Adjuvant therapy for hepatocellular carcinoma:Dilemmas at the start of a new era

Approximately 50%-70%of patients with hepatocellular carcinoma experience recurrence within five years after curative hepatic resection or ablation.As a result,many patients receive adjuvant therapy after curative resection or ablation in order to prolong recurrence-free survival.The therapy recommended by national guidelines can differ,and guidelines do not specify when to initiate adjuvant therapy or how long to continue it.These and other unanswered questions around adjuvant therapies make it difficult to optimize them and determine which may be more appropriate for a given type of patient.These questions need to be addressed by clinicians and researchers.

New method of local adjuvant therapy with bicarbonate Ringer’s solution for tumoral calcinosis: A case report

BACKGROUND Tumoral calcinosis is a condition characterized by deposits of calcium phosphate crystals in extra-articular soft tissues,occurring in hemodialysis patients.Calcium phosphate crystals are mainly composed of hydroxyapatite,which is highly infilt-rative to tissues,thus making complete resection difficult.An adjuvant method to remove or resolve the residual crystals during the operation is necessary.CASE SUMMARY A bicarbonate Ringer’s solution with bicarbonate ions(28 mEq/L)was used as the adjuvant.After resecting calcium phosphate deposits of tumoral calcinosis as much as possible,while filling with the solution,residual calcium phosphate deposits at the pseudocyst wall can be gently scraped by fingers or gauze in the operative field.A 49-year-old female undergoing hemodialysis for 15 years had swelling with calcium deposition for 2 years in the shoulders,bilateral hip joints,and the right foot.A shoulder lesion was resected,but the calcification remained and early re-deposition was observed.Considering the difficulty of a complete rection,we devised a bicarbonate dissolution method and excised the foot lesion.After resection of the calcified material,the residual calcified material was washed away with bicarbonate Ringer’s solution.CONCLUSION The bicarbonate dissolution method is a new,simple,and effective treatment for tumoral calcinosis in hemodialysis patients.

Efficacy and safety of anlotinib as an adjuvant therapy in hepatocellular carcinoma patients with a high risk of postoperative recurrence

Objective:Hepatocellular carcinoma(HCC)has a high rate of postoperative recurrence and lacks an effective treatment to prevent recurrence.This study aims to investigate the efficacy and safety of anlotinib in postoperative adjuvant therapy for HCC patients with high-risk recurrence factors.Methods:For this multicenter,retrospective study,we recruited 63 HCC patients who received either anlotinib(n=27)or transcatheter arterial chemoembolization(TACE)(n=36)from six research centers in China between March 2019 and October 2020.The primary endpoint was disease-free survival(DFS)and the secondary endpoints were overall survival(OS)and safety.Results:In this study,the median follow-up time was 25.9 and 26.8 months in the anlotinib and TACE groups,respectively.There was no significant difference in the median DFS between the anlotinib[26.8 months,95%confidence interval(95%CI):6.8-NE]and TACE groups(20.6 months,95%CI:8.4-NE).The 12-month OS rates in the anlotinib and TACE groups were 96.3%and 97.2%,respectively.In the anlotinib group,19 of 27patients(70.4%)experienced treatment-emergent adverse events,with the most common events(≥10%)being hypertension(22.2%)and decreased platelet count(22.2%).Conclusions:The results indicate that anlotinib,as a new,orally administered tyrosine kinase inhibitor,has the same efficacy as TACE,and side effects can be well controlled.

Prognostic evaluation of postoperative adjuvant therapy for operable cervical cancer:10 years'experience of National Cancer Center in China

Objective： The aim of this study was to investigate the prognostic factors and to evaluate the impact of adjuvant therapy on clinical outcome for early-stage cervical cancer. Methods： The clinical-pathological data of all 1,335 patients with the International Federation of Gynecology and Obstetrics （FIGO） Ib-[Ia cervical cancer treated with primary radical surgery at the Chinese National Cancer Center between May 2007 and Dec 2013 were retrospectively reviewed. The median follow-up was 70 months. Results： Of all the patients, 61.6% of the cases received adjuvant therapy, with 5-year disease-free survival （DFS） of 92.1% and 5-year overall survival （OS） of 95.0%. In multivariate analysis, differentiation of G3 （P〈0.05）, lymph node metastasis （LNM, P〈0.05） and lymphovascular space invasion （LVSI, P〈0.05） were independent predictors for OS, while LNM （P〈0.05）, deep stroma invasion （DSI, P〈0.05） and LVSI （P〈0.05） were independent factors for DFS. The samples were stratified by histologic type, and cervical squamous cell carcinoma （SCC） was found to share the same independent factors except for differentiation of OS. As to patients with cervical adenocarcinoma/adenosquamons carcinoma （AC/ASC）, differentiation was the independent predictor of OS （P〈0.05）; and LVSI of DFS （P〈0.05）. Of 236 patients with high-risk factors, there was no significant difference in survival between concurrent chemoradiotherapy （CCRT, n=195）, radiotherapy （RT, n=24）, and chemotherapy （CT, n=17）. Among the 190 patients with LNM who underwent CCRT, 124 cases showed improved DFS after sequential CT （P=0.118）, with a recurrence rate decrease of 14%, though the difference was not statistically significant. Patients with single intermediate-risk factors like DSI or LVSI were found to partially benefit from adjuvant therapy, but the difference was not statistically significant. Conclusions： LNM, LVSI, DSI and differentiation were found to be independent prognostic factors for operable cervical cancer. Aggressive postoperative adjuvant therapy based on single risk factors in Chinese National Cancer Center could benefit survival. CCRT＋CT outperformed CCRT in high-risk patients. For patients with single non-high-risk factor, the role of adjuvant therapy needs to be further discussed.

Development and controversies of adjuvant therapy for pancreatic cancer

BACKGROUND: Pancreatic cancer is an aggressive malignancy with a dismal prognosis. Radical surgery provides the only chance for a cure with a 5-year survival rate of 7%-25%. An effective adjuvant therapy is urgently needed to improve the surgical outcome. This review describes the current status of adjuvant therapy for pancreatic cancer, and highlights its controversies. DATA SOURCES: A Medline database search was performed to identify relevant articles using the keywords 'pancreatic neoplasm', and 'adjuvant therapy'. Additional papers were identified by a manual search of the references from the key articles. RESULTS: Eight prospective randomized controlled trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation for pancreatic cancer could be identified. The results for adjuvant regimens based on systemic 5-fluorouracil with or without external radiotherapy were conflicting. The recent two RCTs on gemcitabine based regimen gave promising results. CONCLUSIONS: Based on the available data, no standard adjuvant therapy for pancreatic cancer can be established yet. The best adjuvant regimen remains to be determined in large-scale RCTs. Future trials should use a gemcitabine based regimen.

Advances in postoperative adjuvant therapy for primary liver cancer

Hepatocellular carcinoma(HCC)is a highly heterogeneous,invasive,and conventional chemotherapy-insensitive tumor with unique biological characteristics.The main methods for the radical treatment of HCC are surgical resection or liver transplantation.However,recurrence rates are as high as 50%and 70%at 3 and 5 years after liver resection,respectively,and even in Milan-eligible recipients,the recurrence rate is approximately 20%at 5 years after liver transplantation.Therefore,reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer.This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival,including local adjuvant therapy(e.g.,transcatheter arterial chemoembolization),adjuvant systemic therapy(e.g.,molecular targeted agents and immunotherapy),and other adjuvant therapies(e.g.,antiviral and herbal therapy).Finally,potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.

Fertility-sparing surgeries without adjuvant therapy through term pregnancies in a patient with low-grade endometrial stromal sarcoma:A case report

BACKGROUND Low-grade endometrial stromal sarcoma(LGESS)is a rare indolent tumor with a favorable prognosis.With the importance of improving quality of life recognized,fertility-sparing surgery may be an option for those young women.However,most of the reports suggested that stage IA patients might be candidates for fertility-sparing surgery,and adjuvant hormonal treatment was considered a feasible adjuvant therapy for reducing the recurrence risk of patients with LGESS and hysterectomy was recommended after the completion of pregnancy and delivery.CASE SUMMARY A 28-year-old pregnant woman diagnosed with stage IB LGESS was treated by fertility-sparing surgery when term cesarean section delivery was performed.Without any adjuvant treatment,she had the other successful term pregnancy and cesarean section 45 mo after first fertility-sparing surgery.Moreover,only hysteroscopic resection was performed to retain fertility again even when the tumor recurred after 6 years.So far the patient’s fertility and disease-free status have remained for more than 8 years without any adjuvant therapy despite local resection of the sarcoma.And the two babies were in good health.CONCLUSION For young patients with stage I LGESS,it seems that repeated fertility-sparing surgeries could be performed even after two term deliveries and the tumor recurrence,and it might be attempted without adjuvant therapy but the counseling should be considered as mandatory.

Adjuvant therapy for lung neuroendocrine neoplasms

Pulmonary neuroendocrine neoplasms(NENs)represent a minority of lung cancers and vary from slower growing pulmonary carcinoid(PC)tumors to aggressive small cell lung cancer(SCLC).While SCLC can account for up to 15%of lung cancer,PCs are uncommon and represent about 2%of lung cancers.Surgical resection is the standard of care for early-stage PCs and should also be considered in early stage large cell neuroendocrine carcinoma(LCNEC)and SCLC.Adjuvant treatment is generally accepted for aggressive LCNEC and SCLC,however,less well established for PCs.Guidelines admit a lack of trials to support a high-level recommendation for adjuvant therapy.This manuscript will discuss the role for adjuvant therapy in NENs and review the available literature.

Progress of Adjuvant Therapy after Radical Resection of Early Cervical Cancer

Radical surgery is the first choice for the treatment of early cervical cancer.Patients need radiotherapy and chemotherapy according to the risk factors.concurrent chemoradiotherapy with cisplatin is recommended according to NCCN recommended guidelines for the treatment of cervical cancer,with any post-operative high risk factors(lymph node metastasis,positive vaginal margin,and para-uterine infiltration).for cervical cancer patients without high risk factors but with moderate risk factors that meet Sedlis criteria,it is recommended to supplement post-operative pelvic external irradiation±with concurrent chemotherapy with cisplatin.However,these adjuvant treatments can cause radioactive cystitis and proctitis,even vesicovaginal fistula,rectovaginal fistula,long or irreversible adverse reactions,affecting ovarian function in young patients who retain the ovary,which can lead to a decline in the quality of life of patients.These problems make it a hot topic whether chemotherapy can be used in postoperative adjuvant therapy of cervical cancer patients.This article reviews the research progress of adjuvant therapy for early cervical cancer.

Advances in the exploration of adjuvant therapy of colon cancer with Chinese medicine

Colon cancer is currently a highly prevalent cancer with a high mortality rate worldwide.Modern medical technology provides a range of treatments for colon cancer through different means,and research on the modulating adjuvant treatment of colon cancer with Chinese medicine is currently undergoing continuous theoretical and practical exploration to find highly effective herbal remedies to modulate,alleviate or treat the disease.The present study reviews different aspects of colon cancer in relation to different factors and the modulating adjuvant treatment of colon cancer with Chinese medicine.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Immunotherapy as adjuvant therapy for a patient with adenosquamous carcinoma of the intrahepatic bile duct:A case report and literature review

Adenosquamous carcinoma(ASC)is a rare histological type of intrahepatic cholangiocarcinoma,which includes both adenocarcinoma and squamous cell carcinoma.The clinical features,physical examination,routine laboratory tests,and imaging examinations of patients with ASC are nonspecific.ASC is easily misdiagnosed as hepatocellular carcinoma,and patients with ASC always have a poor prognosis.This study reports a patient with ASC who was diagnosed based on pathological results,underwent surgical resection,and received postoperative chemotherapy(gemcitabine plus cisplatin)combined with immunotherapy(sintilimab).During the 1-year follow-up,the patient was in good condition,and no signs of cancer recurrence were noted.This case highlights that surgical resection and chemotherapy combined with immunotherapy may be feasible for patients with ASC.

Comparative effectiveness of several adjuvant therapies after hepatectomy for hepatocellular carcinoma patients with microvascular invasion

BACKGROUND For resectable hepatocellular carcinoma(HCC),radical hepatectomy is commonly used as a curative treatment.However,postoperative recurrence significantly diminishes the overall survival(OS)of HCC patients,especially with microva-scular invasion(MVI)as an independent high-risk factor for recurrence.While some studies suggest that postoperative adjuvant therapy may decrease the risk of recurrence following liver resection in HCC patients,the specific role of adju-vant therapies in those with MVI remains unclear.AIM To conduct a network meta-analysis(NMA)to evaluate the efficacy of various adjuvant therapies and determine the optimal adjuvant regimen.METHODS A systematic literature search was conducted on PubMed,EMBASE,and Web of Science until April 6,2023.Studies comparing different adjuvant therapies or comparing adjuvant therapy with hepatectomy alone were included.Hazard ratios(HRs)with 95%confidence intervals were used to combine data on recurrence free survival and OS in both pairwise meta-analyses and NMA.RESULTS Fourteen eligible trials(2268 patients)reporting five different therapies were included.In terms of reducing the risk of recurrence,radiotherapy(RT)[HR=0.34(0.23,0.5);surface under the cumulative ranking curve(SUCRA)=97.7%]was found to be the most effective adjuvant therapy,followed by hepatic artery infusion chemotherapy[HR=0.52(0.35,0.76);SUCRA=65.1%].Regarding OS improvement,RT[HR:0.35(0.2,0.61);SUCRA=93.1%]demonstrated the highest effectiveness,followed by sorafenib[HR=0.48(0.32,0.69);SUCRA=70.9%].INTRODUCTION Hepatocellular carcinoma(HCC)is the sixth most common malignant tumor in the world and ranks third in terms of worldwide malignant tumor mortality rates in 2020[1].Curative treatments for HCC include ablation,radical hepatectomy,and liver transplantation.However,ablation is suitable only for early-stage HCC patients,who represent a small percentage of the overall HCC population.Although liver transplantation serves as the optimal treatment for HCC patients,the scarcity of donor organs restricts the availability of this procedure.Therefore,hepatectomy is the most commonly employed curative treatment for resectable HCC.Unfortunately,the 5-year recurrence rate for patients who undergoing hepatectomy ranges from 50%to 70%[2,3].Recurrence of HCC is associated with several risk factors[4],including single nodule>5 cm,vascular invasion,and multiple nodules.Among these factors,microvascular invasion(MVI)is an independent risk factor for recurrence.MVI is defined as the presence of cancer cells in the lumen of endothelium-lined vessels,typically in the small branches of the portal and hepatic veins of the paracancerous liver tissue,visible only under the microscope[5].Previous studies have shown that among HCC patients who underwent hepatectomy,those with MVI had a higher risk of recurrence and shorter overall survival(OS)than those without MVI[6].Several studies have indicated that adjuvant therapy following curative hepatectomy can prevent recurrence and improve OS in HCC patients with MVI.These postoperative adjuvant therapies include transarterial chemoembolization(TACE)[7],sorafenib[8],hepatic artery infusion chemotherapy(HAIC)[9],and radiotherapy(RT)[10].However,the existing studies mostly compare individual adjuvant therapy with hepatectomy alone.Direct or indirect comparisons between the various adjuvant therapies are lacking.Therefore,we performed the network meta-analysis(NMA)to compare the relative efficacy of each adjuvant therapy to determine the optimal treatment.

The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma:a systematic review

BACKGROUND: Following curative treatment for hepatocellular carcinoma (HCC), 50%-90% of postoperative death is due to recurrent disease. Intra-hepatic recurrence is frequently the only site of recurrence. Thus, any neoadjuvant or adjuvant therapy, which can decrease or delay the incidence of intra-hepatic recurrence, or any cancer chemoprevention which can prevent a new HCC from developing in the liver remnant, will improve the results of liver resection. This article systematically reviewed the current evidence of neoadjuvant, adjuvant, and chemoprevention in partial hepatectomy of HCC. DATA SOURCES: Studies were identified by searching MEDLINE and PubMed databases for articles from January 1990 to November 2008 using the keywords 'hepatocellular carcinoma', 'hepatectomy', 'adjuvant therapy', 'neoadjuvant therapy', and 'regional therapy'. Additional papers and book chapters were identified by a manual search of the references from the key articles. RESULTS: Neoadjuvant transarterial chemoembolization or adjuvant regional transarterial chemotherapy embolization+systemic chemotherapy did not add benefit. Both adjuvant transarterial radioembolization with (131)I-lipiodol and adjuvant systemic interferon showed promising results. However, there were only a limited number of such studies. CONCLUSIONS: Further randomized controlled studies need to be carried out. Currently, there is no consensus on a standard neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for HCC.

Neoadjuvant and Adjuvant Therapy in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma(ICC)is the second most common primary liver cancer and causes major economic and health burdens throughout the world.Although the incidence of ICC is relatively low,an upward trend has been seen over the past few decades.Owing to the lack of specific manifestations and tools for early diagnosis,most ICC patients have relatively advanced disease at diagnosis.Thus,neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver resection.However,even after radical resection,the recurrence rate is relatively high and is a main cause leading to death after surgery,which makes adjuvant therapy necessary.Because of its low incidence,studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of malignancy.While standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence,some progress has been achieved in recent years.In this review,the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated,and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.

Perspective of neo-adjuvant/conversion and adjuvant therapy for pancreatic neuroendocrine tumors

The incidence rate of pancreatic neuroendocrine tumors(panNET)is increasing continuously.Curative resection was the primary treatment choice for panNET.However,till now,there were few studies concerning neo-adjuvant/conversion and adjuvant therapy for panNET.In this article,we reviewed the currently widely used medical treatments for advanced panNET.It seemed that peptide receptor radionuclide therapy(PRRT),chemotherapy(temozolomide-based or streptozocin-based)and sunitinib might be more effective to induce tumor shrinkage in panNET and therefore,these treatments could be tried in panNET when neo-adjuvant/conversion therapy was considered.As for adjuvant therapy,it was of great importance to identify patients with high risks of recurrence after curative surgery and previous studies found that high ki-67 index,large tumor size,lymphatic metastasis and perineural/vascular invasion,and so on,were correlated with early recurrence of panNET.Since PRRT and chemotherapy were more cytotoxic,these two kinds of therapies might be worth trying as adjuvant therapies in patients with high risks of recurrence after curative resection of panNET.Admittedly,no studies discussed in this review directly investigated neo-adjuvant/conversion and adjuvant therapy for panNET.Therefore,more prospective studies were still warranted.

Adjuvant and neoadjuvant therapy for pancreatic cancer

Pancreatic cancer still remains a major cause of cancer-related mortality;however,there is a slight but continuous improvement in survival over the past 2 decades.Progress in chemotherapy has contributed to the survival improvement in patients with any stage of pancreatic cancer.In this review,we summarize the currently available evidence regarding adjuvant and neoadjuvant therapy with a focus mainly on randomized controlled trial.The median overall survival in resected pancreatic cancer patients has significantly improved to 22.8 to 54.4 months with the use of adjuvant therapy from 11 to 20.2 months with a strategy of observation only.Recent data from randomized trials support the use of neoadjuvant therapy for patients with resectable or borderline resectable pancreatic cancer.But given a variety of neoadjuvant regimens and different definitions of resectability status,data should be interpreted with caution.Several other trials are ongoing and will provide further evidence.

The effect of using long-acting octreotide as adjuvant therapy for patients with grade 2 pancreatic neuroendocrine tumors after radical resection

Objective:To investigate the effect of long-acting octreotide as adjuvant therapy in the prevention of tumor recurrence in patients with grade 2 pancreatic neuroendocrine tumors(pNETs)after radical resection.Methods:The postoperative follow-up data of 130 patients with resectable G2 pNET treated in the Changhai Hospital from 2008 to 2018 were retrospectively analyzed:59 patients received long-acting octreotide as adjuvant therapy for 6 to 12 months(Oct group)and 71 patients received active follow-up(control group),both of which began after the radical resection,with the primary observation endpoint of disease-free survival(DFS)and the secondary study endpoint of overall survival.Results:The median age of the patients in the Oct group and control group was 52 and 54 years,respectively.There were 28 male cases(47.5%)and 33 male cases(46.5%)in the 2 groups.The median maximum tumor diameter was 3.5 and 3.0 cm,respectively;lymph node metastasis was positive in 13 cases(22.0%)and 9 cases(12.7%);there was peripancreatic nerve invasion in 11 cases(18.6%)and 6 cases(8.5%).Survival analysis revealed that there were significant differences in 2-year DFS%(98.3%vs 88.7%,P=.0371)and 3-year DFS%(96.6%vs 85.9%,P=.0498)between the Oct group and control group.Long-acting octreotide treatment was found to reduce the risk of 3-year recurrence of G2 pNET after radical resection(HR=0.2,P=.044)with the application of inverse-probability-of-treatment weighted to balance the limited data bias.Conclusion:Using long-acting octreotide as adjuvant therapy for G2 pNET patients after radical surgery may improve the rate of 3y-DFS,but the benefit needs to be confirmed in a well-designed random control clinical trial.

Recent advances in recurrent hepatocellular carcinoma therapy

Hepatocellular carcinoma(HCC)is the most prevalent form of primary liver cancer,accounting for 75%-85%of cases.Although treatments are given to cure early-stage HCC,up to 50%-70%of individuals may experience a relapse of the illness in the liver after 5 years.Research on the fundamental treatment modalities for recurrent HCC is moving significantly further.The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes.These strategies aim to minimize substantial morbidity,support good life quality,and enhance survival for patients with recurrent HCC.For individuals with recurring HCC after curative treatment,no approved therapeutic regimen is currently available.A recent study presented novel approaches,like immunotherapy and antiviral medication,to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment.The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review.We also discuss the potential for future clinical and translational investigations.

Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors:A systematic review and network meta-analysis

Background:By prolonging overall survival and reducing disease recurrence rates,immune checkpoint inhibitors(ICIs)are an emerging adjuvant therapy option for patients with resectable malignant tumors.However,the safety profile(deaths and adverse events[AEs])of adjuvant ICIs has not been fully described.Methods:We searched the literature for phase III randomized clinical trials that compared PD-1,PD-L1,and CTLA-4 inhibitors in solid malignant tumors.Incidences of death,discontinuation,AEs of any cause,treatment-related adverse events(TRAEs),and immune-related adverse events(IRAEs)were extracted for the network meta-analysis.Network meta-analyses with low incidence and poor convergence are reported as incidences with 95%confidence intervals(95%CIs).Results:Ten randomized clinical trials that included 9243 patients who received ICI adjuvant therapy were eligible.In total,21 deaths due to TRAEs were recorded,with an overall incidence of 0.40%(95%CI:0.26–0.61).The treatment-related mortality rates for ipilimumab(0.76%,95%CI:0.31–1.55)and atezolizumab(0.56%,95%CI:0.18–1.31)were higher than for pembrolizumab(0.24%,95%CI:0.10–0.56)and nivolumab(0.30%,95%CI:0.08–0.77).The most frequent causes of death were associated with the gastrointestinal(0.10%,95%CI:0.04–0.24)and pulmonary(0.08%,95%CI:0.03–0.21)systems.Compared with the control arm,we found that nivolumab(odds ratio[OR]:2.73,95%CI:0.49–15.85)and atezolizumab(OR:12.43,95%CI:2.42–78.48)caused the fewest grade≥3 TRAEs and IRAEs.Commonly reported IRAEs of special interest were analyzed,and two agents were found to have IRAEs with incidences>10%,i.e.,hepatitis for atezolizumab(14.80%,95%CI:12.53–17.32)and hypophysitis for ipilimumab(13.53%,95%CI:11.38–15.90).Conclusions:Ipilimumab and atezolizumab were correlated with higher treatment-related death rates than pembrolizumab and nivolumab,in which the gastrointestinal and pulmonary systems were mostly involved.Regarding severe TRAEs and IRAEs,nivolumab and atezolizumab are likely to be the safest agent,respectively.This study will guide clinical practice for ICI adjuvant therapies.