Liver resection after downstaging with neoadjuvant chemotherapy for "unresectable" colorectal metastases

Hepatic resection is the only treatment that offers a chance of long-term survival in patients with metastases from colorectal cancer. Nevertheless, a curative resection can be performed in only 10-20 per cent of patients: multiple bilobar metastases or "unresectable" disease are the greatest obstacles to surgical radicality. Techniques such as preoperative portal embolisation, preoperative portal ligation, two-stage hepatectomy, and neoadjuvant chemotherapy, have extended the possibility of liver surgery to patients with advanced metastatic colorectal cancer. The outcomes of two patients treated successfully with neoadjuvant chemotherapy (one case with FOL-F-OX, and one with FOL-F-IRI) followed by liver resection were analyzed. In both patients neoadjuvant chemotherapy enabled a curative liver resection to be performed without significant complications. In some patients, neoadjuvant chemotherapy permits the "downsizing" of metastatic disease to such an extent that a surgical approach proves feasible. This advance can dramatically improve the prognosis of patients with multiple or unresectable liver metastases from colorectal cancer.     

Neo-adjuvant therapy improves resectability rates for colorectal liver metastases

PURPOSE: Liver resection improves survival in selected patients with colorectal liver metastases. However, the majority of patients with colorectal liver metastases have inoperable disease at presentation. Neo-adjuvant therapy (systemic or regional chemotherapy and interstitial laser therapy) used singly or in combination may convert a selected group of patients with irresectable liver metastases into an operable state. PATIENTS AND METHODS: We report a series of patients with initially inoperable multiple colorectal liver metastases who became operable after neo-adjuvant therapy. Operability was defined as unilateral disease limited to the liver. Twelve patients (7 female, 5 male, median age 57 years, range 38-69 years) with multiple inoperable colorectal liver metastases (8 synchronous, 4 metachronous) were initially treated with systemic chemotherapy (n = 7), hepatic arterial chemotherapy (n = 2) and chemotherapy plus interstitial laser therapy (n = 3). RESULTS: In all cases, a significant response was achieved which enabled subsequent liver resection to be undertaken. There was only one postoperative complication (8%) and no peri-operative deaths. 3 patients were operated on within the last 12 months and are still alive. Of the remainder, 1 died within 1 year with recurrent disease. The remaining patients have a median survival of 2.5 years, range 1.39-4 years. CONCLUSIONS: These results are similar to those reported for patients undergoing resection for operable metastases without neo-adjuvant therapy. Aggressive multimodality treatment of colorectal liver metastases in specialised centres may improve the resectability rates and survival in a selected group of patients.     

Surgical Therapy for Colorectal Metastases to the Liver

Colorectal cancer is the fourth most common type of cancer in the West and the second leading cause of cancer-related deaths in the United States. Approximately 35 to 55% of patients with colorectal cancer develop hepatic metastases during the course of their disease. Surgical resection of colorectal liver metastases represents the only chance at potential cure, and long-term survival can be achieved in 35 to 58% of patients after resection. The goal of hepatic resection should be to resect all metastases with negative histologic margins while preserving sufficient functional hepatic parenchyma. In patients with extensive metastatic disease who would otherwise be unresectable, ablative approaches can be used instead of or combined with hepatic resection. The use of portal vein embolization and preoperative chemotherapy may also expand the population of patients who are candidates for surgical treatment. Despite these advances, many patients still experience a recurrence after hepatic resection. More active systemic chemotherapy agents are now available and are being increasingly employed as adjuvant therapy either before or after surgery. Modern treatment of colorectal liver metastasis requires a multidisciplinary approach in an effort to increase the number of patients who may benefit from surgical treatment of colorectal cancer liver metastasis.     

Treatment of recurrent colorectal liver metastases by interstitial laser photocoagulation

BACKGROUND: Hepatic resection improves survival in selected patients with colorectal liver metastases. The treatment of recurrent hepatic metastases after resection is controversial. Interstitial laser photocoagulation, performed under local anaesthesia, offers a minimally invasive option to repeat resection. The first series of patients with recurrent colorectal liver metastases treated with photo- coagulation is reported. METHODS: Nineteen patients (five women and 14 men, median age 57 (range 44-71) years) who developed recurrent colorectal liver metastases after hepatectomy (five with bilateral disease) were treated with photocoagulation between 1993 and 1997. Fifteen patients also received chemotherapy (14 systemic, one hepatic arterial) before photocoagulation. RESULTS: There were no major complications or deaths related to the treatment. Six patients developed minor complications related to the procedure but did not require any form of intervention. Median survival from commencement of photocoagulation was 16 (range 4-36) months. CONCLUSION: Photocoagulation is a safe, minimally invasive therapy that may be used as an adjunct to chemotherapy and repeat resection in the treatment of recurrent colorectal liver metastases, and may lead to improved survival.     

Management of colorectal liver metastases

Hepatic metastases occur in 60% of patients following resection for colorectal cancer. Liver resection is the only curative option, with one third of resected patients alive at five years. In those developing recurrence in the liver following resection, further liver surgery may be curative, with similar 5 years survival rates of about 30%. Until recently surgery was feasible in only 15–25% of patients with colorectal liver metastases. New strategies, such as downstaging chemotherapy, portal vein embolization and two‐stage hepatectomy, may increase the resectability rate by 15%. Earlier detection of liver metastases would increase resectability, although good follow‐up trials are lacking. Once suspected, colorectal liver metastases are staged by spiral CT, CT portography and MRI, which have similar overall accuracies. Mortality following liver resection is less than 5% in major centres, with a morbidity rate of 20% to 50%. Prognostic scoring systems can be used to predict the likely cure rate with resection. Pulmonary metastases occur in 10–25% of patients with resected colorectal cancer, but are limited to the lung in only 2% of cases. In these selected cases surgery provides long‐term survival in 20–40%, and repeat lung resection has shown similar rates. For patients with unresectable disease, chemotherapy and ablation techniques have been demonstrated to prolong survival, although chemotherapy alone has been shown to improve quality of life.     

Strategies to increase the resectability of liver metastases from colorectal cancer

Liver resection can provide long-term survival and cure for patients with colorectal liver metastases but is feasible in only 15-25% of patients. In the last few years several major developments have contributed to increase this resectability rate. Neo-adjuvant chemotherapy can provide response rates as high as 50%, allowing surgery in about 10-15% of patients initially deemed unresectable. Patients requiring extensive liver resections with an anticipated small residual liver volume can undergo portal vein embolization to reduce the risk of postoperative liver failure by inducing hypertrophy of the remnant liver. Extensive bilobar disease can be treated by two-stage hepatectomy, with an interval to allow liver regeneration. Ablation techniques can be combined with hepatic resection to reduce local recurrence from incomplete surgical resection margins or to destroy contralateral tumor deposits. Finally, for patients with tumors involving the inferior vena cava or the hepatic veins, in which conventional resection is not feasible, in situ hypothermia or bench resection with reimplantation are suitable for very selected patients. Downstaging strategies may increase the resectability rate of colorectal liver metastases by over 20%.     

Additive Chemotherapie bei Lebermalignomen zur Verbesserung der Operabilität

Complete tumor resection is the only curative option for patients with colorectal liver metastases. Hepatic resection is frequently not possible for technical reasons: because of large tumors, multiple or bilateral metastases, or tumors that are too close to vessels. In these cases chemotherapy might downstage the tumor volume and facilitate secondary curative resection in patients initially not eligible for curative surgery. Treatment with fluorouracil (5-Fu) alone has resulted in disappointing response rates of about 10-20% in patients with colorectal liver metastases, which make these protocols useless in the neoadjuvant setting. Because regional chemotherapy into the hepatic arteria results in significantly higher response rates (40-50%), some studies have documented some success in secondary curative surgery after regional chemotherapy of initially unresectable colorectal liver metastases. However, regional chemotherapy is invasive and therefore not standard therapy for every patient with colorectal liver metastases. Recently new exciting treatment options have become available for colorectal cancer. Combinations of chemotherapy consisting of irinotecan and 5-Fu/FA or oxaliplatin and 5-Fu/FA result in response rates of 50% and can be considered a new standard first-line chemotherapy for patients with metastatic colorectal cancer. Recently, two encouraging retrospective studies have been published with chronomodulated chemotherapy of oxaliplatin and 5-Fu/FA in the setting of neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases. With this multidisciplinary approach, antitumor activity of chemotherapy appears to be translated into a long-term survival benefit and some patients with initially unresectable colorectal liver metastases can potentially be cured. As a consequence, on the premises of close cooperation between surgeons and internists, more patients with metastatic colorectal cancer will be cured in the future.     

Neoadjuvant chemotherapy as a treatment strategy for multiple bilobar liver metastases from colorectal carcinoma

Hepatic resection remains the only potentially curative therapy for patients with colorectal liver metastases. Because most have multiple bilobar liver metastases, surgical resection is possible in only 25-58% of patients with colorectal liver metastases. Currently, attention is focused on the potential for neoadjuvant chemotherapy to render formerly unresectable patients resectable. The availability of more efficacious chemotherapy agents and an inventive approach to delivery schedules have resulted in an increase in the number of candidates for hepatic resection after neoadjuvant chemotherapy. Although tumor response varies with regimen and/or route of chemotherapy for colorectal liver metastases, with 16-63% tumor response rates, hepatic resection for responders after neoadjuvant chemotherapy gives survival benefits, with 20-48% 5-year survival rates after surgery. Provided that neoadjuvant chemotherapy controls multiple bilobar liver metastases well, aggressive hepatic resection should be considered for patients with those lesions. As a treatment strategy for multiple bilobar liver metastases, neoadjuvant chemotherapy is a useful to increase resection rates and may contribute to the improvement of prognosis in patients with such lesions.     

Clinical significance of and future perspectives for hepatic arterial infusion chemotherapy in patients with liver metastases from colorectal cancer

The most common site of metastases in patients with colorectal cancer is the liver. Hepatic resection is considered to be the treatment of choice for liver metastasis from colorectal cancer; however, hepatic resection can be performed in only 20 or 25 % of all patients. Recurrence develops in the remnant liver or other organs after hepatic resection in over half of all patients with liver-only metastasis. Hepatic arterial infusion (HAI) chemotherapy can provide relatively high concentrations of drugs to microscopic or macroscopic metastases in the liver, with less toxicity than systemic administration. Meta-analyses have shown HAI chemotherapy to have a significantly higher response rate than systemic chemotherapy and its effect on extrahepatic metastases is negligible. HAI chemotherapy provides much better local control of liver metastases from colorectal cancer than systemic chemotherapy. However, well-controlled studies are needed to elucidate the optimal treatment strategies for neoadjuvant and postoperative adjuvant chemotherapy that optimally combine HAI chemotherapy, molecular targeted agents, and systemic chemotherapy such as FOLFOX or FOLFIRI.     

Selection criteria for simultaneous resection in patients with synchronous liver metastasis

HYPOTHESIS: While simultaneous resection has been shown to be safe and effective in patients with synchronous metastasis, neoadjuvant chemotherapy followed by hepatectomy has gradually gained acceptance for both initially nonresectable metastasis and resectable metastasis. The boundary between these treatments is becoming unclear. We hypothesized that factors associated with colorectal cancer may play an important role in the prognosis of patients with synchronous metastasis and may be useful for identifying patients who can be expected to have adequate results following simultaneous resection. DESIGN: Outcome study. SETTING: Tertiary referral center. PATIENTS: From January 1980 to December 2002, 187 patients underwent curative resection for synchronous liver metastasis from colorectal cancer. One hundred forty-two patients received simultaneous resection, 18 underwent staged resection, and 27 underwent delayed hepatic resection. Twenty-one clinicopathological factors were analyzed, and long-term prognosis was assessed. MAIN OUTCOME MEASURES: Prognostic factors and patient survival. RESULTS: There was no in-hospital death. In a multivariate analysis, the factors that significantly affected the prognosis of synchronous metastasis were 4 or more lymph node metastases around the primary cancer (P<.001) and multiple liver metastases (P = .003). In patients with 3 or fewer lymph node metastases around the primary cancer, the 5-year survival rates of those with 1, 2 to 3, and 4 or more liver metastases were 63%, 33%, and 40%, respectively, but these rates were 15%, 22%, and 0%, respectively, in patients with 4 or more lymph node metastases around the primary cancer. CONCLUSIONS: The results support the application of simultaneous resection in patients with 0 to 3 colorectal lymph node metastases. However, in patients with 4 or more colorectal lymph node metastases, biological selection by neoadjuvant chemotherapy may be more suitable.     

胃肠肿瘤根治联合肝移植术治疗晚期胃肠肿瘤并肝脏广泛转移

目的 总结胃肠肿瘤根治联合肝移植治疗晚期胃肠肿瘤并发肝脏多发转移的近期疗效。方法 1例胃癌和2例直肠癌并发肝脏多发转移患者，分别接受胃癌和直肠癌根治、联合原位同种异体肝移植手术，其中1例因肺结核同时行左上肺部分切除术。结果 3例患者无围手术期死亡。随访5-7个月，胃癌患者术后5个月死于肿瘤复发；1例直肠癌并肺结核患者术后7个月死于肝功能衰竭，无肿瘤复发；另1例直肠癌患者已完成3个月化疗，术后半年无复发，肝功能和血常规正常，精神食欲好，已恢复工作。结论 胃肠肿瘤根治联合肝移植为部分晚期肿瘤患者提供了生存的希望，远期效果有待进一步观察。     

Liver resection and transplantation — Therapeutic concepts in surgical treatment of hepatic metastases

Summary Background: Surgical procedures such as liver resection or liver transplantation are the only treatment modalities that provide a chance of cure for patients with liver metastases. Methods: This report reviews results of liver resection and liver transplantation for liver metastases from colorectal cancer and neuroendocrine tumors as compared to the natural course. Results: Overall 5 year survival after curative liver resection for colorectal metastases ranges between 25 and 48%. The operative mortality is between 0 and 5%. Risk factors for tumor recurrence are more or less defined. Reresections of metastases can be performed with comparable mortality rates and results. Liver transplantation for unresectable colorectal metastases offers a median survival of 28 months, but the chance of cure only for individual patients. Exclusion of patients with positive lymph nodes of the primary tumor improves median survival. As there are alternative treatment options for neuroendocrine metastases, indication for liver resection or transplantation is not clearly defined, but the chance of cure by means of surgical treatment should not be missed. Curative resections of neuroendocrine liver metastases can achieve 5-year survival rates of more than 80%. Conclusions: Radical surgical removal of liver metastases from colorectal and neuroendocrine cancer can improve the prognosis for selected patients. Further improval is expected from a multimodal approach.      

Diagnosis and treatment of colorectal liver metastases - workflow

In this review, standards of diagnosis and treatment of colorectal liver metastases are described on the basis of a workshop discussion. Algorithms of care for patients with synchronous / metachronous colorectal liver metastases or locoregional recurrent tumour are presented. Surgical resection is the procedure of choice in the curative treatment of liver metastases. The decision about the resection of liver metastases should consider the following parameters: 1. General operability of the patient (comorbidity); 2. Achievability of an R 0 situation: i. if necessary, in combination with ablative methods, ii. if necessary, neoadjuvant chemotherapy, iii. the ability to eradicate extrahepatic tumour manifestations; 3. Sufficient volume of the liver remaining after resection ("future liver remnant = FLR): i. if necessary, in combination with portal vein embolisation or two-stage hepatectomy; 4. The feasibility to preserve two contiguous hepatic segments with adequate vascular inflow and outflow as well as biliary drainage; 5. Tumour biological aspects ("prognostic variables"); 6. Experience of the surgeon and centre! Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases provided a complete resection of both intra- and extrahepatic disease is feasible. Even in bilobar colorectal metastases and 5 or more tumours in the liver, a complete tumour resection has been described. The type of resection (hepatic wedge resection or anatomic resection) does not influence the recurrence rate. Preoperative volumetry is indicated when major hepatic resection is planned. The FLR should be 25 % in patients with normal liver, 40 % in patients who have received intensive chemotherapy or in cases of fatty liver, liver fibrosis or diabetes, and 50-60 % in patients with cirrhosis. In patients with initially unresectable colorectal liver metastases, preoperative chemotherapy enables complete resection in 15-30 % of the cases, whereas the value of neoadjuvant chemotherapy in patients with resectable liver metastases has not been sufficiently supported. In situ ablative procedures (radiofrequency ablation = RFA and laser-induced interstitial thermotherapy = LITT) are local therapy options in selected patients who are not candidates for resection (central recurrent liver metastases, bilobar multiple metastases and high-risk resection or restricted patient operability). Patients with tumours larger than 3 cm have a high local recurrence rate after percutaneous RFA and are not optimal candidates for this procedure. The physician's experience influences the results significantly, both after hepatectomy and after in situ ablation. Therefore, patients with colorectal liver metastases should be treated in centres with experience in liver surgery.     

Liver transplantation for metastatic colon adenocarcinoma: report of a case with 10 years of follow-up without recurrence

Because of dismal mid-term and long-term results, secondary liver cancer is considered an absolute contra-indication to cadaveric liver transplantation, with the relative exception of metastases of symptomatic neuro-endocrine cancers. The authors present in this report the case of a patient who has been enjoying 10 years of cancer-free survival after liver transplantation as rescue therapy for acute liver failure after liver resection for isolated hepatic metastasis of colon adenocarcinoma. This case shows that in some highly selected cases, liver transplantation may be curative in patients with liver metastases of colon carcinoma.     

Surgical and combined treatment of multiple and bilobar metastatic affection of the liver

Short- and long-term results of surgical treatment in combination with local exposures (cryo- and thermo-destruction) and adjuvant chemotherapy in patients treated for multiple and bilobar metastatic affection of the liver were studied. Postoperative lethality was 2,5% (n=2) due to liver insufficiency. Specific for liver resection complications (bile outflow, moderate hepatic failure) do not exceed 20,5%. Five-year survival of patients with solitary bilobar metastatic affection of the liver (not more than two foci) was 39,1+/-14,3%. This demonstrates that solitary bilobar hepatic metastases is not a negative prognostic factor for surgical treatment. Long-term results of treatment of patients with multiple metastases of colorectal cancer to the liver are worse, but 1-, 2-, and 3-year survival demonstrates validity of surgical policy in treatment of these patients. Postoperative chemotherapy significantly improves long-term survival of patients with multiple or/and bilobar metastases of colorectal cancer to the liver.     

Influence of Preoperative Chemotherapy on the Intraoperative and Postoperative Course of Liver Resection for Colorectal Cancer Metastases

Background  

Liver resection is a possibly curative treatment for colorectal cancer (CRC) liver metastases. Preoperative chemotherapy may make initially irresectable tumors resectable. The aim of this study was to compare perioperative course and short-term mortality after liver resection for CRC metastases between patients who were and were not treated with preoperative chemotherapy.     

Management of potentially resectable colorectal cancer liver metastases

Colorectal cancer is a very common malignancy worldwide and development of liver metastases,both synchronous or metachronous,is a common event.Of all patients with metastatic colorectal cancer,up to 77% have a liver-only disease and approximately 10%-20% of patients with colorectal liver metastases are considered resectable at the time of diagnosis.Surgical resection of liver metastases remains the best treatment option and it is associated with a survival plateau and a 20%-25% of long-term survivors.Perioperative chemotherapy for resectable liver metastases may improve resecability of liver metastases and disease free survival,but its impact on overall survival is still unclear and more studies are needed.Moreover,preoperative chemotherapy can increase postoperative complications.Further studies are needed to define the role of adjuvant chemotherapy after a R0 resection of liver metastases and to define the criteria for a better selection of patients candidate to hepatectomy.New strategies such as targeted therapies are emerging with promising results.Optimal management requires a multidisciplinary approach,local and systemic,but it is a still pending question.Colorectal liver metastases represent a major challenge for oncologists and surgeons.In this review will be analyzed available data about assessment and management of the patients with potentially resectable colorectal liver metastases.     

Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases

BACKGROUND: The aim of this case-matched study was to determine the best treatment strategy for patients with asymptomatic colorectal cancer and irresectable synchronous liver metastases. METHODS: Between 1997 and 2002, 27 patients with asymptomatic colorectal cancer and irresectable synchronous liver metastases were treated by chemotherapy without initial primary resection (chemotherapy group). These 27 patients were compared with 32 patients matched for age, sex, performance status, primary tumour location, number of liver metastases, nature of irresectable disease and type of chemotherapy, but who were treated initially by resection of primary tumour (resection group). RESULTS: The 2-year actuarial survival rate was 41 per cent in the chemotherapy group and 44 per cent in the resection group (P = 0.753). In the latter group, the mortality and morbidity rates for primary resection were 0 and 19 per cent (six of 32 patients) respectively. In the chemotherapy group, intestinal obstruction related to the primary tumour occurred in four of 27 patients. The mean overall hospital stay was 11 days in the chemotherapy group and 22 days in the resection group (P = 0.003). CONCLUSION: Systemic chemotherapy without resection of the bowel cancer is the option of choice because, for most patients, it is associated with a shorter hospital stay and avoids surgery without a detrimental effect on survival.     

Liver metastases of colorectal carcinoma--may the DRG-system influence the operative procedure?

The economic analysis of surgery in colorectal liver metastases reveals the different effectiveness of various follow-up programmes after curative surgery for colorectal cancer. Interval hepatic resection for synchronous liver metastases is recommended in the majority of cases with rectal cancer. This procedure provides benefits for the patient and the hospital under the economic point of view. The interval between primary tumor resection and surgery of liver metastases does not deteriorate the prognosis, on the contrary, unnecessary resections will be avoided if additional metastases will grow in the time between, excluding curative treatment (selection mechanism). The identical statement cannot be applied to patients with colon cancer, since the operative risk is only slightly increased in case of easily accessible liver metastases which may be removed simultaneously. However, also in these patients interval hepatic resection after neoadjuvant chemotherapy should be considered as a therapeutic option! In patients with multiple liver metastases liver surgery as well as radiofrequency ablation or a combination of both may be economically justified. Radiofrequency ablation is the preferred palliative procedure under aspects of cost-effectiveness, however, wether this procedure is superior to chemotherapy alone has not be evaluated so far in prospectively randomized trials.     

Surgical treatment of liver metastasis in patients with colorectal cancer

Half of patients with colorectal cancer have liver metastasis during their illness. Surgical resection of metastases represents the only curative treatment with prolonged survival in more than 50 % of patients. The aim of liver resection is complete excision of the lesions with histological negative margins while preserving sufficient functional liver parenchyma. In patients with diffuse liver disease, the radiofrequency ablation of metastases may be associated with surgical resection. The use of portal vein remobilization and neoadjuvant chemotherapy can also increase the number of patients for curative treatment. Despite this progress, from 50 to 60 % of patients relapse after complete resection of MHCCR. Surgical treatment of recurrent aggressive and effective chemotherapy allows the prolonged survival of these patients. The modern treatment of liver metastasis of colorectal cancers can be envisaged as part of a multidisciplinary approach to increase the number of patients for curative treatment.