Hepatic cryosurgery for liver metastases. Long-term follow-up. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Treatment of liver metastases from colorectal cancer with hepatic artery occlusion, intraportal 5-fluorouracil infusion, and oral allopurinol. A randomized clinical trial. 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) Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Clinical outcomes of hepatic resection and radiofrequency ablation in patients with solitary colorectal liver metastasis. Comparative study of resection and radiofrequency ablation in the treatment of solitary colorectal liver metastases. Resection versus laparoscopic radiofrequency thermal ablation of solitary colorectal liver metastasis.
The aim of this prospective study was to evaluate the applicability of cryogenic and conventional surgery in treating liver metastases (LM) with respect to intraoperative tumor reduction and survival rate.
                As have been shown in animal experiments as well as in clinical investigations, cryosurgery has been used for the treatment of many benign and malignant conditions. For the first time, this report summarizes a 10-year follow-up clinical experience with cryosurgery for treatment of LM from 1983 to 1992.
                One hundred twenty-three patients with LM (87 males and 36 females, a ratio 2.4:1.0; age, 41.3 +/- 12.1 years) were stratified and entered into a long-term prospective, randomized clinical trial for cryogenic surgery in group 1 (n = 63) and conventional surgical techniques in group 2 (control subjects, n = 60). Principally, a self-constructed cryogenic clamp was used for hepatic cryoresection with preliminary freezing of the margin resection by a cryosurgical system "Cryoelectronic-2" or "Cryoelectronic-4". Hepatic cryoextirpation (cryoablation) and hepatic cryodestruction were performed by means of probes of different roughly disk design from phi 5 mm to 55 mm by volume of frozen zone of 40 cm3 to 180 cm3 for approximately 7 to 32 minutes.
                In most cases in group 1 and group 2, LM were based on colorectal cancers (65% vs. 68%). The hepatic cryosurgical procedures in group 1 included cryoextirpation (29 patients, 46%), cryoresection (20 patients, 32%), and cryodestruction (14 patients, 22%) solely. Clinical and laboratory parameters showed that the curative effects were significantly higher in group 1 than in group 2. The 3-year survival rate was in group 1 and group 2 (60% vs. 51%, respectively). The 5-year survival rate was 44% in group 1 and 36% in group 2. Twelve patients (19%) versus 5 patients (8%) in group 1 and group 2, respectively, survived 10 years. The disease-free survival was in group 1 and group 2 (30% vs. 18%, respectively). During a follow-up period, recurrence in the liver was observed in 54 patients (85%) in group 1 and in 57 patients (95%) in control subjects. After a 10-year follow-up period in group 1 and group 2, 9 patients (14%) versus 3 patients (5%) remained disease free, 3 patients (4%) versus 2 patients (3%) were surviving with disease, and 51 patients (81%) versus 55 patients (92%) died.
                The data of this 10-year prospective, randomized clinical trial suggest that hepatic cryosurgery is effective in the treatment of resectable and nonresectable LM. The results show intraoperative tumor reduction (> or = 90% < or = 97%) and extended higher survival in these patients. The study indicated a 5-year and 10-year survival rate of 44% and 19% after cryosurgery, respectively. Despite technical improvements that have minimized the morbidity and mortality of hepatic surgery, the long-term outcome of resection of hepatic metastases of colorectal cancer remains poor, with the majority of patients experiencing treatment failure in the liver. Because arterial chemotherapy regimens targeted to the liver have demonstrated high response rates, an intergroup trial of adjuvant therapy for patients undergoing hepatic resection of liver metastases from colorectal cancer was initiated.
                Patients with one to three potentially resectable metastases were randomized preoperatively to receive no further therapy (control arm, 56 patients) or postoperative hepatic arterial floxuridine combined with intravenous continuous-infusion fluorouracil (chemotherapy arm, 53 patients). After exclusion of patients identified as ineligible for the planned treatment at the time of surgery, there were 45 control patients and 30 on the chemotherapy arm. The study was powered to evaluate improvement in time to recurrence and hepatic disease-free survival, not overall survival.
                The 4-year recurrence-free rate was 25% for the control arm and 46% for the chemotherapy group (P =.04). The 4-year liver recurrence-free rate was 43% in the control group and 67% in the chemotherapy group (P =.03). The median survival of the 75 assessable patients was 49 months for the control arm and 63.7 months for the chemotherapy arm (P =.60). The median survival of all 109 patients was 47 months for the control arm compared with 34 months for the chemotherapy arm (P =.19)
                These data demonstrate that adjuvant intra-arterial and intravenous chemotherapy was beneficial in prolonging time to recurrence and pre-venting hepatic recurrence after hepatic resection of colorectal cancer. The majority of patients with primary or metastatic malignancies confined to the liver are not candidates for resection because of tumor size, location, multifocality, or inadequate functional hepatic reserve. Cryoablation has become a common treatment in select groups of these patients with unresectable liver tumors. However, hepatic cryoablation is associated with significant morbidity. Radiofrequency ablation (RFA) is a technique that destroys liver tumors in situ by localized application of heat to produce coagulative necrosis. In this study, we compared the complication and early local recurrence rates in patients with unresectable malignant liver tumors treated with either cryoablation or RFA.
                Patients with hepatic malignancies were entered into two consecutive prospective, nonrandomized trials. The liver tumors were treated intraoperatively with cryoablation or RFA; intraoperative ultrasonography was used to guide placement of cryoprobes or RFA needles. All patients were followed up postoperatively to assess complications, treatment response, and local recurrence of malignant disease.
                Cryoablation was performed on 88 tumors in 54 patients, and RFA was used to treat 138 tumors in 92 patients. Treatment-related complications, including 1 postoperative death, occurred in 22 of the 54 patients treated with cryoablation (40.7% complication rate). In contrast, there were no treatment-related deaths and only 3 complications after RFA (3.3% complication rate, P<0.001). With a median follow-up of 15 months in both patient groups, tumor has recurred in 3 of 138 lesions treated with RFA (2.2%), versus 12 of 88 tumors treated with cryoablation (13.6%, P<0.01).
                RFA is a safe, well-tolerated treatment for patients with unresectable hepatic malignancies. This study indicates that (1) complications occur much less frequently following RFA of liver tumors compared with cryoablation of liver tumors, and (2) early local tumor recurrence is infrequent following RFA. Regional therapy for colorectal liver metastases aimed at prolonging survival has not been tested fully in a randomized trial with untreated control subjects. This study explored the efficacy of temporary hepatic artery occlusion followed by intraportal infusion of 5-fluorouracil (5-FU) and oral allopurinol as biochemical modulators in prolonging the survival of patients with nonresectable liver metastases and no extrahepatic cancer.
                Eighty-four patients were considered for randomization, of whom 24 were excluded at laparotomy because of extrahepatic cancer (n = 17) or resectable lesions (n = 5). In two patients, no cancer was identified in the liver. Thirty-two patients were allocated to receive treatment, and 28 were allocated to receive no regional or systemic treatment. Six patients were excluded after randomization because of major protocol violations.
                The median survival time for patients was 17 months (range, 0-66), and for control subjects, the median was 8 months (range, 0-31). Log rank analysis demonstrated a significant survival benefit for treatment versus no treatment (P = 0.0039). (In two patients, early death was due to toxicity from the wrong dose of 5-FU and the wrong route of administration, respectively; the mean and median survival were reduced by 1 month).
                This study identified a treatment modality that prolongs survival in patients with nonresectable liver metastases and no extrahepatic metastases from colorectal cancer, suggesting that control subjects receiving no therapy may not be necessary in future randomized trials. 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.
                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.
                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.
                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.
                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. About half the patients treated with curative resection for colorectal cancer do not survive long-term. Adjuvant chemotherapy given during and after surgery may prevent hepatic metastases and improve patient survival. In patients with colorectal cancer, we have done a multicentre, randomised controlled trial comparing five-year survival after intraportal infusion of fluorouracil (1 g per day) plus heparin (10,000 U per day) (130 patients) or heparin alone (123) during curative resection and for 7 days thereafter, or after resection alone (145). There was no reduction in liver metastasis or increased overall survival advantage in either active-treatment arm of the study. However, patients who had stage III, Dukes' C (lymph-node-positive) tumours resected and were treated with fluorouracil plus heparin had a significant (p less than 0.03) survival advantage of about 16% compared with surgery-only controls. Further study of intraportal infusion of chemotherapeutic agent as adjuvant treatment to surgery in patients with colorectal cancer appears worthwhile. The role of the radiofrequency ablation (RFA) in treatment of solitary liver metastasis has not been established yet. Both hepatic resection (HR) and RFA have been used increasingly in the treatment of colorectal liver metastases.
                A systemic review was performed to determine the impact of treatment modality of solitary liver metastasis on recurrence patterns, disease-free survival, and overall survival (OS) rates.
                Solitary liver metastases were treated by HR in 116 patients (75.8%) and 37 patients (24.2%) were treated with RFA. Prognostic factors, recurrence rate, recurrence patterns, and survival rates were analyzed. The cumulative 3-year and 5-year local recurrence free survival rates were markedly higher in the HR group (88.0% and 84.6%) as compared with those in the RFA group [53.3% and 42.6%, respectively (P</=0.001)]. The 5-year OS rate was lower in the RFA group as compared with the HR group without statistical significance (5-year OS, 65.7% in the HR, 48.5% in the RFA group, P=0.227).
                Despite of higher local recurrence rate, RFA may be considered as a therapeutic option for patients who are considered unsuitable for conventional surgical treatment. Randomized prospective controlled trials comparing the therapeutic outcome of RFA and HR are definitely warranted. We compared outcomes in patients with solitary colorectal liver metastases treated by either hepatic resection (HR) or radiofrequency ablation (RFA).
                A retrospective analysis from a prospective database was performed on 67 consecutive patients with solitary colorectal liver metastases treated by either HR or RFA.
                Forty-two patients underwent HR and 25 patients underwent RFA. The 5-year overall and local recurrence-free survival rates after HR (50.1% and 89.7%, respectively) were higher than after RFA (25.5% and 69.7%, respectively) (P = .0263 and .028, respectively). In small tumors less than 3 cm (n = 38), the 5-year survival rates between HR and RFA were similar, including overall (56.1% vs 55.4%, P = .451) and local recurrence-free (95.7% vs 85.6%, P = .304) survival rates. On multivariate analysis, tumor size, metastases treatment, and primary node status were significant prognostic factors.
                HR had better outcomes than RFA for recurrence and survival after treatment of solitary colorectal liver metastases. However, in tumors smaller than 3 cm, RFA can be recommended as an alternative treatment to patients who are not candidates for surgery because the liver metastases is poorly located anatomically, the functional hepatic reserve after a resection would be insufficient, the patient's comorbidity inhibits a major surgery, or extrahepatic metastases are present. There is scant data in the literature regarding radiofrequency thermal ablation (RFA) versus resection of colorectal liver metastases. The aim of this study is to compare the clinical profile and survival of patients with solitary colorectal liver metastasis undergoing resection versus laparoscopic RFA.
                Between 1996 and 2007, 158 patients underwent RFA (n = 68) and open liver resection (n = 90) of solitary liver metastasis from colorectal cancer. Patients were evaluated in a multidisciplinary fashion and allocated to a treatment type. Data were collected prospectively for the RFA patients and retrospectively for the resection patients.
                Although the groups were matched for age, gender, chemotherapy exposure and tumor size, RFA patients tended to have a higher ASA score and presence of extra-hepatic disease (EHD) at the time of treatment. The main indication for referral to RFA included technical reasons (n = 25), patient comorbidities (n = 24), extra-hepatic disease (n = 10) and patient decision (n = 9). There were no peri-operative mortalities in either group. The complication rate was 2.9% (n = 2) for RFA and 31.1% (n = 28) for resection. The overall Kaplan-Meier median actuarial survival from the date of surgery was 24 months for RFA patients with EHD, 34 months for RFA patients without EHD and 57 months for resection patients (p < 0.0001). The 5-year actual survival was 30% for RFA patients and 40% for resection patients (p = 0.35).
                This study shows that, although patients in both groups had a solitary liver metastasis, other factors including medical comorbidities, technically challenging tumor locations and extra-hepatic disease were different, prompting selection of therapy. With a simultaneous ablation program, higher risk patients have been channeled to RFA, leaving a highly selected group of patients for resection with a very favorable survival. RFA still achieved long-term survival in patients who were otherwise not candidates for resection.
On the basis of one randomised clinical trial with high risk of bias, there is insufficient evidence to conclude if in patients with liver metastases from various primary sites cryotherapy brings any significant benefit in terms of survival or recurrence compared with conventional surgery. In addition, there is no evidence for the effectiveness of cryotherapy when compared with no intervention. At present, cryotherapy cannot be recommended outside randomised clinical trials.