Chemotherapy for the conversion of unresectable colorectal cancer liver metastases to resection

Resection of colorectal liver metastases (CLM) is the ultimate aim of treatment strategies in most patients with liver-confined metastatic colorectal cancer. Long-term survival is possible in selected patients with initially resectable or unresectable CLM. As a majority of patients have unresectable liver disease at the outset, there is a clear role for chemotherapy to downstage liver disease making resection possible. Studies of systemic chemotherapy with or without biologic therapy in patients with unresectable CLM have resulted in increased response rates, liver resection rates and survival. A sound physiologic rationale exists for the use of hepatic arterial infusion (HAI) therapy. Studies have shown that HAI with floxuridine combined with systemic chemotherapy increases response rates and liver resection rates in those patients with initially unresectable CLM. Toxicity from preoperative chemotherapy, biologic therapy and HAI therapy may adversely affect hepatic resection but can be kept minimal with appropriate monitoring. All conversion strategies should be decided by a multidisciplinary team.     

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.     

Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements

Selection of the optimal surgical and interventional therapies for advanced colorectal cancer liver metastases (CRLM) requires multidisciplinary discussion of treatment strategies early in the trajectory of the individual patient''s care. This paper reports on expert consensus on locoregional and interventional therapies for the treatment of advanced CRLM. Resection remains the reference treatment for patients with bilateral CRLM and synchronous presentation of primary and metastatic cancer. Patients with oligonodular bilateral CRLM may be candidates for one-stage multiple segmentectomies; two-stage resection with or without portal vein embolization may allow complete resection in patients with more advanced disease. After downsizing with preoperative systemic and/or regional therapy, curative-intent hepatectomy requires resection of all initial and currently known sites of disease; debulking procedures are not recommended. Many patients with synchronous primary disease and CRLM can safely undergo simultaneous resection of all disease. Staged resections should be considered for patients in whom the volume of the future liver remnant is anticipated to be marginal or inadequate, who have significant medical comorbid condition(s), or in whom extensive resections are required for the primary cancer and/or CRLM. Priority for liver-first or primary-first resection should depend on primary tumour-related symptoms or concern for the progression of marginally resectable CRLM during treatment of the primary disease. Chemotherapy delivered by hepatic arterial infusion represents a valid option in patients with liver-only disease, although it is best delivered in experienced centres. Ablation strategies are not recommended as first-line treatments for resectable CRLM alone or in combination with resection because of high local failure rates and limitations related to tumour size, multiplicity and intrahepatic location.     

结直肠癌肝转移综合治疗进展

虽然手术仍是目前唯一有可能治愈结直肠癌肝转移的手段,但是在结直肠癌肝转移的诊疗方面发展迅速。多学科团队综合治疗和分组治疗逐渐成为诊疗规范。对可切除的结直肠癌肝转移患者,在围手术期也应实施标准化疗,是否加用靶向药物尚无定论。实施转化性化疗时应选择高效化疗方案,并尽量缩短疗程,且一旦转移灶转化为可切除,就应积极安排手术。肝转移灶不可切除的患者,是否切除原发灶也存在争议。在肝转移灶局部治疗方面的新技术发展迅速,可改善患者生存。     

结直肠癌肝转移外科治疗的共识与争议

结直肠癌肝转移是导致结直肠癌患者死亡的主要原因。目前,循证医学证据表明手术切除是结直肠癌肝转移患者有效且可能获得长期生存的惟一治疗方式。随着外科技术尤其是微创外科技术的进步,越来越多的患者可从外科手术中获益。化学药物的发展以及贝伐单抗和西妥昔单抗等靶向药物的应用,使不可切除的结直肠癌肝转移转化为可切除,从而使更多患者获得治愈的机会。对于无法根治性切除的患者,外科手术联合射频治疗的方法可延长生存期。多学科合作团队诊治模式的广泛应用,使结直肠癌肝转移的治疗更加精准。     

Systemic chemotherapy for pancreatic cancer

Surgical resection offers the only curative strategy for pancreatic cancer. Yet, because early detection of pancreatic cancer is so difficult and diagnosis is delayed, pancreatic cancer in most patients is surgically unresectable. Even in patients with resectable disease, the long-term outcome remains unsatisfactory due to early recurrence after resection. Early appearance of distant metastasis suggests that systemic treatment, such as chemotherapy, should play a major role in improving patient survival. Although the recently developed gemcitabine has renewed interest in clinical research for pancreatic cancer, other currently available chemotherapeutic agents have little impact on survival. Studies to identify more effective agents or treatment regimens must have the highest priority. The expanding understanding of molecular and genetic biology should facilitate research to develop novel molecule-targeted agents and to establish individualized therapy regimens for this disease.     

Perioperative chemotherapy with bevacizumab and liver resection for colorectal cancer liver metastasis

Background:

Surgery remains the only curative option for patients with colorectal cancer liver metastases (CRLM). Perioperative chemotherapeutic strategies have become increasingly popular in the treatment of CRLM. Although the role of bevacizumab (Bev) in this setting remains unclear, its widespread use has raised concerns about the use of Bev as part of perioperative chemotherapy.

Methods:

We retrospectively reviewed all patients who received Bev and underwent liver resection between July 2004 and July 2008 at the McGill University Health Center. Chemotherapy-related toxicity, response to chemotherapy, surgical morbidity and mortality, liver function and survival data were assessed.

Results:

A total of 35 patients were identified. Of these, 26 (74.3%) patients received oxaliplatin-based cytotoxic chemotherapy, six (17.1%) received irinotecan-based therapy and the remainder received both agents. A total of 17 patients (48.6%) underwent portal vein embolization prior to resection and 12 (34.3%) underwent staged resection for extensive bilobar disease. A median of six cycles of preoperative Bev were administered. Nine patients (25.7%) experienced grade 3 or higher chemotherapy-related toxicities. Four events were deemed to be related to Bev. The overall response rate was 65.7% (complete and partial response). One patient progressed on therapy, but this did not prevent R0 resection. The incidence of postoperative morbidity was 42.3%. A total of 21.7% of complications were Clavien grade 3 or higher. There were no perioperative mortalities. There were no cases of severe sinusoidal injury or steatohepatitis. The Kaplan–Meier estimate of 4-year survival was 52.5%.

Conclusions:

These data confirm the safety of chemotherapy regimens which include Bev in the perioperative setting and demonstrate that such perioperative chemotherapy in patients with CRLM does not adversely affect patient outcome. There was no increase in perioperative morbidity compared with published rates. The addition of Bev to standard chemotherapy may improve response rates, which may, in turn, impact favourably on patient survival.     

Evaluation and management of hepatic injury induced by oxaliplatin‐based chemotherapy in patients with hepatic resection for colorectal liver metastasis

Patients with colorectal liver metastasis (CRLM) can be cured with surgical resection. Recent advances in systemic chemotherapy, including molecular target agents, can be used to introduce “conversion surgery” and achieve R0 resection even in patients with initially unresectable CRLM. Furthermore, neoadjuvant chemotherapy also tries to be applied in patients with resectable CRLM to maximize the remnant liver and reduce the residual micrometastasis before surgery. The development of chemotherapy‐induced hepatic injuries is increasingly being recognized, including sinusoidal obstructive syndrome (SOS), steatosis, steatohepatitis and biliary sclerosis. Especially, oxaliplatin (L‐OHP)‐based chemotherapy in clinical settings appears to be primarily associated with SOS. Various reports have tried to demonstrate the rationale of the correlation between L‐OHP‐based chemotherapy and SOS for the following hepatic surgery. While we can recognize that this pathophysiological disadvantage leads to hepatic dysfunction and the increasing postoperative morbidity, the essential part of this problem including clinical disadvantage, onset mechanism, evaluation systems, and targeted agents for prevention and treatment of SOS continue to be unclear. In this review, we summarize the current experience with hepatic injury induced by L‐OHP‐based chemotherapy, focusing on SOS‐based on clinical and experimental data, in order to assist in the resolution of these identified factors. Finally, the need for reliable methods to identify the risk of SOS, to evaluate SOS status and to predict the safety of surgical treatment in patients with chemotherapy prior to surgery will be emphasized.     

Role of surgery in colorectal cancer liver metastases

Colorectal carcinoma (CRC) is the third most common cancer, and approximately 35%-55% of patients with CRC will develop hepatic metastases during the course of their disease. Surgical resection represents the only chance of long-term survival. The goal of surgery should be to resect all metastases with negative histological margins while preserving sufficient functional hepatic parenchyma. Although resection remains the only chance of long-term survival, management strategies should be tailored for each case. For patients with extensive metastatic disease who would otherwise be unresectable, the combination of advances in medical therapy, such as systemic chemotherapy (CTX), and the improvement in surgical techniques for metastatic disease, have enhanced prognosis with prolongation of the median survival rate and cure. The use of portal vein embolization and preoperative CTX may also increase the number of patients suitable for surgical treatment. Despite current treatment options, many patients still experience a recurrence after hepatic resection. More active systemic CTX agents are being used increasingly as adjuvant therapy either before or after surgery. Local tumor ablative therapies, such as microwave coagulation therapy and radiofrequency ablation therapy, should be considered as an adjunct to hepatic resection, in which resection cannot deal with all of the tumor lesions. Formulation of an individualized plan, which combines surgery with systemic CTX, is a necessary task of the multidisciplinary team. The aim of this paper is to discuss different approaches for patients that are treated due to CRC liver metastasis.     

Chemotherapy of nonoperable colorectal liver metastases.

Biomodulated 5-fluorouracil-based therapy is the mainstay of treatment for advanced colorectal cancer. Patients with advanced disease do better with chemotherapy than they do without, but the overall survival in these patients is still poor. Combination of infusional and bolus 5-fluorouracil/folinic acid (leucovorin) regimens with newer agents, such as CPT-11 and oxaliplatin, in the fist-line treatment of patients with advanced colorectal cancer, has yielded increased response rates and progression-free survivals. In the case of CPT-11 this has also led to an increase in overall survival. Improved therapy combinations and the delivery of the therapy directly to the liver by hepatic arterial infusion, either alone or in combination with intravenous delivery, all herald an improvement in the clinical outcome of patients with nonoperable liver metastases. These patients should be offered the best chemotherapy option available coupled, where appropriate, with liver resection.     

Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases

Background

An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM).

Hepatic arterial chemotherapy for colorectal cancer metastatic to the liver

Hepatic metastases of colorectal origin are resistant to radiation and immunotherapy. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients, and surgical resection is feasible in approximately 20% of patients who have a solitary or unilobar lesion. Infusion of cytotoxic agents into the hepatic artery, introduced 2 decades ago, is the most promising form of therapy for unresectable hepatic metastases. Fluorouracil, floxuridine, and mitomycin have been most commonly administered by hepatic arterial infusion. The recent development of a totally implantable pump has allowed prolonged ambulatory infusion of chemotherapeutic agents into the hepatic artery. We review the recent data on the pharmacology, therapeutic outcome, administration techniques, and complications of hepatic arterial chemotherapy. Future trials in this area should use uniform stratification variables and standardized criteria for evaluating response, time to progression, and survival.     

Multimodality approach in treatment of thymic tumors

Thymic tumors are rare neoplasms showing important clinical and pathologic polymorphisms ranging from low-mitotic encapsulated tumors to a highly aggressive and disseminating one. Complete resection of the tumor with surrounding fatty and mediastinal tissue is of paramount importance and provides good prognosis. Diagnosis of the tumor, radiologic evaluation and implementation of multimodal treatment including preoperative chemotherapy, radiotherapy, postoperative radiotherapy, adjuvant chemotherapy or radiotherapy are important components of the treatment strategy. Some of the stage III tumors can be resected without additional treatment, however, there is a good evidence to support administering preoperative and postoperative chemotherapy and postoperative radiotherapy in these patients providing higher complete resection rate and better survival. For stage IVA thymomas, surgery alone should not be considered as an effective approach and these tumors are considered as unresectable. Chemo/radiotherapy can be administered to those patients. Of those, postoperative chemotherapy and radiotherapy should be considered if these patients who were deemed to be previously unresectable become resectable. The combined modality treatment should provide prevention of locoregional and intrathoracic recurrence and eventually long-term survival with cure. New targeted therapies including agents against PI3K, CDK, and immune checkpoint PD-1/PD-L1 may lead to higher response rates with less toxicity.     

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.     

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.     

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.     

Survival after liver resection and liver transplantation for colorectal liver metastases: a comparative analysis stratified by metabolic tumor volume assessed by 18F-FDG PET/CT

BackgroundMany patients undergoing resection for colorectal liver metastases (CRLM) recur with poor survival. Overall survival (OS) following liver transplantation (LT) for CRLM is reported to be about 80% at 5 years. In this study, survival following resection versus transplantation for CRLM in patients with moderate (6–70 cm³) metabolic tumor volume (MTV) from the preoperative positron emission tomography (PET) was compared.MethodsDisease-free survival (DFS), OS and post recurrence survival (PRS) following resection (n = 18) and LT (n = 12) was compared by using the Kaplan Meier method and log rank test for patients with moderate MTV.ResultsPatients undergoing LT had unresectable metastases, significantly lower age, higher tumor burden score and number of liver metastases, longer time from diagnosis to surgery, and more patients received neoadjuvant chemotherapy. OS at 5 years was 39% in the resection group and 83% in the LT group (P = 0.012). PRS was significantly improved in patients treated with LT compared to resection with 71% alive at 5 years from recurrence compared to 17% in the resection group (P = 0.017).ConclusionLT for selected patients seems to be superior to resection as treatment for CRLM for patients with moderate MTV.     

Resection margin influences the outcome of patients with bilobar colorectal liver metastases

AIM To evaluate the outcome of patients with bilobar colorectal liver metastases(CRLM) and identify clinicopathological variables that influenced survival.METHODS Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period(January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatinor Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type. Response to neo-adjuvant therapy was assessed at the multidisciplinary team meeting and considered for surgery if all macroscopic CRLM were resectable with a clear margin while preserving sufficient liver parenchyma.RESULTS Of the 136 patients included, thirty-two(23.5%) patients were considered inoperable and referred for palliative chemotherapy, and thirty-four(25%) patients underwent liver resection. Seventy(51.4%) patients underwent down-staging therapy, of which 37(52.8%) patients responded sufficiently to undergo liver resection. Patients that failed to respond to down-staging therapy(n = 33, 47.1%) were referred for palliative therapy. There was a significant difference in overall survival between the three groups(surgery vs down-staging therapy vs inoperable disease, P 0.001). All patients that underwent hepatic resection, including patients that had down-staging therapy, had a significantly better overall survival compared to patients that were inoperable(P 0.001). On univariate analysis, only resection margin significantly influenced disease-free survival(P = 0.017). On multi-variate analysis, R0 resection(P = 0.030) and female(P = 0.036) gender significantly influenced overall survival. CONCLUSION Patients undergoing liver resection with bilobar CRLM have a significantly better survival outcome. R0 resection is associated with improved disease-free and overall survival in this patient group.     

Neoadjuvant and adjuvant therapy in relation to surgery for colorectal liver metastases

Liver resection is associated with prolonged survival in patients with colorectal liver metastases. At diagnosis, 15-20% of patients have resectable colorectal liver metastases whereas other patients have too advanced disease to enable surgical treatment and receive chemotherapy. In patients undergoing resection of colorectal liver metastases, disease relapse occurs in up to 70%. Therefore, a combined approach including preoperative or postoperative chemotherapy or both has been tested to improve outcome after surgery. In patients with unresectable colorectal liver metastases, chemotherapy is initially the sole treatment option. The considerable improvement of the efficacy of anticancer agents has contributed to increase the response rate in patients with advanced colorectal cancer. In case of major response to chemotherapy, surgery with curative intent can be offered to patients with initially unresectable liver metastases.     

胆管癌的分子靶向治疗

胆管癌是起源于胆管上皮细胞的恶性肿瘤,临床较少见.中国胆管癌患者数较多,因而胆管癌研究在我国具有特殊意义.手术切除是所有胆管癌的最佳治疗,但由于早期诊断困难,仅10%患者得到手术治疗.胆管癌患者术后5年生存率约5%,未切除胆管癌患者生存期<1年.胆管癌的临床化疗效果并不尽理想.近期开展的进展期胆管癌分子靶向治疗临床研究是令人期待的探索.本文归纳分析胆管癌靶向治疗药物的分子生物学基础以及临床探索的研究结果.