Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Options and survival benefits of conversion therapy for unresectable hepatocellular carcinoma

In the study by Wu et al,patients with unresectable hepatocellular carcinoma were subjected to transarterial chemoembolization(TACE)as a conversion therapy in order to render their tumors suitable for resection.A nomogram was devised and shown to be effective in predicting the survival of these patients.Generalization of the results,however,is questionable since the study subjects consisted of patients who had resection after TACE while excluding patients with the same disease but not suitable for TACE.Immunotherapy can be considered to be an option for conversion therapy.However,markers for determining responses to a conversion therapy and for guiding the decision between TACE and sequential immunotherapy have been lacking.The question of whether effective conversion therapy can truly enhance overall survival remains unanswered.

Downstaging strategies for unresectable hepatocellular carcinoma

A significant number of patients with hepatocellular carcinoma(HCC)are usually diagnosed in advanced stages,that leads to inability to achieve cure.Palliative options are focusing on downstaging a locally advanced disease.It is wellsupported in the literature that patients with HCC who undergo successful conversion therapy followed by curative-intent surgery may achieve a significant survival benefit compared to those who receive chemotherapy alone or those who are successfully downstaged with conversion therapy but not treated with surgery.Hepatic artery infusion chemotherapy can be a potential downstaging strategy,since recent studies have demonstrated excellent outcomes in patients with colorectal liver metastatic disease as well as primary liver malignancies.

Conversion therapy for unresectable hepatocellular carcinoma:Advances and challenges

Recently,the World Journal of Gastrointestinal Oncology published an article entitled“Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of the literature”,in which the authors shared their successful experience with complete surgical resection after multidisciplinary conversion therapy.The study by Chu et al demonstrates the great challenges that the advanced hepatocellular carcinoma(HCC)poses to surgical oncology,reveals the complexity of conversion therapy for unresectable HCC,emphasizes the important role of a multidisciplinary management model in conversion therapy,and enriches our understanding of the dynamics of personalized treatment for different patients.At present,conversion therapy is a hot research topic in the treatment of unresectable HCC,which has brought new hope to many patients with moderately advanced HCC.However,there are still many urgent problems to be solved in conversion therapy.Here,we would like to further discuss the advances and challenges of conversion therapy for unresectable HCC with the authors and the general readers.

Small particle drug-eluting beads-transarterial chemoembolization combined with targeted therapy in the clinical treatment of unresectable liver cancer

BACKGROUND Liver cancer is a highly malignant tumor with significant clinical impact.Chemotherapy alone often yields suboptimal outcomes in both the short and long term,characterized by high rates of local recurrence and distant metastasis,leading to a poor long-term prognosis.AIM To evaluate the clinical efficacy of small particle drug-eluting beads-transarterial chemoembolization(DEB-TACE)combined with targeted therapy for the treatment of unresectable liver cancer.METHODS We analyzed clinical data from 74 patients with unresectable liver cancer admitted between January 2019 and December 2020.Based on the different treatment regimens administered,patients were divided into the control(36 patients receiving sorafenib alone)and joint(38 patients receiving small particle DEB-TACE combined with sorafenib)groups.We compared liver function indicators[alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),albumin(ALB)]and serum tumor markers[alpha fetoprotein(AFP)]before and after treatment in both groups.Short-term efficacy measures[complete response(CR),partial response,progression disease,stable disease,objective response rate(ORR),and disease control rate(DCR)]were assessed post-treatment.Long-term follow-up evaluated median overall survival(OS),progression-free survival(PFS),and adverse reaction rates between the two groups.RESULTS One month post-treatment,the joint group demonstrated significantly higher rates of CR,ORR,and DCR compared to the control group(P<0.05).Three days after treatment,the joint group showed elevated levels of ALT,AST,and TBIL but reduced levels of ALB and AFP compared to the control group(P<0.05).The median OS was 18 months for the control group and 25 months for the joint group,while the median PFS was 15 months for the control group and 22 months for the joint group,with significant differences observed(log-rank:χ2=7.824,6.861,respectively;P=0.005,0.009,respectively).The incidence of adverse reactions was not significantly different between the groups(P>0.05).CONCLUSION The combination of small particle DEB-TACE and sorafenib significantly improves both short-and long-term outcomes in the treatment of unresectable liver cancer while preserving liver function.

Systemic treatment for unresectable hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is most commonly found in the context of liver cirrhosis and,in rare cases,in a healthy liver.Its prevalence has risen in recent years,particularly in Western nations,due to the increasing frequency of nonalcoholic fatty liver disease.Advanced HCC has a poor prognosis.For many years,the only proven therapy for unresectable HCC(uHCC)was sorafenib,a tyrosine kinase inhibitor.Recently,the synergistic effect of an immune checkpoint inhibitor,atezolizumab,and bevacizumab outperformed sorafenib alone in terms of survival,making it the recommended first-line therapy.Other multikinase inhibitors,lenvatinib and regorafenib,were also recommended as first and second-line drugs,respectively.Intermediate-stage HCC patients with retained liver function,particularly uHCC without extrahepatic metastasis,may benefit from trans-arterial chemoembolization.The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function.Indeed,all study patients had a Child-Pugh class A,and the best therapy for other individuals is unknown.Additionally,in the absence of a medical contraindication,atezolizumab could be combined with bevacizumab for uHCC systemic therapy.Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs,and the first findings are encouraging.The paradigm of uHCC therapy is changing dramatically,and many obstacles remain for optimum patient management in the near future.The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.

Modified albumin-bilirubin predicted survival of unresectable hepatocellular carcinoma patients treated with immunotherapy

BACKGROUND Modified albumin-bilirubin(mALBI)grade has been established as a survival determinant in hepatocellular carcinoma(HCC)patients who receive locoregional and targeted therapies.AIM To investigate whether mALBI could predict survival in unresectable HCC(uHCC)patients who were treated with atezolizumab plus bevacizumab(AB).METHODS A single-center,retrospective cohort study enrolled uHCC patients who received AB treatment between September 2020 and April 2023 and were followed up until June 2023.An association between mALBI and patient survival was determined using Cox proportional hazards analysis.RESULTS Of the 83 patients,67 patients(80.7%)were male with the mean age of 60.6 years.Among them,22 patients(26.5%)were classified as Barcelona Clinic Liver Cancer B,and 61 patients(73.5%)were classified as Barcelona Clinic Liver Cancer C.Cirrhosis was present in 76 patients(91.6%),with 58 patients classified as Child-Turcotte-Pugh(CTP)A and 18 as CTP B.The median overall survival(OS)and progression-free survival were 13.0 mo[95%confidence interval(CI):5.2-20.8]and 9.0 mo(95%CI:5.0-13.0),respectively.The patients were divided into two groups based on mALBI grades:42 patients(50.6%)in the mALBI 1+2a group;and 41 patients(49.4%)in the mALBI 2b+3 group.During the median follow-up period of 7.0 mo,the mALBI 1+2a group exhibited significantly better survival compared to the mALBI 2b+3 group,with a median OS that was not reached vs 3.0 mo(95%CI:0.1-6.0,P<0.001).In a subgroup of patients with CTP A,the mALBI 1+2a group also showed significantly longer survival compared to the mALBI 2b+3 group,with a median OS that was not reached vs 6.0 mo(95%CI:3.4-8.6,P<0.001).In the multivariate analysis,both CTP class and mALBI grade were independently associated with survival,with adjusted hazard ratios(95%CI)of 2.63(1.19-5.78,P=0.020)and 3.90(1.71-8.90,P=0.001),respectively.CONCLUSION mALBI grades can determine survival of uHCC patients receiving AB treatment,particularly those who have mildly impaired liver function.This highlights the importance of assessing mALBI before initiating AB treatment to optimize therapeutic efficacy in clinical practice.

Interventional treatment for unresectable hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the sixth most common cancer and third leading cause of cancer-related death in the world. The Barcelona clinic liver cancer classification is the current standard classification system for the clinical management of patients with HCC and suggests that patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization(TACE). Interventional treatments such as TACE, balloon-occluded TACE, drug-eluting bead embolization, radioembolization, and combined therapies including TACE and radiofrequency ablation, continue to evolve, resulting in improved patient prognosis. However, patients with advanced-stage HCC typically receive only chemotherapy with sorafenib, a multi-kinase inhibitor, or palliative and conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidatesfor systemic therapy. However, these patients require therapy that is more effective than sorafenib or conservative treatment. Several researchers try to perform more effective therapies, such as combined therapies(TACE with radiotherapy and sorafenib with TACE), modified TACE for HCC with arterioportal or arteriohepatic vein shunts, TACE based on hepatic hemodynamics, and isolated hepatic perfusion. This review summarizes the published data and data on important ongoing studies concerning interventional treatments for unresectable HCC and discusses the technical improvements in these interventions, particularly for advanced-stage HCC.

Conversion therapy and suitable timing for subsequent salvage surgery for initially unresectable hepatocellular carcinoma: What is new?

AIM To review the conversion therapy for initially unre-sectable hepatocellular carcinoma(HCC) patients and the suitable timing for subsequent salvage surgery. METHODS A Pub Med search was undertaken from 1987 to 2017 to identify articles using the keywords including "unresectable" "hepatocellular carcinoma", "hepate-ctomy", "conversion therapy", "resection", "salvage surgery" and "downstaging". Additional studies were investigated through a manual search of the references from the articles. The exclusion criteria were duplicates, case reports, case series, videos, contents unrelated to the topic, comments, and editorial essays. The main and widely used conversion therapies and the suitable timing for subsequent salvage surgery were discussed in detail. Two members of our group independently performed the literature search and data extraction. RESULTS Liver volume measurements [future liver remnant(FLR)/total liver volume or residual liver volume/bodyweight ratio] and function tests(scoring systems and liver stiffness) were often performed in order to justify whether patients were suitable candidates for surgery. Successful conversion therapy was usually defined as downstaging the tumor, increasing FLR and providing subsequent salvage surgery, without increasing com-plications, morbidity or mortality. The requirementsfor performing salvage surgery after transcatheter arterial chemoembolization were the achievement of a partial remission in radiology, the disappearance of the portal vein thrombosis, and the lack of extrahepatic metastasis. Patients with a standardized FLR(sF LR) > 20% were good candidates for surgery after portal vein embolization, while other predictive parameters like growth rate, kinetic growth rate were treated as an effective supplementary. There was probably not enough evidence to provide a standard operation time after associating liver partition and portal vein ligation for staged hepatectomy or yttrium-90 microsphere radioembolization. The indications of any combinations of conversion therapies and the subsequent salvage surgery time still need to be carefully and comprehen-sively evaluated. CONCLUSION Conversion therapy is recommended for the treatment of initially unresectable HCC, and the suitable subse-quent salvage surgery time should be reappraised and is closely related to its previous therapeutic effect.

Successful treatment of conversion chemotherapy for initially unresectable synchronous colorectal liver metastasis

A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis(CRLM),which involved the right hepatic vein(RHV)and the inferior vena cava(IVC),was referred to our hospital.The metastatic lesion was diagnosed as initially unresectable because of its invasion into the confluence of the RHV and IVC.After she had undergone laparoscopic sigmoidectomy for the original tumor,she consequently had 3 courses of modified 5-fluorouracil,leucovorin,and oxaliplatin(m FOLFOX6)plus cetuximab.Computed tomography revealed a partial response,and the confluence of the RHV and IVC got free from cancer invasion.After 3 additional courses of m FOLFOX6 plus cetuximab,preoperative percutaneous transhepatic portal vein embolization(PTPE)was performed to secure the future remnant liver volume.Finally,a right hemihepatectomy was performed.The postoperative course was uneventful.The patient was discharged from the hospital on postoperative day 13.She had neither local recurrence nor distant metastasis 18 mo after the last surgical intervention.This multidisciplinary strategy,consisting of conversion chemotherapy using FOLFOX plus cetuximab and PTPE,could contribute in facilitating curative hepatic resection for initially unresectable CRLM.

Intraoperative radiofrequency ablation combined with ^(125)iodine seed implantation for unresectable pancreatic cancer

AIM: To evaluate the feasibility, efficacy and safety of intraoperative radiofrequency ablation (RFA) combined with 125 iodine seed implantation for unresectable pancreatic cancer. METHODS: Thirty-two patients (21 males and 11 females) at the age of 68 years (range 48-90 years) with unresectable locally advanced pancreatic cancer admitted to our hospital from January 2006 to May 2008 were enrolled in this study. The tumor, 4-12 cm in diameter, located in pancreatic head of 23 patients and in pancreatic body and tail of 9 patients, was found to be unresectable during operation. Diagnosis of pancreatic cancer was made through intraoperative biopsy. Patients were treated with FRA combined with 125 iodine seed implantation. In brief, a RFA needle was placed, which was confirmed by intraoperative ultrasound to decrease the potential injury of surrounding vital structures, a 125 iodine seed was implanted near the blood vessels and around the tumor border followed by bypass palliative procedure (cholangio-jejunostomy and/or gastrojejunostomy) in 29 patients.RESULTS: The serum CA 19-9 level was decreased from 512 ± 86 U/mL before operation to 176 ± 64 U/mL, 108 ± 42 U/mL and 114 ± 48 U/mL, respectively, 1, 3 and 6 mo after operation (P < 0.05). The pain score on day 7 after operation, 1 and 3 mo after combined therapy was decreased from 5.86 ± 1.92 before operation to 2.65 ± 1.04, 1.65 ± 0.88 and 2.03 ± 1.16, respectively, after operation (P < 0.05). The rate of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) in 32 patients was 21.8% (7/32), 56.3% (18/32), 15.6% (5/32) and 6.3% (2/32), respectively, 6 mo after operation, with a median overall survival time of 17. 5 mo. The median survival time of patients at stage Ⅲ was longer than that of those at stage Ⅳ (19 mo vs 10 mo, P = 0.0026). The median survival time of patients who received and did not receive chemotherapy after operation was 20 mo and 16 mo, respectively (P = 0.0176). Of the 32 patients, 3 (10.6%) experienced postoperative complications including transient biliary leaks in 2 patients and acute pancreatitis in 1 patient. All the patients recovered well after conservative support treatment. CONCLUSION: Intraoperative RFA combined with 125 iodine seed implantation is a feasible and safe procedure for unresectable pancreatic cancer with acceptable minor complications, and can prolong the survival time of patients, especially those at stage Ⅲ.

Improvement of prognosis for unresectable biliary tract cancer

AIM:To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer.METHODS:A total of 186 consecutive patients with unresectable biliary tract cancer,who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan,were retrospectively analyzed.These patients were divided into three groups based on the year beginning chemotherapy:Group A(2000-2003),Group B(2004-2006),and Group C(2007-2009).The data were fixed at the end of December 2011.Overall survival and time-to-progression were analyzed and compared chronologically.RESULTS:No patient characteristics were significantly different among the three groups.The gallbladder was involved in about half of the patients in each group,and metastatic biliary tract cancer was present in three quarters of the enrollees.In Group A,5-fluorouracilbased chemotherapies were primarily selected as firstline chemotherapy,and only 24% were treated with second-line chemotherapy.In Group B,gemcitabine or S-1 monotherapy was mainly introduced as firstline chemotherapy,and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy.In Group C,the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy,and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy.The median timeto-progressions were 4.4 mo,3.5 mo and 5.9 mo in Groups A,B and C,respectively(4.4 mo vs 3.5 mo vs 5.9 mo,P < 0.01).The median overall survivals were 7.1,7.3,and 11.7 mo in Groups A,B and C(7.1 mo vs 7.3 mo vs 11.7 mo,P = 0.03).Induction rates of all three drugs(gemcitabine,platinum analogs,and fluoropyrimidine) in Groups A,B and C were 4%,2% and 27%(4% vs 2% vs 27%,P < 0.01).CONCLUSION:The prognosis of unresectable biliary tract cancer has improved recently.Using three effective drugs(gemcitabine,platinum analogs,and fluoropyrimidine) may improve the prognosis of this cancer.

Prognosis following transcatheter arterial embolization for 121 patients with unresectable hepatocellular carcinoma with or without a history of treatment

AIM： To retrospectively evaluate the prognosis of patients with hepatocellular carcinoma （HCC） with or without a history of therapy for HCC following transcatheter arterial embolization （TAE）. METHODS： One hundred and twenty-one patients with HCC treated with TAE from 1992 to 2004 in our hospital were enrolled in this study. Eighty-four patients had a history of treatment for HCC, while 37 did not. At the time of entry, patients with extra-hepatic metastasis, portal vein tumor thrombosis, or Child-Pugh class C were excluded. TAE was repeated when recurrence of HCC was diagnosed by elevated tumor markers, or ultrasonography or dynamic computed tomography findings. RESULTS： Tumor size was larger and the number of tumors was fewer in patients without past treatment （P〈0.01）. However, there were no differences in tumor node metastasis （TNM） stage or survival rate between the 2 groups. A bilobular tumor and high level of α-fetoprotein （AFP） （〉100 ng/mL） were factors related to a poor prognosis in patients with a history of HCC. CONCLUSION： The prognosis following TAE is similar between HCC patients with and without past treatment. Early diagnosis of HCC or recurrent HCC and obtaining good local control against HCC before entry to a repeated TAE course can improve prognosis.

Sorafenib Combined with Cryoablation to Treat Unresectable Hepatocellular Carcinoma

Objective：To evaluate the efficacy and tolerability of sorafenib combined with cryoablation in treating unresectable hepatocellular carcinoma （HCC）.Methods：Patients with unresectable advanced HCC received cryoablation and sorafenib at a dose of 400 mg twice daily in 4-week cycles on the same day of the cryoablation.Tumor response,median overall survival and the median time to radiological progression were calculated and the toxicity was evaluated.Results：Seventy-eight patients with unresectable HCC were involved in this study.The median age was 52 years （range,22-81 years）.The Eastern Cooperative Oncology Group （ECOG） performance status scores were 0 （39.7%）,1 （55.1%）,and 2 （5.1%）.Nine （11.5%） patients were at Barcelona clinic liver cancer （BCLC） stage A,twenty-four （30.8%） patients were at stage B and 45 （57.7%） patients were at stage C.Five （6.4%） achieved partial responses,and 34 （43.6%） achieved stable disease.The median time to progression （TTP） for all enrolled patients was 6.6 months and the median overall survival （OS） was 12.2 months.Conclusion：Cryoablation combined with sorafenib demonstrates good efficacy and acceptable tolerability in treating unresectable advanced HCC patients.

Endoscopic biliary drainage for patients with unresectable pancreatic cancer with obstructive jaundice who are to undergo gemcitabine chemotherapy

AIM: To assess optimum endoscopic biliary drainage (EBD) in cases with unresectable pancreatic cancer in the era of gemcitabine (GEM). METHODS: Thirty patients with unresectable pancreatic cancer, who presented with jaundice and underwent chemotherapy using GEM after EBD were included in this study (GEM group). Fifteen cases with the same clinical manifestation and stage of pancreatic cancer treated with EBD alone were also included as controls. A covered metallic stent (CMS) or a plastic stent (PS) was used for EBD. The mean survival time (MST) in each group, risk factors of survival time, type of stent used and associated survival time, occlusion rate of stent, patency period of stent, and risk factors of stent occlusion were evaluated. RESULTS: MST in the GEM group was longer than that in the control (9.9 mo vs 6.2 mo). In the GEM group, the survival time was not different between those who underwent metallic stenting and those who underwent plastic stenting. Stent occlusion occurred in 60% of the PS group and 7% of the CMS group. The median stent patency in the PS-GEM group and the CMS-GEM group was 5 mo and 7.5 mo, respectively. Use of a PS was the only risk factor of stent occlusion. CONCLUSION: A CMS is recommended in cases presenting with jaundice due to unresectable pancreatic cancer, since the use of a CMS makes it possible to continue chemotherapy using GEM without repetition of stent replacement.

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.

THE ROLE OF TARGETING THERAPY IN CYTOREDUCTION AND SEQUENTIAL RESECTION OF UNRESECTABLE HEPATOCELLULAR CARCINOMA

Despite unquestionable progress has been made inresection of small and large hepatocellular carcinoma'(HCC),the dismal outcome of unresectable HCC remains a great challenge.Fortunately,the progress of multidisciplinary approach,particularly with new treatment modalities,has provided a new hope for unresectable HCC.This paper reports 477 patients with surgically verified unresectable HCC treated by different modalities, sequential resection was done in 55 patients(11.5%)due to marked shrinkage of the tumor.Patients treated with hepatic artery ligation(HAL),cannulation with infusion (HAI)and plus intraarterial targeting therapy(131I-antiHCC Ferritin IgG,131I-antiHCC monoclonal antibody,or 131I-Lipiodol)has higher sequential resection rate(33. 0%,31/94)when compared with other combination treatment(HAL+HAI,HAL+HAI+radiotherapy,11.7% ,22/188),and single treatment group(Cryosurgery,HAL,or HAI,1.0%,2/195). The combination of targeting therapy played an important role to the increasing number of sequential resection during 1978 through 1992.The 5-year survival of the 55 patients with sequential resection was as nigh as 60.8%.By the end of June 1993,13 patients survived more than 5 years, the longest being 15 years.

A patient with unresectable advanced pancreatic cancer achieving long-term survival with Gemcitabine chemotherapy

A 68-year-old female visited a local clinic with epigastralgia. A routine laboratory test revealed jaundice and liver dysfunction. She was referred to this hospital. Abdominal computed tomography (CT) and endoscopic retrograde cholangio-pancreatography (ERCP) revealed that the density of the entire pancreas had decreased,and showed dilatation of the common bile duct (CBD) and the main pancreatic duct (MPD). Pancreatic cancer was diagnosed by cytological examination analyzing the pancreatic juice obtained by ERCP. When jaundice had decreased the tumor was observed via laparotomy. No ascites,liver metastasis,or peritoneal dissemination was observed. The entire pancreas was a hard mass,and a needle biopsy was obtained from the head,body and tail of the pancreas. These biopsies diagnosed a poorly differentiated adenocarcinoma. Hepaticojejunostomy was thus performed,and postoperative progress was good. Chemotherapy with 1000 mg/body per week of gemcitabine was administered beginning 15 d postoperatively. However,the patient suffered relatively severe side effects,and it was necessary to change the dosing schedule of gemcitabine. Abdominal CT revealed a complete response (CR) after 3 treatments. Therefore,weekly chemotherapy was stopped and was changed to monthly administration. To date,for 4 years after chemotherapy,the tumor has not reappeared.

CONVERSION OF SURGICALLY VERIFIED UNRESECTABLE TO RESECTABLE HEPATOCELLULAR CARCINOMA(A REPORT OF 26 PATIENTS WITH SUBSEQUENT RESECTION)

During the period 1978-1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were determined by laparotomy to be un-resectable, 155 (60.8%) out of them had their tumor mainly confined in right or left lobe and considered to be potentially resectable if remarkable tumor shrinkage appears after treatment. Second look operation was performed in 26 (16.8%) out of the 155 patients after marked reduction of tumor size, resection was done in all of these 26 patients. Triple or quadruple combination treatment with hepatic artery ligation (HAL), hepatic artery infusion (HAI) with chemotherapy, radiotherapy using linear accelerator, and radioimmunotherapy using 131-I antihu-man HCC ferritin antibody yielded the highest conversion rate (29.8%, 14/47) as compared to double combination treatment with HAL+HAI, or cryosur-gery+HAL (16.9%, 12/71) and single treatment with HAL or HAI or HAE (embolization) (0%, 0/37). The median tumor size of these 26 patients was reduced from 9.5 cm to 5.0 cm after combination treatment. The median interval between the first laparotomy and the subsequent resection was 5.0 (2-16) months. The survival rates calculated by life table method were: 1-year 86.5%, 2-year 74.3% and 3-year 74.3%. Nine cases have survival more than 3 years. Thus, multimodality combination treatment with subsequent resection might prolong survival significantly for some patients with unresectable HCC particularly confined in right lobe of a cirrhotic liver.