of spread rendered these patients unresectable for cure. If lymphatic metastases occur from hepatic tumor this implies a need for frequent and thorough follow-up of patients following resection of a primary colon cancer, and indicates urgency in treatment of liver metastases.     

Surgical resection of pulmonary metastases from colorectal cancer. 10-year follow-up

Pulmonary resection of metastatic lesions from colorectal cancer was performed in 62 patients, and their cumulative 5-year and 10-year survival rates were 42% and 22%, respectively. The overall median survival was 24 months. The survival curve decrease even after 5 years after pulmonary resection; four of 13 patients who survived more than 5 years subsequently died of metastatic disease and only two patients survived more than 10 years. The number and size of the pulmonary metastases were significantly correlated with postthoracotomy survival. Solitary metastases less than 3.0 cm in diameter were good indicators of favorable postthoracotomy survival. There were no significant differences in survival based on Dukes' classification or location of the primary lesion. Sex, age, disease-free interval between the primary tumor and appearance of metastasis, and extent of pulmonary resection had no influence on survival. It is impossible to say from our experience that surgical resection of pulmonary metastases increased the cure rate. Presumably a good 5-year survival rate after thoracotomy would be a reflection of a length bias caused by the biologic behavior of the metastatic pulmonary lesions.     

Liver metastases from colorectal cancer: Technique of liver resection

Liver resection has become standard for the treatment of metastatic colorectal cancer (CRC): anterior approach, hanging manoeuvre, or total vascular exclusion techniques as well as 3‐dimensional imaging enable safe resections even in difficult cases. Furthermore, modern chemotherapy, portal vein embolization/ligation, and two‐stage procedures increase the resectability of metastasis, and repeat resections are feasible for recurrence. In addition to characteristics of the primary, CEA, extent of metastasis, resection margins, and extrahepatic disease, hilar lymph node metastases appear prognostic. J. Surg. Oncol. 2013;107:579–584. © 2012 Wiley Periodicals, Inc.     

Combined adjuvant therapy of radically operated colorectal cancer patients

Summary Seventy-three patients with Dukes' B₂ and C colorectal cancer were randomized to adjuvant therapy after radical surgery. One group was treated with chemotherapy either alone or in combination with radiotherapy (RC). The second group was treated by chemotherapy (with or without radiotherapy) plus MER/BCG (RCM). In patients with Dukes' C disease, the survival at 54 months and the disease-free interval up to 24 months were significantly better in the RCM than in the RC subgroup. There were no significant differences in the survival and disease-free interval between RC- and RCM-treated patients with Dukes' B₂ disease. Entry of additional patients and further follow-up are needed before we can decide whether the combination of RCM increases the cure rate in Dukes' C cancer or merely delays recurrence and prolongs survival. Reprint request should be addressed to E. Robinson, Professor and Head, Department of Oncology     

Levels of serum cathepsin L and several glycosidases in patients operated for colorectal cancer.

The activities of several glycosidases and cathepsin L were determined in the blood serum of a control group of ten healthy humans in comparison with a group (group I: 32 subjects) of preoperative colorectal cancer patients (1 week before surgical exeresis) and with another two groups: group II, comprising 18 operated subjects (1 week after surgery), and group III, of 15 operated subjects (4 months after surgery). All subjects were 48-88 years old. Both 'enzyme activity' and 'specific activity' determinations of serum beta-galactosidase, alpha-L-fucosidase and cathepsin L revealed peculiar profiles that differed from one another. Control values differed from those of some stages of the pathological groups, but not of others. These values were compared also with the levels of total, lipid- and glycoprotein-associated serum sialic acid. The usefulness of some assays (especially cathepsin L activity measurement) in the follow-up of the health status of humans operated for colorectal cancer is discussed.     

结直肠癌肝转移的术前化疗

结直肠癌在西方国家占肿瘤患者死亡的第2位,发病率为56.1/10万。我国结直肠癌发病率约为20.6/10万,占肿瘤患者死亡的第5位。Parkin等[1]报道,2002年,全世界新诊断结直肠癌为l 020 000例,占发病率第3位,死亡529 000例,占死亡率第4位。     

Endoscopic follow-up in resected colorectal cancer patients

Patients resected for colorectal cancer are at risk for anastomotic recurrence, for adenomatous polyps and for metachronous cancer. The present retrospective study was conducted to evaluate the incidence of neoplasms of the colon, both metachronous or recurrent, in 322 patients. They were observed and resected for colorectal cancer between 1970 and 1988, with complete staging, and all agreed to be included in a follow-up program (median followup: 105 months). All the patients were submitted to colonoscopy once yearly for the first 5 years and then every 2 years. Anastomotic recurrence was observed in 22 of the 253 patients who underwent resection for rectal or sigmoid adenocarcinoma (8.7%). Sixteen of these patients were submitted to a second curative resection with a median survival of 35 months; the median survival was 6 months in the 6 patients who could not undergo this operation (p=0.0018). Metachronous adenomas of the residual colon were found in 24 patients and metachronous cancers in 5 at Stage A, according to Dukes' classification. In conclusion, a regular colonoscopic surveillance in patients resected for colorectal cancer is justified for early detection and potential resection of anastomotic recurrences, new primary cancer and adenomatous polyps. In patients resected for rectal or sigmoid carcinoma, a sigmoidoscopy should be performed every 6 months for the first 2 years for the early detection of anastomotic recurrences. In all cases, a colonoscopy should be performed every 5 years after surgery to detect metachronous lesions. Before surgery, a "clean colon" should always be established to detect possible synchronous lesions.     

Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer.

PURPOSE: The outcome of patients with colorectal cancer is more favorable when the tumor exhibits high-frequency microsatellite instability (MSI). Although associated with earlier-stage tumors, MSI has been proposed as an independent predictor of survival. We tested the prognostic value of MSI in a large series of patients diagnosed with colorectal cancer in the last decade. EXPERIMENTAL DESIGN: The survival of 893 consecutive patients with colorectal cancer characterized by microsatellite status was analyzed. The 89 (10%) patients with MSI cancer were classified according to tumor mismatch repair (MMR) defect, MMR germ-line mutation, hMLH1 and p16 promoter methylation, BRAF and K-ras mutations, and frameshifts of target genes. RESULTS: The colorectal cancer-specific survival was significantly (P = 0.02) better in patients with MSI cancer than in those with stable tumor (MSS). MSI did not predict a significantly lower risk of cancer-related death if tumor stage was included in the multivariate analysis [hazard ratio, 0.72; 95% confidence interval (95% CI), 0.40-1.29; P = 0.27]. Instead, MSI was strongly associated with a decreased likelihood of lymph node (odds ratio, 0.31; 95% CI, 0.17-0.56; P < 0.001) and distant organ (odds ratio, 0.13; 95% CI, 0.05-0.33; P < 0.001) metastases at diagnosis, independently of tumor pathologic features. Molecular predictors of reduced metastatic risk, and then of more favorable prognosis, included TGFbetaRII mutation for all MSI tumors, hMSH2 deficiency for hereditary non-polyposis colorectal cancer, and absence of p16 methylation for sporadic hMLH1-deficient cancers. CONCLUSIONS: Tumor MSI is a stage-dependent predictor of survival in patients with colorectal cancer. The decreased likelihood of metastases in patients with MSI cancer is associated with specific genetic and epigenetic changes of the primary tumor.     

Neoadjuvant chemotherapy for patients with liver metastases from colorectal cancer

Colorectal cancer is the second most common type of cancer in industrialized countries. Despite improved resection procedures and optimized adjuvant chemotherapy, local or distant recurrences occur in 22-25% of patients with stage II/III colon cancer. Approximately 30% of patients have advanced disease at presentation. The liver is the most common site of colorectal metastases and, interestingly, 20-30% of patients with colorectal cancer have liver-only metastases. The combined modality of chemotherapy and surgery increases overall survival and the chance of cure for metastatic patients, even if there is no agreement in terms of the best schedule and how long the treatment must last. In this paper, we review the role and the rationale of neoadjuvant chemotherapy within a multimodal approach, and discuss remaining questions and future directions.     

乳腺癌术后骨转移回顾性分析

目的 分析乳腺癌术后骨转移的临床特征.方法 对407例原发乳腺癌术后发生骨转移的情况进行回顾性分析.结果 50例患者术后发生骨转移.这50例患者中,术后30个月内发生骨转移的病例占54.0%,5年内骨转移发生率为76.0%,发病年龄≤50岁的占60%.病理类型以浸润性导管癌为主的占82.0%.骨转移部位最多发生在脊柱,以胸椎、腰椎为主.其次是骨盆、肋骨、胸骨、颅骨、下肢骨.乳腺癌术后是否出现骨转移在年龄、腋淋巴结转移、孕激素受体(PR)、癌基因CerbB2表达方面无统计学差异(P＞0.05).但在肿瘤病理类型及雌激素受体(ER)表达方面的差异有统计学意义(P＜0.05).结论 乳腺癌术后30个月内为骨转移高发期,骨转移部位以脊柱及骨盆、肋骨、胸骨多见.乳腺癌术后发生骨转移与年龄、腋淋巴结转移、PR、CerbB2表达方面无关,与肿瘤病理类型、ER有关.     

Liver fatty acid-binding protein is a new prognostic factor for hepatic resection of colorectal cancer metastases.

BACKGROUND AND OBJECTIVES: Liver fatty acid-binding protein (L-FABP) is reported as a biological marker for enterocytic differentiation. We evaluated the prognostic value of L-FABP expression for patients undergoing hepatic resection of colorectal cancer metastases. METHODS: The study group comprised 68 patients who underwent hepatic resection for colorectal cancer metastases between 1982 and 1996 at Niigata University Medical Hospital, Niigata, Japan. L-FABP expression was immunohistochemically studied in metastatic liver tumors and their primary colorectal cancers. The relationship between L-FABP expression and patient prognoses was statistically analyzed. RESULTS: L-FABP was positively stained in 56% (38/68) of liver metastases from colorectal cancers and in 56% (38/68) of their primary tumors. Of 68 cases, 54 (79%) showed similar immunohistochemical findings between primary and metastatic tumors. Patients with L-FABP-positive liver metastases showed better prognosis than patients with L-FABP-negative metastases (P = 0.046). L-FABP expression in primary colorectal cancers more significantly (P = 0.009) affected long-term survival after hepatic surgery. Multivariate analysis revealed that the prognostic effect of L-FABP expression in primary colorectal cancers was exerted independently and that its impact was larger than conventional pathological prognosticators. CONCLUSIONS: L-FABP expression is suitable for use as a new presurgical prognostic factor for patients undergoing hepatic surgery for colorectal cancer metastases.     

Antipyrine metabolism in patients with liver metastases from colorectal cancer.

BACKGROUND. The influence of cancer on antipyrine metabolism is under debate. METHODS. To assess the functional activity of a liver with solid metastases from primary colorectal cancer, antipyrine metabolism was studied after the drug was administered orally (18 mg/kg body weight) to 55 healthy volunteers, 62 patients with well-compensated cirrhosis, and 42 patients with small (Class A) or massive (Class B) metastatic liver involvement. RESULTS. In patients with cancer, antipyrine clearance (0.472 +/- 0.177 ml/min/kg) was similar to that in healthy volunteers (0.456 +/- 0.198 ml/min/kg) and significantly higher than in those with cirrhosis (0.259 +/- 0.17 ml/min/kg, P less than 0.001). There was no difference in antipyrine pharmacokinetics between Class A and B involvement. In the entire population, antipyrine clearance was correlated with serum albumin levels (r = 0.294, P = 0.0002) and prothrombin activity (r = 0.416, P = 0.001). This positive correlation was not present when only the neoplastic group was considered. No correlation was found between antipyrine clearance and alkaline phosphatase levels. In patients with cancer, no relationship was found between antipyrine clearance and carcinoembryonic antigen and lactic dehydrogenase levels. CONCLUSIONS. These results show that patients with livers largely replaced by solid metastases are able to metabolize antipyrine to the same extent as healthy subjects.     

Preoperative ultrasonography screening for liver metastases of patients with colorectal cancer

The clinical value of preoperative ultrasonography in screening for synchronous liver metastases was prospectively evaluated in 338 patients with colorectal cancer. Synchronous liver metastases were observed at laparotomy in 11.5% (39/338) of the patients. The liver metastases had been found by preoperative ultrasonography in 30 patients and missed in nine. The overall accuracy rate, sensitivity and specificity, and the positive and negative predictive values of this modality were 0.970, 0.769, 0.997, 0.968 and 0.971, respectively. In detecting liver metastases, the results were superior to those of biochemical blood tests and measurements of carcinoembryonic antigen serum levels. The accuracy of the ultrasonography was also superior to that of these other tests combined. The results indicate ultrasonography to be an indispensable preoperative examination for patients with colorectal cancer.