Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement

Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.     

Selection for hepatic resection of colorectal liver metastases: expert consensus statement

Hepatic resection offers a chance of a cure in selected patients with colorectal liver metastases (CLM). To achieve adequate patient selection and curative surgery, (i) precise assessment of the extent of disease, (ii) sensitive criteria for chemotherapy effect, (iii) adequate decision making in surgical indication and (iv) an optimal surgical approach for pre-treated tumours are required. For assessment of the extent of the disease, contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is recommended depending on the local expertise and availability. Positron emission tomography (PET) and PET/CT may offer additive information in detecting extrahepatic disease. The RECIST criteria are a reasonable method to evaluate the effect of chemotherapy. However, they are imperfect in predicting a pathological response in the era of modern systemic therapy with biological agents. The assessment of radiographical morphological changes is a better surrogate of the pathological response and survival especially in the patients treated with bevacizumab. Resectability of CLM is dependent on both anatomic and oncological factors. To decrease the surgical risk, a sufficient volume of liver remnant with adequate blood perfusion and biliary drainage is required according to the degree of histopathological injury of the underlying liver. Portal vein embolization is sometimes required to decrease the surgical risk in a patient with small future liver remnant volume. As a complete radiological response does not signify a complete pathological response, liver resection should include all the site of a tumour detected prior to systemic treatment.     

结直肠癌靶向治疗中国专家共识

近年来,随着新型靶向药物的应用,靶向治疗已成为结直肠癌个体化治疗和综合治疗的一线方案,中国医师协会结直肠肿瘤专业委员会、中国抗癌协会大肠癌专业委员会以及国家癌症中心国家肿瘤质控中心结直肠癌质控专家委员会组织全国多位专家,讨论了结直肠肿瘤靶向药物的规范应用。     

Locoregional therapy for liver metastases from colorectal cancer: the possibilities of intraarterial chemotherapy, and new hepatic-directed modalities

Liver metastasis of colorectal cancer is a life-threatening prognostic factor. Hepatic resection, when possible, is the best therapeutic modality, although the overall survival rate is still low (30%). The diagnosis has been carried out by clinical examination, abnormal alkaline phosphatase, lactic acid dehydrogenase and tumor markers, abdominal liver echography and computed tomography scan. Angiography and intraoperative echography are useful for resection. The number of hepatic metastases and the surgical margin are probably the most significant prognostic factors. Colorectal cancer may spread predominantly to the liver making regional treatment strategies viable options. Subtotal hepatic resections and segmentectomies are potentially curable procedures for single or small numbers of hepatic metastases without other sites of disease. However, there have been no prospective randomized trials comparing patients with unresected liver metastases and resected metastases. Regional chemotherapy with floxuridine seems useful combined with hepatic resection or as palliative therapy. Gastric ulcer and biliary sclerosis are the main related toxicities. Patients with localized, unresectable hepatic metastases or concomitant bad medical condition may be candidates for radiation, percutaneous ethanol injection, cryosurgery, radiofrequency, hypoxic flow-stop perfusions with bioreductive alkylating agents, hepatic arterial ligation, embolization and chemoembolization. These new hepatic-directed modalities of treatment are being investigated and may offer new approaches to providing palliation and prolonging survival. This review reports the possibilities of intraarterial chemotherapy and other novel hepatic directed approaches to the treatment of liver metastases from this common disease.     

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement

Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.     

结直肠癌腹膜转移预防和治疗腹腔用药中国专家共识（V 2019）

我国结直肠癌发病率和死亡率均位于恶性肿瘤的前列，腹膜转移作为常见转移部位，是治疗失败的常见原因之一。目前结直肠癌腹膜转移的腹腔预防和治疗性药物种类繁多，但作用剂量和时间尚未形成规范化的治疗模式。因此为了规范术中预防和治疗性腹腔干预方法，中国医师协会结直肠肿瘤专业委员会组织国内相关领域权威专家，制定《结直肠癌腹膜转移预防和治疗腹腔用药中国专家共识》（以下简称《共识》），旨在提高我国结直肠肿瘤的整体诊治水平，延长结直肠癌患者生存时间并改善生活质量。     

SCAI expert consensus statement for advanced training programs in pediatric and congenital interventional cardiac catheterization

Pediatric and Congenital Interventional Cardiology is the practice of catheter‐based techniques that improve cardiac physiology and circulation through the treatment of heart disease in children and adults with congenital or acquired heart defects. Over the last decade, and since last published training guidelines for pediatric cardiac catheterization and interventional cardiology were published in 2005 [1] the field of Pediatric and Congenital Cardiac Catheterization has evolved into a predominantly interventional discipline. As there is no sub‐specialty certification for interventional cardiac catheterization in pediatrics, the Congenital Heart Disease Committee of the Society of Cardiovascular Angiography and Interventions has put together this consensus statement for advanced training in pediatric and congenital interventional cardiac catheterization. The statement puts forth recommendations for program infrastructure in terms of teaching, personnel, equipment, facilities, conferences, patient volume and trainee assessment. This is meant to set a standard for training programs as well as giving applicants a basis on which to judge and compare programs. © 2014 Wiley Periodicals, Inc.     

结直肠癌腹膜转移诊治中国专家共识（2022版）

我国结直肠癌发病率居恶性肿瘤第二位,死亡率居第四位,而腹膜作为其常见转移部位,发病率高,早期诊断困难,并且预后很差。由于目前结直肠癌腹膜转移的诊断及治疗尚未形成规范化的模式,2017年中国医师协会结直肠肿瘤专业委员会组织国内相关领域权威专家,制定《结直肠癌腹膜转移诊治中国专家意见（2017）》,在行业内起到了积极的作用。这几年,大家对结直肠癌腹膜转移的关注度越来越高,开展了一系列临床研究,积累了一些经验。因此,专委会特对2017版《结直肠癌腹膜转移诊治中国专家意见》进行修改,制定2022版《结直肠癌腹膜转移诊治中国专家共识》。以期指导和规范结直肠癌腹膜转移的诊断和治疗,制定合理有效的综合治疗方案,延长结直肠癌腹膜转移患者生存时间并改善生活质量,提高我国结直肠癌的整体诊治水平。     

Anti-EGFR and anti-VEGF agents:Important targeted therapies of colorectal liver metastases

Colorectal liver metastasis(CLM)is common worldwide.Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials,and are now becoming standards for patients with CLM.Thedevelopment and application of anti-epidermal growth factor receptor(anti-EGFR)and anti-vascular endothelial growth factor(anti-VEGF)antibodies represents significant advances in the treatment of this disease.However,new findings continue to emerge casting doubt on the efficacy of this approach.The Kirsten ratsarcoma viral oncogene(KRAS)has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM.Whereas a recent study summarizedseveral randomized controlled trials,and showed thatpatients with the KRAS G13D mutation significantlybenefited from the addition of cetuximab in terms of progress-free survival(PFS,4.0 mo vs 1.9 mo,HR=0.51,P=0.004)and overall survival(OS,7.6 mo vs5.7 mo,HR=0.50,P=0.005).Some other studiesalso reported that the KRAS G13D mutation might notbe absolutely predictive of non-responsiveness to antiEGFR therapy.At the same time,"new"RAS mutations,including mutations in neuroblastoma RAS viral(vras)oncogene homolog(NRAS)and exons 3 and 4 of KRAS,have been suggested to be predictors of a poor treatment response.This finding was first reported by the update of the PRIME trial.The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations,panitumumab-fluorouracil,leucovorin,and oxaliplatin(FOLFOX)4 treatment led to inferior PFS(HR=1.28,95%CI:0.79-2.07)and OS(HR=1.29,95%CI:0.79-2.10),which was consistent with the findings in patients with KRAS mutations in exon 2.Then,the update of the PEAK trial and the FIRE-Ⅲtrial also supported this finding,which would reduce candidates for anti-EGFR therapy but enhance the efficacy.In firstline targeted combination therapy,the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-Ⅶtrial.Also,bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966trial.By the update and further analysis of the COIN trial and the NORDIC-Ⅶtrial,cetuximab plus FOLFOX was reported to be reliable again.But bevacizumab plus oxaliplatin-based chemotherapy was still controversial.In addition,some trials have reported that bevacizumab is not suitable for conversion therapy.The results of the FIRE-Ⅲtrial showed that cetuximab led to a significant advantage over bevacizumab in response rate(72%vs 63%,P=0.017)for evaluable population.With the balanced allocation of second-line treatment,the FIRE-Ⅲtrial was expected to provide evidence for selecting following regimens after first-line progression.There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM,although the combined regimen is often administered based on experience.Combination therapy with more than one targeted agent has been proven to provide no benefit,and even was reported to be harmful as first-line treatment by four large clinical trials.However,recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment.The mechanism of antagonism between different targeted agents deserves further study,and may also provide greater understanding of the development of resistance to targeted agents.     

Comparative study of different interventional therapies for primary liver cancer

AIM: To compare the therapeutic effect of three types of inter-ventional management for primary liver cancer.METHODS: A total of 468 patients with primary liver cancer were randomly allocated to the following three groups: 138 cases treated with chemotherapy alone using mitomycin C, adriamycin and 5-FU (group A); 158 cases treated with chemoembolization using lipiodol (group B); and 172 cases with chemoembolization using lipiodol and gelfoam (group C). All patients were angiographically and sonographically followed-up.RESULTS: In group C, 67.5% patients had AFP value decreased by > 50%, which was much higher than the 43.3% in group B and 32.2% in group A. Tumor size reduction by ≥ 50% occurred in 20.3% of patients in group A, 41.2% of patients in group B and 44.8% of patients in group C. The intergroup differences between group A and group B or C were significant (P < 0.01). The 1-year and 3-year survival rates were 20.5% ± 3.6% and 1.9% ± 2.4% for group A, 51.3% ± 4.4% and 10.1% ± 4.9% for group B, and 63.0% ± 2.4% and 13.9% ± 5.0% for group C, respectively. The differences between all three groups were significant (P < 0.05). The mean survival time for patients in groups A, B and C were 9.6 mo, 16.1 mo and 17.9 mo, respectively.CONCLUSION: Chemoembolization with lipiodol and gelfoam was the most effective therapy for primary liver cancer in this study. The position of the embolization should be far and middle sections of the hepatic artery, and the proximal section should be reserved as the route of the next intra-arterial chemoembolization.     

The effects of surgical margin and edge cryotherapy after liver resection for colorectal cancer metastases

Background. A 1 cm margin seen at operation is typically the minimally acceptable margin for liver resections. Patients who fail to achieve this margin are routinely treated with edge cryotherapy at our unit. This paper aims to assess the benefit of edge cryotherapy on survival in patients with such suboptimal margins. Patients and methods. Between January 1990 and February 2006, 608 patients underwent liver resection and/or cryotherapy for colorectal cancer metastases. All liver resections were performed using the CUSA transection method. Data on marginal status were available for 398 patients. Patient demographics, number and size of liver lesions, preoperative and postoperative carcinoembryonic antigen (CEA), extent of liver resection, margin status, site and date of recurrence, date of last follow-up and death were examined. Results. There were 175 patients in the R0 group (>1 cm macroscopic and ≥1 mm microscopic margin), 103 patients in the R1 group (>1 cm macroscopic and <1 mm microscopic margin) and 120 patients in the R2 group (≤1 cm macroscopic margin and received edge cryotherapy). After a median follow-up of 63 months, there were no significant difference between the 5-year survival rates for R0, R1 and R2 (40%, 30% and 28%, respectively). Conclusion. As long as the surgical margin is clear macroscopically, the microscopic margin width does not affect survival. In patients with suboptimal margins, the addition of edge cryotherapy improves the prospect for long-term survival and may lower recurrence risk.     

Evidence-based medical oncology and interventional radiology paradigms for liver-dominant colorectal cancer metastases

Colorectal cancer metastasizes predictably, with liver predominance in most cases. Because liver involvement has been shown to be a major determinant of survival in this population, liver-directed therapies are increasingly considered even in cases where there is(limited) extrahepatic disease. Unfortunately, these patients carry a known risk of recurrence in the liver regardless of initial therapy choice. Therefore, there is a demand for minimally invasive, non-surgical, personalized cancer treatments to preserve quality of life in the induction, consolidation, and maintenance phases of cancer therapy. This report aims to review evidence-based conceptual, pharmacological, and technological paradigm shifts in parenteral and percutaneous treatment strategies as well as forthcoming evidence regarding next-generation systemic, locoregional, and local treatment approaches for this patient population.     

Current treatment for liver metastases from colorectal cancer

The liver is the commonest site of distant metastasis of colorectal cancer and nearly half of the patients with colorectal cancer ultimately develop liver involved during the course of their diseases. Surgery is the only therapy that offers the possibility of cure for patients with hepatic metastatic diseases. Five-year survival rates after resection of all detectable liver metastases can be up to 40 %. Unfortunately, only 25 % of patients with colorectal liver metastases are candidates for liver resection, while the others are not amenable to surgical resection. Regional therapies such as radiofrequency ablation and cryotherapy may be offered to patients with isolated unresectable metastases but no extrahepatic diseases. Hepatic artery catheter chemotherapy and chemoembolization and portal vein embolization are often used for the patients with extensive liver metastases but without extrahepatic diseases, which are not suitable for regional ablation. For the patients with metastatic colorectal cancer beyond the liver, systemic chemotherapy is a more appropriate choice. Immunotherapy is also a good option when other therapies are used in combination to enhance the efficacy. Selective internal radiation therapy is a new radiation method which can be used in patients given other routine therapies without effects.     

Liver metastases from colorectal cancer: present surgical approach

BACKGROUND/AIMS: New developments in surgical techniques and strategies are modifying the indications to resection of liver metastases. METHODOLOGY: From January 1986 to December 2000, 246 consecutive patients with colorectal liver metastases underwent curative hepatic resection. Surgical strategies included simultaneous resection of primary and metastatic colorectal tumor, re-resection of colorectal liver recurrences, two-stage resection and resection of the inferior vena cava when involved by the tumor. Disease-free survival in relation to clinical, pathological and surgical factors was retrospectively assessed with univariate and multivariate analyses. RESULTS: The overall operative mortality was 0.8%. The 1-, 3- and 5-year disease-free survival rates were 75%, 47% and 40%, respectively. Tumors larger than 7 centimeters, multiple lesions, tumors involving more than 2 segments and those requiring major hepatectomy had a worse prognosis at univariate analysis. A size of the tumor above 7 centimeters was the only independent prognostic factors at multivariate analysis. Two-stage and inferior vena cava resection increased operability; re-resection of recurrent colorectal secondaries prolonged survival. CONCLUSIONS: Resection of colorectal liver metastases is safe and effective; it should be considered the treatment of choice for this disease and proposed even for advanced lesions. Counseling of the hepatobilary surgeon should be asked for once a liver secondary is detected in the preoperative work-up of a colorectal cancer.     

Simultaneous colorectal and parenchymal-sparing liver resection for advanced colorectal carcinoma with synchronous liver metastases: Between conventional and mini-invasive approaches

The optimal timing of surgery in case of synchronous presentation of colorectal cancer and liver metastases is still under debate. Staged approach, with initial colorectal resection followed by liver resection (LR), or even the reverse, liver-first approach in specific situations, is traditionally preferred. Simultaneous resections, however, represent an appealing strategy, because may have perioperative risks comparable to staged resections in appropriately selected patients, while avoiding a second surgical procedure. In patients with larger or multiple synchronous presentation of colorectal cancer and liver metastases, simultaneous major hepatectomies may determine worse perioperative outcomes, so that parenchymal-sparing LR should represent the most appropriate option whenever feasible. Mini-invasive colorectal surgery has experienced rapid spread in the last decades, while laparoscopic LR has progressed much slower, and is usually reserved for limited tumours in favourable locations. Moreover, mini-invasive parenchymal-sparing LR is more complex, especially for larger or multiple tumours in difficult locations. It remains to be established if simultaneous resections are presently feasible with mini-invasive approaches or if we need further technological advances and surgical expertise, at least for more complex procedures. This review aims to critically analyze the current status and future perspectives of simultaneous resections, and the present role of the available mini-invasive techniques.