Infusional versus systemic chemotherapy for liver metastases from colorectal cancer

It is clear from these studies that intrahepatic arterial infusion of floxuridine produces significantly higher response rates than does systemic infusion of the same drugs. Nevertheless, survival is the most important consideration when comparing two methods of treatment, and at present, there is only a slightly improved survival rate in those patients who receive intrahepatic infusional therapy. However, palliation of the patient and the effect on the quality of life should be taken into account, and these high response rates suggest an effective palliative measure to be offered to patients with this advanced disease. It is hoped that in the future the development of methods to identify those patients who will respond to this form of therapy, together with new ways to increase drug uptake by the tumors, will translate the better response rates achieved into better survival rates.     

Infusion pumps for systemic and intra-arterial chemotherapy of colorectal liver metastases.

Over a 12 month period, we prospectively evaluated the use of an ambulatory infusion pump for intra-arterial and intravenous chemotherapy in patients with colorectal liver metastases. In all, 274 separate infusions were given with minor complications occurring on six occasions. Administering treatment on an outpatient basis rather than as an inpatient has resulted in savings of over Pounds 17000 in the first year.     

Regional chemotherapy of diffuse liver metastases of colorectal cancer]

From 1970 to 1987, a total of 112 patients underwent regional chemotherapy as primary treatment of colorectal liver metastases. 68 patients received 250-750 mg 5-FU 2-3 times per week via external devices, 40 patients with port catheters had 5-day courses of Mitomycin C (8 mg/m2/day 1) and 5-FU (600 mg/m2/day 1-5) at 4 week intervals, and four patients were treated with FUDR (0.2 mg/m2/day 1-14/28) using an Infusaid pump. Median and maximum survival were 13.2 and 58 months, respectively. The overall response rate in patients suitable to imaging criteria who underwent treatment for more than three months and was 83% (CR 14%, PR 40%, SD 29%). The influence of various factors on Kaplan/Meier survival was checked the Logrank test. Response to treatment was of superior importance (p = 0.0000016), but hepatomegaly, Karnofski index, the percentage of liver volume replaced by tumour, and various liver related biochemical tests were also highly significant prognostic determinants (p greater than 0.01). There was no difference between external and fully implantable devices. A subgroup of 68 patients without extrahepatic disease, treatment of more than three months was retrospectively compared to 121 untreated patients with a similar stage of disease. There was no obvious effect of regional chemotherapy on survival (p = 0.16). Although the untreated patients consist a historical control group only, this result indicates that regional chemotherapy must continuously be restricted to well prospective clinical trials.     

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.     

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 for colorectal hepatic metastases

One-third of colorectal cancer patients suffer from liver metastases on initial diagnosis. Overt liver metastases appear to be the first site of relapse for 40% to 50% of the patients with operable disease. The fact that tumor cells can be discovered in the mesenteric blood during surgery may indicate that circulating tumor cells give rise to metastases. Experimental investigations have shown that metastatic tumors reaching a diameter of 5 to 7 mm are predominantly perfused by the arterial route, which explains the unsuccessful attempts to treat established liver metastases through the portal vein. However, because metastases in the liver presumably arise via blood flow through the portal vein, adjuvant intraportal chemotherapy might permit ready access of the drug to small liver deposits in a way that systemic chemotherapy might not. The interest in portal adjuvant cytotoxic liver infusion in radically resected colorectal cancer patients is based on an early publication by Taylor, who in 1979 reported on a significant reduction of the incidence of liver metastases in a group of patients randomly assigned to perioperative adjuvant portal infusion with 5-fluorouracil. Based on these results, several groups initiated prospective randomized trials comparing intraportal infusion of various regimens to surgery alone. Results of most of these trials have been published during the last few years. All but one demonstrate improved overall survival and disease-free survival and a reduction of the incidence of liver recurrences in the adjuvant-treated patient group. Ongoing meta-analyses of the randomized trial data may confirm this tendency soon.

---

Resumen La tercera parte de los pacientes con cáncer colorrectal exhibe metástasis hepáticas en el momento del diagnóstico. Evidentes metástasis en el hígado son el primer lugar de recidiva en 40% a 50% de los pacientes con enfermedad operable. El hecho de que se puedan hallar células tumorales en la sangre mesentérica en el curso de la cirugía puede ser indicativo de que sean las células circulantes as que dan lugar a las metástasis. Estudios experimentales han demostrado que los tumores metastásicos que llegan a diámetros entre 5 y 7 mm son predominantemente perfundidos por la ruta arterial. Esto explica los intentos fallidos de tratar las metástasis hepáticas establecidas a través de la vena porta. Sin embargo, puesto que las metástasis en el hígado presumiblemente se inician por vía del flujo sanguíneo de la vena porta, la quimioterapia intraportal coadyuvante podría permitir el fácil acceso de la droga a los depósitos hepáticos más pequeños en forma no puede ser lograda por la quimioterapia sistémica. El interés en la infusión portal citotóxica coadyuvante en el cáncer colorrectal radicalmente resecado se fundamenta en una publicación de Taylor quien, en 1979, reportó una reducción significativa de la incidencia de metástasis hepáticas en un grupo de pacientes aleatoriamente asignados a infusión portal perioperatoria coadyuvante con 5-Fluorouracilo. Con case en estos resultados, varios grupos han iniciado ensayos prospectivos y randomizados para compara diversos regímenes de infusión intraportal con cirugía sola. Los resultados de la mayoría de estos ensayos han sido publicados en los últimos pocos años y todos, menos uno, demuestran una majoría tanto en la sobrevida global como en la sobrevida libre de enfermedad, así como reducción en la incidencia de recurrencias hepáticas en los pacientes tratodos con la modalidad coadyuvante. Los metaanálisis de la información de los ensayos clínicos randomizados actualmente en progreso pueden confirmar pronto tal tendencia.

---

Résumé Un tiers des patients atteints d'un cancer colorectal ont également des métastases hépatiques lorsqu'ils sont vus pour la première fois. Quarante à 50% de patients traités pour cancer colorectal avec intention de guérison récidivent avec des métastases hépatiques. La détection des cellules tumorales dans le sang du système porte est peut-être annonciateur de leur pouvoir de métastaser au niveau du foie par la suite. Des investigations expérimentales ont démontré que les tumeurs métastatiques ayant déjà atteint un diamètre de 5 à 7 mm sont essentiellement perfusées par voie artérielle. Ceci explique les essais infructueux de traiter par voie portale des métastases hépatiques établies. Comme ces métastases se «greffent» au niveau du foie par voie porte, cependant, une chimiothérapie adjuvante par voie porte pourrait influencer l'évolution des petites métastases hépatiques plus efficacement que par voie systémique. L'intérêt d'un traitement cytotoxique par voie porte après chirurgie à visée curatrice pour cancer colorectal est basé sur une publication de Taylor qui, en 1979, rapportait une réduction significative de l'incidence des métastases hépatiques chez des patients ayant eu de façon randomisée du 5-FU par voie porte dans la période périopératoire. D'après ces résultats, plusieurs groupes ont commencé des études randomisées comparant l'infusion intraportale de différentes combinaisons de chimiothérapie à la chirurgie seule. Les résultats de la plupart de ces études ont été publiés pendant ces dernières années et toutes sauf une ont démontré une amélioration de la survie globale et sans maladie ainsi qu'une réduction de l'incidence des métastases hépatiques dans le groupe traités par chimiothérapie. Les méta-analyses actuellement en cours vont peur-être confirmer cette tendance.

     

Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver

BACKGROUND: The role of neoadjuvant chemotherapy for patients with multiple (five or more) bilobar hepatic metastases irrespective of initial resectability is still under scrutiny. The purpose of this study was to compare the outcome of hepatectomy alone with that of hepatectomy after neoadjuvant chemotherapy for multiple bilobar hepatic metastases from colorectal cancer. METHODS: Retrospective data were collected from 71 patients after hepatectomy for five or more bilobar liver tumours. The outcome of 48 patients treated by neoadjuvant chemotherapy followed by hepatectomy was compared with that of 23 patients treated by hepatectomy alone. RESULTS: Patients who received neoadjuvant chemotherapy had better 3- and 5-year survival rates from the time of diagnosis than those who did not (67.0 and 38.9 versus 51.8 and 20.7 per cent respectively; P = 0.039), and required fewer extended hepatectomies (four segments or more) (39 of 48 versus 23 of 23; P = 0.027). Multivariate analysis showed neoadjuvant chemotherapy to be an independent predictor of survival. CONCLUSION: In patients with bilateral multiple colorectal liver metastases, neoadjuvant chemotherapy before hepatectomy was associated with improved survival and enabled complete resection with fewer extended hepatectomies.     

大肠癌肝转移术前化疗后的最佳手术时机

化疗联合手术治疗已逐渐成为结直肠癌肝转移病人的标准治疗方式。对于可切除的大肠癌肝转移病人是否需要术前化疗仍存在争议。存在预后不良因素时应接受术前化疗,术前化疗不应＞6周期。不可切除的肝转移病人均应接受术前化疗,术前化疗后定期复查,如转化为可切除,应立即切除。一般认为,停用化疗4周后可以手术切除肝转移灶,但如果联合贝伐单抗,应在停止治疗6~8周后进行手术。     

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.     

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.     

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.     

结直肠癌肝转移的外科治疗

外科手术是治疗结直肠癌肝转移的重要手段。手术切除的适应证已扩展至满足肝内肿瘤能全部切除、切缘阴性、肝脏储备功能足够即可;而手术切除联合局部治疗进一步扩大了手术适应证。转移癌及原发癌一期或二期手术的远期生存率比较,差异无统计学意义。腹腔镜手术治疗结直肠癌肝转移安全可行,疗效确切。围手术期辅助化疗疗效并不明确,新辅助化疗可能不会使所有患者都受益。     

Repeat hepatectomy for colorectal liver metastases

This study includes 16 patients (9 men, 7 women; mean age 64 years) who underwent a total of 19 repeat hepatectomies for metastasis after colon (n=7) or rectal (n=9) carcinoma. All patients were reoperated for recurrent liver metastasis after the first resection (mean, 21 months; range, 7-40 months), and three had a third hepatectomy 13, 24, or 65 months after the second. Perioperative mortality was 0% and morbidity was 37%. The 3- and 5-year survival rates after the second resection were 56.8% and 28.4%, respectively, with a median survival of 42.3 months. Seven patients died (mean survival, 25.7 months; range, 9-58 months) before the end of the study. Six patients were alive with one or more recurrences, and three (24, 51, and 173 months of follow-up) were alive without known recurrence. Survival rates for repeat resections of colorectal liver metastases in selected patients were comparable with those obtained after resection of a first liver metastasis.     

Non-resection approaches for colorectal liver metastases

The field of in situ destruction of liver tumors has expanded rapidly with various institutions' results suggesting that these methods represent viable palliative options, primarily because of the low associated morbidity and mortality. Despite this enthusiasm, clinical trials are needed to determine the true nature and degree of palliation. Treating a systemic disease such as colorectal liver metastases with local therapy strategies alone is of dubious value. In fact, it has been shown by most reports that the limiting factor inpatient outcome is disease progression rather than technical failure. For optimal results, physicians performing in situ ablation of liver lesions should be familiar with tumor biology and the natural history of the malignancy, and possess expertise in proper integration of other therapeutic modalities (eg, systemic chemotherapy and hepatic artery chemotherapy). Patients with liver metastases from colorectal carcinoma should therefore be evaluated for curability by a surgical oncologist within the context of a multidisciplinary team, as surgical resection remains the best treatment to achieve long-term survival. Such an assessment offers the patient the opportunity of a tailored therapy that may consist of hepatic resection, intravenous or regional chemotherapy, and local ablative therapy. Furthermore, results of RF ablation should be reported in terms of well-established oncological outcomes (eg, overall survival, disease-free survival, progression-free survival) that are more meaningful to the patient, rather than lesion-oriented outcomes. Because most of the ablative techniques have not yet been validated, it is imperative that well-designed clinical trials are conducted under the auspices of national cooperative groups. To consider them standard independent therapies otherwise would be premature.     

Cytotoxic perfusion for colorectal liver metastases

A clinical trial to assess the value of different perfusion techniques in the management of colorectal liver metastases is presented. The perfusion with 5-fluorouracil was commenced at the time of resection of the primary tumour when palpable liver metastases were found. In terms of survival, no benefit was found with hepatic artery ligation and perfusion and with portal vein perfusion alone compared with the control group. However, the combination of the two improved the survival rate and a possible explanation for this is discussed.