Adjuvant regional chemotherapy after hepatic resection for colorectal metastases.

BACKGROUND: This study explored the possibility of achieving a better survival rate and reduced recurrence in the remaining liver in patients with colorectal hepatic metastases undergoing hepatic resection. Adjuvant postoperative regional chemotherapy was administered via the hepatic artery or the portal vein. METHODS: A retrospective study was performed on 174 patients after hepatic resection for colorectal metastases. These comprised 78 patients who had hepatic artery infusion (HAI) chemotherapy (HAI group), 30 who had portal vein infusion (PVI) chemotherapy (PVI group) and 66 who had no regional chemotherapy (resection alone group). The three groups were compared with one another in terms of complications, survival rate and patterns of recurrence. RESULTS: Severe complications did not occur at any point during adjuvant HAI or PVI chemotherapy. The 5-year disease-free survival rate of patients in the HAI, PVI and resection alone groups were 35, 13 and 9 per cent respectively, including six hospital deaths. Patients in the HAI group showed significantly improved recurrence rates in the remaining liver compared with the resection alone group (P = 0.03), and more prolonged disease-free and overall survival than those in the PVI (P = 0.01 and P = 0.02 respectively) and resection alone (P = 0.0001 and P = 0.0006 respectively) groups. CONCLUSION: This study suggests that adjuvant HAI chemotherapy after hepatic resection may have therapeutic potential for improved management of patients with colorectal metastases.     

Perioperative chemotherapy and hepatic resection for resectable colorectal liver metastases

The role of perioperative chemotherapy in the management of initially resectable colorectal liver metastases (CRLM) is still unclear. The EPOC trial [the European Organization for Research and Treatment of Cancer (EORTC) 40983] is an important study that declares perioperative chemotherapy as the standard of care for patients with resectable CRLM, and the strategy is widely accepted in western countries. Compared with surgery alone, perioperative FOLFOX therapy significantly increased progression-free survival (PFS) in eligible patients or those with resected CRLM. Overall survival (OS) data from the EPOC trial were recently published in The Lancet Oncology, 2013. Here, we discussed the findings and recommendations from the EORTC 40983 trial.     

Intraportal chemotherapy in colorectal carcinoma as an adjuvant modality

Liver metastases of colorectal origin arise from malignant cells entering the portal venous circulation. Four hundred sixty patients from 7 participating institutions have been entered in a prospective randomized trial to assess the value of adjuvant portal venous infusion to prevent liver metastases following curative colorectal cancer surgery. By preoperative randomization, patients were assigned to surgery alone (control arm) or to portal liver infusion with 5-fluorouracil (5-FU) (500 mg/m² daily × 7, continuous infusion during the first 7 postoperative days) and mitomycin C (10 mg/m², 24 hours postoperatively as a 2-hour infusion). A portal venous catheter was placed through any side branch of the mesenteric venous system during laparotomy for the primary tumor. Using the transabdominal route, there have been no catheter-related complications. Despite a large cumulative dose of 5-FU given during the immediate postoperative period, the systemic side effects were minimal. Overall hospital mortality in this study was 1.85% and was not influenced by the adjuvant treatment. This rate is considerably lower than that reported by previous multicenter trials and by the surgical literature, and it indicates an advance in surgical technique and pre-/postoperative patient management in this type of elective surgery.Three hundred seventy-eight patients (187 controls, 191 infusion patients) are completely evaluable for recurrence and survival. After a median follow-up of 24 months, 43 recurrences have been observed in the control group and 34 in the infusion group (p<0.05). Liver metastases were present in 18 control patients and in 14 infusion patients. Twenty-five patients in the control group and 18 patients in the infusion group died of recurrent disease. Due to the low number of recurrences in this study, it is too early to draw survival conclusions. Several controlled trials using adjuvant portal infusion are in progress. They also showed the feasibility of this approach and they suggested that adjuvant cytotoxic liver infusion may reduce the incidence of liver metastases without significantly increasing morbidity and mortality. It is too early, however, to recommend adjuvant portal infusion outside a clinical trial setting and such treatment should still be restricted to well-designed prospective protocols.

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Resumen Las metástasis hepáticas de origen colorrectal se originan en células malignas que ingresan a la circulación venosa portal. Cuatro cientos sesenta pacientes de 7 instituciones participantes han sido introducidos a un ensayo clínico prospectivo y aleatorizado para determinar el valor de la terapia adyuvante con perfusión venosa portal en la prevención de las metástasis hepáticas después de cirugía colorrectal curativa. Mediante aleatorización preoperatoria, los pacientes fueron asignados a un grupo manejado con cirugía solamente (grupo control) o al grupo de infusión portal del hígado con 5-fluoruracilo (500 mg/m² diarios × 7 en infusión continua por los 7 primeros días postoperatorios) y mitomicina-C (10 mg/m² por 24 horas postoperatorias como infusión de 2 horas). El catéter venoso portal fue colocado a través de cualquier rama del sistema venoso mesentérico en el curso de la laparotomía para el tumor primario. Con el uso del abordaje transabdominal no se han presentado complicaciones relacionadas con el catéter. A pesar de la elevada dosis acumulativa de 5-FU administrada en el periodo postoperatorio inmediato, los efectos sistémicos han sido mínimos. La tasa global de mortalidad hospitalaria en este estudio es de 1.85% y no aparece afectada por la terapia adjuvante. Esta tasa es considerablemente menor que la informada en ensayos multicéntricos y en la literatura quirúrgica y es indicativa de un avance en la técnica operatoria y en el manejo pre-/postoperatorio de los pacientes en este tipo de cirugía electiva.Tres cientos setenta y ocho pacientes (187 del grupo control, 191 del grupo de infusión) son susceptibles de valoración total en cuanto a recurrencia y supervivencia. Después de un seguimiento promedio de 24 meses, se han presentado 43 recurrencias en el grupo control y 34 en el grupo de infusión (p <0.05). Se presentaron metástasis hepáticas en 18 pacientes del grupo control y en 14 del grupo de infusión. Veinte y cinco pacientes en el grupo control y 18 en el grupo de infusión murieron como consecuencia de enfermedad recurrente. Debido al bajo número de recurrencias observado en el estudio, es todavía demasiado temprano para derivar conclusiones en cuanto a supervivencia.Varios ensayos clínicos controlados utilizando infusión portal adyuvante están siendo realizados; también han demostrado la factibilidad de este enfoque y sugieren que la infusión hepática con agentes citotóxicos puede reducir la incidencia de metástasis hepáticas sin que haya un aumento significativo en la morbilidad o mortalidad. Sin embargo, es todavía muy pronto para poder recomendar la terapia adyuvante con infusión portal por fuera del marco de los ensayos clínicos y tal forma de tratamiento debe permanecer restringida a protocolos prospectivos debidamente diseñados.

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Résumé Les métastases hépatiques des cancers colo-rectaux trouvent leur origine dans les cellules malignes qui pénètrent dans la circulation portale. Quatre cent soixante malades provenant de 7 institutions ont constitué la base d'un essai prospectif randomisé destiné à évaluer la valeur d'une perfusion portale à l'aide d'un agent chimique dont le but est de prévenir les métastases après chirurgie curative du cancer colo-rectal. En préopératoire, les malades ont été choisis au hasard pour constituer 2 groupes: (a) malades traités par la chirurgie (groupe de contrôle), (b) opérés recevant une perfusion portale de 5-FU (500 mg/m²/jour × 7) infusée continuement les 7 premiers jours post-opératoires et de mitomycine C (10 mg/m²/24 heures après l'intervention) pendant 2 heures. Le cathéter veineux portal fut placé dans une collatérale quelconque du système veineux mésentérique au cours de l'opération. Il n'y eut aucune complication dûe au cathéter intra-abdominal. Malgré une dose importante de 5-FU administrée dans la période post-opératoire immédiate, les effets secondaires systémiques furent minimes. La mortalité globale au cours de l'hospitalisation fut de 1.85% et sans relation avec la chimiothérapie. Ce taux est remarquablement inférieur à ceux rapportés par de multiples centres ou dans la littérature. Il est l'expression d'un progrès dans la technique chirurgicale et les soins pré- et postopératoires.378 malades (groupe de contrôle: 187, perfusés: 191) ont permis une évaluation exacte de la récidive et de la survie. Après un suivi moyen de 24 mois, il a été observé 43 récidives dans le groupe de contrôle et 34 dans le groupe traité (p<0.05). Des métastases hépatiques furent découvertes 18 fois dans le premier groupe et 14 fois dans le second. Les malades moururent de récidive 25 fois dans le groupe de contrôle et 18 fois dans le groupe traité par perfusion. En raison du faible nombre des récidives dans cette étude il est trop tôt pour tirer des conclusions sur la durée de la survie.Plusieurs essais contrôlés de traitement par perfusion portale sont en cours. Ils montrent également que la méthode peut être pratiquée et ils suggèrent que la perfusion hépatique par un agent cytotoxique peut réduire le nombre des métastases sans augmenter significativement la morbidité et la mortalité. Il est trop tôt cependant pour recommander la pratique courante de cette méthode. Elle reste sous essai clinique contrôlé et doit s'appliquer seulement à partir de protocoles prospectifs bien définis.

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See Acknowledgment for principal investigators.     

Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases

Background: Although the survival benefit of hepatic resection for colorectal metastasis has been established, some controversy remains regarding the significance of adjuvant chemotherapy after hepatic resection. Methods: One hundred thirty-two consecutive patients who had liver resection for colorectal metastasis at our hospital between 1980 and 1997 were studied. After curative hepatic resection, 37 patients underwent systemic chemotherapy, administered orally or intraportally. Forty patients had no adjuvant chemotherapy. The chemotherapeutic agents used for oral administration were uracil and Tegafur or Tegafur alone. Mitomycin C (MMC) or 5-FU was used for IV chemotherapy. Combinations of 5-FU/leucovorin or MMC/5-FU (doxorubicin) were used for regional chemotherapy. Univariate and multivariate analyses were applied to test the significance of adjuvant chemotherapy for patient survival or disease-free survival. Results: Overall 5-year survival was 42.2% (95% CL: 31.2%, 53.2%). Among the possible prognostic factors studied, univariate analysis showed a significant difference in survival based on the number of tumors and lymph node metastases in the hepatic hilum. There was a significant difference in disease-free survival based on adjuvant chemotherapy and lymph node metastasis. The multivariate analysis for patient survival selected four prognostic factors (P<.05), including adjuvant chemotherapy, lymph node metastasis, disease-free interval, and tumor size. The multivariate analysis for disease-free survival selected adjuvant chemotherapy, lymph node metastasis, and disease-free interval as significant factors. The most common recurrence site was remnant liver, regardless of adjuvant chemotherapy. Conclusions: Adjuvant chemotherapy significantly improved survival and disease-free survival after hepatic resection for colorectal metastases. It did not decrease recurrence rate in the remnant liver.Presented at the 51st Annual Cancer Symposium of The Society of Surgical Oncology, San Diego, California, March 26–28, 1998.     

Management of hepatic metastases from colorectal cancer: Systemic chemotherapy

The current phase III studies of chemotherapy in advanced colorectal cancer include 60% to 85% of patients with the liver as a site of metastatic disease. Within the past 10 years, various modulatory combinations of 5-fluorouracil (5-FU) with agents such as leucovorin, interferon, N-(phosphonacetyl)-L-aspartate (PALA), and methotrexate have produced higher response rates than 5-FU alone. A major sevenarm study, conducted by the Southwestern Oncology Group and reported in 1995, suggested that singleagent, continuous-infusion 5-FU demonstrated the most encouraging results. Nine of 12 reported randomized studies comparing the combination of 5-FU and leucovorin with 5-FU alone report significant increases in response rates; two studies reported significant increases in survival. The meta-analysis project involving 1381 patients confirmed the increase in response rate with the combination (23%) vs. 5-FU alone (11%) but did not demonstrate any significant difference in median survival. The current issues involving 5-FU administration largely concentrate on the best approach (modulation vs. scheduling) and comprehensive evaluation of end points (quality of life, survival, and pharmacoeconomics). The current literature examining quality-of-life issues suggests that 5-FU and low-dose leucovorin produce the best overall improvement in symptoms. Others argue that continuous-infusion scheduling is also associated with a very good quality of life (although the increased cost and morbidity of continuous-infusion administration has to be factored into this consideration). An important phase III study is currently being conducted by the national Cancer Institute of Canada comparing immediate vs. delayed (until symptomatic) chemotherapy in patients with advanced colorectal cancer. Of the new approaches to therapy, perhaps the most immediately applicable are the new thymidylate synthase inhibitors (in patrticular, Tomudex, which produces a response rate equivalent to that of 5-FU plus leucovorin with less toxicity and a more convenient schedule). Presented as part of the SSAT Consensus Conference on the Treatment of Hepatic Metastases From Colorectal Cancer, San Francisco, Calif., May 19–22, 1996.     

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.     

Surgery for multiple hepatic colorectal metastases

The purpose of this review is to address three important questions concerning hepatic resection for multiple colorectal metastases. (1) Is the number of tumors truly a significant prognostic factor? (2) Are patients with four or more tumors contraindicated for hepatic resection? (3) Up to how many nodules should we attempt to resect? Although the efficacy of surgical resection for one to three hepatic metastases is clear, based on several reports, the literature regarding the resection of four or more metastatic lesions is conflicting. Review of the data at our institutions showed that the number of tumors was a significant prognostic factor, because patient survival after liver resection for multiple metastases was worse than that for single metastasis. However, patients with two or three nodules and those with four or more nodules showed the same survival curves, or those with four or more metastases fared even better. Therefore, patients with four or more metastases should be considered for hepatic resection. The maximum number of hepatic tumors in longterm survivors reported in the literature has been increasing, and the limit for the number of respectable metastases has not yet been determined. Because liver resection is still the only treatment that offers a cure, surgery for multiple metastases may be justified as long as the operation is safe and technically feasible.     

Safety of hepatic resection for colorectal metastases in the era of neo-adjuvant chemotherapy

Purpose  

The relationship between neo-adjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases and post-operative morbidity still has to be clarified.     

Percutaneous radiofrequency ablation of colorectal hepatic metastases - initial experience. An adjunct technique to systemic chemotherapy for those with inoperable colorectal hepatic metastases

BACKGROUND AND AIM: Most patients with hepatic metastases from colorectal carcinoma are unsuitable for resection. Radiofrequency ablation (RFA) has been applied to such lesions at laparotomy. This study aimed to evaluate the less invasive approach of percutaneous RFA. METHOD: Patients with unresectable liver metastases identified on cross-sectional imaging were considered for percutaneous RFA either alone or in combination with systemic chemotherapy. Subjects with >6 lesions or lesions of maximum size >70 mm were excluded. Percutaneous RFA was applied under sedation and radiological guidance (CT/US). Treatment effect was determined by follow-up imaging. Actuarial survival was calculated by the Kaplan-Meier analysis. RESULTS: Thirty patients (21 males), median age 74.5 years (range 44-85 years), underwent percutaneous RFA to 56 lesions during 54 treatment sessions. The median size of lesion was 30 mm (range 8-70 mm). Fifteen lesions were treated more than once because of recurrence or incomplete ablation. The median ablation time per lesion was 12 min (range 4.5-36 min). Eleven patients had pre-procedural chemotherapy and 15 patients received chemotherapy after treatment. There was minimal associated morbidity (5.6% of treatments). Median hospital stay per treatment was 1 day (range 1-7). Median actuarial survival from the date of first percutaneous RFA was 22 months (95% CI 12.9-31.1 months). Eleven patients were alive at the time of data collection. CONCLUSION: Percutaneous RFA is a safe, well-tolerated intervention for unresectable hepatic metastases which can be repeated, if required. The technique may be associated with prolonged survival in this selected group of subjects. Future studies should consider the role of percutaneous RFA either in place of or as an adjunct to palliative chemotherapy.     

Repeat hepatic resections for colorectal metastases

We identified 106 patients who had undergone complete resection of isolated colorectal hepatic metastases. Nine of these patients subsequently underwent repeat liver resections for isolated hepatic recurrences. The median follow-up for these patients was 21 months. One postoperative death was related to the second hepatectomy. At the time of last follow-up, five patients were alive and free of recurrent disease at 9, 19, 31, 50, and 67 months after their second hepatic resection. The remaining three patients were alive, but disease had recurred 11 months after resection in the first patient, 12 months after resection in the second, and 18 months after resection in the third. Among these three patients, two had solitary pulmonary nodules, which were resected, and one had unresectable liver disease. Our experience and a review of the literature suggest that repeat hepatic resection for isolated colorectal metastases can result in long-term survival in selected patients.     

Parenchyma-preserving hepatic resection for colorectal liver metastases

Background  

Hepatic resection of colorectal liver metastases is the only curative treatment option. As clinical and experimental data indicate that the extent of liver resection correlates with growth of residual metastases, the present study analyzes the potential benefit of a parenchyma-preserving liver surgery approach.     

Regional chemotherapy for colorectal hepatic metastases: Evidence for improved survival with new drug combinations

Background: In patients with colorectal hepatic metastases, response rates with hepatic arterial infusion (HAI) FUdR (5-Fluoro-2-deoxyuridine) are significantly higher than with systemic fluoropyrimidines. We report a novel animal model of intrahepatic therapy for hepatic metastasis for the study of methods to increase response rates and improve survival. Methods: BD-IX rats are injected intrasplenically with K12/TRb cells. When hepatic metastases are established, animals are treated with hepatic or systemic chemotherapy, and the response to treatment, survival, and cause of death is determined. Results: Significant responses were observed with low- and high-dose HAI FUdR (p=0.03 and 0.001, respectively). Only high-dose FUdR controlled hepatic disease. HAI FUdR alone did not prolong survival compared with control, but combination systemic FUdR and HAI FUdR did (p=0.04). Continuous HAI of either 5-fluorouridine or mitomycin C has not previously been reported. There was no significant difference in response to FUdR, 5-fluorouridine, or mitomycin C. However, combination HA bolus mitomycin C plus either HAI 5-fluorouridine or HAI mitomycin C showed synergy with improved survival compared with all other treatment groups (p<0.0001). Conclusions: The combination of bolus hepatic artery mitomycin C with either HAI mitomycin C or HAI 5-fluorouridine yields significant response rates, and survival is improved by this novel combination therapy.     

Major hepatic resection for colorectal liver metastases

A 6 1/2 year experience in the management of hepatic colorectal metastases in a specialist unit is reviewed. During the period studied, 48 patients were referred of whom only 24 actually came to resection. There were two in-hospital deaths, at 20 and 60 days, and six patients had non-fatal complications. Although the extent of resection was greater than in most reported series (13 right hepatectomies and 6 extended right hepatectomies), the results of resection were broadly the same as those of others, with a median survival of 30 months and 2 and 3 year survivals of 50 and 44 per cent respectively. A number of factors which others have considered to be of prognostic significance were examined. Tumour clearance was the only important prognostic indicator, where a 5 mm clear margin between the tumour and cut surface produced a significant difference in survival. It is suggested that a much larger number of patients in the UK with hepatic colorectal metastases might be considered for resection.     

Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer

BACKGROUND: Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases. METHODS: Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival. RESULTS: There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater. CONCLUSIONS: IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.     

Percutaneous hepatic venous isolation and extracorporeal charcoal hemoperfusion for high-dose intraarterial chemotherapy in patients with colorectal hepatic metastases

The results of treating 12 consecutive patients with unresectable colorectal hepatic metastases with a hepatic arterial infusion of high-dose Adriamycin, 100–120 mg/m², using hepatic venous isolation (HVI) and charcoal hemoperfusion (CHP) are reported herein. Adriamycin was administered over 5–15 min under extracorporeal drug elimination by HVI-CHP. HVI was percutaneously accomplished by either the double-balloon technique using a Fogarty occlusion catheter (8/22F) or a balloon-tipped catheter (16F). During the infusion, isolated hepatic venous blood was filtered by CHP and pumped into the left axillary vein. There were no lethal complications, and good hemodynamic tolerance to HVI-CHP was confirmed. Tumor liquefaction accompanied by a sharp decrease in serum carcinoembryonic antigen levels by more than 50% of pretreatment levels was observed in 6 of the 12 patients 1 month after treatment. Apart from chemical hepatitis, which developed in 11 (92%) of the patients, the Adriamycin toxicities were well controlled following the development of nausea and vomiting in 2 patients (17%), leukopenia <2,000/mm³ in 3 (25%), and gastric ulcer in 1 (8%). These results indicate that this method is a safe and useful procedure for otherwise hazardous high-dose intraarterial chemotherapy in patients with unresectable hepatic tumors.