结直肠癌肝转移的术前化疗

结直肠癌在西方国家占肿瘤患者死亡的第2位,发病率为56.1/10万。我国结直肠癌发病率约为20.6/10万,占肿瘤患者死亡的第5位。Parkin等[1]报道,2002年,全世界新诊断结直肠癌为l 020 000例,占发病率第3位,死亡529 000例,占死亡率第4位。     

Hepatic artery infusion of chemotherapy as a treatment for hepatic metastases from colorectal cancer

Hepatic artery infusion (HAI) of chemotherapy as a treatment for hepatic metastases from colorectal cancer has become more commonly used after the introduction of the totally implantable hepatic artery pump in the early 1970s. Floxuridine (FUDR) is the generally used chemotherapy agent in the pump because of its high solubility and high extraction rates by the liver on the first pass of the chemotherapy through the hepatic circulation. HAI has been used mainly to treat unresectable liver metastases in patients who have liver metastases only. The other scenario for pump use has been as an adjuvant therapy after resection of all metastatic disease inthe liver. The rationale for HAI includes the unique dual blood supply of the liver allowing chemotherapy given into the artery and sparing the normal cells, which get their predominant blood supply from the portal vein. The details of pump design will be reviewed. Complications from HAI are specific for this therapy and will be reviewed. Treatment of unresectable liver metastases with HAI has been the subject of a number of prospective randomized studies. These will be presented, along with newer phase II studies. Three randomized studies on the usefulness of HAI after hepatic resection will be presented.     

Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival

Background:

Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.

Methods:

The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)–BRCA pathway, ATM–ATR pathway and enzymatic activation of MMC. Functionality of the FA–BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).

Results:

High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA–BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).

Conclusions:

Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.     

Microwave coagulation therapy for multiple hepatic metastases from colorectal carcinoma

BACKGROUND: Compared with other treatments, microwave coagulation is a relatively less invasive treatment for various kinds of solid tumors. Although its effectiveness in primary hepatocellular carcinoma has been shown, its effectiveness in the treatment of hepatic metastases from colorectal carcinoma has been unclear. The aim of this study was to evaluate its effectiveness in the treatment of multiple hepatic metastases from colorectal carcinoma by comparing this technique with that of hepatic resection. METHODS: Thirty patients with multiple metastatic colorectal tumors in the liver who were potentially amenable to hepatic resection were randomly assigned to treatment with microwave coagulation (14 patients) or hepatectomy (16 patients). Tumors in the microwave group were coagulated after laparotomy at an output of 60-100 W for 2-20 minutes under the guide of ultrasonography, whereas tumors in the hepatectomy group were treated with lobectomy, segmentectomy, subsegmentectomy, and/or wedge resection. RESULTS: One-, 2-, and 3-year survival rates and mean survival times were 71%, 57%, 14%, and 27 months, respectively, in the microwave group, whereas they were 69%, 56%, 23%, and 25 months, respectively, in the hepatectomy group. The difference between these two groups was statistically not significant (P = 0.83). On the other hand, the amount of intraoperative blood loss in the microwave group (360 +/- 230 mL) was smaller than that in the hepatectomy group (910 +/- 490 mL, P < 0.05). Blood transfusion was necessary for 6 patients in the hepatectomy group, but it was not necessary in the microwave group. CONCLUSIONS: Microwave coagulation therapy is suggested to be equally effective as hepatic resection in the treatment of multiple (two to nine) hepatic metastases from colorectal carcinoma, whereas its surgical invasiveness is less than that of hepatic resection.     

Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose Mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma

BACKGROUND: In vitro data suggest increased cytotoxicity with Mitomycin C (Mit-C) and Floxuridine (FUDR). Based on these data, we performed a phase II trial of hepatic arterial infusion (HAI) of FUDR and Dexamethasone (Dex) plus high-dose Mit-C for patients with unresectable hepatic metastases from colorectal carcinoma. METHODS: High-dose Mit-C (15 mg/m2) was added via the pump sideport to HAI FUDR and Dex for 14 days of a 28-day cycle. Mit-C was given on days 1 and 29, and FUDR was given indefinitely until disease progression or discontinuation of therapy due to toxicity. RESULTS: Sixty-three patients with unresectable liver metastases were entered. The chemotherapy-na?ve group (n = 26) and those previously treated (n = 37) had similar response and median survival: 73% and 70%, and 23 and 20 months, respectively. The major toxicities were liver bilomas (7.9%), elevation in bilirubin level >3 (22%), and biliary sclerosis (9.5%). Hematologic and gastrointestinal toxicity was less than 2%. CONCLUSION: The addition of high-dose Mit-C to HAI FUDR and Dex produced a high response rate even in previously treated patients. The median survival was 21 months even though half the patients were previously treated with chemotherapy. Biliary toxicity was higher than expected; therefore, alternatives to high dose Mit-C should be investigated when exploring additions to HAI therapy with FUDR and Dex.     

Evaluation of hepatic metastases from colorectal carcinoma with MR-superparamagnetic iron oxide

The purpose of this study was to compare the results obtained with superparamagnetic iron oxide-enhanced and unenhanced Magnetic Resonance at 1.5 T with that of spiral-computed tomography (CT) in order to select those patients suitable for liver resection; the intraoperative US (IOUS) comprised the gold standard. Thirty five candidates for liver resection with known colorectal neoplasm were studied; 26 patients underwent surgery, one patient underwent RF ablation and 8 of them were submitted to follow-up. MR examination was performed using a 1.5 T superconductive instrument, CT examination was performed on a Somatom-Plus (Siemens) scanner. Dimensions and number of the lesions were defined in all patients as well as the sensitivity of spiral CT and MR imaging, using either the plain technique or after Ferumoxides c.m.. In those patients submitted to surgery, results have been correlated to those of IOUS. From 26 patients, a total of 48 lesions were removed surgically. With CT, 34 lesions with 3 false positive cases were detected; 32 with plain MR imaging, while MR imaging with Ferumoxides detected 41 lesions. In the patients not submitted to surgery, MR iron-oxide imaging identified 15 lesions, while both plain MR imaging and CT showed 8 lesions. The smallest lesion was 6 mm. as shown by MR imaging with Ferumoxides. In the cases submitted to surgery, the CT sensitivity was 71%, plain MR imaging 66% and MR imaging with Ferumoxides 85%. In our experience, Ferumoxides-enhanced MR imaging of the liver shows increased sensitivity compared to plain and spiral-CT in the evaluation of hepatic metastases. We think that MR superparamagnetic iron oxide should be used in all patients selected for liver resection.     

Surgical treatment of hepatic metastases from colorectal cancer

Colorectal carcinoma is one of the most frequent cancers in Western societies with an incidence of around 700 per million people.About half of the patients develop metastases from the primary tumor and liver is the primary metastatic site.Improved survival rates after hepatectomy for metastatic colorectal cancer have been reported in the last few years and these may be the result of a variety of factors,such as advances in systemic chemotherapy,radiographic imaging techniques that permit more accurate determination of the extent and location of the metastatic burden,local ablation methods,and in surgical techniques of hepatic resection.These have led to a more aggressive approach towards liver metastatic disease,resulting in longer survival.The goal of this paper is to review the role of various forms of surgery in the treatment of hepatic metastases from colorectal cancer.     

结直肠癌肝转移外科治疗

结直肠癌肝转移的治疗方法多样,包括手术治疗、化疗及其他局部治疗,但肝切除术被认为是首选疗法.新辅助化疗方案的使用,使越来越多的患者得以手术治疗.以手术治疗为核心的多种方法综合治疗是结直肠癌肝转移治疗的发展方向.     

Phase II study of hepatic artery infusion with 5-fluorouracil,adriamycin, and mitomycin C (FAM) in liver metastases from colorectal carcinoma

Summary Twenty-seven patients with liver metastases from colorectal carcinoma were treated with 5-fluorouracil, adriamycin, and mitomycin C (FAM) by hepatic artery infusion (HAI) every 2–3 months for a maximum of eight courses. Median survival for all patients was 22 months. Toxicity was acceptable and consisted in severe myelosuppression (8%), duodenal ulceration (8%), moderate nausea and vomiting (50%), and alopecia (100%). HAI with FAM is feasible and may have an impact on survival. Further studies are needed to determine the role of HAI, which may be of potential benefit to a substantial number of patients with metastatic colorectal carcinoma.Presented at the EORTC symposium on treatment of advanced gastrointestinal cancer, Padua, Italy, 1983     

Yttrium-90 radioembolization as salvage therapy for colorectal cancer with liver metastases

BackgroundFew patients with metastatic colorectal cancer (mCRC) are candidates for resection of their hepatic disease. Yttrium-90 (⁹⁰Y) radioembolization has promise in the treatment of unresectable mCRC. We conducted a retrospective study to assess the efficacy in patients with refractory mCRC who underwent ⁹⁰Y radioembolization.Materials and methodsPatients with unresectable mCRC with liver metastases treated at The Ohio State University were included in this analysis. Demographic data, carcinoembryonic antigen (CEA) values, observed toxicities, and information on prior therapies were collected. Response was assessed by RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method.ResultsTwenty-four patients (median age, 63 years) were included. Of the patients, 54% had extrahepatic disease; 67% had bilobar involvement. The patients had received a median of 3 prior therapies. No objective responses were observed. Five patients had a CEA response. Median PFS and OS were 3.9 months (95% CI, 2.4-4.8 months) and 8.9 months (95% CI, 4.2-16.7 months), respectively. Patients older than 65 years had improved PFS (4.6 vs. 2.4 months) and OS (14 vs. 5.5 months) vs. younger patients, likely due to receipt of ⁹⁰Y treatment earlier in their disease course. The presence of extrahepatic disease and the absence of CEA response appeared negatively predictive of efficacy. Toxicities were expected and manageable.Conclusion⁹⁰Y radioembolization is active in select patients with refractory mCRC and with liver metastases, and is safe and well tolerated in the elderly. In patients with extensive extrahepatic disease, ⁹⁰Y should be used in combination with chemotherapy. CEA may be a predictor of efficacy.     

Intraoperative electron radiotherapy as a component of salvage therapy for patients with colorectal cancer and advanced nodal metastases

PURPOSE: To define the survival rates and relapse patterns in patients with isolated advanced nodal metastases secondary to colorectal cancer, treated with curative intent using aggressive combined-modality treatment. METHODS AND MATERIALS: Forty-eight patients with isolated advanced lymph node metastases secondary to colorectal cancer received intraoperative radiotherapy as part of curative-intent treatment. Forty-seven patients also received external beam radiotherapy (EBRT). Chemotherapy was delivered concomitantly with EBRT in 35 patients. The median intraoperative radiotherapy dose was 1250 cGy. End points included local failure within the EBRT field, central failure within the intraoperative radiotherapy field, distant metastases, survival, and toxicity. RESULTS: The median survival time and 5-year survival rate were 35 months and 34%, respectively. At 3 years, the local control and central control rates were 81% and 93%, respectively. Macroscopically complete resection and colonic primary site were predictors of survival and disease control. The median survival time and 5-year survival rate in patients with colonic primary sites and macroscopically complete resection were 53 months and 49%, respectively. Intraoperative radiotherapy-related neuropathy occurred in 3 patients and ureteral fibrosis in 1. CONCLUSION: With aggressive combined-modality therapy that includes intraoperative radiotherapy, long-term survival is achievable in colorectal cancer patients presenting with nodal relapse or advanced nodal disease. Survival and disease control rates are highest in those without gross residual disease.     

Uracil-tegafur/leucovorin and mitomycin C salvage therapy in patients with advanced colorectal cancer: a phase II study

Abstract

We investigated the efficacy and safety of oral Uracil/tegafur (UFT) with leucovorin and mitomycin C (MMC) as third-line treatment for patients with extensively pretreated metastatic colorectal cancer (mCRC). This was a multicenter, prospective phase II study. Patients received MMC 7 mg/m² on day 1 and UFT 300 mg/m² with leucovorin 90 mg, both divided into three daily doses, on days 1–28 every 5 weeks. All patients had failed prior treatment with irinotecan, oxaliplatin, fluoropyrimidine, bevacizumab, and cetuximab. The primary endpoint was tumor control rate evaluated after 2 cycles. Twenty-one patients were included: median age was 66 years (41·1–87·8 years). Tumor control rate was observed in 26·7% of the 15 patients evaluable for response. Median overall survival was 6·4 months. Grade 3 adverse events were asthenia, anorexia, and vomiting. In patients with mCRC who have progressed after as many as two prior therapies, the combination of UFT/leucovorin and MMC is safe and may produce a short stabilization of disease in approximately 25% of patients.     

结直肠癌肝转移经肝动脉栓塞及持续灌注化疗的临床疗效

背景与目的：结直肠癌肝转移患者经肝动脉介入栓塞或静脉持续滴注化疗药物,治疗效果有所提高,但尚存肿瘤局部化疗药物浓度不够高,化疗药物对肿瘤细胞的杀伤力不够强,晚期结肠直肠癌的治疗效果仍然不够好的缺陷。本文将动脉介入与持续灌注化疗药物两种方法相结合,观察结直肠癌肝转移患者经肝动脉介入栓塞或持续灌注化疗的临床疗效。方法：对26例结直肠癌肝转移患者经肝动脉介入治疗93次,单用肝动脉持续灌注化疗42次,肝动脉介入栓塞联合持续灌注化疗51次。化疗药物选用阿霉素（ADM）、顺铂（DDP）、丝裂霉素（MMC）、醛氢叶酸（CF）和5-氟尿嘧啶（5-FU）。先将ADM30mg/m^2和MMC6mg/m^2加入超液化碘油10-30ml中进行肝动脉灌注栓塞,然后留置导管进行持续动脉滴注。方案为CF200mg/m^2,d1-3,静脉滴注;DDP80mg/m^2d1,如肾功能改变则改用Vp-1660mg/m^2,d1-3,应用电动输液泵动脉滴注;5-FU2500mg/m^2,采用便携式输液泵将5-FU持续动脉滴注72h。结果：近期疗效以实体瘤疗效评价标准评价,CR1例,CR率3.85%;PR14例,PR率53.84%,总有效率为57.69%。本组0.5、1、2、3和5年生存率分别为92.31%、76.92%、38.46%、23.07%和3.85%,肝转移后中位生存期为11.5个月。全组病人出现的不良反应主要有肝功能损害、胃肠道反应和骨髓抑制,经护肝、制酸、止呕、水化和应用升白细胞药物对症治疗后可缓解。结论：经肝动脉持续灌注化疗及栓塞是治疗结直肠癌肝转移瘤的较好方法,能提高治疗效果。     

改良FOLFOXIRI方案作为三线或三线后方案治疗晚期结直肠癌的回顾性研究

  目的  标准治疗失败后,评估改良FOLFOXIRI方案后线治疗不可切除的晚期转移性结直肠癌患者的安全性及疗效。  方法  回顾性分析杭州市第一人民医院和杭州市肿瘤医院2011年1月至2016年12月收治的晚期结直肠癌患者。共13例患者在标准疗失败后应用了改良FOLFOXIRI方案(5-氟尿嘧啶或卡培他滨、亚叶酸钙联合伊立替康、奥沙利铂)治疗,并接受了随访。  结果  13例患者中位年龄为54(41~68)岁,接受了中位化疗周期为4(1~8)个周期的改良FOLFOXIRI方案治疗,并进行了疗效和不良反应的评估。其中10例(76.9%)患者接受了超过4个周期的方案,中位无进展生存期(median progression-free survival,mPFS)为4.5(95% CI:2.5~6.5)个月。由于观察时间较短,4例未达到观察终点,中位总生存期(median overall survival,mOS)为14(95% CI:5.7~22.3)个月,客观缓解率(objective remission rate,ORR)为30%,临床获益率(clinical benefit rate,CBR)为90%。最常出现的3~4级不良发应事件为贫血、白细胞减少、血小板减少和周围神经病变。未发生治疗相关性死亡。  结论  本研究中,患者体力状况允许的前提下,标准治疗失败后应用改良FOLFOXIRI方案的晚期结直肠癌患者可获得mPFS与mOS的获益。不良反应均在可控范围内。      

Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer

This study was designed to assess the safety and efficacy of capecitabine and mitomycin C (MMC) in previously untreated patients with advanced colorectal cancer (CRC). Patients received capecitabine 2500 mg m(2) day 1, orally divided in two doses of 1250 mg m(-2) in the morning and evening for 14 days every 21 days and MMC 7 mg m(-2) (maximum total dose 14 mg) as an intravenous bolus every 6 weeks for a total of four courses. The median age was 70 years (range 24-85) and the majority of patients (86.9%) were of performance status 1/2. The most common metastatic site was liver. In all, 84 patients were assessable for response. The overall response rate was 38% (95% CI: 27.7-49.3) and a further 33.3% of patients achieved stable disease over 12 weeks. There was good symptom resolution ranging from 64 to 86%. Grade 3/4 toxicity was as follows: hand-foot syndrome 19.7%; diarrhoea 10%; neutropenia 2.4%; infection 2.3%. Capecitabine and MMC have shown encouraging activity with a favourable toxicity profile, a convenient administration schedule, and could be considered for patients deemed unsuitable for oxaliplatin and irinotecan combinations.     

Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases

Background

The value of surgical treatment for patients with pulmonary and hepatic metastases from colorectal carcinoma is controversial. The purpose of this study was to analyze our initial experience with this aggressive strategy, and to define the prognosis and the surgical indications.

Methods

The records of 35 patients who underwent surgical treatments for both hepatic and pulmonary metastases from colorectal carcinoma, from January 1997 to December 2008, were retrospectively analyzed.

Results

There were 18 females and 17 males with a median age was 62.0 years. The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection, respectively. For patients who underwent metachronous hepatic and pulmonary surgical treatment, the 10-year survival rate was 40.9%, which was significantly better than that of those undergoing synchronous hepatic and pulmonary surgical treatment (p = 0.0265). Patients who have pulmonary less than ten of metastasis thus seemed to have a better prognosis than those with more than ten, but the difference was quite significant (p = 0.0719). In a multivariate Cox proportional hazards model, synchronous hepatic and pulmonary metastases was identified as an independent predictor of adverse survival (p = 0.0073).

Conclusions

The results of our study suggest that hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma. We believe that aggressive metastasectomy can be an option for selected patients, even if a patient has been previously treated for hepatic and pulmonary metastases from colorectal carcinoma.     

Prognostic significance of intrahepatic lymphatic invasion in patients with hepatic resection due to metastases from colorectal carcinoma

BACKGROUND: Intrahepatic spread from liver metastases of colorectal carcinoma has been well described; however, its prognostic value after hepatectomy is controversial. To clearly determine factors predicting survival after hepatectomy in such patients, the authors evaluated 14 clinicopathologic factors of liver metastasis from colorectal carcinoma with special reference to intrahepatic lymphatic invasion. METHODS: The authors retrospectively analyzed data obtained from 67 consecutive patients who underwent hepatectomy for liver metastasis from colorectal carcinoma. Intrahepatic spread was classified into discreet categories that were evaluated separately: invasion to the portal vein, hepatic vein, bile duct, and lymphatic or perineural space. Overall survival and disease free survival periods were examined as functions of clinicopathologic determinants by univariate and multivariate analyses. RESULTS: Intrahepatic spread was found in a total of 28 (43.1%) of the 65 evaluable cases. Portal vein invasion was found in 15 (23.1%) of these cases, hepatic vein invasion in 3 (4.6%), bile duct invasion in 10 (15.4%), and intrahepatic lymphatic invasion in 10 (15.4%). Five year overall and disease free survival rates after hepatectomy were 33.4% and 28.5%, respectively. A short interval (< 12 months) from treatment of primary colorectal carcinoma to liver metastasis and the presence of intrahepatic lymphatic invasion significantly and adversely affected the overall and disease free survival rates. CONCLUSIONS: Intrahepatic lymphatic invasion was shown statistically to be an independent predictor of recurrence and death after hepatectomy in patients with liver metastases from primary colorectal carcinoma.     

Dihydropyrimidine dehydrogenase gene expression in patients with hepatic metastases from colorectal cancer

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for 5-FU catabolism. Recently, much interest has been taken in the relation between the antitumor effect of 5-FU and DPD expression in gastrointestinal cancers. In this study, we compared DPD mRNA of 11 hepatic metastatic foci with that of 50 primary foci in colorectal cancer patients. DPD mRNA levels in hepatic metastatic foci were significantly higher than those in primary foci (median DPD/GAPDH ratio 0.79 vs 0.44, p = 0.035). Even in 6 cases available to compare DPD mRNA expression in matched primary and metastatic foci, the same significant difference was obtained (median DPD/GAPDH ratio 0.80 vs 0.36, p = 0.028). Our results suggested that the efficacy of intra-arterial infusion for metastatic liver tumor is mainly due to the fact that the high concentration of 5-FU is enough to overcome the high clearance of 5-FU, which is caused by DPD.     

Multiple resections for hepatic and pulmonary metastases of colorectal carcinoma

BACKGROUND: Resections are effective for some patients with both hepatic and pulmonary metastases of colorectal cancer, but the best selection criteria for the resections and effective treatment for recurrence after the resections have not been determined. METHODS: A retrospective analysis was performed for 30 consecutive patients who received aggressive multiple resections for both hepatic and pulmonary metastases of colorectal cancer. Recurrences after resections were surgically treated whenever resectable. RESULTS: For the 30 patients, 45 hepatectomies and 40 pulmonary resections were performed and 17 patients received three or more resections. No mortality was observed. Overall survival after the first metastasectomy for the second organ (liver or lung) was 58% and nine 5-year survivors were observed. Multivariate analyses revealed that primary colon cancer, stage IV in TNM classification and maximum size of hepatic tumor >3 cm at initial hepatectomy were poor prognostic factors, but several long-term survivors were observed even among patients with those factors. CONCLUSIONS: Multiple resections for hepatic and pulmonary metastases of colorectal cancer are safe and effective. No single factor is considered to be a contraindication for the resections. For recurrence after the resections, surgical resection is also recommended if resectable.