Preventive treatments for recurrence after curative resection of hepatocellular carcinoma--a literature review of randomized control trials

To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications. reporting randomized control trial indexed in PubMed. The treatment approaches presented above included preoperative transcatheter arterial chemoembolization (TACE),post-operative TACE, systemic or locoregional chemotherapy,immunotherapy, Interferons and acyclic retinoic acid Although no standard treatment has been established,several approaches presented promising results, which were both effective and tolerable in post-operative patients. Preoperative TACE was not effective on prolonging survivals,while post-operative TACE was shown with both diseasefree survival and overall survival benefits in some papers,however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant toxicities.Adoptive immunotherapy using LAK cells was proved to be beneficial to patients‘ survival in a recent paper. Interferon and Interferon β can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multi-centric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities;in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation.     

Arterial chemotherapy of 5—fluorouracil and mitomycin Cin the treatment of liver metastases of colorectal cancer

AIM：Regional chemotherapy using hepatic artery catheters is a good method of treating patients with colorectal cancer liver metastases.We investigated the survival of patients with liver metastases from colorectal cancer using 5-fluorouracil(5-FU)and mitomycin C Cthrough implantable hepatic arterial infusion port.METHODS:Seventy-five patents with inoperable liver metastases forom colorectal cancer were included between March,1992 and November,2001,We placed implantable hepatic arterial cathter(HAC)port by laparotomy,5-FU,1000mg/m^2/d continuors infusion for five days every four weeks,was delivered in the hepatic arterial catheter through the port.Mitomycin C,30mg/m^2/d infusion in the first day every cycel through the port.Response to the treatment was evaluated by serial determinations of plasma CEAand imaping techniques consisting of computerized tomography and sonography of liver.RESULTS:Sixty-eight were performed hepatic artery chemotherapy and fifty-six were followed up among seventy-five HAC patients.Twenty-six patients(46.4%)have responded and4complete remission were achieved.Eight patients(14.3%)had stable liver metastases.Twenty-two patients(39.3%)were progressed with increased tumor size and number.Twenty-nine patients(51.8%)had a decreased serum CEAlevel.while10patients(17.9%) were stable and 17patients(30.4%)had an increased serum CEAlevel.There were no operative death in this serise.Complications,which occurred in 18patients(32.1%),were as followed:hepatic artery thrombosis in11,Upper gastric and intestinal bleeding in3,liver abscess in1,pocket infection in1,cholangitis in1,and hepatic artery pseudo-aneurysm in one patient.CONCLUSION:Combined infusion of 5-FU and mitomycin C by hepatic artery catheter port is an effective treatment for liver metastases from colorectal cancer.The high response and lower complication rater prove the adjuvant treatment of colorectal cancer with this treatment.     

Hepatectomy for hepatocellular carcinoma with portal vein tumor thrombus

Despite surgical removal of tumors with portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) patients, early recurrence tends to occur, and overall survival(OS) periods remain extremely short. The role that hepatectomy may play in long-term survival for HCC with PVTT has not been established. The operative mortality of hepatectomy for HCC with PVTT has also not been reviewed. Hence, we reviewed recent literature to assess these parameters. The OS of patients who received hepatectomy in conjunction with multidisciplinary treatment tended to be superior to that of patients who did not. Multidisciplinary treatments included the following: preoperative radiotherapy on PVTT; preoperative transarterial chemoembolization(TACE); subcutaneous administration of interferon-alpha(IFN-α) and intra-arterial infusion of 5-fluorouracil(5-FU) with infusion chemotherapy in the affected hepatic artery; cisplatin, doxorubicin and 5-FU locally administered in the portal vein; and subcutaneous injection of IFN-α, adjuvant chemotherapy(5-FU + Adriamycin) administration via the portal vein with postoperative TACE, percutaneous isolated hepatic perfusion and hepatic artery infusion and/or portal vein chemotherapy. The highest reported rate of operative mortality was 9.3%. In conclusion, hepatectomy for patients affected by HCC with PVTT is safe, has low mortality and might prolong survival in conjunction with multidisciplinary treatment.     

Peritoneal carcinomatosis

Several gastrointestinal and gynecological malignancies have the potential to disseminate and grow in the peritoneal cavity.The occurrence of peritoneal carcinomatosis(PC)has been shown to significantly decrease overall survival in patients with liver and/or extraperitoneal metastases from gastrointestinal cancer.During the last three decades,the understanding of the biology and pathways of dissemination of tumors with intraperitoneal spread,and the understanding of the protective function of the peritoneal barrier against tumoral seeding,has prompted the concept that PC is a loco-regional disease:in absence of other systemic metastases,multimodal approaches combining aggressive cytoreductive surgery,intraperitoneal hyperthermic chemotherapy and systemic chemotherapy have been proposed and are actually considered promising methods to improve loco-regional control of the disease,and ultimately to increase survival.The aim of this review article is to present the evidence on treatment of PC in different tumors,in order to provide patients with a proper surgical and multidisciplinary treatment focused on optimal control of their locoregional disease.     

Chemotherapy as a component of multimodal therapy for gastric carcinoma

Prognosis of locally advanced gastric cancer remains poor, and several multimodality strategies involving surgery, chemotherapy, and radiation have been tested in clinical trials. PhaseⅢtrial testing the benefit of postoperative adjuvant chemotherapy over treatment with surgery alone have revealed little impact on survival, with the exception of some small trials in Western nations. A large trial from the United States exploring postoperative chemoradiation was the first major success in this category. Results from Japanese trials suggest that moderate chemotherapy with oral fluoropyrimidines may be effective against less-advanced (T2-stage) cancer, although another confirmative trial is needed to prove this point. Investigators have recently turned to neoadjuvant chemotherapy, and some promising results have been reported from phaseⅡtrials using active drug combinations. In 2005, a large phaseⅢtrial testing pre-and postoperative chemotherapy has proven its survival benefit for resectable gastric cancer. Since the rate of pathologic complete response is considered to affect treatment results of this strategy, neoadjuvant chemoradiation that further increases the incidence of pathologic complete response could be a breakthrough, and phaseⅡstudies testing this strategy may be warranted in the near future.     

Phase Ⅱ study of protracted irinotecan infusion and a low-dose cisplatin for metastatic gastric cancer

INTRODUCTIONIn Japan,for advanced gastric cancer,surgery is still the most effective treatment and good survival can be achieved if the tumor is resectable.On the contrary,unresectable advanced or recurrent gastric cancer still has a poor prognosis and chemotherapy is the most important treatment for survival prolongation.To date,combination chemotherapy with5-fluorouracil(5-FU)and cisplatin has been used most widely.This two-drug regimen showed superior response rate in comparison with …     

Will the collaboration of surgery and external radiotherapy open new avenues for hepatocellular carcinoma with portal vein thrombosis?

Portal invasion of hepatocellular carcinoma(HCC)occurs in 12.5%-40%of patients diagnosed with cancer and yields poor clinical outcomes.Since it is a common cause of inoperability,sorafenib was regarded as the standard treatment for HCC in the Barcelona Clinic of Liver Cancer guidelines.However,the median survival of the Asian population was only approximately 6 mo,and the tumor response rate was less than moderate(<5%).Various locoregional modalities were performed,including external beam radiotherapy(EBRT),transarterial chemoembolization,hepatic arterial infusion chemotherapy,and surgery,alone or in combination.Among them,EBRT is a noninvasive method and can safely treat tumors involving the major vessels.Palliative EBRT has been commonly performed,especially in East Asian countries,where locally invasive HCC is highly prevalent.Although surgery is not commonly indicated,pioneering studies have demonstrated encouraging results in recent decades.Furthermore,the combination of neo-or adjuvant EBRT and surgery has been recently used and has significantly improved the outcomes of HCC patients,as reported in a few randomized studies.Regarding systemic modality,a combination of novel immunotherapy and vascular endothelial growth factor inhibitor showed results superior to that of sorafenib as a first-line agent.Future clinical trials investigating the combined use of these novel agents,surgery,and EBRT are expected to improve the prognosis of HCC with portal invasion.     

Secondary hepatic resection as a therapeutic goal in advanced colorectal cancer

Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase Ⅲ trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapyrelated hepatotoxicity, such as steatosis （5-fluorouracil）, steatohepatitis （irinotecan）, and sinusoidal obstruction （oxaliplatin）. Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.     

Update on the management of pancreatic cancer:Surgery is not enough

Pancreatic ductal adenocarcinoma(PDAC) represents the fourth cause of death in cancer and has a 5-year survival of < 5%.Only about 15% of the patients present with a resectable PDAC with potential to undergo "curative" surgery.After surgery,local and systemic recurrence,is though very common.The median survival of resected patients with adjuvant chemotherapy after surgery is only 20-23 mo.This underscores the significant need to improve PDAC management strategies.Increased survival rate is dependent on new breakthroughs in our understanding of not at least tumor biology.The aim of this review is to update and comment on recent knowledge concerning PDAC biology and new diagnostics and treatment modalities.One fundamental approach to improve survival rates is by earlier and improved diagnosis of the disease.In recent years,novel blood-based biomarkers have emerged based on genetic,epigenetic and protein changes in PDAC with very promising results.For biomarkers to enter clinical practice they need to have been developed using adequate control groups and provide high sensitivity and specificity and by this identify patients at risk already in a pre-symptomatic stage.Another way to improve outcomes,is by employing neoadjuvant treatments thereby increasing the number of resectable cases.Novel systemic treatment regimes like FOLFIRINOX and nab-paclitaxel have demonstrated improvements in prolonging survival in advanced cases,but long-term survival is still scarce.The future improved understanding of PDAC biology will inevitably render new treatment options directed against both the cancer cells and the surrounding microenvironment.     

Adjuvant chemotherapy for resected colorectal cancer metastases:literature review and meta-analysis

Surgical resection is the only option of cure for patients with metastatic colorectal cancer(CRC). However, the risk of recurrence within 18 mo after metastasectomy is around 75% and the liver is the most frequent site of relapse. The current international guidelines recommend an adjuvant therapy after surgical resection of CRC metastases despite the lower level of evidence(based on the quality of studies in this setting). However, there is still no standard treatment and the effective role of an adjuvant therapy remains controversial. The aim of this review is to report the state-of-art of systemic chemotherapy and regional chemotherapy with hepatic arterial infusion in the management of patients after resection of metastases from CRC, with a literature review and meta-analysis of the relevant randomized controlled trials.     

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.     

Resection and local therapy for liver metastases

In 30-50% of patients the liver is a preferred site of distant disease for many malignant tumours. Due to the high incidence, most of the available data relate to metastases arising from colorectal primaries. Surgical resection is at present the only treatment offering potential cure. The achievable 5-year survival rate is 30%. However, only 10-15% of patients with colorectal liver metastases can undergo potentially curative liver resection. Therefore, accurate staging is an important prerequisite in selecting patients who would benefit from surgery. Recurrence of hepatic metastases after potentially curative resection occurs in up to 60% of the cases. Results demonstrate that re-resection of liver metastases can provide long-term survival rates in a carefully selected group of patients without extrahepatic disease. Because of the high rate of recurrences following an apparently curative resection several authors investigated the use of adjuvant chemotherapy (systemic, intraportal, and hepatic arterial infusion). Until recently none had shown effectiveness. Pre-operative chemotherapy seems to be a promising approach in patients with liver metastases initially considered unsuitable for radical surgery. Recently, neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery as initial management with the aim of improving the results in resectable liver metastases. Interventional strategies (ethanol injection, cryosurgery, laser-induced thermotherapy, radio-frequency ablation) and combined modalities (surgical/interventional) are additive methods which may help to improve treatment results in the future.     

Arterial, portal, or systemic chemotherapy for patients with hepatic metastasis of colorectal carcinoma

Hepatic metastases from colorectal carcinoma are common and may be resected for cure. The response of liver metastases to systemic chemotherapy is low. In contrast, hepatic arterial chemotherapy produces higher response rates than systemic chemotherapy, but randomized trials have not definitely proved a survival advantage because they allowed cross over. Most adjuvant portal vein chemotherapy studies have shown a survival advantage over the control group, but it is not clear whether this benefit is from the portal vein therapy or from immediate postoperative chemotherapy, since there is rarely a reduction in liver metastases. We describe the results of systemic, hepatic artery infusion, and portal therapy for patients with liver metastases of colorectal carcinoma.     

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.     

Kurativer Ansatz für metastasierte kolorektale Karzinome

Synchronous or metachronous metastases of colorectal cancer (CRC), although being the expression of systemic disease, allow a curative approach for a selected group of patients. Mainly patients presenting with colorectal liver metastases (CLM) should be evaluated for multimodal management with curative intent. Preoperative and/or postoperative systemic chemotherapy show beneficial impact on progression-free and overall survival, without significantly increasing postoperative complication rates. Concerning the complex definition of resectability and the number of patients with ?borderline“ resectable CLM, preoperative chemotherapy plays an important role in both improvement of prognosis and ?conversion“ to a resectable status. Advances in hepatic surgery and the addition of either locally ablative procedures, such as radiofrequency and SIRT are extending resectability to a larger group of patients and have joined the armamentarium for cases of positive resection margins or technically unresectable disease or add to surgery with a large loss of liver parenchyma. Moreover, multimodal approaches should be considered in pulmonary and peritoneal metastases of CRC.     

The impact of hepatic arterial infusion pump chemotherapy on hepatic recurrences and survival in patients with resected colorectal liver metastases

BackgroundThe objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM).MethodsRecurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses.Results2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60–0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57–0.78,p < 0.001).ConclusionAdjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.     

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.     

Peventive treatments for recurrence after curative resection of hepatocellular carcinoma - A literature review of randomized control trials

To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications reporting randomized control trial indexed in PubMed. The treatment approaches presented above included preoperative transcatheter arterial chemoembolization (TACE),post-operative TACE, systemic or locoregional chemotherapy,immunotherapy, Interferons and acyclic retinoic acid.Although no standard treatment has been established,several approaches presented promising results, which were both effective and tolerable in post-operative patients. Preoperative TACF was not effective on prolonging survivals,while post-operative TACE was shown with both diseasefree survival and overall survival benefits in some papers,however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant toxicities.Adoptive immunotherapy using LAK cells was proved to be beneficial to patients′ survival in a recent paper. Interferon α and Interferon β can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multicentric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities;in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation.