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.     

肝细胞癌合并门静脉癌栓的手术切除及疗效观察

目的 探索肝细胞癌合并门静脉癌栓（ＰＶＴＴ）手术切除的疗效及其影响预后因素。方法 总结近１０年１１１例肝细胞癌合并门静脉主干或第一分支癌栓的患者,均行肝癌联同门静脉左或右支癌栓切除或经左、右支断端取栓或切开主干取栓,其中２２例患者切除肿瘤及癌栓后行肝动脉和（或）门静脉插管。３２例患者术后经肝动脉化疗栓塞和（或）经门静脉导管化疗。另１４例ＰＶＴＴ患者仅行保守治疗（非手术组）,２０例ＰＶＴＴ患者行探查     

不同化疗模式及不同给药途径对肝癌合并门静脉癌栓术后化疗作用的比较研究

目的 比较研究不同化疗模式及不同给药途径对肝癌合并门静脉癌栓术后化疗作用及其疗效。方法 56例肝癌合并门静脉癌栓手术切除病人，按术后化疗给药途径不同随机分为：(1)未行化疗组(n＝18)；(2)门静脉置管(PVI)化疗组(n＝19例)；(3)PVI 肝动脉置管(HAI)化疗组(n＝19例)；按术后化疗模式不同随机分为：(1)未行化疗组(n＝18)；(2)推注化疗组(n＝18例)，其中10例经PVI给药，8例经PVI HAI给药；(3)持续灌注化疗组(n＝20例)，其中8例经PVI给药，12例经PVI HAI给药。结果 PVI化疗组和PVI HAI化疗组平均生存时间分别为14个月和17个月，两组比较无显著差异(P＞0．05)，但均明显高于术后未化疗组7个月(P＜0．05)。推注化疗组和持续灌注化疗组的平均生存时间分别为13个月和19个月，两组比较有显著差异(P＜0．05)，均明显高于未化疗组(P＜0．05)。结论 肝癌合并门静脉癌栓术后经PVI化疗或经PVI HAI化疗可明显提高疗效，而持续灌注化疗疗效明显优于推注化疗。     

Experimental studies on the treatment of nonresectable liver cancer

In cases of metastatic cancer of the liver in rats, the effect of ligation of the hepatic artery (HAL) or portal vein (PVL) with or without intraportal chemotherapy with Mitomycin C (MMC) was studied in Experiment I. HAL or PVL alone and chemotherapy alone induced only a slight anti-cancer effect. The most striking effect was found in the group treated with HAL plus MMC. PVL plus MMC produced intermediate results. To evaluate which route,via the hepatic artery or portal vein, is more effective for the adjuvant chemotherapy after HAL, Experiment II was conducted on the rats with a minute and/or a rather advanced metastatic cancer of the liver. Chemotherapy with MMC by either route alone and HAL alone did not substantially prolong the survival time, irrespective of the tumor size. HAL plus chemotherapyvia, both routes produced a statistically longer survival time compared with the control, however, better results were obtained by intraarterial chemotherapy. When compared with the two groups treated by the same procedures but at the different times, the earlier treatments produced better results. In the light of the present studies, it can be concluded that if cytocidal drugs with dose independent effects are given in a single bolus, HAL in connection with intra-arterial chemotherapy is a beneficial modality for the treatment of nonresectable liver cancer.     

超选择置泵灌注化疗在大肠癌中的应用

目的　评价术中超选择靶区动脉置泵 ,术后皮下泵内反复区域性灌注化疗药物治疗大肠癌的临床疗效。方法　对我院 2 93例大肠癌患者 ,经术中选择性肿瘤供血动脉内置泵 ,术后泵内灌注化疗药物的疗效进行回顾性分析 ,其中根治性切除 2 14例 ,晚期不能手术切除 79例。结果　根治性切除组 1年、3年、5年生存率分别为 10 0 %、84 .6 %、57.5% ,局部复发率和肝转移率分别为 13.6 %、12 .1% ;不能手术切除组完全缓解 4例 ;部分缓解 6 2例 ;稳定 13例 ,治疗有效率 (PR CR)为 83.5% ,置泵术后 0 .5年、1年、2年生存率分别为 96 %、86 .6 %、4 4.6 %。结论　超选择动脉置泵灌注化疗是治疗大肠癌的有效方法 ,它可以降低局部复发率和肝脏转移率 ,提高患者生存率。     

Regional chemotherapy of non-resectable liver metastases from colorectal cancer – literature and institutional review

Background: Cure is possible by resecting colorectal isolated liver metastases. In non-resectable isolated colorectal liver metastases (CRLM), regional chemotherapy has been advocated to optimize the disease control in the liver in order to improve the results of the alternative, systemic chemotherapy. The drugs are delivered by means of hepatic artery infusion (HAI) via ports or pumps; pharmacological modifications of the hepatic arterial blood-flow-like HAI with starch microspheres or stop-flow and perfusion techniques were applied to improve HAI. Methods: We reviewed the literature and report our progress, up to May 1999, in analyzing the validity of HAI for CRLM therapy. Results: In the majority of phase-II and -III trials, the response rates to HAI were significantly higher than those from systemic chemotherapy, and local disease control could be achieved even when HAI was used second line to systemic chemotherapy. The meta-analysis of randomized trials comparing HAI with either systemic chemotherapy (five trials) or, optionally, either 5-fluorouracil (FU) or symptomatic treatment (two trials) showed a significant advantage of HAI in response (41% vs 14%, P<10^–10) and median survival time (15 months vs 11 months, P<0.0009). The active anabolite of 5-FU, 5-fluordeoxyuridine (5-FUDR), the drug of choice for HAI in those trials, may cause severe hepatotoxicity. To avoid this toxicity, we developed a HAI protocol using mitoxantrone, 5-FU plus folinic acid (FA) and mitomycin C (MFFM). The response rates of HAI with 5-FU plus FA or MFFM were 45% and 66%, the interim median survival times 19.8 months and 27.4 months. 5-Year survivors were observed in all our protocols. Since no severe hepatotoxicity occurred, 9 of 74 patients were resected after response to HAI with 5-FU plus FA or MFFM, without surgical mortality and with survival times from 2+ months to 58+ months. Conclusion: The high response rates, the long survival times, the possibility of achieving 5-year-survival either by HAI alone or by resection after down staging with HAI all sum up to the evidence that HAI could be the primary choice of treatment for CRLM. Phase-III trials are conducted to compare the protocols with optimal regional versus systemic chemotherapy. Received: 16 June 1999 Accepted: 29 June 1999     

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.     

Hepatic arterial infusion after curative resection of colorectal cancer metastases: A meta-analysis of prospective clinical trials

The use of hepatic arterial infusion (HAI) for the delivery of chemotherapeutic agents to treat residual microscopic disease after curative hepatic resection for colorectal cancer metastases remains controversial. In recent years, a number of studies examining adjuvant HAI have shown conflicting results. A meta-analysis of prospective clinical trials was performed to determine if adjuvant HAI confers a survival benefit in this setting. Tworeviewers independently performed a literature search ofMEDLINE, PubMed, EMBASE, the Cochrane library, and the Cochrane Clinical Trials Registry. Prospective clinical trials comparing hepatic arterial chemotherapy after curative hepatic resection for colorectal cancer metastases against a control arm were included. Non-English-language publications were excluded. The outcome measure was survival difference at 1 and 2 years after surgery. Seven studies met the inclusion criteria, and all except one were randomized trials. The survival difference in months (positive values favoring the treatment arm) was 1.8 at 1 year (95% confidence interval, -4.9, 8.5) and 9.6 at 2 years (95% confidence interval, -2.2, 21.4). Neither was statistically significant (at 2 years, P = 0.11). Based on these findings, routine adjuvant HAI after curative resection for colorectal cancer of the liver cannot be recommended. However, given the trend toward a survival benefit at 2 years, further study is recommended.     

门静脉灌注化疗治疗肝癌伴门静脉瘤栓的临床价值

目的 探讨肝细胞肝癌伴门脉癌栓（tumor thrombi in portal vein,PVTT)外科手术后，门静脉灌注化疗的价值。方法 45例伴门脉主干或I级分支癌栓的肝癌病人，在行手术切除后随机分组，一组行肝动脉化疗，同时行门静脉灌注化疗（治疗组），另一组仅行肝动脉化疗（对照组）。结果 治疗组6，12，18个月生存率分别为85.1%,76.5%和47.2%。对照组为73.3%，59.2%和33.4%，两组比较差异均有显著性（P＜0.05)。结论 肝癌伴PVTT，手术切除术后，为防治门脉癌栓导致肝内转移复发，术中除应尽量取净癌栓组织外，门脉灌注化疗是有效的措施之一。     

Locoregional chemotherapy of liver tumors

Experiences with different protocols of intraarterial chemotherapy in the treatment of primary or secondary liver malignancies in 38 cases were reported. The follow-up period was two years in all patients. Complications due to chemotherapy were observed only in very few patients. In 15 patients complications during chemotherapy from the implantable infusion system (Port a Cath) like leckage (n = 8), thrombosis of the system (n = 4), thrombosis of the hepatic artery (n = 1) and aneurysma of the hepatic artery (n = 2) occurred. Highest survival rates for the first and second year were achieved in patients with resectable liver metastases from colorectal cancer. A prophylactic implantation of an intraarterial catheter can be considered in patients in which a liver resection was performed because of multilocular uni- or bilateral metastases. CEA- and CA-19-9 levels did not correspond to the tumor progress in many cases.     

FOLFOX-6与肝动脉灌注化疗对结直肠癌肝转移治疗效果的比较

目的 比较FOLFOX-6方案全身化疗与传统以氟尿嘧啶为主的肝动脉灌注化疗对结直肠癌术后肝转移病人的疗效并分析影响结直肠癌术后肝转移病人的预后因素.方法 46名结直肠癌术后肝转移病人随机分配到全身化疗组(实验组)和介入治疗组(对照组),对比观察近远期疗效、毒副作用和生活质量.将影响预后的临床特征和治疗方式进行单因素和多因素分析.结果 实验组、对照组总生存率差异有统计学意义(P=0.048),中位生存时间分别为15.0个月和11.2个月(P＜0.05);治疗总有效率两组差异有统计学意义(50%和10%;P=0.011);两组治疗期间的PS评分差异无统计学意义(P=0.126).毒副作用除骨髓抑制、腹痛外,其它比较差异均无统计学意义.单因素分析显示,原发病灶是否浸润浆膜、肝转移灶分布、肝转移病灶最大直径、肝转移灶数目、原发癌有无淋巴结转移以及治疗方式与预后相关.多因素分析后发现,肝转移灶最大直径、肝转移病灶数目、原发癌灶是否浸透浆膜层和治疗模式为影响预后的独立因素.结论 以草酸铂为主的FOLFOX-6方案比传统的以氟尿嘧啶为主的肝动脉灌注化疗有更好的治疗缓解率和远期疗效;肝转移灶最大直径＞5 cm、肝转移灶多发和原发病灶浸透浆膜层提示病人预后不良,采取以草酸铂为主的全身化疗,预后更好.传统药物介人治疗需要改进,局部介入与全身治疗结合的方式值得进一步探究.     

结直肠癌肝转移的治疗分析

目的总结多种方法治疗结直肠癌肝转移的效果. 方法回顾性分析1995年1月至2003年12月收治的120例结直肠癌肝转移患者的治疗及生存情况. 结果 1、3年生存率,手术切除组分别为83.3%和33.3%,经动脉化疗栓塞组分别为50.0%和15.2%,肝动脉插管皮下埋泵术组分别为47.1%和5.9%,冷冻治疗组分别为55.5%和11.1%,综合治疗组分别为86.7%和40.0%. 结论手术是治疗结直肠癌肝转移的最佳方法,以个体化为原则的术后综合治疗可以提高生存率,降低复发率.     

Treatment of hepatocellular carcinoma with associated cirrhosis.

During the recent 10 years, 105 patients with hepatocellular carcinoma were admitted to our clinic. Seventy of them had an associated cirrhosis of the liver. The therapeutic results of these 70 patients were analyzed according to the mode of treatment. The mean survival periods after admission were as follows; No cancer treatment group (12 patients) 79 days, Chemotherapy group regardless of the mode of administration (25 patients) 97 days, Hepatic artery ligation with chemotherapy group (16 patients) 197 days. Hepatic resection was carried out in 17 patients; partial hepatectomy in 5, left lateral segmentectomy in 1, left lobectomy in 3, and right lobectomy in 8. The 50% survival period of all the hepatectomized patients was 8.5 months. Seven patients are living 5 months to 3 years after operation. Five patients died of recurrence of hepatoma between 4 months and 3 years and 2 months postoperatively. Five individuals died of causes related to the operation; two hepatic failure, two fatal infection, and one massive haemorrhage from acute duodenal ulcer. The results indicated that hepatic resection, from partial to extensive, might be possible even in patients with associated cirrhosis but more exact criteria are mandatory in selecting patients for major hepatic resection. Hepatic artery ligation with chemotherapy should be the first choice for those with nonresectable hepatoma. Continuous infusion of oncolytic agents into the hepatic artery may be considered for those in whom arterial ligation is contraindicated.     

Hepatic Cryotherapy and Subsequent Hepatic Arterial Chemotherapy for Colorectal Metastases to the Liver

This paper presents an experience of thirty consecutive patients with hepatic colorectal metastases who were treated with hepatic cryotherapy and subsequent hepatic arterial infusion (HAI) chemotherapy using 5FU.Patients with colorectal metastases confined to the liver but not suitable for resection, and with liver involvement of less than 50% were offered the treatment. Prospective documentation of all patients was undertaken with data being recorded on a computerised database.Patients had a median of 6 (2–15) lesions with sizes ranging from 1–12 cm. There was no 30 day mortality. Postoperative complications developed in 8 patients but were followed by full recovery in all instances. Side effects from chemotherapy occured in 23% of cycles. Twenty seven patients have died. Median survival from the time of cryotherapy was 18.2 months (7–34), or 23months (9–44) from diagnosis of liver lesions.Hepatic cryotherapy with subsequent arterial chemotherapy is safe and well tolerated. The results suggest survival of patients with colorectal hepatic metastases can be improved by the use of this modality of treatment.     

Clinical significance of and future perspectives for hepatic arterial infusion chemotherapy in patients with liver metastases from colorectal cancer

The most common site of metastases in patients with colorectal cancer is the liver. Hepatic resection is considered to be the treatment of choice for liver metastasis from colorectal cancer; however, hepatic resection can be performed in only 20 or 25 % of all patients. Recurrence develops in the remnant liver or other organs after hepatic resection in over half of all patients with liver-only metastasis. Hepatic arterial infusion (HAI) chemotherapy can provide relatively high concentrations of drugs to microscopic or macroscopic metastases in the liver, with less toxicity than systemic administration. Meta-analyses have shown HAI chemotherapy to have a significantly higher response rate than systemic chemotherapy and its effect on extrahepatic metastases is negligible. HAI chemotherapy provides much better local control of liver metastases from colorectal cancer than systemic chemotherapy. However, well-controlled studies are needed to elucidate the optimal treatment strategies for neoadjuvant and postoperative adjuvant chemotherapy that optimally combine HAI chemotherapy, molecular targeted agents, and systemic chemotherapy such as FOLFOX or FOLFIRI.     

Hepatic Arterial Infusion and Systemic Chemotherapy for Breast Cancer Liver Metastases

Hepatic failure from breast cancer liver metastases (BCLM) is a major cause of morbidity and mortality. We reviewed the treatment histories and outcomes of nine patients with heavily treated BCLM, who received hepatic arterial infusion (HAI) of floxuridine (FUDR)/dexamethasone (Dex) and systemic chemotherapy at our institution. Patients received a median of five (range 1–15) HAI treatments. There were seven (78%) objective responses. Four patients had grade 3 elevations in liver enzymes attributable to HAI. There were no treatment‐related deaths. Median hepatic and extrahepatic time to progression on HAI were both 6 months. Median survival after starting HAI was 17 months (range 1–115). Median overall survival from the original breast cancer diagnosis was 110 months (range 52–248). One patient is alive with stable disease on systemic therapy alone. HAI and systemic chemotherapy is feasible and can benefit selected patients with BCLM, who have progressed on prior therapies. Patients require close monitoring for treatment‐limiting toxicities.     

埋植式药泵在肝癌治疗中的应用

目的　探讨对不能切除的肝癌患者术中应用埋植式药泵治疗的临床意义。方法　对2 8例肝癌患者 ,术中作肝动脉和门静脉插管并皮下埋植药泵 ,术中、术后经药泵进行肝脏局部灌注化疗取得了较好的疗效。结果　本组治疗后有效率为 6 4.2 % ,其中生存时间小于 6个月 15例 ,6～12个月 10例 ,12个月以上 3例其中 1例存活 2 2个月以上。结论　肝动脉局部灌注化疗对不能手术切除的晚期肝癌 ,作为治疗手段不失为一种有效的方法。     

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

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

Combination of hepatic arterial infusion and systemic chemotherapy for gastric cancer with synchronous hepatic metastases

Between 1964 and 1981, seventy-two Japanese patients with gastric cancer associated with hepatic metastases, in whom the primary tumor had been resected, were treated in a nonrandomized manner at the Second Department of Surgery, Kyushu University Hospital. Fourteen received hepatic arterial infusion (HAI) of 5-FU and Mitomycin C (MMC) combined with systemic chemotherapy, 26 combination systemic chemotherapy of MMC, Futraful and PSK, 18 single drug (MMC) therapy, and 14 no chemotherapy. The average survival was 264 days in HAI combined with systemic chemotherapy, 208 in the combination systemic chemotherapy, 156 in the single drug therapy and 135 in those given no chemotherapy. One year survival and nine month survival rates were 21.4 per cent and 42.9 per cent in HAI combined with systemic chemotherapy, 11.5 per cent and 19.2 per cent in the combination systemic chemotherapy, 5.6 per cent and 11.1 per cent in the single drug therapy and 7.1 per cent and 14.3 per cent in the no chemotherapy group, respectively (HAI vs single drug therapy and no chemotherapy, p<0.01). Five of 14 patients treated with HAI combined with systemic chemotherapy showed a partial response (>50 per cent reduction in tumor size), and the average survival time was 335 days, while that of nonresponders was 224 days. Six of 14 patients treated with combination infusion therapy with MMC and 5-FU survived 314 days, as compared to 201 days for patients with infusion of 5-FU alone.     

Combination of hepatic arterial infusion and systemic chemotherapy for gastric cancer with synchronous hepatic metastases

Between 1964 and 1981, seventy-two Japanese patients with gastric cancer associated with hepatic metastases, in whom the primary tumor had been resected, were treated in a nonrandomized manner at the Second Department of Surgery, Kyushu University Hospital. Fourteen received hepatic arterial infusion (HAI) of 5-FU and Mitomycin C (MMC) combined with systemic chemotherapy, 26 combination systemic chemotherapy of MMC, Futraful and PSK, 18 single drug (MMC) therapy, and 14 no chemotherapy. The average survival was 264 days in HAI combined with systemic chemotherapy, 208 in the combination systemic chemotherapy, 156 in the single drug therapy and 135 in those given no chemotherapy. One year survival and nine month survival rates were 21.4 per cent and 42.9 per cent in HAI combined with systemic chemotherapy, 11.5 per cent and 19.2 per cent in the combination systemic chemotherapy, 5.6 per cent and 11.1 per cent in the single drug therapy and 7.1 per cent and 14.3 per cent in the no chemotherapy group, respectively (HAI vs single drug therapy and no chemotherapy, p less than 0.01). Five of 14 patients treated with HAI combined with systemic chemotherapy showed a partial response (greater than 50 per cent reduction in tumor size), and the average survival time was 335 days, while that of nonresponders was 224 days. Six of 14 patients treated with combination infusion therapy with MMC and 5-FU survived 314 days, as compared to 201 days for patients with infusion of 5-FU alone.