Expression of multidrug resistance protein in metastatic colorectal carcinomas

To clarify the relationship between multidrug resistance protein (MRP) and clinicopathologic features, the influence of adjuvant chemotherapy, and prognosis of patients who underwent resection of metastatic liver carcinomas originating from colorectal carcinomas, we examined the expression of MRP in tumor tissues by immunostaining. Specimens of 38 primary colorectal tumors and 44 metastatic liver tumors of colorectal origin were examined (metastatic group). We also examined 28 nonmetastatic colorectal carcinomas. The percentages of nonmetastatic tumors and of primary and metastatic tumors of the metastasis group that expressed MRP were similar. MRP expression in primary and metastatic tumors did not correlate with any clinicopathologic features. The use of adjuvant chemotherapy after operation for primary colorectal carcinomas was associated with increased MRP expression among metastatic liver tumors. Expression of MRP in the tumor did not influence the prognosis or survival rate after resection of primary or metastatic tumors. Our data suggest that MRP expression in metachronous liver metastases from colorectal carcinomas may be induced by administration of anticancer drugs but is not associated with clinicopathologic features of the tumor, liver metastasis, or prognosis. Received: November 19, 1998 / Accepted: May 28, 1999     

结直肠癌肝转移同期肝切除的原则剖析

结直肠癌(CRC)是常见的消化系统恶性肿瘤,其发病率及病死率逐年升高,肝脏是其最常见转移部位。手术治疗是目前治疗结直肠癌肝转移最有效的方法。对于结直肠癌肝转移同期肝切除的手术时机的选择一直是外科医生争论的话题。诸如围手术期化疗或者一些其他新的方法,都可以影响手术时机的选择。随着对结直肠癌肝转移研究的不断深入以及外科手术技巧的不断进步,目前对于同期肝切除的原则仍在很大程度上依赖于新辅助化疗、外科医生对于可切除性的判断以及病人的体质。笔者综述了近些年来对于结直肠癌肝转移同期肝切除的原则剖析,并加以分析。     

Benefit of FOLFOX to unresectable liver metastases secondary from colorectal carcinoma in an oncologic emergency

Liver metastasis is an important prognostic factor in colorectal cancer. The efficacy of resection of metastatic lesions in liver metastasis of colorectal cancer is also widely recognized. However, studies on treatment methods of unresectable cases have not been sufficient and obtaining complete remission (CR) for liver metastasis is rare with chemotherapy. Selection of reliable chemotherapy for unresectable liver metastasis is an urgent necessity. The usefulness of oxaliplatin, 5-flurouracil and leucovorin combination therapy (FOLFOX) has recently been reported, but CR of liver metastasis is rare. The current status and new therapeutic significance of FOLFOX therapy are discussed based on the literature of colorectal cancer chemotherapy to date, and the clinical experience in which we obtained CR for liver metastasis is reported. The patient had stage IV rectal cancer, perforative peritonitis, pelvic abscess and simultaneous multiple liver metastasis. The patient underwent an emergency operation using the Hartmann's procedure. Liver metastasis is considered to be a prognostic factor and FOLFOX was selected as the postoperative chemotherapy, CR of the liver metastasis was obtained. FOLFOX was suggested to have new clinical significance in oncologic emergencies against unresectable liver metastasis in colorectal cancer and should serve as adjuvant chemotherapy that will contribute to improvement of treatment results.     

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.     

Synchronous resections of primary colorectal tumor and liver metastasis by laparoscopic approach

Liver metastasis of colorectal cancer is common. Resection of solitary tumors of primary and metastatic colorectal cancer can have a favorable outcome. Open resection of primary colorectal tumor and liver metastasis in one operation or in separate operations is currently common practice. Reports have shown that synchronous resections do not jeopardize short or long-term surgical outcomes and that this is a safe and effective approach in open surgery. The development of laparoscopic colorectal surgery and laparoscopic hepatectomy has made a minimally invasive surgical approach to treating colorectal cancer with liver metastasis feasible. Synchronous resections of primary colorectal tumor and liver metastasis by laparoscopy have recently been reported. The efficacy and safety of laparoscopic colorectal resection and laparoscopic hepatectomy have been proven separately but synchronous resections by laparoscopy are in hot debate. As it has been shown that open resection of primary colorectal tumor and liver metastasis in one operation results in an equally good short-term outcome when compared with that done in separate operations, laparoscopic resection of the same in one single operation seems to be a good option. Recent evidencehas shown that this new approach is a safe alternative with a shorter hospital stay. Large scale randomized controlled trials are needed to demonstrate the effectiveness of this minimally invasive approach.     

腹腔镜下结直肠癌肝转移一期切除的临床研究

目的分析腹腔镜下同时行结直肠癌切除术合并肝转移癌切除术的可行性及安全性。 方法选取26例江苏省人民医院结直肠外科在2013年8月至2015年5月期间完成一期切除结直肠癌原发灶合并肝转移癌切除术的病历资料,观察一期切除的可行性（术中出血、手术时间和中转开腹率）、安全性（术后并发症）和治疗效果（术后恢复情况）。 结果26例一期手术过程顺利,都获得成功。其中腔镜下结直肠癌原发灶及肝转移癌同时切除共有16例,腔镜下结直肠癌切除术加开放肝转移癌切除术共有10例。手术时间为（205.12±49.09）min,术中出血量为（296.84±376.53）ml,术后消化道排气时间（2.62±0.56）d,术后住院时间（13.92±6.80）d。术后发生腹腔感染2例,肠瘘1例,自发性气胸1例。余者均恢复良好。 结论腹腔镜结直肠癌原发灶及肝转移癌的一期切除安全可行,具有较好的疗效。     

Liver metastases

Opinion Statement Liver metastases, especially from colorectal primary cancers, are treatable and potentially curable. Imaging techniques such as CT, MRI, and sonography have advanced in recent years and led to increased sensitivity and specificity in the diagnosis of liver metastases. Liver surgery also has been revolutionized in the past two decades. Dissections along nonanatomic lines have permitted the resection of multiple lesions that previously might have been considered unresectable. We regard resection of a solitary hepatic metastasis or up to four metastases from colorectal carcinoma as the best treatment for this condition. In patients over 70 years of age and those with medical conditions preventing surgery, we endorse expectant follow-up as long as the tumor remains stable. But if the tumor begins growing rapidly and local techniques cannot be used, we consider systemic chemotherapy. In patients with progressive metastatic liver disease, we initiate systemic therapy or hepatic arterial infusion. In young patients with metastatic disease, even when the disease is indolent or symptomatic, it may be difficult not to treat. We use either local regional therapy (resection or regional infusion) or systemic chemotherapy followed by regional therapy. In patients with neuroendocrine tumors metastatic to the liver, the first approach we use is not to treat because there may be a long period of stable disease. We use Sandostatin (Sandoz Pharmaceuticals, East Hanover, NJ) to treat symptoms. If the tumor progresses and symptoms cannot be controlled, these vascular tumors can be treated by embolization or chemoembolization, with high expectations of response. Newer approaches to liver metastases such as cryosurgery, chemoembolization, and interstitial radiation are also available. Cryosurgery is an ablative procedure that has not been proven yet to be as effective as surgical removal of metastases. However, in a situation where surgery cannot be performed, cryosurgery is an alternative. Chemoembolism has not been proven to be more effective than systemic therapy for liver metastases, but it allows another regional approach. External localized radiation can be used for patients who fail first-line treatment or in new protocols to delineate its value, perhaps in concert with chemotherapy. We also consider offering external localized radiation in patients who fail first-line treatment, perhaps in concert with chemotherapy. The usefulness of these techniques compared with surgery or regional therapy is being investigated.     

Effects of Yttrium-90 selective internal radiation therapy on non-conventional liver tumors

The liver is a common site of metastasis, with essentially all metastatic malignancies having been known to spread to the liver. Nearly half of all patients with extrahepatic primary cancer have hepatic metastases. The severe prognostic implications of hepatic metastases have made surgical resection an important first line treatment in management. However, limitations such as the presence of extrahepatic spread or poor functional hepatic reserve exclude the majority of patients as surgical candidates, leaving chemotherapy and locoregional therapies as next best options. Selective internal radiation therapy (SIRT) is a form of catheter-based locoregional cancer treatment modality for unresectable tumors, involving trans-arterial injection of microspheres embedded with a radio-isotope Yttrium-90. The therapeutic radiation dose is selectively delivered as the microspheres permanently embed themselves within the tumor vascular bed. Use of SIRT has been conventionally aimed at treating primary hepatic tumors (hepatocellular carcinoma) or colorectal and neuroendocrine metastases. Numerous reviews are available for these tumor types. However, little is known or reviewed on non-colorectal or non-neuroendocrine primaries. Therefore, the aim of this paper is to systematically review the current literature to evaluate the effects of Yttrium-90 radioembolization on non-conventional liver tumors including those secondary to breast cancer, cholangiocarcinoma, ocular and percutaneous melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.     

Colorectal liver metastases: an update on palliative treatment options

Only approximately 30% of patients with colorectal cancer liver metastasis qualify for curative therapy, which is in most cases liver lesion resection. Due primarily to the extent of the tumors and patient comorbidities, palliative therapy remains the only option in non-resection cases. Palliation enables local, symptomatic control and prolonged survival in some cases. As established methods are continuously improved, new palliative therapy methods are tested in clinical trials and subsequently introduced into clinical practice. The present review provides an overview of current colorectal liver metastasis treatment when resection is not an option. This review gives the basis for an interdisciplinary decision making process for the treatment of liver metastasis.     

Hepatic resection for liver metastasis of sigmoid colon cancer after incomplete percutaneous microwave coagulation therapy

We report a case of colon cancer with liver metastasis that had been treated previously by sigmoidectomy and partial hepatic segmentectomy. A 55-year-old woman presented with two asynchronous liver metastases, which were treated with percutaneous microwave coagulation therapy. However, evaluation by dynamic computed tomography one week later showed incomplete necrosis in at least one tumor. Surgical resection was subsequently performed and histopathological examination showed the presence of viable cancer cells in both tumors. We conclude that surgical resection is perhaps the best curative method of treatment of metastatic liver tumors of colorectal carcinomas and that dynamic computed tomography is not always accurate for evaluating the effect of microwave coagulation therapy.     

Chemotherapy of primary and secondary liver tumors

Liver is the most common site of metastatic disease. Although primary liver tumors are relatively rare in the Czech Republic, liver tumors represent a frequently encountered problem because of high incidence of colorectal and pancreatic cancer. Regimens of systemic chemotherapy or biologic therapy are used for secondary liver tumors according the primary site. It was demonstrated in randomized clinical studies that some of these regimens significantly prolong survival. Although only palliative therapy is possible for most of the patients with liver metastases, resection should be considered in patients with isolated liver involvement. Liver resection represents a curative approach and long-term success seems to be enhanced by neoadjuvant (preoperative) chemotherapy or adjuvant (postoperative) hepatic arterial chemotherapy. Hepatic arterial chemotherapy is also effective in the palliative treatment of unresectable liver metastases. Although it is still uncertain whether hepatic arterial chemotherapy increases survival of patients compared to systemic chemotherapy, it may be regarded as the best available treatment in selected patients because of better palliation associated with higher objective response rate and less systemic toxicity. Along with systemic and hepatic arterial chemotherapy, other approaches are being currently investigated in the treatment of primary and secondary liver tumors, including the use of biologic agents, agents with non-cytotoxic mechanism of action, or chronomodulated chemotherapy.     

Therapeutic strategies for hepatic metastasis of colorectal cancer: overview

To determine the treatment strategy for hepatic metastases of colorectal cancer, it is important to take into account whether metastases are still localized in the liver, or whether the tumor has metastasized throughout the body. For liver-limited metastasis, hepatectomy is the therapeutic strategy that offers the best prospect of improving a patient's prognosis if the case is deemed resectable. In cases when surgery is not indicated for hepatic metastases of colorectal cancer, chemotherapy is the first-choice treatment. Chemotherapy for colorectal cancer has made vast strides in recent years through advances such as the development of molecular targeted drugs. In cases where chemotherapy is effective and surgical resection becomes possible (conversion chemotherapy), the long-term prognosis may be good. The value of preoperative chemotherapy in resectable cases (neoadjuvant chemotherapy) has also been reported. The improvement in prognosis achieved by eradicating tiny latent metastases is important in conversion therapy, as well as in neoadjuvant chemotherapy. It will be important to achieve further improvements in the prognoses of patients with hepatic metastases of colorectal cancer through a combination of advances in diagnostic imaging, improvements in surgical techniques, and more effective chemotherapy treatments.     

Hepatocellular carcinoma. Part 2. Treatment

Recent improvements on the therapeutical management of hepatocellular carcinoma are revised with special attention to evaluate the role of surgery for the disease. Considering that definitive surgical intervention is not feasible in most cases because of extreme tumor extension, multiplicity of tumor foci, and associated advanced liver cirrhosis at the time of diagnosis, others forms of treatment are listed, such as transcatheterarterial chemoembolization, percutaneous ethanol and acetic acid injections, and chemotherapy only to a small portion of patients with no indication for standard treatments. The emerging role of retinoic acid metabolism blocking agents, was examined and may offer a significant new potential treatment for cancer, inclusive the possibility of combining other anticancer drugs with exogenous retinoids or modulation of endogenous retinoids as a real opportunity to advance our ability to treat or prevent human cancer effectively Octreotide, nitrosamine and other drugs are analyzed and is concluded that improves survival and is a valuable alternative in the treatment of inoperable hepatocellular carcinoma. The potential role of intersticial laser coagulation for patients with irresectable hepatic tumors was investigated, and in terms of experience, it has now been developed sufficiently to study its effect on these patients survival. The homeostatic control of angiogenesis and its influences on the tumor growth and for migration of metastatic cells, was focused in this concise review, given that hepatocytes are the source of much of the precursor pool, regulation of angiogenesis may be regarded as a new liver function with important consequences for tissue repair and cancer. Early hepatocellular carcinoma and its recognition in routine clinical practice contributes to improved patients survival. Recombinant-Interferon-alpha therapy surely prevents, the development of cirrhosis or hepatocellular carcinoma in about one-third of patients, with chronic hepatitis C, with sustained response. Finally, in individuals with life-threatening liver disease, such as those with cirrhosis and hepatocellular carcinoma, the liver transplantation, must be considered, besides controversial, however, with increasing experience the results of the procedure in these patients have improved, and may offer a better long-term survival than liver resection.     

Complete resection of unresectable liver metastases from colorectal cancer without deterioration of liver function after cetuximab and irinotecan: two case reports

Complete resection for colorectal metastases is the only treatment that can provide long-term survival and may lead to cure. Recent reports have shown that liver resection following systemic chemotherapy in patients with initially unresectable metastases from colorectal cancer may also result in a good long-term survival, and rescue surgery after chemotherapy has become a strategy of choice. A 29-year-old male and a 35-year-old female with unresectable liver metastases from colorectal cancer underwent complete resection after administration of third-line combination therapy of cetuximab and irinotecan. Although systemic chemotherapy may decrease liver function, which may make liver resection unfeasible, in the two cases reported, liver function did not deteriorate after cetuximab plus irinotecan. The indocyanine green retention rate at 15 minutes, which is useful in deciding the safe limit of hepatectomy, was optimal after the administration of cetuximab plus irinotecan in both patients. Cetuximab plus irinotecan may be beneficial as neoadjuvant chemotherapy for metastatic colorectal cancer, not only because of its oncological efficacy but also for preservation of liver function.     

结直肠癌肺转移的外科治疗

结直肠癌是我国的常见恶性肿瘤,发病率居第三位。约20%的结直肠癌初诊时就伴有远处转移,其中肺是最常见的转移部位之一。大量文献表明,对于结直肠癌伴有局限性肺转移的患者手术切除转移病灶,术后的5年生存率为21%～64%。存在其他可切除转移灶并不是手术禁忌。对于手术耐受良好的肺部转移瘤术后复发的患者,再次手术仍可生存获益。距离病灶0.5cm～1.0cm楔形切除是肺外周型病灶的经典术式。对于结直肠癌肺转移瘤手术胸腔淋巴结清扫仍有不同观点。目前公认的结直肠癌肺转移预后不良的因素包括：多发肺转移瘤、癌胚抗原水平升高、胸内淋巴结转移、无瘤间期较短。基于精准医学的个体化治疗将是未来进一步改善预后的关键。     

结直肠癌肝转移新辅助治疗研究进展

结直肠癌的发病率及死亡率在全世界范围内逐年上升,其主要的死亡原因是肝转移。现代医学技术快速发展推动了诊治理念不断更新。个体化治疗及多学科综合治疗协作组（MDT）诊治理念的提出,外科技术以及局部治疗的迅速发展,使患者的生存期得以明显延长。结直肠癌肝转移新辅助治疗的应用有助于降低肿瘤分期,提高手术切除率,进而转化为患者生存获益,这一点在其他实体瘤中也已得到证实。但新辅助治疗是否延长所有患者生存期以及患者能否从局部治疗中获益仍存在争议,本文就结直肠癌肝转移新辅助治疗研究进展进行综述。     

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.     

Minimally invasive image-guided therapy of primary and metastatic pancreatic cancer

Pancreatic cancer is a challenging malignancy with limited treatment options and poor life expectancy. The only curative option is surgical resection, but only 15%-20% of patients are resectable at presentation because more than 50% of patients has distant metastasis at diagnosis and the rest of them has locally advanced pancreatic cancer (LAPC). The standard of care first line treatment for LAPC patients is chemotherapy with or without radiation therapy. Recent developments in minimally invasive ablative techniques may add to the treatment armamentarium of LAPC. There are increasing number of studies evaluating these novel ablative techniques, including radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation. Most studies which included pancreatic tumor ablation, demonstrated improved overall survival in LAPC patients. However, the exact protocols are yet to set up to which stage of the treatment algorithm ablative techniques can be added and in what kind of treatment combinations. Patients with metastatic pancreatic cancer has dismal prognosis with 5-year survival is only 3%. The most common metastatic site is the liver as 90% of pancreatic cancer patients develop liver metastasis. Chemotherapy is the primary treatment option for patients with metastatic pancreatic cancer. However, when the tumor is not responding to chemotherapy or severe drug toxicity develops, locoregional liver-directed therapies can provide an opportunity to control intrahepatic disease progression and improve survival in selected patients. During the last decade new therapeutic options arose with the advancement of minimally invasive technologies to treat pancreatic cancer patients. These new therapies have been a topic of increasing interest due to the severe prognostic implications of locally advanced and metastatic pancreatic cancer and the low comorbid risk of these procedures. This review summarizes new ablative options for patients with LAPC and percutaneous liver-directed therapies for patients with liver-dominant metastatic disease.     

从ESMO共识看结直肠癌肝转移的治疗策略

肝脏转移是结直肠癌最常见的远处转移,大多数的结直肠癌肝转移患者为初始不可切除,为了获得最佳的治疗效果,需要在多学科团队的基础上,讨论并确定治疗策略和治疗目标。欧洲临床肿瘤学会指南被广泛用于结直肠癌患者治疗策略的制定,是临床医生需要遵循的标准。     

Sum of the longest diameters of metastatic liver tumors is a possible new prognostic factor after hepatectomy in patients with colorectal liver metastases

BACKGROUND/AIMS: Although the size and number of the metastatic liver tumors have been considered to be prognostic factors after hepatectomy in patients with colorectal liver metastases, the importance of these parameters is still controversial. The aim of this study was to evaluate the importance of the new factor, namely, the sum of longest diameters of the metastatic liver tumors (SLD). METHODOLOGY: The medical records of 59 patients who had undergone hepatic resection for colorectal liver metastases were abstracted and these patients were completely followed-up. RESULTS: The overall 5-year survival rate after hepatectomy was 38.5%, and median survival time was 25.9 months. The significant prognostic factors by the univariate analysis were the extents of vessel permeation and lymph node metastasis of primary colorectal carcinoma, the presence of extrahepatic metastasis, the longest diameter and SLD of the liver tumor, surgical margin of the liver, and the serum level of carcinoembryonic antigen. Multivariate analysis showed that SLD (P=0.026) and extrahepatic distant organ metastasis (P=0.008) were the independent prognostic factor. CONCLUSIONS: SLD is a useful and significant predictor for survival after hepatectomy in patients with colorectal liver metastases.