Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

TRIANGLE operation,combined with adequate adjuvant chemotherapy,can improve the prognosis of pancreatic head cancer:A retrospective study

BACKGROUND The TRIANGLE operation involves the removal of all tissues within the triangle bounded by the portal vein-superior mesenteric vein,celiac axis-common hepatic artery,and superior mesenteric artery to improve patient prognosis.Although previously promising in patients with locally advanced pancreatic ductal adenocarcinoma(PDAC),data are limited regarding the long-term oncological outcomes of the TRIANGLE operation among resectable PDAC patients undergoing pancreaticoduodenectomy(PD).AIM To evaluate the safety of the TRIANGLE operation during PD and the prognosis in patients with resectable PDAC.METHODS This retrospective cohort study included patients who underwent PD for pancreatic head cancer between January 2017 and April 2023,with or without the TRIANGLE operation.Patients were divided into the PD_(TRIANGLE)and PD_(non-TRIANGLE)groups.Surgical and survival outcomes were compared between the two groups.Adequate adjuvant chemotherapy was defined as adjuvant chemotherapy≥6 months.RESULTS The PD_(TRIANGLE)and PD_(non-TRIANGLE) groups included 52 and 55 patients,respectively.There were no significant differences in the baseline characteristics or perioperative indexes between the two groups.Furthermore,the recurrence rate was lower in the PD_(TRIANGLE) group than in the PD_(non-TRIANGLE) group(48.1%vs 81.8%,P<0.001),and the local recurrence rate of PDAC decreased from 37.8%to 16.0%.Multivariate Cox regression analysis revealed that PD_(TRIANGLE)(HR=0.424;95%CI:0.256-0.702;P=0.001),adequate adjuvant chemotherapy≥6 months(HR=0.370;95%CI:0.222-0.618;P<0.001)and margin status(HR=2.255;95%CI:1.252-4.064;P=0.007)were found to be independent factors for the recurrence rate.CONCLUSION The TRIANGLE operation is safe for PDAC patients undergoing PD.Moreover,it reduces the local recurrence rate of PDAC and may improve survival in patients who receive adequate adjuvant chemotherapy.

Optimal extent of lymphadenectomy improves prognosis and guides adjuvant chemotherapy in esophageal cancer: A propensity scorematched analysis

BACKGROUND The optimal extent of lymphadenectomy in esophageal squamous cell carcinoma(ESCC)patients remained debatable.AIM To explore the ideal number of cleared lymph nodes in ESCC patients undergoing upfront surgery.METHODS In this retrospective,propensity score-matched study,we included 1042 ESCC patients who underwent esophagectomy from November 2008 and October 2019.Patients who underwent neoadjuvant therapy were excluded.We collected pa-tients’clinicopathological features and information regarding lymph nodes,in-cluding the total number of resected lymph nodes(NRLN),and pathologically diagnosed positive lymph nodes(RPLN).SPSS and R software were used for statistical analysis.RESULTS Among the included 1042 patients,two cohorts:≤21(n=664)and>21 NRLN(n=378)were identified.The final prognostic model included four variables:T stage,N,venous thrombus,and the number of removed lymph nodes.Among them,NRLN>21 was determined as an independent prognosticator after surgery for esophageal cancer(hazards regression=0.66,95%confidence interval:0.50-0.87,P=0.004).A nomogram was created based on the regression coefficients of the variables in the final model.In the training cohort,the predictive model dis-played an uncorrected five-year overall survival C-index of 0.659,with a bootstrap-corrected C-index of 0.654.In the subgroup analysis,adjuvant chemotherapy was beneficial in the subgroup with NRLN>21 and RPLN≤0.16 and NRLN≤21 and RPLN>0.16.CONCLUSION NRLN>21 was an independent prognostic factor after ESCC surgery.The combination of NRLN and RPLN may provide a reference for adjuvant chemotherapy use in potential beneficiaries.

Adjuvant chemotherapy for isolated resectable colorectal lung metastasis: A retrospective study using inverse probability treatment weighting propensity analysis

BACKGROUND The benefit of adjuvant chemotherapy(ACT)for patients with no evidence of disease after pulmonary metastasis resection(PM)from colorectal cancer(CRC)remains controversial.AIM To assess the efficacy of ACT in patients after PM resection for CRC.METHODS This study included 96 patients who underwent pulmonary metastasectomy for CRC at a single institution between April 2008 and July 2023.The primary end-point was overall survival(OS);secondary endpoints included cancer-specific survival(CSS)and disease-free survival(DFS).An inverse probability of treat-ment-weighting(IPTW)analysis was conducted to address indication bias.Sur-vival outcomes compared using Kaplan-Meier curves,log-rank test,Cox regre-ssion and confirmed by propensity score-matching(PSM).RESULTS With a median follow-up of 27.5 months(range,18.3-50.4 months),the 5-year OS,CSS and DFS were 72.0%,74.4%and 51.3%,respectively.ACT had no significant effect on OS after PM resection from CRC[original cohort:P=0.08;IPTW:P=0.15].No differences were observed for CSS(P=0.12)and DFS(P=0.68)between the ACT and non-ACT groups.Multivariate analysis showed no association of ACT with better survival,while sublobar resection(HR=0.45;95%CI:0.20-1.00,P=0.049)and longer disease-free interval(HR=0.45;95%CI:0.20-0.98,P=0.044)were associated with improved survival.CONCLUSION ACT does not improve survival after PM resection for CRC.Further well-designed randomized controlled trials are needed to determine the optimal ACT regimen and duration.

Predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa squamous cell lung cancer:A retrospective analysis

BACKGROUND Lung cancer(LC)is a global medical,social and economic problem and is one of the most common cancers and the leading cause of mortality from malignant neoplasms.LC is characterized by an aggressive course,and in the presence of disease recurrence risk factors,patients,even at an early stage,may be indicated for adjuvant therapy to improve survival.However,combined treatment does not always guarantee a favorable prognosis.In this regard,establishing predictors of LC recurrence is highly important both for determining the optimal treatment plan for the patients and for evaluating its effectiveness.AIM To establish predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa lung squamous cell carcinoma(LSCC).METHODS A retrospective case-control cohort study included 69 patients with LSCC who underwent radical surgery at the Orenburg Regional Clinical Oncology Center from 2009 to 2018.Postoperatively,all patients received adjuvant chemotherapy.Histological samples of the resected lung were stained with Mayer's hematoxylin and eosin and examined under a light microscope.Univariate and multivariate analyses were used to identify predictors associated with the risk of disease recurrence.Receiver operating characteristic curves were constructed to discriminate between patients with a high risk of disease recurrence and those with a low risk of disease recurrence.Survival was analyzed using the Kaplan-Meier method.The log-rank test was used to compare survival curves between patient subgroups.Differences were considered to be significant at P<0.05.RESULTS The following predictors of a high risk of disease recurrence in patients with stage IIb-IIa LSCC were established:a low degree of tumor differentiation[odds ratio(OR)=7.94,95%CI=1.08-135.81,P=0.049];metastases in regional lymph nodes(OR=5.67,95%CI=1.09-36.54,P=0.048);the presence of loose,fine-fiber connective tissue in the tumor stroma(OR=21.70,95%CI=4.27-110.38,P=0.0002);and fragmentation of the tumor solid component(OR=2.53,95%CI=1.01-12.23,P=0.049).The area under the curve of the predictive model was 0.846(95%CI=0.73-0.96,P<0.0001).The sensitivity,accuracy and specificity of the method were 91.8%,86.9%and 75.0%,respectively.In the group of patients with a low risk of LSCC recurrence,the 1-,2-and 5-year disease-free survival(DFS)rates were 84.2%,84.2%and 75.8%,respectively,while in the group with a high risk of LSCC recurrence the DFS rates were 71.7%,40.1%and 8.2%,respectively(P<0.00001).Accordingly,in the first group of patients,the 1-,2-and 5-year overall survival(OS)rates were 94.7%,82.5%and 82.5%,respectively,while in the second group of patients,the OS rates were 89.8%,80.1%and 10.3%,respectively(P<0.00001).CONCLUSION The developed method allows us to identify a group of patients at high risk of disease recurrence and to adjust to ongoing treatment.

Dose-dense paclitaxel plus carboplatin vs.epirubicin and cyclophosphamide with paclitaxel as adjuvant chemotherapy for high-risk triple-negative breast cancer

Objective:The objective of this open-label,randomized study was to compare dose-dense paclitaxel plus carboplatin(PCdd)with dose-dense epirubicin and cyclophosphamide followed by paclitaxel(ECdd-P)as an adjuvant chemotherapy for early triple-negative breast cancer(TNBC).Methods:We included Chinese patients with high recurrence risk TNBC who underwent primary breast cancer surgery.They were randomly assigned to receive PCdd[paclitaxel 150 mg/m2 on d 1 and carboplatin,the area under the curve,(AUC)=3 on d 2]or ECdd-P(epirubicin 80 mg/m2 divided in 2 d and cyclophosphamide 600 mg/m2 on d 1 for 4 cycles followed by paclitaxel 175 mg/m2 on d 1 for 4 cycles)every 2 weeks with granulocyte colony-stimulating factor(G-CSF)support.The primary endpoint was 3-year disease-free survival(DFS);the secondary endpoints were overall survival(OS)and safety.Results:The intent-to-treat population included 143 patients(70 in the PCdd arm and 73 in the ECdd-P arm).Compared with the ECdd-P arm,the PCdd arm had significantly higher 3-year DFS[93.9%vs.79.1%;hazard ratio(HR)=0.310;95%confidence interval(95%CI),0.137-0.704;log-rank,P=0.005]and OS(98.5%vs.92.9%;HR=0.142;95%CI,0.060-0.825;log-rank,P=0.028).Worse neutropenia(grade 3/4)was found in the ECdd-P than the PCdd arm(47.9%V5.21.4%,P=0.001).Conclusions:PCdd was superior to ECdd-P as an adjuvant chemotherapy for early TNBC with respect to improving the 3-year DFS and OS.PCdd also yielded lower hematological toxicity.Thus,PCdd might be a preferred regimen for early TNBC patients with a high recurrence risk.

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.

Current Status and Research Progress of Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer

Gastric cancer is one of the most common malignant tumours worldwide, with a high degree of malignancy and a poor prognosis. While early gastric cancer can be cured by surgical treatment, locally advanced gastric cancer requires neoadjuvant therapy to shrink the tumour, suppress potential metastases, achieve down-staging, and provide patients with the opportunity for radical surgery to prolong their survival. This article reviews the current status and progress of neoadjuvant chemotherapy for locally advanced gastric cancer.

Adjuvant therapy for orbital non-rhabdomyosarcoma soft tissue sarcoma:comparison of long-term outcome between radiotherapy and chemotherapy

AIM:To illustrate clinicopathological features of orbital non-rhabdomyosarcoma soft tissue sarcoma(NRSTS),and to compare the treatment outcome between postoperative radiotherapy(RT) and chemotherapy in a retrospective analysis nearly 20y.METHODS:A retrospective cohort study of 56 patients with orbital NRSTS were reviewed,34 of whom received postoperative RT,and 22 received postoperative chemotherapy.The clinicopathological features,local recurrence,metastases,and survival data were recorded.Survival analysis was performed using the Kaplan-Meier method.RESULTS:During follow-up(111.8mo,ranged 8-233mo) for 56 patients,19 patients of them developed local recurrence,and 7 patients developed distant metastases.Fifteen patients died during follow-up period.Overall survival rates considering the whole study group was 78.57% at 5y,and 72.16% at 10y after the initial diagnosis.Compared with chemotherapy,RT was associated with lower risk of local recurrence [hazard ratio for RT vs chemotherapy,0.263,95% confidence interval(CI),0.095-0.728,P=0.0015];with lower risk of distant metastasis(hazard ratio for RT vs chemotherapy,0.073,95%CI,0.015-0.364,P=0.0014);and with lower risk of death from disease(hazard ratio for RT vs chemotherapy,0.066,95%CI,0.022-0.200,P<0.0001).The 5-year survival rate in RT group was 97.06% compared to 50% in chemotherapy group.CONCLUSION:In patients with orbital NRSTS,postoperative RT provides better control of local recurrence,distant metastasis,and death from disease than chemotherapy.RT is the more preferrable adjuvant therapy compared to chemotherapy possibly.

Role of adjuvant chemotherapy on recurrence and survival in patients with resected ampulla of Vater carcinoma

BACKGROUND Owing to rarity of disease and lack of prospective studies, data supporting the role of adjuvant chemotherapy in ampulla of Vater(AoV) carcinoma is limited.AIM To evaluate whether adjuvant chemotherapy cases for AoV carcinoma had better disease-free survival(DFS) rates than cases of observation following curative surgery.METHODS We retrospectively analyzed the association between adjuvant chemotherapy and DFS and overall survival(OS) in patients with stage IB-Ⅲ AoV carcinoma who underwent curative surgical resection. Fluorouracil-based adjuvant chemotherapy was administered after surgery at the discretion of the physician. Adjusted multivariate regression models were used to evaluate the association between adjuvant chemotherapy and survival outcomes.RESULTS Of the total 104 patients who underwent curative surgery, 52 received adjuvant chemotherapy. Multivariate analysis revealed that higher histologic grade [hazard ratio(HR) = 2.24, P = 0.046], advanced tumor stage(HR = 1.85, P = 0.030), and vascular invasion(HR = 2.14, P = 0.010) were associated with shorter DFS. Adjuvant chemotherapy improved DFS compared to the observation group(HR =0.50, P = 0.015) and tended to be associated with a longer OS, although the difference was not statistically significant(HR = 0.58, P = 0.098).CONCLUSION Among patients with resected AoV carcinoma, the adjuvant chemotherapy group was not associated with a significant survival benefit compared to the observation group. However, on multivariate analysis adjusting for prognostic factors, adjuvant chemotherapy following surgery was an independent prognostic factor for DFS in patients with resected AoV carcinoma. Further studies are needed to investigate the effectiveness of adjuvant chemotherapy according to histologic phenotype.

Effect of postoperative adjuvant chemotherapyon the prognosis of patients with ypT0-3N0 rectalcancer undergoing neoadjuvant chemoradiotherapy

Objective The aim of this study was to investigate the effect of adjuvant chemotherapy (AC) on theprognosis of patients with ypT0-3N0 rectal cancer undergoing neoadjuvant chemoradiotherapy.Methods The study participants were 110 patients with locally advanced rectal cancer. Thirty-fourpatients did not receive postoperative AC treatment, and the other 76 patients received postoperative ACtreatment. The differences in the 5-year overall survival (OS) and disease-free survival (DFS) between thetwo groups were compared.Results Age was an important determinant of the patients’ decision to undergo postoperative treatment.Patients who did not receive AC treatment were significantly older than those who received AC treatment(P < 0.05). The tumor location (distance above anal margin) in the AC group was significantly larger thanthat in the non-AC group (P < 0.05). Moreover, there was no significant difference in the 5-year DFS andOS between the two groups. Postoperative AC did not significantly improve the prognosis of patients withrectal cancer. Age, tumor differentiation, and the number of resected lymph nodes were independent factorsaffecting the OS of patients (P < 0.05). Older patients, patients with lower degree of tumor differentiation,and patients with <12 resected lymph nodes showed worse prognosis (P < 0.05).Conclusion Patients with rectal cancer whose ypT0-3N0 stage is reduced after neoadjuvantchemoradiotherapy, especially those without adverse prognostic factors, do not need AC after surgery.

Adjuvant chemotherapy for resected colorectal cancermetastases: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.

Adjuvant chemotherapy with paclitaxel and cisplatin in lymph node-positive thoracic esophageal squamous cell carcinoma

Objective： No standard postoperative adjuvant chemotherapy has ever been established in node-positive esophageal squamous cell carcinoma （ESCC）. This is a study to explore the effect of postoperative paelitaxel （PTX） and cisplatin （DDP） in lymph node-positive, completely resected thoracic ESCC patients. Methods： We conducted a prospective phase II trial. Patients had pathologically node-positive thoracic ESCC with negative margins. Outcomes of disease-free survival （DFS） and overall survival （OS） were compared with a matched historical control cohort. The postoperative chemotherapy regimen consisted of 4 to 6 cycles of PTX 150 mg/m2 administered intravenously on d 1 followed by DDP 50 mg/m2 on d 2 every 14 d. Results： Forty-three patients were accrued from December 2007 to May 2012 at Cancer Hospital of Chinese Academy of Medical Sciences for adjuvant chemotherapy. The historical control group consisted of 80 patients who received complete resection but no adjuvant chemotherapy during the same period of time. Of the 43 patients with adjuvant chemotherapy, 37 （86.0%） patients completed 4 to 6 cycles of chemotherapy. The 3-year DFS rates were 56.3% in the adjuvant group and 34.6% in the control group （P=0.006）. The 3-year OS rates were 55.0% in the adjuvant group and 37.5% in the control group （P=0.013）. Multivariate analysis revealed that postoperative chemotherapy was the significant predictor for improved OS （P=0.005）. Conclusions： Biweekly adjuvant PTX and DDP might improve 3-year DFS and OS in lymph node-positive, curatively resected thoracic ESCC patients. These conclusions warrant further study in randomized phase III clinical trials.

Oxaliplatin plus S-1 or capecitabine as neoadjuvant or adjuvant chemotherapy for locally advanced gastric cancer with D2lymphadenectomy: 5-year follow-up results of a phase II-III randomized trial

Objective： To compare the effect of neoadjuvant chemotherapy （NACT） with adjuvant chemotherapy （ACT） using oxaliplatin plus S-1 （sex） or capecitabine （CapeOX） on gastric cancer patients with D2 lymphadenectomy. Methods： This was a two-by-two factorial randomized phase Ⅱ-Ⅲ trial, and registered on ISRCTN registry （No. ISRCTN12206108）. Locally advanced gastric cancer patients were randomized to neoadjuvant sex, neoadjuvant CapeOX, adjuvant sex, or adjuvant CapeOX arms. Primary analysis was performed on an intention- to-treat （ITT） basis using overall survival （OS） as primary endpoint. Results： This trial started in September 2011 and closed in December 2012 with 100 patients enrolled. Treatment completion rate was 56%, 52%, 38% and 30% in the four arms, respectively. NACT group had fewer dropouts due to unacceptable toxicity （P=0.042）. Surgical complication rate did not differ by the four groups （P=0.986）. No survival signifcant difference was found comparing NACT with ACT （P=0.664; 5-year-OS： 70% vs. 74% respectively）, nor between the sex and CapeOX groups （P=0.252; 5-year-OS： 78% vs. 66% respectively）. Subgroup analysis showed sex significantly improved survival in patents with diffuse type （P=0.048）. Conclusions： No significant survival difference was found between NACT and ACT. sex and CapeOX had good safety and efficacy as neoadjuvant regimens. Diffuse type patients may survive longer due to sex.

Adjuvant chemotherapy for gastric cancer:Current evidence and future challenges

Gastric cancer still represents one of the major causes of cancer mortality worldwide.Patients survival is mainly related to stage,with a high proportion of patients with metastatic disease at presentation.Thus,the cure rate largely depend upon surgical resection.Despite the additional,albeit small,benefit of adjuvant chemotherapy has been clearly demonstrated,no general consensus has been reached on the best treatment option.Moreover,the narrow therapeutic index of adjuvant chemotherapy(i.e.,limited survival benefit with considerable toxicity)requires a careful assessment of expected risks and benefits for individual patients.Treatment choices vary widely based on the different geographic areas,with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States.In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses.The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery;the same Authors also showed that disease free survival may be used as a surrogate end-point for overall survival.We finally discuss future research issues such as the need of economic evaluations,development of prognostic or predictive biomarkers,and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment.

The effect of adjuvant chemotherapy in resectable cholangiocarcinoma: A meta-analysis and systematic review

Background: The benefit of adjuvant chemotherapy for resectable cholangiocarcinoma remains unclear due to the lack of randomized control studies. This study aimed to investigate the possible benefit of postoperative adjuvant chemotherapy for resectable cholangiocarcinoma. Data sources: Relevant research articles published before 1 st March 2018 in Pub Med, Embase and the Cochrane library databases were retrieved. Published data were extracted and analyzed by RevMan 5.3, and the results were presented as hazard ratios(HRs) [95% confidence intervals(CI)] and forest plots. Results: One prospective and eighteen retrospective studies were included, with a total number of 11,458 patients, 4696 of whom received postoperative chemotherapy. There was a significant improvement of the overall survival(OS) for patients who underwent operation + adjuvant chemotherapy compared to those who underwent operation alone(HR = 0.61; P < 0.001). Subgroup analyses show that the postoperative chemotherapy group compared with operation alone group are indicated as follows: hilar cholangiocarcinoma group(HR = 0.60; P < 0.001), intrahepatic cholangiocarcinoma group(HR = 0.60; P < 0.001), R1 resection group(HR = 0.71; P = 0.04), LN-positive diagnosis group(HR = 0.58; P < 0.001), gemcitabine-based chemotherapy group(HR = 0.42; P < 0.001), distal cholangiocarcinoma group(HR = 0.48; P = 0.17), R0 resection group(HR = 0.69; P = 0.43), and 5-flurouracil-based chemotherapy group(HR = 0.90; P = 0.66), respectively. Conclusions: Postoperative adjuvant chemotherapy can improve the OS in intrahepatic and hilar cholangiocarcinoma patients. However, distal cholangiocarcinoma patients gain no benefit from postoperative adjuvant chemotherapy. Prospective randomized trials are warranted in order to define the standard chemotherapy regimen.

Adjuvant chemotherapy for early-stage cervical cancer

The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery （RS） has not yet been established, and radiation therapy （RT） or concurrent chemoradiotherapy （CCRT） is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life （QOL） or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival （OS） with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin （TP） regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group （GOG）, had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial （RCT） of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable condition, it is necessary that the therapeutic strategies should be improved with considering adverse events and QOL for long-term survivors.

Current status of adjuvant chemotherapy for gastric cancer

Although radical gastrectomy is a standard treatment for advanced gastric cancer,recurrence remains high.After several large-scale controlled studies have shown the beneficial effects of adjuvant chemotherapy,that treatment emerged as a standard option for advanced gastric cancer after gastrectomy.However,various guidelines from different countries have suggested different adjuvant chemotherapies.Understanding the differences between guidelines is very important for investigating further therapeutic strategies.Fortunately,because there are many ongoing studies about new regimens for adjuvant treatment,it is expected that patients with gastric cancer after surgery will have better outcome.

Neoadjuvant plus adjuvant chemotherapy benefits overall survival of locally advanced gastric cancer

Neoadjuvant chemotherapy (NAC) has drawn more attention to the treatment of locally advanced gastric cancer (AGC) in the current multidisciplinary treatment model. EORTC trial 40954 has recently reported that NAC plus surgery without postoperative adjuvant chemotherapy could not benefit the locally AGC patients in their overall survival. We performed a meta-analysis of 10 studies including 1518 gastric cancer patients. Stratified subgroups were NAC plus surgery and NAC plus both surgery and adjuvant chemotherapy (AC), while control was surgery alone. The results showed that NAC plus surgery did not benefit the patients with locally AGC in their overall survival [odds ratio (OR) = 1.20, 95% CI 0.80-1.80, P = 0.37] and the number needed to treat (NNT) was 74. However, the NAC plus both surgery and AC had a slight overall survival benefit (OR = 1.33, 95% CI 1.03-1.71, P = 0.03) and NNT was 14, which is superior to the NAC plus surgery. Therefore, we recommend that combined NAC and AC should be used to improve the overall survival of the locally AGC patients.

Adjuvant chemotherapy with S-1 plus oxaliplatin improves survival of patients with gastric cancer after D2 gastrectomy: A multicenter propensity score-matched study

AIM To investigate the safety and efficacy of S-1 plus oxaliplatin(SOX) as an adjuvant chemotherapy regimen in gastric cancer(GC) after D2 dissection.METHODS GC Patients who underwent D2 gastrectomy from September 2009 to December 2011 in four Chinese institutions were enrolled. Patients with stage ⅠB-ⅢC GC, who received adjuvant SOX treatment were matched by propensity scores with those who underwent surgery alone and those who conducted capecitabine plus oxaliplatin(XELOX) regimen. Disease-free survival(DFS) and overall survival(OS) were compared among the groups. In addition, adverse events in SOX patients were analyzed.Of 1944 GC patients who underwent D2 dissection, 867 were included for analysis. One hundred and seventeen patients treated with SOX were matched to 234 patients who conducted surgery alone. Fifty-seven patients treated with SOX were matched to 57 patients who received XELOX. The estimated five-year DFS was 57.5% in the adjuvant SOX group which was higher than that(44.6%) in the surgery alone group(P = 0.001); and the estimated five-year OS was 68.3% which was higher than that(45.8%) of surgery alone group(P < 0.001). Survival benefit was also revealed in stage III and > 60 years old subgroups(P < 0.001 and P = 0.015, respectively). Compared with XELOX regimen, SOX showed no significant difference in DFS(P = 0.340) and OS(P = 0.361). The most common ≥ 3 grade adverse events of SOX regimen were neutropenia(22.6%), leukopenia(8.9%) and thrombocytopenia(5.6%).CONCLUSION Compared with surgery alone, SOX regimen significantly improves the long-term survival and has acceptable toxicity in patients with stage ⅠB-ⅢC GC after D2 dissection. It may be a novel adjuvant chemotherapy regimen in GC patients.