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.     

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.     

个体化治疗直肠癌同时性肝转移

肝转移是影响结直肠癌预后的重要因素之一。一般认为手术切除是唯一可能治愈结直肠癌肝转移的治疗手段。而近年随着新辅助化疗与肿瘤物理消融技术以及微创技术的进展,尤其在生物一心理一社会的现代医学模式背景下,对可以手术切除的结直肠癌同时性肝转移患者如何选择更为合理的手术方式尚存在较多争议。中国医科大学附属盛京医院收治1例直肠癌同时性肝转移患者经新辅助化疗后腹腔镜下肝转移癌微波消融＋开腹结直肠癌根治性切除术的联合序贯治疗,为同类患者治疗方式的个体化选择提供参考。     

The management of solitary colorectal liver metastases

Surgical resection of solitary colorectal liver metastases is associated with long-term survival. Radiofrequency ablation used as the primary treatment option of solitary resectable colorectal liver metastases is associated with an increased risk of local recurrence that generally leads to worse survival compared to resection. In contrast with treatment of other hepatic malignancies, radiofrequency ablation is not equivalent to resection for colorectal liver metastases and should not be used as an alternative but limited to inoperable patients. Although overall survival rate after resection can be up to 71% at 5 years, the majority of patients develop recurrence. Preoperative chemotherapy contributes to decrease the risk of recurrence after resection of colorectal liver metastases. In patients with advanced solitary colorectal liver metastasis initially non suitable for resection, chemotherapy and portal vein embolization contribute to increase the number of surgical candidates whereas radiofrequency is rarely an option.     

Surgical therapy for recurrent liver metastases from colorectal cancer

Forty percent of patients whose disease recurs after hepatic resection for liver metastases from colorectal cancer initially will have liver-only metastases. We have retrospectively reviewed our experience with repeated surgical treatment for liver-only recurrence after previous hepatic resection for colorectal metastases. Repeated hepatic procedures were performed with no mortality in 10 patients. Intraoperative ultrasound allowed identification of three unsuspected metastases and determination of unresectability of two metastases during 11 procedures. Three patients were free of disease at 31, 41, and 48 months from the first hepatic procedure and at 15, 31, and 43 months from the second procedure. Five patients have remained free of hepatic disease. Patients whose initial metastases were less than 6 cm in diameter and had single liver recurrences after hepatic resection appeared to be the best candidates for further surgical therapy. These data and a review of the literature suggest that surgical treatment of recurrent liver metastases from colorectal cancer can be performed safely, and it is associated with long-term disease-free survival in up to 38% of highly selected patients.     

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.     

Surgical treatment of liver metastases from colorectal cancer

We analyze our experience over a 10-year period in the surgical treatment of liver metastases from colorectal cancer. Between 01.01.1995 and 08.31.2005 189 liver resections were performed in 171 patients with liver metastases from colorectal cancer (16 re-resections - 2 in the same patient and a "two-stage" liver resection in 2 patients). In our series there were 83 patients with synchronous liver metastases (69 simultaneous resections, 12 delayed resections and 2 "two-stage" liver resection were performed) and 88 metachronous liver metastases. Almost all types of liver resections have been performed. The morbidity and mortality rates were 17.4% and 4.7%, respectively. Median survival was 28.5 months and actuarial survival at 1-, 3- and 5-year was 78.7%, 40.4% and 32.7%, respectively. Between January 2002 and August 2005 hyperthermic ablation of colorectal cancer liver metastases has been performed in 6 patients; in other 5 patients with multiple bilobar liver metastases liver resection was associated with radiofrequency ablation and one patient underwent only radiofrequency ablation for recurrent liver metastasis. In conclusion, although the treatment of colorectal cancer liver metastases is multimodal (resection, ablation, chemotherapy and radiation therapy), liver resection is the only potential curative treatment. The quality and volume of remnant liver parenchyma is the only limitation of liver resection. The morbidity, mortality and survival rates after simultaneous liver and colorectal resection are similar with those achieved by delayed resection. Postoperative outcome of patients with major hepatic resection is correlated with the surgical team experience. The long-term survival was increased using the new multimodal treatment schemes.     

转移性肝癌的治疗理念和策略

转移性肝癌是恶性肿瘤发展的终末阶段,是导致患者死亡的主要原因,其中胃肠道是常见的原发癌部位。人们正尝试通过根治转移性肝癌或控制其发展等多种治疗策略,延长患者生存期。手术治疗、全身化疗、分子靶向治疗、射频消融术、门静脉栓塞术、肝动脉导管栓塞术是转移性肝癌的有效治疗方法,其中手术治疗是转移性肝癌可能获得治愈的有效手段。相比结肠癌肝转移癌,胃癌肝转移癌的治疗正处于探索阶段,但是随着新型有效化疗药物及化疗方案的出现、肝转移癌手术适应证的拓展以及大规模多中心临床试验循证医学证据的涌现,包括胃癌肝转移在内的转移性肝癌的治疗必将朝着一个更加规范,更为有效的方向发展。     

Surgical treatment for colorectal liver metastases involving the paracaval portion of the caudate lobe

BACKGROUND: Hepatic neoplasms in the paracaval portion of the caudate lobe (S1r) are usually difficult to treat surgically because such neoplasms often invade the hepatic veins and/or inferior vena cava (IVC). We reevaluated resected cases of colorectal liver metastases involving S1r to confirm the significance of aggressive surgical treatments. METHODS: Between July 1977 and December 2002, 95 consecutive patients with colorectal liver metastases underwent hepatic resection. Seven patients with liver metastases involving the S1r underwent resection. RESULTS: The surgical procedures for liver metastases comprised 3 isolated caudate lobectomies, 2 right hepatectomies, and 2 right hepatic trisectionectomies with caudate lobectomy. Combined resections included partial resection of the hepatic vein in 2 patients, wedge resection of the IVC in 3, and segmental resection of the IVC in 1. Six of the 7 patients with S1r metastasis had recurrent disease in liver and/or lung. A second hepatectomy was carried out in 4 patients and a partial lung resection in 2 patients. Four of the 7 patients survived more than 5 years, but 2 of them died of recurrent disease at 61 and 95 months after initial hepatectomy. The remaining 2 patients are alive 72 and 118 months without any sign of recurrence. The median survival time of the 7 patients was 60 months. CONCLUSION: Liver metastases involving the S1r could be resected radically with en bloc resection of the major hepatic veins and/or the inferior vena cava. An aggressive surgical approach with combined resection of the adjacent major vessels may offer a better chance of long-term survival in selected patients with caudate lobe metastasis from colorectal cancer.     

结直肠癌肝转移外科治疗的争议

肝脏是结直肠癌最常见的转移部位,肝转移是结直肠癌治疗失败的主要原因。外科切除在结直肠癌肝转移综合治疗模式中占据主导地位．也是患者获得治愈机会的重要手段。尽管如此,在结直肠癌肝转移外科治疗领域目前还存在很多困惑和争议．包括结直肠癌肝转移分期系统尚不完善、潜在可切除标准尚未统一、可切除肝转移灶是否需要新辅助化疗、根治切除后辅助化疗方案的选择以及不可切除肝转移灶患者无症状原发灶的处理等。本文依据近年来发表的研究资料,结合自身临床实践,剖析肝转移外科研究领域中不同的观点和依据。     

Survival after resection of multiple bilobar hepatic metastases from colorectal carcinoma

OBJECTIVE: To define the long-term outcome and treatment complications for patients undergoing liver resection for multiple, bilobar hepatic metastases from colorectal cancer. METHODS: A retrospective analysis of 165 consecutive patients undergoing liver resection for metastatic colorectal cancer was performed. Patients were divided into a simple hepatic metastasis group, consisting of patients with three or fewer metastases in a unilobar distribution, and a complex hepatic metastases group, consisting of patients with four or more unilobar metastases or at least two bilobar metastases. RESULTS: The 5-year survival rate was 36% for the simple group and 37% for the complex group. Multivariate analysis revealed that the number of hepatic segments involved by tumor and the maximum diameter of the largest metastasis correlated significantly with the 5-year survival rate. The surgical death rate was 4.9% for the simple group and 9.1% for the complex group; this difference was not significant. Multivariate analysis revealed that extended lobar resection and concomitant colon and hepatic resection were significant and independent predictors of surgical death. The combination of extended lobar resection and concomitant colon resection was used significantly more frequently in the complex group than in the simple group. CONCLUSIONS: Resection of complex hepatic metastases, as defined in this study, results in a 5-year survival rate of 37% and confers the same survival benefit as does resection of limited hepatic metastases. The surgical death rate for this aggressive approach is significantly higher if extended lobar resections are necessary and if concomitant colorectal resection is performed. Patients who have complex hepatic metastases at the time of diagnosis of the primary colorectal cancer and who would require extended hepatic lobectomy should have hepatic resection delayed for at least 3 months after colon resection.     

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.     

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.     

结直肠癌肝转移的外科治疗

目的　探讨结、直肠癌肝转移的外科治疗。方法　对１９９３ 年１ 月至１９９９ 年１ 月的１９ 例结、直肠癌肝转移患者行外科治疗。其中６ 例同期切除,１０ 例分期切除,１ 例肝动脉结扎加无水乙醇注射,２ 例通过肝动脉结扎加化学药物治疗（化疗） 泵灌注化疗而获得二期手术切除机会。手术方式行肝不规则楔形切除１６ 例,左半肝切除２ 例。结果　术后１、３、５ 年生存率分别为８９％ 、５８％ 、２１％ 。６ 例同期肝切除者平均生存期２３ 个月,１０ 例分期肝切除者的平均生存期为３２ 个月。结论　掌握手术时机和适应证,积极进行肝动脉灌注化疗,提高手术切除成功率是提高存活率的关键。     

Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases

OBJECTIVE: To examine recurrence and survival rates for patients treated with hepatic resection only, radiofrequency ablation (RFA) plus resection or RFA only for colorectal liver metastases. SUMMARY BACKGROUND DATA: Thermal destruction techniques, particularly RFA, have been rapidly accepted into surgical practice in the last 5 years. Long-term survival data following treatment of colorectal liver metastasis using RFA with or without hepatic resection are lacking. METHODS: Data from 358 consecutive patients with colorectal liver metastases treated for cure with hepatic resection +/- RFA and 70 patients found at laparotomy to have liver-only disease but not to be candidates for potentially curative treatment were compared (1992-2002). RESULTS: Of 418 patients treated, 190 (45%) underwent resection only, 101 RFA + resection (24%), 57 RFA only (14%), and 70 laparotomy with biopsy only or arterial infusion pump placement ("chemotherapy only," 17%). RFA was used in operative candidates who could not undergo complete resection of disease. Overall recurrence was most common after RFA (84% vs. 64% RFA + resection vs. 52% resection only, P < 0.001). Liver-only recurrence after RFA was fourfold the rate after resection (44% vs. 11% of patients, P < 0.001), and true local recurrence was most common after RFA (9% of patients vs. 5% RFA + resection vs. 2% resection only, P = 0.02). Overall survival rate was highest after resection (58% at 5 years); 4-year survival after resection, RFA + resection and RFA only were 65%, 36%, and 22%, respectively (P < 0.0001). Survival for "unresectable" patients treated with RFA + resection or RFA only was greater than chemotherapy only (P = 0.0017). CONCLUSIONS: Hepatic resection is the treatment of choice for colorectal liver metastases. RFA alone or in combination with resection for unresectable patients does not provide survival comparable to resection, and provides survival only slightly superior to nonsurgical treatment.     

Colorectal metastasis (liver and lung)

Distant metastases are the major cause of death for colorectal carcinoma patients. Depending on the primary tumor's stage, liver metastases occur in 20% to 70% of patients and lung metastases in 10% to 20%. Unlike many other cancers, the presence of distant metastases from colorectal cancer does not preclude curative treatment. Surgical resection remains the only treatment that can ensure long-term survival and cure in some patients, but only a minority of liver metastases are amenable to surgery. New treatment modalities including portal vein embolization, perioperative chemotherapy and local destruction with cryotherapy or radiofrequency ablation may make more patients suitable for surgical resection of hepatic metastases and may prolong survival in cases of nonresectabilitv. The availability of new active drugs has changed the treatment of liver metastases from colorectal cancer.     

Synchronous Hepatic Metastases from Colon Cancer: Changing Treatment Strategies and Results of Surgical Intervention

More effective chemotherapeutic agents have broadened the role of hepatic resection in the management of patients with synchronous hepatic metastases from colon cancer. This study examines the management patterns and the role of hepatobiliary surgical evaluation in patients with synchronous stage IV colon cancer. Patients with synchronous hepatic metastases from colon cancer evaluated and treated from 1/99 to 11/04 were analyzed retrospectively. Demographic, disease-related, and treatment-related variables were reviewed and correlated with disease-specific survival (DSS). One hundred and fifty-one patients were evaluated. The majority of patients (60%) were first evaluated by a medical oncologist while 34% were first evaluated by a hepatobiliary surgeon. Ultimately, 128 patients (85%) underwent surgical evaluation and 77% of those evaluated underwent surgical intervention. Patients who underwent operative exploration ± debulking had less hepatic disease but also received more chemotherapy than patients not explored and those who never underwent hepatobiliary surgical evaluation. Sixty-eight patients (53%) who underwent hepatobiliary surgical evaluation underwent hepatic resection. Negative independent predictors of hepatic resection were bilobar metastases and extrahepatic disease found during exploration. Variables associated with improved DSS included: carcinoembryonic antigen level ≤200 ng/ml, node-negative primary tumor, ≤4 liver metastases, unilobar metastases, largest metastasis ≤5 cm, and hepatic resection. Five-year DSS following hepatic resection was 54%. We conclude that hepatobiliary surgical evaluation of patients with synchronous hepatic metastases is warranted since many are candidates for hepatic resection. A multidisciplinary treatment approach which combines both medical and surgical modalities may be associated with improved survival.     

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.     

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??Treatment strategies for management of colorectal cancer liver metastases YE Ying-jiang, WANG Shan. Department of Gastroenterology Surgery, Peking University People’s Hospital, Beijing 100044, China Corresponding author:YE Ying-jiang, E-mail:yjye101@yahoo.com.cn Abstract Liver metastases is the most common distant metastasis of colorectal cancer. Surgical resection is believed the only effective treatment for metastatic hepatic cancer currently. With increased experience and multiple disciplines development, the surgical indication for metastatic liver cancer has been expanded gradually, and the standard of hepatic surgery has also been improved constantly. Importantly, multidisciplinary team (MDT) model remains the fundamental for optimal treatment for liver metastasis from colorectal cancer. The participation of MDT brings more opportunities for metastatic liver cancer, and improves the surgery outcomes indirectly. Diagnostic radiology is an important way for R0 resection of metastatic liver cancer; the intraoperative ultrasound increases metastatic liver cancer detection rate and surgery safety. Preoperative chemotherapy brings operation opportunity for those patients with initially unresectable lesions, and postoperative adjuvant therapy contributes to reduce the post-operation recurrence and metastasis. Radiofrequency ablation combined with hepatic resection provides unresectable metastatic liver cancer the best opportunity for long term survival.     

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.