PhaseⅡstudy of induction chemotherapy followed by concurrent chemoradiotherapy with raltitrexed and cisplatin in locally advanced nasopharyngeal carcinoma

Objective:For locally advanced nasopharyngeal carcinoma(LA-NPC)patients,high incidences of distant metastases and severe treatment related toxicities are the main obstacles needed to be overcome.Raltitrexed,a specific thymidylate synthase inhibitor with a convenient administration schedule,has an acceptable and manageable toxicity,and possesses radio-sensitizing properties.To investigate the efficacy and safety of raltitrexed and cisplatin induction chemotherapy and concurrent chemoradiotherapy(IC+CCRT)in patients with LA-NPC,a phaseⅡclinical study was conducted.Methods:Sixty eligible patients with LA-NPC were enrolled into this study.A raltitrexed-cisplatin combination was used as part of an IC+CCRT regimen.Raltitrexed-cisplatin IC was given once every 3 weeks(q3 w)for two cycles,followed by raltitrexed-cisplatin based CCRT q3 w for two cycles.Intensity-modulated radiotherapy(IMRT)was given for all enrolled patients.Results:All patients were included in survival analysis according to the intent-to-treat principle.The objective response rate(ORR)3 months after treatment was 98%.The 2-year overall survival(OS)rate was 92%.The median relapse-free survival(RFS)time was 30.5[95%confidence interval(95%CI),28.4-32.3]months.The 2-year RFS rate was 85%.The 2-year local failure-free survival(LFFS)rate was 97%and the 2-year distant metastasis-free survival(DMFS)rate was 88%.Acute toxicities were mostly grade 2 and 3 reactions in bone marrow suppression,gastrointestinal side effect and oropharyngeal mucositis.Only two patients occurred grade 4 acute toxicities,one was bone marrow suppression and the other was dermatitis radiation.Conclusions:The combination of raltitrexed and cisplatin has a comparable efficacy to those in standard firstline therapy.

Induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma

The value of adding induction chemotherapy(IC) to concurrent chemoradiotherapy(CCRT) for the treatment of locoregionally advanced nasopharyngeal carcinoma(NPC) remains unclear.In our recent article entitled "Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma:a phase 3,multicentre,randomised controlled trial" published in the Lancet Oncology,we reported the results of a phase Ⅲ,multicenter,randomized controlled trial comparing cisplatin,5-fluorouracil,and docetaxel(TPF) IC plus CCRT versus CCRT alone in patients wit hT3-4N1/TxN2-3M0 NPC(Clinical Trials.gov registration number NCT01245959).The IC-plus-CCRT group showed significantly higher 3-year failure-free survival,overall survival,and distant failure-free survival rates than the CCRT-alone group,with an acceptable toxicity profile.Our study suggests that adding TPF IC to CCRT could increase survival rates and reduce distant failure in patients with locoregionally advanced NPC.However,long-term follow-up is required to assess the eventual efficacy and toxicity of this strategy,and a more accurate method to determine prognosis is needed to enable better tailoring of treatment strategy for individual patients.

Induction chemotherapy with albumin-bound paclitaxel plus lobaplatin followed by concurrent radiochemotherapy for locally advanced esophageal cancer

BACKGROUND Albumin-bound paclitaxel(ABP)has been used as second-and higher-line treatments for advanced esophageal cancer,and its efficacy and safety have been well demonstrated.Lobaplatin(LBP)is a third-generation platinum antitumor agent;compared with the first two generations of platinum agents,it has lower toxicity and has been approved for the treatment of breast cancer,small cell lung cancer,and chronic granulocytic leukemia.However,its role in the treatment of esophageal cancer warrants further investigations.AIM To investigate the efficacy and safety of induction chemotherapy with ABP plus LBP followed by concurrent radiochemotherapy(RCT)for locally advanced esophageal cancer.METHODS Patients with pathologically confirmed advanced esophageal squamous cell carcinoma(ESCC)at our hospital were enrolled in this study.All patients were treated with two cycles of induction chemotherapy with ABP plus LBP followed by concurrent RCT:ABP 250 mg/m^(2),ivgtt,30 min,d1,every 3 wk;and LBP,30 mg/m^(2),ivgtt,2 h,d1,every 3 wk.A total of four cycles were scheduled.The dose of the concurrent radiotherapy was 56-60 Gy/28-30 fractions,1.8-2.0 Gy/fraction,and 5 fractions/wk.RESULTS A total of 29 patients were included,and 26 of them completed the treatment protocol.After the induction chemotherapy,the objective response rate(ORR)was 61.54%,the disease control rate(DCR)was 88.46%,and the progressive disease(PD)rate was 11.54%;after the concurrent RCT,the ORR was 76.92%,the DCR was 88.46%,and the PD rate was 11.54%.The median progression-free survival was 11.1 mo and the median overall survival was 15.83 mo.Cox multivariate analysis revealed that two cycles of induction chemotherapy followed by concurrent RCT significantly reduced the risk of PD compared with two cycles of chemotherapy alone(P=0.0024).Non-hematologic toxicities were tolerable,and the only grade 3 non-hematologic toxicity was radiation-induced esophagitis(13.79%).The main hematologic toxicity was neutropenia,and no grade 4 adverse event occurred.CONCLUSION Induction chemotherapy with ABP plus LBP followed by concurrent RCT is effective in patients with locally advanced ESCC,with mild adverse effects.Thus,this protocol is worthy of clinical promotion and application.

Haploidentical hematopoietic stem-cell transplantation for acute myeloid leukemia in first relapse after complete remission by standard induction chemotherapy

Objective To investigate the therapeutic effects of haploidentical hematopoietic stem - cell transplantation ( Haplo - PBSCT) for acute myeloid leukemia in first relapse after complete remission by standard induction chemotherapy. Methods Eighty - nine cases of AML in first relapse after complete remission by standard DA

Effect of induction chemotherapy with cisplatin, fluorouracil, with or without taxane on locoregionally advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis

Background:Available data in the literature comparing different induction chemotherapy(IC)regimens on locoregionally advanced nasopharyngeal carcinoma(NPC)are scarce.The purpose of the present study was to evaluate the outcomes of locoregionally advanced NPC patients who were treated with taxane,cisplatin and 5-fluorouracil(TPF)or cisplatin and 5-fluorouracil(PF)as IC followed by concurrent chemoradiotherapy(CCRT).Methods:In total,1879 patients with locoregionally advanced NPC treated with IC and CCRT from a prospectively maintained database were included in the present observational study.We compared overall survival(OS),disease-specific survival(DSS),distant metastasis-free survival(DMFS),and locoregional relapse-free survival,using the pro-pensity score method.Results:In total,1256 patients received TPF or PF as IC backbone.The TPF group showed significantly better OS(hazard ratio[HR],0.660;95%confidence interval[CI]0.442-0.986;P=0.042),DSS(HR,0.624;95%CI 0.411-0.947;P=0.027)and DMFS(HR,0.589;95%CI 0.406-0.855;P=0.005)compared with the PF group in multivariable analy-ses.Propensity score matching identified 294 patients in each cohort and confirmed that TPF was associated with significantly improved 5-year OS(88.1%vs.80.7%;P=0.042),DSS(88.5%vs.80.7%;P=0.021)and DMFS(87.9%vs.78.6%;P=0.012)rates compared with the PF group.There were no significant differences in locoregional relapse-free survival before or after matching.Conclusions:In our study,IC with the TPF regimen combined with CCRT showed improved long-term survival for the patients with locoregionally advanced NPC compared with the PF regimen.However,a prospective randomized clinical trial to validate these findings is necessary.

Clinical outcomes for nasopharyngeal cancer with intracranial extension after taxanebased induction chemotherapy and concurrent chemo-radiotherapy in the modern era

Objective:To evaluate the survival outcomes for a cohort of nasopharyngeal cancer with intracranial extension(ICE)treated with induction chemotherapy(ICT)followed by chemo-intensity-modulated radiotherapy(CTRT)at a tertiary cancer center.Methods:We retrospectively analyzed 45 patients with histologically proven,non-metastatic NPC with ICE treated at our institute between October 2008 and October 2016.Patients were classified as minor ICE or major ICE,based on the extent of ICE.All the patients received 2-3 cycles of a taxane-based ICT regimen followed by CTRT.Radiotherapy was delivered with"riskadapted"intensity-modulated radiotherapy(IMRT)technique in all patients.Results:After a median follow up of 45 months(range:8-113 months),the estimated 5-year DFS,LRFS,DMFS,and OS of the entire cohort was 58%,82%,67%and 74%respectively.On multivariate analysis,histological subtype was an independent predictor of LRFS,and age was an independent predictor of DFS.The extent of ICE showed only a trend towards worse DFS(P=0.06).None of the factors significantly predicted for DMFS or OS.Gender,N-stage,and response to ICT did not significantly affect any of the outcomes.Grade 2 or worse subcutaneous fibrosis was seen in 22%of patients and grade 2 or worse xerostomia was seen in 24%of patients at last follow up.Thirty-three percent of the patients developed clinical hypothyroidism at last follow up.None of the patients experienced any neurological or vascular complications.Conclusions:Taxane-based induction chemotherapy followed by chemo-intensity modulated radiotherapy resulted in excellent locoregional control and survival with acceptable toxicities in patients of nasopharyngeal cancer with intracranial extension.Distant metastasis continues to be the predominant problem in these patients.

Intraperitoneal chemotherapy and its evolving role in management of gastric cancer with peritoneal metastases

Advanced gastric cancer （GC） has been recognized as lethal disease when peritoneal metastases （PM） occurred.There is no standard treatment for advanced GC with PM.Until 1980s,the therapeutic arena for these patients had remained stagnant,with no therapeutic approach having shown a survival gain in GC with PM.However,cytoreductive surgery （CRS） with peritonectomy procedures and intraperitoneal chemotherapy （IPC） promising new combined therapeutic approach to achieve disease control for GC with PM.The recent publications changed the GC with PM treatment landscape by providing an evidence that CRS and IPC led to prolongation in overall survival （OS）.This review will provide an overview of the evolving role of CRS and IPC in the management of advanced GC with PM in the current era.

Microarray gene expression analysis of chemosensitivity for docetaxel,cisplatin and 5-fluorouracil(TPF)combined chemotherapeutic regimen in hypopharyngeal squamous cell carcinoma

Objective: To screen out a set of candidate genes which could help to determine whether patients with hypopharyngeal squamous cell carcinoma (HSCC) could benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy. Methods: Gene-expression profiles in 12 TPF-sensitive patients were compared to 9 resistant controls by microarray analysis. Subsequently, expression levels of potential biomarkers in chemosensitive cell line FaDu after TPF treatment were observed by quantitative real-time polymerase chain reaction (qRT-PCR). Results: Through microarray analysis, 1,579 differentially expressed genes were identified, of which 815 were up-regulated in TPF chemotherapy-responsive tissues whereas 764 were down-regulated. Gene ontology (GO) analysis suggested these genes participating in physiological processes including transcription and its regulation, cellular signal transduction and metabolic process. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed that MAPK and Jat/STAT signaling pathways occupied important roles in TPF chemotherapeutic sensitivity. Moreover, in vitro cell culture experiments revealed the expression alternations of IL-6, MAPK14, JUN, CDK5 and CAMK2A exposed to TPF treatment by qRT-PCR, whilst providing an insight into the mechanism underlying TPF chemotherapeutic response in HSCC. Conclusions: These results provided a battery of genes related to TPF chemotherapeutic sensitivity and might act as molecular targets in HSCC treatment. Moreover, these candidate biomarkers could contribute to HSCC individualized treatment.

Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage Ⅲ non-small cell lung cancer:a preliminary report

Objective： In recent years, the combination of cetuximab and chemoradiotherapy （CRT） has been used to treat stage III non-small cell lung cancer （NSCLC）; however, limited data are available for Chinese patients. Herein, we report preliminary data from a phase I/II study testing the combination of cetuximab with inductive chemotherapy, followed by concurrent CRT （CCRT） in Chinese patients with stage III NSCLC. Methods： Eligibility criteria were Zubrod performance status （PS） 0-1, forced expiratory volume in 1 second （FEV1） 〉_1.2 L and adequate organ function. Enrolled patients received weekly cetuximab （initial dose of 400 mg/m2 on day 1 of week 1 and a maintenance dose of 250 mg/m2 on week 2 to the end of CCRT） with cisplatin/vinorelbine （NP） chemotherapy （every 3 weeks for 2 cycles from week 2, followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy （TRT） （60-66 Gy/2 Gy）. The primary endpoints were toxicity and feasibility. All patients received positron emission tomography- computerized tomography （PET-CT） scans within the 2 weeks prior to enrollment. Univariate analyses were used to assess the correlation between SUV-T, SUV-N, SUV-TOTAL, gender, age, histology, tumor-node- metastasis （TNM） stage, PS and smoking status and survival. Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test. Results： Seventeen patients were enrolled and 16 completed the full regime. The overall response rate （ORR） was 58.8% and 82.3% after the induction and CCRT phases, respectively. With a median follow-up duration of 27.6 months, the median survival was 27.6 months [95% confidence interval （CI）： 11.3-43.9 months] with 1- and 2-year survival rates of 88.2% （95% CI, 60.6-96.9%） and 58.8% （95% CI, 60.6-77.8%）, respectively. Three patients remain progression-free to date, and the median progression-free survival （PFS） was 13.5 months （95% CI, 6.8-20.2 months）. No treatment-related death occurred; however, 76% of the patients experienced grade 3＋ adverse events （AEs）, including nansea/vomiting, intestinal obstruction, and esophagitis （〈6%）, while other AEs were mostly of hematological nature （71%）. The cut-off values for SUV-T and SUV-TOTAL were 11 and 20, respectively. Univariate analyses revealed SUV-TOTAL （P=0.027）, SUV-T （P=0.025）, and PS （P=0.006） as potential survival predictors, with a hazard ratio （HR） of 3.4, 3.7, and 9.9, respectively. Conclusions： The combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising. Local and locoregional maximal SUVs, defined by 18F-FDG PET-CT scanning, may represent a prognostic indicator for long-term survival for these patients, which warrants further study.

Induction gemcitabine and cisplatin in locoregionally advanced nasopharyngeal carcinoma

The standard of care for patients with locoregionally advanced nasopharyngeal carcinoma is concurrent platinum-based chemoradiotherapy.Existing literature have demonstrated that the addition of gemcitabine and cisplatin as induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma may have promising efficacy but were from phase 2 clinical trials.Stronger evidence-based data in forms of phase 3 clinical trial investigating the survival benefits of adding gemcitabine and cisplatin induction chemotherapy for such patients have been urgently warranted.In one of our recent studies published in the New England Journal of Medicine,“Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma”,480 locoregionally advanced nasopharyngeal carcinoma patients from 12 hospitals across China were randomly assigned in a 1:1 ratio to receive either chemoradiotherapy alone or gemcitabine plus cisplatin and chemoradiotherapy.Our findings evinced that,as compared to chemora-diotherapy alone,the addition of induction chemotherapy comprising of gemcitabine plus cisplatin to concurrent cisplatin-radiotherapy to patients with locoregionally advanced nasopharyngeal carcinoma was safe,demonstrated improved recurrence-free survival,overall survival,and distant recurrence-free survival,and marginally superior locore-gional recurrence-free survival.

Neutropenic enterocolitis in pediatric leukemia patients treated with intensive chemotherapy in Upper Egypt

Importance: In low resource countries, there has been scarcity of research on the risk factors associated with neutropenic enterocolitis, a serious complication that commonly develops during treatment of cancer patients.Objective: To identify the pattern of intestinal complications in pediatric leukemia patients treated with intensive chemotherapy, including those with neutropenic enterocolitis;to assess the outcome;and to evaluate the risk factors associated with the mortality in these patients.Methods: During the period from June 2015 to December 2016, a prospective study was carried out on pediatric patients diagnosed with acute leukemia who received induction/or re-induction phases of chemotherapy at South Egypt Cancer Institute. Patients with documented episodes of intestinal complications were included in the study. Recovery or death from an episode of intestinal complication was utilized as the primary outcome measure for the study. Using univariable and multivariable methods, potential risk factors associated with mortality were delineated by logistic regression analysis, both for the entire intestinal complications episodes as a whole and for those episodes of neutropenic enterocolitis only.Results: Out of 88 documented episodes of intestinal complications from 77 patients;58 episodes were identified as neutropenic enterocolitis from 47 patients. In those patients who were having episodes of neutropenic enterocolitis, the presence of abdominal tenderness (OR 4.529, 95%CI 1.062-19.317,P = 0.041);a longer duration of neutropenia (OR 1.215, 95%CI 1.030-1.434,P = 0.021);and hemodynamic instability (OR 17.023, 95%CI 4.095-70.772,P < 0.001), were found to be independently associated with worse outcome.Interpretation: In Upper Egypt, the use of intensive systemic chemotherapy during the induction phase of acute leukemia was found to be associated with potentially lethal intestinal complications. A high index of clinical suspicion is warranted.

Pre-transplantation cytoreduction does not benefit advancedmyelodysplastic syndrome patients after myeloablative transplantation with grafts from family donors

Background:The role of pre-hematopoietic stem cell transplantation(HSCT)cytoreduction with either induction chemotherapy(IC)or hypomethylating agents(HMAs)in treating advanced myelodysplastic syndrome(MDS)remains debatable.We aimed to evaluate pre-HSCT strategies by comparing the endpoints related to disease control between advanced MDS patients with pre-HSCT cytoreduction and those with best supportive care.Methods:We described 228 consecutive advanced MDS patients who received HSCT from a haploidentical donor(HID,n=162)or matched related donor(MSD,n=66)with uniform myeloablative conditioning regimens between January 2015 and December 2018.Of these 228 patients,131(57.5%)were treated exclusively with pre-HSCT best supportive care(BSC),49(22.5%)were given HMA,and 48(21.1%)received both IC and HMA.Propensity score-matching analysis,multivariate analyses,and subgroup analyses were performed to elucidate the impact of pre-HSCT strategies on transplant outcomes.Results:The 3-year relapse-free survival(RFS)rates were 78.2% and 70.0% for the BSC and cytoreduction cohorts(P=0.189)and were 78.2%,66.7%,and 73.2% for the BSC,HMA,and HMA+IC groups,respectively(P=0.269).A propensity score-matching analysis confirmed that the 3-year RFS rates were 81.9%,87.5%,and 66.9% for BSC,cytoreduction complete remission(CR),and cytoreduction non-CRgroups,respectively(P=0.051).Multivariate analyses demonstrated that pre-HSCT cytoreduction,older patient age,monosomal karyotype,and interval between diagnosis and HSCT were poor prognostic factors for RFS.In the subgroup analyses,BSC was associated with longer RFS compared to cytoreduction among the younger patients,those with international prognostic scoring system intermediate-2/high risk at diagnosis,and those with intermediate/poor cytogenetics.Conclusions:Different pre-HSCT therapies did not yield discrepant post-HSCT outcomes.No benefit in terms of post-HSCT outcomes were correlated with pre-HSCT cytoreduction in advanced MDS even for cytoreduction CR patients.Early referral to HSCT is essential for advanced MDS patients.