Intra-arterial chemotherapy in the treatment of liver metastases of colorectal cancer]

AIM: The authors evaluate the value of hepatic intrarterial chemotherapy (HAC) as an alternative treatment for hepatic metastases from colo-rectum cancer unsuited to radical surgery. METHODS: This study evaluates the physiopathological and pharmacodynamic bases for this type of treatment, the correct procedure for patient staging and selection, the surgical technique used to insert the infusional system, surgical complications and those linked to endoarterial treatment, the evaluation of response and the results. Complications correlated to the infusional system were evaluated in a total of 1223 patients in 10 non-randomised studies and 7 randomised studies taken from the literature. Complications correlated to chemotherapy were analysed in a total of 777 patients from 8 randomised studies and 7 randomised using FUDR. Special emphasis was placed on the possible association of locoregional and systemic treatment in order to prevent extrahepatic progression, the main cause of death in patients undergoing a single cycle of HAC. RESULTS: By comparing locoregional and systemic treatment taken from a number of randomised and non-randomised studies, the results were evaluated in terms of objective response and survival. CONCLUSIONS: There was no proportional increase in survival rates compared to systemic treatment only, in spite of the large proportion of objective responses achieved using locoregional treatment alone.     

Prospective pilot study of neoadjuvant chemotherapy with 5-fluorouracil,folinic acid and oxaliplatin in resectable liver metastases of colorectal cancer. Analysis of 42 neoadjuvant chemotherapies

PURPOSE: Since there are currently no data available from a prospective trial, the primary objective of this prospective study was to investigate whether the rate of R0-liver resections without morbidity would be at least 50 % in patients with neoadjuvant chemotherapy for colorectal liver metastases. PATIENTS AND METHODS: 42 patients were treated with a biweekly FOLFOX regimen. Chemotherapy consisted of a 2-hour infusion of folinic acid (FOL) 500 mg/m2, followed by a 24-hour infusion of 5- fluorouracil (F) 2000 mg/m2 daily for two days. Oxaliplatin (OX) 85 mg/m 2 was given simultaneously with FOL. Treatment allocation was randomized with either 3 or 6 cycles for the final 30 patients. A liver resection was performed 2 to 5 weeks after the final infusion. RESULTS: An objective response was observed in 20 of 42 patients (response rate was 27 % higher after 6 cycles). Liver resection (R0) could be performed in 34 patients. Postoperative complications were reported in 14 patients (13 occurring within 30 days after resection) and severe complications in 5 cases (including two deaths after extended resection). Liver failure and persistent biliary fistula were the most frequently documented complications. There was no relevant difference in safety criteria between 3 and 6 applications. CONCLUSION: The use of neoadjuvant chemotherapy in resectable liver metastases induced significant remissions without increasing morbidity. The rate of severe complications and cases of no R0-resection in this study was 31 % and was with that significantly lower than 50 % (95 % CI 17.6 %-47.1 %). The risk to the patient is therefore acceptable when undergoing neoadjuvant treatment in a prospective intergroup trial.     

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.     

结直肠癌肝转移的手术治疗

目的 探讨手术治疗结直肠癌肝转移的疗效以及影响因素.方法 收集74例手术治疗的结直肠癌肝转移病例,进行回顾性分析.结果 本组患者3年和5年生存率分别为63.8%和49.8%.原发灶淋巴结转移者5年生存率(33.3%)显著低于无转移者(63.7%,P=0.002),脉管侵犯者(39.6%)显著低于无侵犯者(61.6%,P=0.025).转移灶个数≤3个者(53.7%)显著高于＞3个者(34.6%,P=0.021).肝转移灶局限于半肝者,其5年生存率(65.2%)显著高于双侧弥漫者(23.9%,P=0.001).结论 手术切除是唯一可能治愈结直肠癌肝转移的方法.原发灶无淋巴结转移、无脉管侵犯,转移灶个数不超过3个、局限于半肝者预后较好.     

大肠癌伴肝转移时的外科治疗

肝脏是大肠癌最常见的远端侵犯器官.手术是治疗大肠癌伴肝转移的首选方法,甚至可获得根治的机会,其5年生存率可达30％ ～40％.本文就大肠癌肝转移的手术指征、手术时机、手术方式等新理念进行综述,并探讨外科治疗的决策流程,强调以手术治疗为中心的多学科治疗模式,以提高手术后疗效和生存率.     

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.     

Pathologic support for limited hepatectomy in the treatment of liver metastases from colorectal cancer.

OBJECTIVE: The authors determined an appropriate surgical treatment for liver metastases from colorectal cancers. Clinicopathologic features of metastatic lesions of colorectal cancers were studied. SUMMARY BACKGROUND DATA: Major hepatic resection is the usual procedure for treatment of hepatic metastases from colorectal cancers. METHODS: Forty consecutive patients who underwent hepatic resections were prospectively studied, for a total of 89 metastatic liver tumors. RESULTS: Metastatic tumor often extended along Glisson's capsule, including invasion to the portal vein (9 cases), the hepatic vein (3 cases), the bile duct (16 cases), and the nerve (6 cases). The main tumor had small satellite nodules in only one patient, and there were no microscopic deposits in the parenchyma, even within 10 mm from the metastatic tumors. Fibrous pseudocapsule formation was observed in 28 patients. DISCUSSION: The rarity of intrahepatic metastasis from metastatic tumor supports nonanatomic limited hepatic resection as the procedure of choice for metastatic colorectal cancer in the liver. The spread via Glisson's capsule should be taken into consideration for complete tumor clearance.     

Regional chemotherapy for colorectal liver metastases: a phase II evaluation of targeted hepatic arterial 5-fluorouracil for colorectal liver metastases

The results of systemic chemotherapy in patients with liver metastases from colorectal cancer remain dismal. Regional chemotherapy has been advocated as a method of improving the delivery of cytotoxic drugs to tumour, while minimizing systemic toxicity. The use of vasoactive agents to redistribute arterial blood flow towards tumour, and of biodegradable microspheres to slow tumour blood flow, have also been suggested as methods of further improving tumour exposure to drug. We present 21 patients who received intrahepatic arterial chemotherapy for colorectal liver metastases. Combined treatment (angiotensin II, albumin microspheres and 5-fluorouracil) was administered 4-6 weekly, and bolus 5-fluorouracil was given in the intervening weeks. Toxicity was minimal. Responses were seen in seven patients. Fewer than half of the deaths were from liver metastases; a quarter of the patients died from non-cancer-related causes. Survival was prolonged in the treated group compared with historical controls. These results suggest that this regimen has activity in patients with colorectal liver metastases.     

Current state of surgical treatment of liver metastases from colorectal cancer

Hepatic resection is the procedure of choice for curative treatment of colorectal liver metastases(CLM).Objectives of surgical strategy are low intraoperative blood loss,short liver ischemic times and minor postoperative morbidity and mortality.Blood loss is an independent predictor of mortality and compromises,in common with postoperative complications,long-term outcome after hepatectomy for CLM.The type of liver resection has no impact on the outcome of patients with CLM;wedge resections are not inferior to anatomical resections in terms of tumor clearance,pattern of recurrence or survival.Despite the lack of proof of survival benef it,routine lymphadenectomy has been advocated,allowing the detection of microscopic lymph node metastases and with prognostic value.In experienced hands,minimally invasive liver surgery is safe with acceptable morbidity and mortality and oncological results comparable to open hepatic surgery,but with reduced blood loss and earlier recovery.The European Colorectal Metastases Treatment Group recommended treating up front with chemotherapy for patients with both resectable and unresectable CLM.However,neoadjuvant chemotherapy can induce damage to the remnant liver,dependent on the number of chemotherapy cycles.Therefore,in our opinion,preoperative chemotherapy should be reserved for patients whose CLM are marginally resectable or unresectable.A meta analysis of randomized trials dealing with perioperative chemotherapy for the treatment of resectable CLM demonstrated a benefit of systemic chemotherapy but did not answer the question of whether a neoadjuvant or adjuvant approach should be preferred.Analysis of the literature demonstrates that the results of specialized centers cannot be attained in the reality of comprehensive patient care.Reasons behind the commonly poorer results seen in cancer networks as compared with literature-based data are,on the one hand,geographical disparities in access to specialized surgical and medical care.On the other hand,a selection bias in the reports of the literature may be assumed.Studies of surgical resection for CLM derive almost exclusively from case series generally drawn from large academic centers where patient selection or surgical expertise is superior to what is found in many communities.Therefore,we may conclude that the comprehensive propagation of the standards outlined in this paper constitutes a major task in the near future to reduce the variations in survival of patients with CLM.     

Comparative efficacy of antitumor treatment for liver metastases from colorectal cancer

A retrospective study of 37 colorectal cancer patients with synchronous liver metastases was made. Of these patients, 6 who had undergone primary tumor removal were treated with considerable success by hepatic arterial infusion of 5-FU and mitomycin C. Ten patients who underwent primary tumor excision were treate by oral chemotherapy using fluorinated pyrimidines. These patients survived about 23 months. On the other hand, 12 patients after primary tumor removal without cancer chemotherapy survived for about 10 months. Six patients without antitumor treatment for both primary tumor and hepatic metastasis survived about 5.2 months. The overall results of this study suggest that intrahepatic arterial infusion is of practical importance for hepatic metastases from colorectal cancer and that oral chemotherapy is indeed effective for selected patients.     

Results of a prospective randomized study of hepatic artery infusion with 5-fluorouracil versus intravenous 5-fluorouracil in patients with hepatic metastases from colorectal cancer: A Central Oncology Group study.

In a controlled, prospectively randomized trial, 74 patients with hepatic metastases from colorectal cancer were randomized to either intra-arterial hepatic artery infusion with 5-fluorouracil (5-FU) or systemic chemotherapy with 5-FU. In 61 acceptable patients, there was no significant difference in terms of response rate, time to progression, duration of the response, and survival rate. Though the response rate for the intra-arterial infusion arm was slightly higher than for the systemic arm, the difference was not significant, and the intra-arterial infusion arm was associated with a greater incidence of nausea, vomiting, diarrhea, in addition to complications of femoral-arterial thrombosis, bleeding, and infection at the catheter site not seen in patients treated by systemic chemotherapy. Patients with an objective response to chemotherapy on either treatment arm survived twice as long as the nonresponders. Long-term survival in one patient, 77 months, can occasionally be achieved in patients with hepatic metastases.     

Technical complications of continuous intra-arterial chemotherapy with 5-fluorodeoxyuridine and 5-fluorouracil for colorectal liver metastases

BACKGROUND: Intra-arterial chemotherapy is an effective modality to treat unresectable hepatic metastases from colorectal primaries if systemic chemotherapy has failed. Response rates of more than 40% and a median survival of 15 to 25 months have been reported from randomized trials. In this retrospective study, we analyzed specific technical complications associated with continuous intra-arterial chemotherapy for colorectal liver metastases. METHODS: From 1982 to 1995, single-center clinical data from 180 patients with colorectal liver metastases were evaluated. Continuous intra-arterial chemotherapy was administered using either an implanted infusion pump or an intra-arterial port with an external infusion pump. The intra-arterial catheter was implanted according to the Watkins' technique. The treatment protocols consisted of 5-fluorouracil- or 5-fluorodeoxyuridine-based regimens. RESULTS: A total of 70 patients (39%) received an intra-arterial infusion pump and 110 patients (61%) an intra-arterial port. Sixty-eight technical complications affected port systems (62%), whereas 29 patients with pumps (41%) were affected by technical complications. Therapy-relevant complications were observed in 47% of the ports and 30% of the infusion pumps. The median complication-free survival was 12.2 months for infusion pumps and 7.3 months for ports (P =.0016). CONCLUSIONS: Our data demonstrate that pumps are superior to ports in terms of complication rate and complication-free survival. On the basis of our results, pumps have a potential for a longer treatment, which may result in a prolonged median survival.     

Surgical treatment of hepatic metastases from colorectal cancer.

From 1980 to 1984, 48 patients were subjected to liver resection for hepatic metastases from colorectal cancer. The disease was staged according to the original staging system proposed by the authors: stage I, single metastasis involving less than 25% of hepatic parenchyma (21 patients); stage II, multiple metastases involving less than 25% of hepatic parenchyma or single metastasis involving between 25-50% (9 patients); and stage III, multiple metastases involving between 25-50% or more than 50% of hepatic parenchyma, irrespective of the number of metastases (18 patients). The extent of hepatic resection was generally related to that of liver disease; a typical lobectomy was performed in 28 patients and segmentectomies in 20. One patient died after operation (mortality, 2.1%), and major complications occurred in seven patients (morbidity, 14.9%). Morbidity was related to operatory blood loss: 45% of patients with blood replacement of more than 2000 cc developed major complications versus 5.4% with blood replacement of less than 2000 cc (p less than 0.05). The actuarial 3-year survival for stages I, II, and III was 73%, 60%, and 29%, respectively (p less than 0.05). Twenty-two patients (45%) have had recurrences, all stage III patients within 2 years of resection versus 28% of stage I patients (30 months disease-free survival, 49%). The liver only was the site of recurrence in 10 patients, distant sites in seven, and both liver and distant in five. Analysis of the different features of the primary tumor, the interval between bowel resection and detection of hepatic metastases, and the number and extent of liver secondaries demonstrated that prognosis after surgery was mainly related to the latter; they are considered in the staging system adopted in this study. It is a simple system and shows a good prognostic correlation. The results reported here are in agreement with those of the literature; the low mortality and morbidity and the survival benefit support the growing acceptance of surgery in treatment of hepatic metastases from colorectal cancer, in particular stage I patients. For the other stages, surgery should represent, when applicable, only the first step of a multimodality treatment.     

Resection of synchronous liver metastases from colorectal cancer

Whereas resection for metachronous liver metastases from colorectal cancer is considered to be a potentially curative approach, little is known about the prognosis after resection of synchronous liver metastases. In the past, these patients usually underwent only palliative therapy. Therefore, we have analyzed the data of 36 patients who underwent curative hepatic resection of synchronous liver metastases from colorectal carcinomas from 1977 to 1987 at the Department of Surgery, Hannover Medical School. In 19 patients, liver resection was combined with colonic resection; in the other 17 patients, hepatic resection was performed after a median interval of 2 months following resection of the primary tumor. No operative mortality was observed in either of the approaches. The median survival time was 28 months for all patients with a median recurrence-free interval of 13.5 months. Overall 5-year survival probability for all patients was 20%. There were no significant differences observed between immediate or delayed liver resection (median survival 18 months versus 31 months). Survival rates were not different after resection of solitary versus multiple liver metastases (26 versus 28 months). Twenty-one of the 36 patients had a recurrence of their liver metastases. In 7 of them, curative liver resection could be performed again. These 7 patients had a significantly improved survival (p<0.05) compared to the residual 14 patients. It is concluded that patients with synchronous liver metastases from colorectal cancer may profit from resection of the primary tumor and liver metastases. Timing of liver resection—immediate versus delayed—obviously has no impact on survival rates.

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Resumen En tanto que la resección de metástasis hepáticas, metacrónicas del cancer colorrectal es considerada como un aproche potencialmente curativo, poco se conoce sobre el pronóstico después de la resección de metástasis hepáticas sincrónicas; en el pasado estos pacientes han sido generalmente sometidos a terapia paliativa solamente. Por consiguiente, nos propusimos analizar la información sobre 36 pacientes sometidos a resección curativa de metástasis sincrónicas de carcinomas colorrectales en el período 1977–1987 en el Departamento de Cirugía de la Escuela de Medicina de Hannover. En 19 pacientes se combinó la resección hepática con la resección del colon; en los otros 17 pacientes la resección hepática fue realizada después de un intervalo promedio de 2 meses de efectuada la resección primaria. No hubo mortalidad operatoria con ninguno de los 2 aproches. El tiempo promedio de sobrevida fue de 28 meses para la totalidad de los pacientes con un intervalo libre de recurrencia promedio de 13.5 meses. La probabilidad global de supervivencia a 5 anos para la totalidad de los pacientes fue de 20%. No se hallaron diferencias significativas entre los pacientes sometidos a resección hepática inmediata o diferida (sobrevida promedio de 18 meses versus 31 meses). Las tasas de sobrevida no fueron diferentes para la resección de metástasis solitarias o de metástasis mÚltiples (26 versus 28 meses). Veinte y uno de los 36 pacientes presentaron recurrencia de sus metástasis hepáticas. En 7 de ellos se pudo realizar de nuevo una resección curativa; estos 7 pacientes exhibieron una sobrevida significativamente mejor (p<0.05) en comparación con los 14 pacientes residuales. Es nuestra conclusión que pacientes con metástasis hepáticas sincrónicas de cancer colorrectal pueden beneficiarse de la resección del tumor primario y de las metástasis hepáticas. Es obvio que el momento de la resección hepática—inmediata versus diferida—no influye sobre las tasas de sobrevida.

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Résumé Alors que la résection de métastases hépatiques métachrones des cancers colorectaux peut Être considérée comme une thérapeutique à visée curative dans certains cas, on sait peu de choses en ce qui concerne le pronostic après résection de lésions hépatiques synchrones. Auparavant, ces lésions n'étaient traitées qu'à visée palliative. Nous avons analysé les observations de 36 patients ayant eu une résection à visée curative de métastases hépatiques synchrones des cancers colorectaux traités entre 1977 et 1987 dans le service de chirurgie de l'Hôpital Universitaire de Hanovre. Dans 19 cas, la résection hépatique était effectuée en mÊme temps que la colectomie et dans 17 cas, après un intervalle médian de 2 mois. Il n'y avait aucune mortalité dans les deux séries. La survie médiane était de 28 mois pour tous les patients: le temps de récidive médian était de 13.5 mois. La probabilité de survie à 5 ans pour tous les patients était de 20%. Il n'y avait aucune différence observée selon que la lésion hépatique avait été réséquée simultanément ou pas (survie médiane 18 mois vs 31 mois). La survie n'était pas différente selon que les lésions hépatiques étaient simples ou multiples (26 vs 28 mois). Chez 21 des 36 patients, les métastases ont récidivé. Chez sept de ces patients, une résection à visée curative a pu Être proposée à nouveau. La survie chez ces sept patients était significativement améliorée par rapport aux 14 autres patients (p<0.05). On conclut que la résection de métastases hépatiques synchrones des cancers colorectaux est valable. Le fait que la résection soit simultanée ou retardée n'a pas d'importance.

     

Epidemiology and management of liver metastases from colorectal cancer

OBJECTIVE/BACKGROUND: Little is known about the epidemiology and the management of liver metastases from colorectal cancer at a population level. The aim of this population-based study was to report on the incidence, treatment, and prognosis of synchronous and metachronous liver metastases. METHODS: Data were obtained from the population-based cancer registry of Burgundy (France). RESULTS: The proportion of patients with synchronous liver metastases was 14.5%. Age-standardized incidence rates were 7.6 per 100,000 in males, 3.7 per 100,000 in females. The 5-year cumulative metachronous liver metastasis rate was 14.5%. It was 3.7% for TNM stage I tumors, 13.3% for stage II, and 30.4% for stage III (P < 0.001). The risk of liver metastasis was also associated to gross features. Resection for cure was performed in 6.3% of synchronous liver metastases and 16.9% of metachronous liver metastases. Age, presence of another site of recurrence, and period of diagnosis were independent factors associated with the performance of a resection for cure. The 1- and 5-year survival rates were 34.8% and 3.3% for synchronous liver metastases. Their corresponding rates were, respectively, 37.6% and 6.1% for metachronous liver metastases. CONCLUSION: Liver metastases from colorectal cancer remain a substantial problem. More effective treatments and mass screening represent promising approaches to decrease this problem.     

The combined treatment of colorectal cancer with liver metastases

The direct and follow-up results of surgical and combined treatment of colorectal cancer with liver metastases are presented. Complication rate after liver resections was 28.4% and lethality was 3.5%. Follow-up results evidence the decrease of survival in patients with adjuvant chemotherapy after surgery. The safety of oxalyplatin in patients after liver resections, including its intraarterial infusion through the hepatic artery is shown. Oxalyplatin-based chemotherapy regimen tended to be more effective in comparison with 5-fluorouracil scheme, especially in patients with synchronous or multiple liver metastases. Considering that the difference is not statistically significant, further studies of oxalyplatin influence on survival of patients with colorectal liver metastases are necessary.     

结肠直肠癌肝转移外科治疗进展

结肠直肠癌是常见恶性肿瘤,年发病率在欧美地区占消化道肿瘤首位及全部恶性肿瘤第3位．在我国占消化道肿瘤第2位及全部恶性肿瘤第4位。流行病学统计表明．其发病率还在上升。结肠直肠癌如能早发现、早诊断及早手术,则预后较好,然而约40％～75％的病人确诊时已有结肠直肠外转移,其中肝转移占15％～35％,接受根治性结肠直肠癌切除术的病人最终有25％～50％出现肝转移。