结直肠癌肝转移围手术期的治疗进展

手术切除是结直肠癌肝转移最主要和最有效的治疗手段,但如何应对术后较高的复发风险并进一步改善生存是临床上亟待解决的问题。近年来,术后全身化疗、术前化疗和围手术期化疗已经在相关研究中进行了探讨,以期降低相关的复发风险。同时随着新的药物和治疗手段的不断涌现,第3代化疗药物和最新的靶向治疗药物以及肝动脉灌注化疗等局部治疗也用于结直肠癌肝转移的临床研究,并取得了一定成果。本文就这方面的相关进展作一综述。     

复方苦参注射液对结直肠癌肝转移肝动脉灌注化疗的影响

 目的 探讨复方苦参注射液对结直肠癌肝转移肝动脉灌注及栓塞治疗（TACE）患者免疫功能及在化疗中的作用。方法 32例行TACE治疗患者分为治疗组（A组）18例，对照组(B组)14例，A组用复方苦参注射液30 ml，1次／d，共1周，B组不用。观察治疗前、后两组患者近期疗效、细胞免疫情况及化疗后毒性反应。结果 A组近期疗效好于B组（A组为66.7 %，B组为35.7 %）； A组Karmofsky评分提高率高于治疗前，B组低于治疗前；A组CD+3，CD+4，CD+8和NK细胞均值均有提高，与治疗前相比差异有统计学意义（P＜0.01）；A组毒副作用较B组轻。结论 复方苦参注射液能提高近期疗效，提高患者机体免疫功能，减轻患者疼痛及化疗毒副反应。     

初始可切除结直肠癌肝转移术后辅助化疗的研究进展

结直肠癌是目前全球第三大常见的恶性肿瘤,大约有50%的患者在病程中发生肝转移。结直肠癌肝转移(CRLM)分为初始可切除和不可切除。肝切除术目前被认为是治疗CRLM唯一潜在的治愈方法,患者5年生存率约为37%～40%。但肝切除术后这部分患者仍然存在较高的复发风险,因此选择合适的辅助治疗尤为重要。目前CRLM患者术后辅助化疗存在争议,以往前瞻性临床研究发现术后辅助化疗能延长无进展生存时间,但无法改善总生存时间。最近部分研究在化疗基础上联合靶向药物或肝动脉灌注化疗(HAIC)等应用于术后CRLM患者,以期获得更好的疗效。本文就可切除CRLM术后辅助化疗的应用现状及研究进展作一综述。     

结直肠癌肝转移术后化疗远期疗效的Meta分析

目的用Meta分析的方法,评价化疗对可切除结直肠肝转移患者长期疗效的影响。方法检索1990-01-2013-12发表于PubMed、Embase、Cochrane Library和万方数据库中收集化疗对可切除结直肠肝转移患者长期疗效随机对照试验的文章,有2名评价员独立按照纳入及排除标准,筛选及提取数据并评估研究的方法学质量,利用Cochrane协作网提供的RevMan 5.1.4软件进行Meta分析。结果共纳入8篇随机对照试验,样本量885例,手术+化疗组409例,单纯手术组476例。Meta分析结果显示,与单纯手术组患者相比,手术+化疗组患者并不具备长期生存的优势,两组差异无统计学意义,HR=0.92,95%CI为0.80~1.06,P=0.25,I2=17%。但在亚组分析中,手术+静脉化疗组与单纯手术组相比,两组差异有统计学意义,HR=0.80,95%CI为0.63~1.00,P=0.05,I2=0;手术+肝动脉化疗组与单纯手术组相比,两者差异无统计学意义,HR=1.00,95%CI为0.84~1.21,P=0.96,I2=30%。在分析无疾病进展时间时,化疗组可以增加患者的无疾病进展时间,HR=0.77,95%CI为0.67~0.88,P=0.000 2,I2=25%。在亚组分析中,手术+静脉化疗组(HR=0.75,95%CI为0.62~0.92,P=0.004,I2=0)与单纯手术组相比差异有统计学意义,但手术+肝动脉化疗组与单纯手术组差异无统计学意义,HR=0.72,95%CI为0.51~1.02,P=0.07,I2=54%。结论全身静脉化疗对于提高和改善结直肠癌肝转移手术患者的长期生存及无疾病进展时间是有帮助的,但静脉化疗的时间及方案选择还需大样本前瞻性研究进一步证实。     

结直肠癌肝转移术前化疗与手术切除疗效的Meta分析

目的：探讨结直肠癌肝转移术前化疗能否提高患者的生存率。方法：计算机文献检索ISI Web ofKnowledge、Pubmed及中国期刊网,检索国内外自1990年1月至2010年12月间公开发表的有关结直肠癌肝转移治疗的文章。Meta分析比较术前化疗组与未接受术前化疗组术后生存率的差异。结果：术前化疗组与未接受术前化疗组相比较,1年生存率（OR=0.44,CI：0.17-1.13,P=0.07）、3年生存率（OR=1.02,CI：0.64-1.62,P=0.93）、5年生存率（OR=0.69,CI：0.42-1.14,P=0.16）均无统计学意义。结论：对于结直肠癌肝转移患者,术前化疗不能提高术后生存率。     

Ⅲ期结直肠癌术后经肝动脉灌注联合静脉辅助化疗的临床观察

  目的  通过与静脉辅助化疗对照, 观察经肝动脉灌注联合静脉辅助化疗对Ⅲ期结直肠癌术后肝转移、无病生存期及总生存期的影响。   方法  2002年1月至2006年3月, 21例Ⅲ期结直肠癌患者作为治疗组, 术后给予肝动脉灌注FUDR联合静脉应用草酸铂化疗, 同期对照21例Ⅲ期结直肠癌患者, 术后给予草酸铂联合CF/5-FU静脉化疗。主要观察终点为肝转移率及DFS, 次要终点为OS和用药安全性。   结果  中位随访65(9~119)个月, 治疗组肝转移发生率较低(9.5%vs.28.6%, P=0.109), 肺转移发生率略高(28.6%vs.14.3%, P=0.256)。2组5年DFS(38.1%vs.42.9%, P=0.671)及OS(47.9%vs.45.0%, P=0.784)无统计学差异。化疗副反应多为Ⅰ~Ⅱ度血白细胞减少、恶心呕吐及感觉神经障碍。   结论  Ⅲ期结直肠癌术后给予经肝动脉联合静脉系统化疗, 与静脉化疗相比, 可能会降低肝转移的发生率, DFS及OS无统计学差异, 化疗副反应较轻, 可耐受。      

肝动脉插管栓塞化疗联合腹腔灌注化疗治疗结直肠癌肝转移48例疗效观察

目的 探讨肝动脉插管栓塞化疗联合腹腔灌注化疗治疗结直肠癌肝转移的疗效.方法 48例结直肠癌分别行左半结肠、右半结肠或经腹直肠癌根治术后行肝动脉置泵,经药泵给药栓塞化疗及腹腔灌注化疗.结果 本组48例,完全缓解(CR)5例(10.42%),部分缓解(PR)23例(47.92%),总有效率(CR+PR)58.34%.生存期最短3个月,最长3年以上.结论 肝动脉插管栓塞化疗联合腹腔灌注化疗治疗结直肠癌肝转移,毒副反应小,疗效确切,是治疗结直肠癌肝转移的有效方法.     

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。     

肝动脉药盒灌注氟脲苷联合全身化疗治疗不可切除老年结直肠癌肝转移

目的 探讨经肝动脉药盒灌注（HAI）氟脲苷（FUDR）联合全身化疗治疗不可切除老年结直肠癌肝转移患者的疗效及安全性.方法 对18例不可手术切除的老年结直肠癌肝转移回顾性分析.所有患者采用一种改进的介入方法植入肝动脉药盒,术后第2天开始接受HAI FUDR联合全身化疗.对治疗疗效、毒副反应及随访结果进行分析.结果 18例患者的总有效率为94.4%,其中完全缓解1例（5.6%）,部分缓解16例（88.9%）,疾病进展1例（5.6%）.8例患者转化为可手术切除,转化率为44.4%.中位无进展生存时间为26.0个月,中位总生存时间为30.2个月.结论 HAI FUDR联合全身化疗是治疗不可切除老年结直肠癌肝转移的一种安全有效的方法,可获得较高的手术切除率.     

肝动脉插管及腹腔注药联合化疗治疗结直肠癌肝转移28例报告

探讨肝动脉插管及腹腔注药联合化疗治疗结直肠癌肝转移的治疗效果。方法　 2 8例结直肠癌 ,分别行左半结肠、右半结肠或经腹直肠癌根治性切除术后 ,行肝动脉插管及腹腔置管 ,药盒埋植于皮下 ,经药盒给药化疗。结果　本组 2 8例 ,完全缓解(CR) 2例 ,部分缓解 (PR) 13例 ,总有效率 (CR PR) 5 3 6 %。生存期最短 2个月 ,最长者 3年以上至今存活。结论　肝动脉插管及腹腔注药联合化疗治疗结直肠癌肝转移 ,毒副作用小 ,疗效确切 ,是治疗结直肠癌肝转移有效的治疗方法。     

Echogenicity of liver metastases from colorectal carcinoma is an independent prognostic factor in patients treated with regional chemotherapy

BACKGROUND: Echogenicity of liver metastases was found to be a predictive biologic factor influencing long-term outcome after curative liver resection. The current analysis focuses on the influence of echogenicity on survival in patients treated with intraarterial chemotherapy for unresectable colorectal carcinoma liver metastases. METHODS: A retrospective analysis of prospectively collected data at the Department of Surgery at the University of New South Wales-affiliated St. George Hospital was performed. Two hundred twelve consecutive patients with unresectable hepatic metastases from colorectal carcinoma treated between May 1992 and September 2000 were analyzed. Echogenicity of metastases was measured intraoperatively using a 5 MHz probe. Overall survival difference was compared between hyper- and hypoechoic metastases on an intention-to-treat basis. RESULTS: At a median followup of 15.1 months, 47 patients (22%) were alive and 165 (78%) had died. A significant survival benefit was observed in patients having hyperechoic lesions (median survival 16.2 months, 95% confidence interval [CI] 13.9-18.5) compared to hypoechoic lesions (median survival 11.6 months, 95% CI 8-15.2), P < 0.01. Other prognostic factors were differentiation of the primary tumor (P < 0.02), percentage hepatic replacement (P < 0.05) and carcinoembryonic antigen decrease (P < 0.03). Echogenicity was identified as an independent prognostic factor in multivariate analysis (P < 0.009). CONCLUSIONS: Echogenicity is an important prognostic survival parameter.     

Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma.

Colorectal carcinoma is one of the most common cancers in the world, and more than 50% of these patients develop liver metastases. Despite recent advances, systemic chemotherapy for metastatic disease without the use of surgery is considered palliative, as there are rarely long-term survivors. However, patients who are candidates for surgical resection of their liver metastases can have a prolonged survival or possibly a cure. Consensus guidelines on criteria for resection and prognostic scores help facilitate patient selection, yet only 25% of patients with liver metastases are considered to have resectable metastases. Neoadjuvant chemotherapy has been explored in an attempt to render more patients candidates for resection. First reports using neoadjuvant systemic chemotherapy in patients with unresectable disease found that 13% to 16% of patients could be rendered resectable. Efforts to increase response rates using hepatic arterial infusion or biologic agents may increase resection rates. This review summarizes the current data on neoadjuvant chemotherapy, the rationale for this approach, potential complications, and future prospects.     

Neoadjuvant chemotherapy for patients with liver metastases from colorectal cancer

Colorectal cancer is the second most common type of cancer in industrialized countries. Despite improved resection procedures and optimized adjuvant chemotherapy, local or distant recurrences occur in 22-25% of patients with stage II/III colon cancer. Approximately 30% of patients have advanced disease at presentation. The liver is the most common site of colorectal metastases and, interestingly, 20-30% of patients with colorectal cancer have liver-only metastases. The combined modality of chemotherapy and surgery increases overall survival and the chance of cure for metastatic patients, even if there is no agreement in terms of the best schedule and how long the treatment must last. In this paper, we review the role and the rationale of neoadjuvant chemotherapy within a multimodal approach, and discuss remaining questions and future directions.     

Pathologic response to bevacizumab-containing chemotherapy in patients with colorectal liver metastases and its correlation with survival

For patients with colorectal liver metastases (CLM), hepatic resection currently offers the best chance for long-term survival. Preoperative chemotherapy is now integral to the management of these patients, conferring a disease-free survival advantage over surgery alone in patients with ‘upfront’ resectable disease and enabling some initially unresectable CLM to become resectable. However, although surgery may improve long-term survival, up to 65.0% of patients will experience disease recurrence at 5 years and reliable prognostic factors are needed to predict those patients who are more likely to experience recurrence after resection. Recently, pathologic tumor response, defined as the ‘objective measurement of residual cancer cells in resected tissue,’ has been identified as a reliable prognostic factor in patients with colorectal cancer (CRC) receiving preoperative chemotherapy and has been shown to correlate with improved survival after resection of CLM. Addition of the targeted biologic agent bevacizumab to preoperative chemotherapy is associated with an increase in pathologic response rate and an increase in survival compared with chemotherapy alone in patients undergoing hepatic resection. This review discusses the data in support of pathologic response rate as an important new outcome endpoint after hepatic resection of CLM and considers the evidence to date on pathologic response to bevacizumab-containing chemotherapy in metastatic CRC and its correlation with survival.     

Hepatic vascular isolation and perfusion for patients with progressive unresectable liver metastases from colorectal carcinoma refractory to previous systemic and regional chemotherapy

BACKGROUND: Many patients with colorectal carcinoma develop unresectable metastases confined to the liver that remain the life-limiting component of disease despite best available systemic or regional chemotherapy. In the current study, the authors present their results using vascular isolation and perfusion of the liver for individuals with progressive, unresectable liver metastases from colorectal carcinoma that were refractory to both previous systemic and regional chemotherapy. METHODS: Seven patients with refractory, progressive, unresectable colorectal carcinoma metastases confined to the liver underwent a 60-minute hyperthermic (39-40 degrees C) isolated hepatic perfusion (IHP) and were followed for toxicity, response, and survival. RESULTS: There was no surgical- or treatment-related mortality; all patients experienced transient Grade 3-4 (according to National Cancer Institute common toxicity criteria) hepatic toxicity. At a median potential follow-up of 16 months, the overall objective radiographic response rate (all partial responses) was 71% (5 of 7 assessable patients). It is interesting to note that two patients who were treated with tumor necrosis factor (TNF) alone demonstrated no response to therapy compared with all five patients who were treated with melphalan and TNF (three patients) or melphalan alone (two patients). For the 5 patients who responded to treatment, the median duration of response was 10 months (range, 10-13 months) and in all 7 patients the mean overall survival was 19.7 months (range, 2-33 months), including 5 months and 7.5 months, respectively, for the 2 patients treated with TNF alone. CONCLUSIONS: The results of the current study demonstrate that IHP using melphalan with or without TNF has significant antitumor activity in this patient population. IHP deserves continued clinical evaluation as a therapeutic modality for patients with unresectable colorectal carcinoma metastases to the liver.     

Determinants of survival in patients with unresectable colorectal liver metastases

Prognostic indicators in 67 patients with unresectable colorectal liver metastases were analyzed. These patients were identified to have isolated hepatic metastases after extensive radiological evaluation and demonstrated good performance status without evidence of liver failure. Univariate analysis revealed 6 of 22 factors that were associated with survival: alkaline phosphatase (AP), lactic dehydrogenase (LDH), occult intra-abdominal extrahepatic disease, percent hepatic replacement by tumor (PHR), sex, and carcinoembryonic antigen (CEA). A multivariate analysis identified two independent factors that jointly influenced survival: AP and PHR. Patients with an AP greater than 175 U/liter had a greater than threefold relative risk of dying compared with patients with AP less than or equal to 175 U/liter (P = 0.0001). Patients with PHR II or III (25-75%, greater than 75%) also had a greater than threefold relative risk of dying compared with patients with PHR 1 (less than 25%; P = 0.0074). Our patient population is typical of that being entered into trials examining experimental therapies. Alkaline phosphatase and extent of liver involvement by tumor are significant prognostic indicators that should be accounted for in such studies.     

Recurrence-risk stratification using the Beppu score and selection of perioperative chemotherapy for colorectal liver metastases

The annual postoperative disease-free survival for colorectal liver metastases can be easily estimated by weighting six preoperative clinical parameters (Beppu score). We identified three recurrence-risk stratification groups: the low (≤6 points), moderate (7–10 points), and high-risk (≥11 points). For low-, moderate-, and high-risk patients, hepatectomy alone, hepatectomy with adjuvant chemotherapy, and hepatectomy with preoperative chemotherapy are recommended, respectively. The Beppu score enables the decision on the necessity and timing of perioperative chemotherapy.     

Radiological heterogeneity in response to chemotherapy is associated with poor survival in patients with colorectal liver metastases

BackgroundIn patients with colorectal liver metastases (CLM) there is limited knowledge about the occurrence of radiological heterogeneity in response to chemotherapy.MethodsA retrospective analysis was performed in the CAIRO and CAIRO II studies on the incidence of intermetastatic heterogeneity in patients with CLM and its association with survival. Mixed response (MR) was defined as >30% difference in individual lesion response, with all lesions showing a similar behaviour; true mixed response (TMR) as two lesions showing progression versus response; homogeneous response (HR) as similar behaviour of all lesions. Patients were classified according to the Response Evaluation Criteria in Solid Tumours (RECIST) categories (partial response (PR), stable disease (SD), progressive disease (PD), complete response (CR)) and then subdivided into MR and TMR in order to compare survival.ResultsIn the CAIRO and CAIRO II studies, 140 and 150 patients with liver-only disease were identified. 73/290 (25.2%) patients showed MR, and 25/290 (8.6%) patients TMR, and 192/290 (66.2%) patients HR. Overall survival (OS) at 1–4 years was significantly higher for the homogeneous partial responders category compared to other response categories. Median OS was 22.0 months for the entire population. In the partial response category, patients with MR showed significant poorer survival compared to patients with HR (median OS 23.7 versus 36.0 months, respectively, p = 0.019). Multivariate analysis identified four independent predictors for OS: serum lactate dehydrogenase (LDH) level (p = 0.002), number of first-line chemotherapy cycles (p = 0.001), resection of primary tumour (p = 0.001) and response category (p = 0.012).ConclusionRadiological heterogeneity is present in approximately 35% of patients with CLM. Partial responders according to the RECIST criteria, show a significant poorer survival if classified as heterogeneous partial responder compared to homogeneous partial responders.     

Assessing the optimal duration of chemotherapy in patients with colorectal liver metastases

BACKGROUND AND OBJECTIVES: Few studies have addressed the optimal duration of chemotherapy, particularly prior to liver resection for colorectal liver metastases (CLM). The purpose of this retrospective analysis was to evaluate time to maximal response in patients receiving systemic +/- hepatic arterial infusion (HAI) chemotherapy alone for the treatment of CLM. METHODS: We reviewed 35 patients with CLM on clinical trials of HAI floxuridine/dexamethasone plus systemic oxaliplatin with 5-fluorouracil/leucovorin or irinotecan (PUMP + SYSTEMIC). We retrospectively identified 35 patients with CLM who received first-line systemic 5FU/leucovorin/oxaliplatin (FOLFOX) +/- bevacizumab (SYSTEMIC) during the same time period. Measurable disease was evaluated on CT scans performed at 2-month intervals. The sum of the products of bi-dimensional tumor measurements for representative lesions was compared both to baseline imaging and between consecutive time points. RESULTS: In responders to therapy, mean cumulative tumor reduction increased from 61% at 2 months to 73% at 4 months in the PUMP + SYSTEMIC group (P < 0.01) and from 39% to 56% in the SYSTEMIC group (P < 0.01). No significant incremental tumor reduction occurred between 4 and 6 months in either group. CONCLUSIONS: In responders to preoperative therapy, surgical resection should be considered after 2-4 months, when most patients have achieved maximal response.     

Downstaging by regional chemotherapy of non-resectable isolated colorectal liver metastases.

AIMS: To improve the course of isolated non-resectable colorectal liver metastases (CRLM) by hepatic arterial infusion treatment. Patients with CRLM have a worse prognosis than those whose liver metastases are resectable. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases with 5-fluorouracil+folinic acid (5-FU+FA) i.v. may result in median survival times of 6.4-14.3 months. Hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (5-FUDR) has been demonstrated in a meta-analysis of randomized trials to be superior to i.v. treatment/palliative care (median survival 15 vs. 10 months). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver cirrhosis. We have developed a stepwise protocol for HAI in CRLM, which is superior to HAI with 5-FUDR and to systemic chemotherapy. METHODS: Between 1982 and 1997, 168 CRLM patients were treated within the following protocols. In protocol A, 48 CRLM patients received HAI with 5-FUDR. In protocol B, 46 patients received 5-FUDR i.a. (HAI)+i.v. In protocol C 5-FU+FA were delivered via HAI in 24 patients with CRLM. In protocol D, based on in vitro phase II studies and the results of protocol C, mitoxantrone and mitomycin C were added to 5-FU+FA (MFFM). Fifty (50) CRLM patients received HAI with HFFM. RESULTS: The response rates, median survival time, systemic toxicity and SC rate were: 42%, 20.8 months, 0-19% and 38% for protocol A; 46%, 20.8 months, 0-20% and 41% for protocol B; 45%, 19.8 months, 4-25% and 0% for protocol C; and 66%, 27.4 months, 2-26% and 0% for protocol D. The surgically placed ports for HAI in protocols C and D functioned in 90%, 82% and 76% of patients, 6, 9, and 11 months after beginning HAI. Quality of life in protocol D was high. Nine patients from protocols C and D with either partial (PR, seven patients) or complete (CR, two patients) remissions received a secondary liver resection without hospital mortality, and seven of nine patients are alive 2-58 months after liver resection. The other two died 11 and 22 months after resection. CONCLUSIONS: Optimal treatment of CRLM was found to be protocol D: HAI with MFFM. The results of this protocol, including high remission rate, long median survival time, good port function, good quality of life and, interestingly, the possibility of downstaging and resecting primarily non-resectable metastases, seem to be superior to HAI with 5-FUDR or 5-FU+FA and to systemic chemotherapy with 5-FU+FA. This hypothesis is currently being examined in a phase III study (HAI with MFFM vs. 5-FU+FA i.v.).