Current treatment options for patients with initially unresectable isolated colorectal liver metastases

The development of liver metastases is a common clinical entity in the clinical course of colorectal cancer. For patients with isolated liver involvement, surgical resection is the only treatment that can provide a chance of prolonged survival and cure. However, most of these patients are not initially eligible for the surgery. Selected patients with initially considered to have unresectable disease may become resectable after systemic (chemotherapy ± biological therapy) and loco-regional treatment modalities including hepatic arterial infusion. Patients who have colorectal liver metastases ideally should be referred to a multidisciplinary cancer care team in order to identify the most optimal management approach.     

A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment

The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital.     

西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌的疗效分析

目的 观察西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌的疗效及安全性,探讨可能影响疗效及预后的因素。方法 收集2007年5月至2012年5月解放军总医院收治的K Ras野生型转移性结直肠癌患者共90例,采用西妥昔单抗（400mg／m2,静滴,第1周,维持剂量每周250mg／m2或每2周500mg／m2）联合化疗方案,主要为含伊立替康为基础方案（FOLFIRI或XELIRI或单药CPT-11）、含奥沙利铂为基础方案（FOLFOX或XELOX）、5 FU／LV方案或单药卡培他滨。回顾性评估西妥昔单抗联合化疗在治疗中的疗效和安全性,分析患者临床病理特征,并探讨影响疗效的因素以及此类患者预后相关的因素。结果 西妥昔单抗中位治疗时间为16周（6～44周）,客观缓解率（ORR）为45.6％,疾病控制率（DCR）为87.8％。其中一线治疗ORR为51.6％,二线治疗ORR为40.0％,三线治疗ORR为18.2％。单因素分析显示,年龄、原发灶部位、西妥昔单抗治疗时间与疗效有关,差异具有统计学意义（P＜0.05）。90例患者中位随访时间为20.2个月,82例（91.1％）复发转移,60例（66.7％）死亡。患者中位无疾病进展时间（PFS）为7.8个月,中位总生存时间（OS）为22.5个月。其中一线中位PFS为9.1个月,中位OS为27.6个月;二线中位PFS为7.7个月,中位OS为14.5个月;三线中位PFS为2.9个月,中位OS为6.7个月。单因素分析显示：原发灶部位、早期肿瘤缓解者以及西妥昔单抗治疗时间与PFS有关;原发灶部位、早期肿瘤缓解者、西妥昔单抗治疗时间以及转移侵及范围与OS有关。Cox多因素生存分析显示：原发肿瘤病灶部位、早期肿瘤缓解是PFS的独立预后因素,转移侵及范围是OS的独立预后因素。西妥昔单抗相关治疗最常见的不良反应是痤疮样皮疹（78.0％）,化疗相关的不良反应主要为腹泻、恶心呕吐、骨髓抑制,经对症处理后,患者均可耐受。结论 西妥昔单抗联合多种方案化疗治疗晚期转移性结直肠癌患者,各线治疗均能取得较好的疗效,不良反应可耐受;原发灶部位可能是西妥昔单抗联合化疗的疗效预测因素,其与患者预后生存可能相关;早期肿瘤缓解可作为判断患者预后相关指标。     

FOLFOX 4方案联合西妥昔单抗新辅助治疗大肠癌肝转移的临床观察

目的 观察西妥昔单抗联合FOLFOX 4方案新辅助治疗大肠癌肝转移的疗效及安全性。方法 收集2009年11月至2011年11月共18例大肠癌肝转移患者,采用西妥昔单抗（400mg／m2静滴,第1周,维持剂量为250mg／m2 静滴,每周1次,共6周）联合FOLFOX 4方案（奥沙利铂 85mg／m2 静滴,d1;亚叶酸钙200mg／m2静滴,d1、d2;氟尿嘧啶400mg／m2 静推,d1、d2,继以600mg／m2持续静滴22h,d1、d2,14天为1周期）治疗,3个周期评价疗效。结果 全组均可评价疗效,获PR 15例、SD 2例、PD 1例,有效率为83.3％,疾病控制率为94.4％。18 例患者均接受了手术,同期进行大肠癌根治术+肝转移灶切除14例,分期切除4例。原发灶R0切除18例;转移灶R0切除15例,R1切除3例。18例患者的中位总生存时间（OS）为30.4个月,中位无进展生存期（PFS）为21.2个月。主要不良反应为3级皮肤痤疮样皮疹及1～2级中性粒细胞减少和延迟性腹泻。结论 FOLFOX 4方案联合西妥昔单抗新辅助治疗大肠癌肝转移安全有效,并能够提高手术切除率,延长生存时间,为大肠癌肝转移提供了新的治疗策略。     

A successful treatment of conversion chemotherapy by mFOLFOX6 plus cetuximab for initially unresectable synchronous colorectal liver metastases

A 63-year-old woman with a synchronous huge colorectal liver metastasis was referred to our institution.The lesion was technically diagnosed unresectable because the estimated future remnant liver volume was insufficient due to the invasion of the three hepatic veins and hepatic hilum.She underwent 7 courses of mFOLFOX6 and 14 administrations of cetuximab as conversion chemotherapy.Periodic abdominal CT scans revealed the tumor becoming PR, and she was free of cancer invasion to the left hepatic vein.After the remainder of chemotherapy lasting 4 weeks, right trisectionectomy and combined partial resection of the inferior vena cava and primary closure was performed.The postoperative course was uneventful and the patient was discharged at 20 days after the operation.She underwent chemotherapy postoperatively, and then underwent laparoscopic sigmoidectomy.A conversion chemotherapy using cetuximab may contribute to ward rapidly reducing tumor size and improving the resectability of initially unresectable huge colorectal liver metastases, thus leading to prolonged survival.     

西妥昔单抗治疗结直肠癌肝转移研究进展

 结直肠癌肝转移发病率很高。目前,对结直肠癌肝转移患者的治疗,不管肝转移灶是否可手术切除,均推荐实施新辅助化疗后再行肝转移灶切除术。分子靶向治疗药物西妥昔单抗联合以奥沙利铂或伊立替康为主的化疗作为结直肠癌肝转移的二线或一线治疗方案,可获得较高的有效率和良好的远期生存,并使更多的患者得到肝转移灶切除的机会,提高肝转移灶切除率,但只推荐应用于k-ras基因为野生型的结直肠癌肝转移患者。     

Long-term results of resection following downstaging of initially unresectable colorectal metastases

Colorectal carcinoma is a significant health problem with over half of all patients experiencing systemic metastasis. Fortunately for these patients, the recent introduction of more effective systemic chemotherapy drugs has ushered in a new and exciting era in the treatment of metastastic colorectal cancer. Not only have these novel regimens improved the outlook for patients with unresectable disease, lengthening the median survival from 10 months to 24 months, they are allowing patients previously thought to be unresectable the opportunity for a potentially curative hepatic resection. A growing literature has been written describing chemotherapy response rates in patients who were initially considered “unresectable” and describing the long-term outcome for the subset of these responders who are resected. This report summarizes this literature, focusing on the prognostic factors that have been identified to determine which patients receive the most and those who receive the least benefit from resection following treatment with systemic chemotherapy.     

Locoregional therapy and systemic cetuximab to treat colorectal liver metastases

AIM: To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads (DEBIRI) and cetuximab (DEBIRITUX) of unresectable colorectal liver metastases.METHODS: Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma (CRC-LM), progression after first line chemotherapy (any type of chemotherapeutic drug and combination was allowed), second line treatment (mandatory), which included for each patient (unregarding the KRas status) two cycles of DEBIRI (using 100-300 μm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m² and then 250 mg/m²; good performance status (0-2) and liver functionality (alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/mL). Data were collected retrospectively and included: tumor response (evaluated monthly for 6 mo then every 3 mo), overall response rate (ORR), KRas status, type and intensity of adverse events (G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival (OS) and progression free survival (PFS).RESULTS: Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo (range, 4.0-6.5). Sixteen patients (40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders (10%) and 16 (40%) partial responders. The most observed side effects (G2) were: post-embolization syndrome (30%), diarrhea (25%), skin rushes (38%) and asthenia (35%). The retrospective evaluation of KRas status (24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo (8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy.CONCLUSION: DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.     

Two-stage hepatectomy combined with converting chemotherapy achieved a successful treatment for initially unresectable multiple bilobar colorectal liver metastases

A 60-year-old man having metachronous multiple bilobar colorectal liver metastases was referred to our institution. The lesions were diagnosed unresectable due to a lack of the estimated future remnant liver volume. He underwent 13 courses of mFOLFOX6 + bevacizumab as down-staging chemotherapy. The periodic abdominal CT scans revealed metastatic lesions to become PR. We had decided to perform two-stage hepatectomy to preserve a hepatic functional reserve. After the rest of chemotherapy for 4 weeks, four tumors were resected and right branch of the portal vein embolization was performed at the first operation. Right hemihepatectomy was performed 5 weeks after the first operation to achieve curative resection. Postoperative course was uneventful and the patient was discharged at 17 days after the operation. He has no signs of tumor recurrence during the follow-up. The combination of two-stage hepatectomy and neoadjuvant systemic chemotherapy may contribute to improve prognoses of initially unresectable multiple bilobar colorectal liver metastases, leading to prolonged survival.     

‘Close Shave’ in liver resection for colorectal liver metastases

Introduction

The optimal size of clear liver resection margin width in patients with colorectal liver metastases (CRLM) remains controversial. The aim of this study was to investigate the effects of margin width on long-term survival after liver resection for CRLM with a policy of standard neo-adjuvant chemotherapy.

Methods

Consecutive patients (n = 238) who underwent liver resection for CRLM were included over a ten-year period. All patients with synchronous or early (<2 years) metachronous tumours were treated with neo-adjuvant chemotherapy. Data were recorded prospectively.

Results

Overall survival of the cohort at 1, 3 and 5 years were 90.3%, 68.1% and 56.1% respectively. The incidence of cancer involved resection margins (CIRM) was 5.8%. Patients with macroscopically involved resection margins had a poorer overall survival than those with microscopically involved margins (p = 0.04). Involved resection margins had a poorer overall survival (p = 0.002) than patients with clear margins. Width of clear resection margin did not affect long-term survival.

Conclusion

CIRM independently predicts poor outcome in patients with CRLM. Clear margin width does not affect survival. A standard policy of neo-adjuvant chemotherapy may be associated with a low incidence of CIRM and improved long-term outcome of sub-centimetre margin widths, resembling those with >1 cm resection margins.     

The role of adjuvant therapy after liver resection for colorectal cancer metastases

Intrahepatic recurrence is common after major resection for colorectal cancer (CRC) metastases to the liver. In this review, the available data on different adjuvant therapies from systemic chemotherapy to regional approaches by direct perfusion of chemotherapeutic agents via the hepatic artery and portal vein will be discussed. Intraperitoneal administration of chemotherapy is another form of regional therapy. Novel approaches with immunotherapy and trials of neoadjuvant therapy in association with resection of CRC hepatic metastases have also been reported. The purpose of this review is to outline these various strategies and their role in combination with resection of CRC liver metastases. Although improved hepatic disease-free survival has been demonstrated with some strategies, overall survival is minimally affected and recurrence of metastatic disease at distant sites is still a major problem. Therefore, future directions should incorporate the use of new systemic agents effective against CRC metastases. Identification of subgroups through clinical features, molecular markers, proteins, or specific tumor properties may also help to individualize treatment.     

Advances in neoadjuvant therapy for colorectal cancer with liver metastases

Metastatic colorectal cancer (CRC) is most frequently seen in the liver. Resection of metastases remains the treatment of choice; however, the majority of patients are ineligible for surgery due to unfavorable location, size, or number of metastases; insufficient liver reserve; or extrahepatic disease. The activity of irinotecan- and oxaliplatin-based regimens as first-line therapy has prompted the investigation of these agents as neoadjuvant therapy in patients with resectable and unresectable disease. Although studies suggest considerable promise for a neoadjuvant strategy in patients with unresectable liver metastases, the heterogeneity, small size, and retrospective nature of many of these studies precludes drawing firm clinical conclusions at this time, especially in patients with resectable disease. Therefore large, prospective trials that examine the impact of preoperative chemotherapy in patients with initially unresectable or resectable liver metastases are needed. These trials must include well-defined criteria for resectability and clear reporting of the extent of resection.     

The emerging role of cetuximab in head and neck cancer: a 2007 perspective

The integration of targeted therapies into clinical practice constitutes the paradigm of oncology treatment in the current era. Cetuximab, a recombinant human/mouse chimeric epidermal growth factor (EGFR) monoclonal antibody is a targeted agent that has seen expanding indication in recent years. Originally approved for colorectal cancer, its role in the treatment of squamous cell carcinoma of the head and neck has augmented treatment options for patients who are refractory to or cannot tolerate platinum. This article will review the science underlying cetuximab, data supportings its use in patients with locally advanced and recurrent/metastatic disease, common toxicities of therapy, and the integration of this treatment with radiation therapy.     

西妥昔单抗单周和双周方案治疗晚期大肠癌的对比研究

 目的　比较西妥昔单抗250 mg／m2单周方案和500 mg／m2双周方案分别联合化疗治疗晚期大肠癌的近期疗效及安全性。方法　56例晚期大肠癌患者,ECOG行为状态评分0～2分,均有可评价病灶（RECIST 2000标准）。西妥昔单抗单周方案联合化疗组30例,给药方法为400 mg／m2第1周,以后250 mg／m2每周重复应用;双周方案联合化疗组26例,给药方法为500 mg／m2第1周,以后每两周重复应用。两组均以完成8周治疗或出现疾病进展为治疗终点。结果　西妥昔单抗单周方案联合化疗组28例可评价疗效：完全缓解（CR）1例,部分缓解（PR）7例,疾病稳定（SD）11例,疾病进展（PD）9例,有效率28.6 %,疾病控制率67.9 %;双周方案联合化疗组26例可评价疗效：CR 0例,PR 8例,SD 9例,PD 9例,有效率30.8 %,疾病控制率65.4 %,两组比较差异无统计学意义（P＞0.05）。两组Ⅲ～Ⅳ度不良反应主要表现为皮疹、恶心、中性粒细胞减少及白细胞减少,两组比较差异也无统计学意义（P＞0.05）。结论　西妥昔单抗单周和双周方案分别联合化疗治疗晚期大肠癌疗效相近,不良反应均可耐受。     

Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study)

BackgroundInitially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation.Patients and methodsPatients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012.ResultsBetween December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2–44.2] months [arm A: 35.8 (95% CI 28.1–43.6), arm B: 29.0 (95% CI 16.0–41.9) months, HR 1.03 (95% CI 0.66–1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3–12.2) months [arm A: 11.2 (95% CI 7.2–15.3), arm B: 10.5 (95% CI 8.9–12.2) months, HR 1.18 (95% CI 0.79–1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9–71.9) months] than those who did not [21.9 (95% CI 17.1–26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8–14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%).ConclusionsThis study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for ‘conversion’ treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional ‘line of therapy’ in those patients who are not cured.Clinical Trial NumberNCT00153998, www.clinicaltrials.gov.     

The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab

Preclinical data suggested that, in the presence of human epidermal growth factor receptor (HER)-3-altered activation, colorectal cancer cells may escape anti-epidermal growth factor receptor (EGFR)-mediated cell death. HER-3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER-3 expression and clinical outcome in wild-type K-RAS advanced colorectal cancer patients receiving cetuximab and irinotecan. We retrospectively analyzed immunoreactivity for HER-3 in wild-type K-RAS advanced colorectal cancer patients receiving irinotecan and cetuximab. Eighty-four advanced wild-type K-RAS colorectal cancer patients were available for HER-3 analysis. Forty patients (48%) had a HER-3(-) colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER-3(+). In patients with HER-3(-) and HER-3(+) tumors, we observed a partial response in 17 (42%) and eight (18%) patients respectively; progressive disease occurred in 11 (35%) and 26 (53%) patients with HER-3(-) and HER-3(+) tumors, respectively (p = .003). The median progression-free survival time was 6.3 months in patients with HER-3(-) tumors and 2.8 months for those who had HER-3-overexpressing tumors (p < .0001). The median overall survival time was 13.6 months in patients showing HER-3(-) tumors and 10.5 months for those who had HER-3-expressing tumors (p = .01). HER-3 proved to be a predictive factor for clinical outcome in wild-type K-RAS colorectal cancer patients treated with cetuximab. Combined HER-3 and K-RAS analysis may represent an effective strategy for better selection of responding colorectal cancer patients.     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的：观察西妥昔单抗联合含伊立替康或奥沙利铂化疗方案治疗转移性结直肠癌的近期疗效及毒副反应。方法：１０例经病理组织学确诊的转移性结直肠癌患者,给予西妥苷单抗联合ＦＯＬＦＩＲＩ方案或ＦＯＬＦＯＸ方案治疗,西妥昔单抗首次给予负荷剂量４００ｍｇ／ｍ^２,每周给予维持剂量为２５０ｍｇ／ｍ^２。结果：全组１０例患者中,完全缓解（ＣＲ）１例,部分缓解（ＰＲ）４例,稳定（ＳＤ）２例,进展（ＰＤ）３例,有效率为５０％,疾病控制率为７０％,中位肿瘤进展时间（ＴＴＰ）为６.４个月。主要毒副反应为痤疮样皮疹和腹泻。结论：西妥昔单抗联合ＦＯＬＦＩＲＩ方案或ＦＯＬＦＯＸ方案治疗转移性结直肠癌疗效较好,毒副反应可耐受。     

Neoadjuvant treatment of unresectable liver metastases from colorectal cancer

There has been increasing interest in the use of neoadjuvant treatment for downstaging and downsizing disease in patients with initially unresectable liver metastases from colorectal cancer with a view to potentially curative surgery. This has been increasingly feasible with the more active treatment combinations presently available based on oxaliplatin or irinotecan. This article reviews the evidence supporting the use of this treatment strategy and discusses the implications of advances in treatment in other metastatic disease settings for these patients and the issues of patient selection and prognostic factors.     

Repeated liver resection for recurrence of colorectal cancer metastases

Background  

Resection of liver metastases is accepted as treatment for diverse tumours, implying a survival improvement. Metastases often recur after first hepatectomy and, very few would be potentially resectable.     

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.