Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma,a malignancy that arises in the cells of the pancreas,is a devastating disease with unclear etiology and often poor prognosis.Locally advanced pancreatic cancer,a stage where the tumor has grown significantly but has not yet spread to distant organs,presents unique challenges in treatment.This article aims to discuss the current strategies,challenges,and future directions in the management of locally advanced pancreatic adenocarcinoma(LAPC).AIM To investigate the feasibility and efficacy of programmed cell death 1(PD-1)inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC.METHODS Eligible patients had LAPC,an Eastern cooperative oncology group performance status of 0 or 1,adequate organ and marrow functions,and no prior anticancer therapy.In the observation group,participants received intravenous sintilimab 200 mg once every 3 wk,and received concurrent chemoradiotherapy(concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-140 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression,death,or unacceptable toxicity).In the control group,participants only received concurrent chemoradiotherapy.From April 2020 to November 2021,64 participants were finally enrolled with 34 in the observation group and 30 in the control group.RESULTS Thirty-four patients completed the scheduled course of chemoradiotherapy,while 32(94.1%)received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group.Thirty patients completed the scheduled course of chemoradiotherapy in the control group.Based on the Response Evaluation Criteria in Solid Tumors guidelines,the analysis of the observation group revealed that a partial response was observed in 11 patients(32.4%),stable disease was evident in 19 patients(55.9%),and 4 patients(11.8%)experienced progressive disease;a partial response was observed in 6(20.0%)patients,stable disease in 18(60%),and progressive disease in 6(20%)in the control group.The major toxic effects were leukopenia and nausea.The incidence of severe adverse events(AEs)(grade 3 or 4)was 26.5%(9/34)in the observation group and 23.3%(7/30)in the control group.There were no treatment-related deaths.The observation group demonstrated a significantly longer median overall survival(22.1 mo compared to 15.8 mo)(P<0.05)and progression-free survival(12.2 mo vs 10.1 mo)(P<0.05)in comparison to the control group.The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group(P>0.05).CONCLUSION Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients,and warrants further investigation.

Developments and challenges in neoadjuvant therapy for locally advanced pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed countries.Despite advances in cancer treatment,the 5-year survival rate for patients with PDAC remains less than 5%.In recent years,neoadjuvant therapy(NAT)has emerged as a promising treatment option for many cancer types,including locally advanced PDAC,with the potential to improve patient outcomes.To analyze the role of NAT in the setting of locally advanced PDAC over the past decade,a systematic literature search was conducted using PubMed and Web of Science.The results suggest that NAT may reduce the local mass size,promote tumor downstaging,and increase the likelihood of resection.These findings are supported by the latest evidence-based medical literature and the clinical experience of our center.Despite the potential benefits of NAT,there are still challenges that need to be addressed.One such challenge is the lack of consensus on the optimal timing and duration of NAT.Improved criteria for patient selection are needed to further identify PDAC patients likely to respond to NAT.In conclusion,NAT has emerged as a promising treatment option for locally advanced PDAC.However,further research is needed to optimize its use and to better understand the role of NAT in the management of this challenging disease.With continued advances in cancer treatment,there is hope of improving the outcomes of patients with PDAC in the future.

Role of neoadjuvant therapy for nonmetastatic pancreatic cancer:Current evidence and future perspectives

Pancreatic adenocarcinoma(PDAC)is one of the most common and lethal human cancers worldwide.Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC,although only approximately 20%of the patients have resectable tumors when diagnosed.Neoadjuvant chemotherapy(NACT)is recommended for borderline resectable pancreatic cancer.Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology,as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC.In such challenging cases,new potential tools,such as ct-DNA and molecular targeted therapy,are emerging as novel therapeutic options that may improve old paradigms.This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.

Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer:A multicenter retrospective observational comparative study

BACKGROUND Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy(CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electrohyperthermia(mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer.AIM To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer.METHODS This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer(stage Ⅲ and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128(59%) of them were treated with CHT(no-mEHT) and 89(41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT.RESULTS Median patients’ age was 67 years(range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group(20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses(45% vs 24%, P = 0.0018) and a lower number of progressions(4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions.CONCLUSION mEHT seems safe and has beneficial effects on survival and tumor response of stage Ⅲ-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Implantation of Radioactive ^(125)I Seeds Improves the Prognosis of Locally Advanced Pancreatic Cancer Patients:A Retrospective Study

Locally advanced pancreatic cancer is associated with a very poor prognosis. This study was performed to evaluate whether patients with locally advanced pancreatic cancer benefit from 125 ^I seed implantation. This retrospective study included 224 patients with locally advanced pancreatic cancer, with 137 patients（61.2%） in the implantation（IP） group and 87（38.9%） in the non-implantation（NIP） group. The survival status, complications and objective curative effects were compared between the groups. The average operative time in the IP group was significantly longer than that in the NIP group（243±51 vs. 214±77 min）. The tumor response rates were 9.5% and 0 at the 2nd month after surgery in the IP and NIP groups, respectively（P〈0.05）. The IP group exhibited a trend toward pain relief at the 6th month after surgery. The global health status scores of the IP group were higher than those of the NIP group at the 3rd and 6th month after surgery. The median survival time in the IP group was significantly longer than that in the NIP group. In conclusion, patients with locally advanced pancreatic cancer can benefit from 125 I seed implantation in terms of local tumor control, survival time, pain relief and quality of life.

Gemcitabine plus concurrent irreversible electroporation vs gemcitabine alone for locally advanced pancreatic cancer

BACKGROUND Locally advanced pancreatic cancer(LAPC)is a common malignant digestive system tumor that ranks as the fourth leading cause of cancer-related death in the world.The prognosis of LAPC is poor even after standard treatment.Irreversible electroporation(IRE)is a novel ablative strategy for LAPC.Several studies have confirmed the safety of IRE.To date,no prospective studies have been performed to investigate the therapeutic efficacy of conventional gemcitabine(GEM)plus concurrent IRE.AIM To compare the therapeutic efficacy between conventional GEM plus concurrent IRE and GEM alone for LAPC.METHODS From February 2016 to September 2017,a total of 68 LAPC patients were treated with GEM plus concurrent IRE(n=33)or GEM alone(n=35).Overall survival(OS),progression free survival(PFS),and procedure-related complications were compared between the two groups.Multivariate analyses were performed to identify any prognostic factors.RESULTS There were no treatment-related deaths.The technical success rate of IRE ablation was 100%.The GEM+IRE group had a significantly longer OS from the time of diagnosis of LAPC(19.8 mo vs 9.3 mo,P<0.0001)than the GEM alone group.The GEM+IRE group had a significantly longer PFS(8.3 mo vs 4.7 mo,P<0.0001)than the GEM alone group.Tumor volume less than 37 cm3 and GEM plus concurrent IRE were identified as significant favorable factors for both the OS and PFS.CONCLUSION Gemcitabine plus concurrent IRE is an effective treatment for patients with LAPC.

Arterial complication of irreversible electroporation procedure for locally advanced pancreatic cancer

Irreversible electroporation(IRE) is a non-thermal ablation technique used especially in locally advanced pancreatic carcinomas that are considered surgically unresectable.We present the first case of acute superior mesenteric artery(SMA) occlusion secondary to pancreatic IRE procedure that has not been reported before in the literature.A 66-year-old man underwent neoadjuvant chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma.IRE procedure was applied to the patient during laparotomy under general anesthesia.After finishing the procedure,an acute intestinal ischemia was detected.A conventional vascular angiography was performed and a metallic stent was successfully placed to the SMA and blood flow was maintained.It is important to be careful in such cases of tumor involvement of SMA when evaluating for IRE procedure of pancreatic tumor.

Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities

Pancreatic carcinoma(PC)is one of the leading causes of cancer-related deaths worldwide.Despite early detection and advances in therapeutics,the prognosis remains dismal.The outcome and therapeutic approach are dependent on the stage of PC at the time of diagnosis.The standard of care is surgery,followed by adjuvant chemotherapy.The advent of newer drugs has changed the landscape of adjuvant therapy.Moreover,recent trials have highlighted the role of neoadjuvant therapy and chemoradiotherapy for resectable and borderline resectable PC.As we progress towards a better understanding of tumor biology,genetics,and microenvironment,novel therapeutic strategies and targeted agents are now on the horizon.We have described the current and emerging therapeutic strategies in PC.

Postoperative inflammation as a possible cause of portal vein thrombosis after irreversible electroporation for locally advanced pancreatic cancer

Portal vein thrombosis(PVT) is a rare but serious postoperative complication associated with irreversible electroporation(IRE). We report a case of postoperative PVT in a 54-year-old woman who underwent IRE for locally advanced pancreatic cancer. Drain removal and discharge of the patient from the hospital were scheduled on postoperative day(POD) 7; however, a magnetic resonance imaging scan revealed the presence of PVT. We suspected postoperative inflammation in the pancreas as the main cause of PVT. However, the patient did not undergo any medical treatment because she did not have any clinical symptoms, and she was discharged on POD 8.

Computed tomography-based radiomic to predict resectability in locally advanced pancreatic cancer treated with chemotherapy and radiotherapy

BACKGROUND Surgical resection after neoadjuvant treatment is the main driver for improved survival in locally advanced pancreatic cancer(LAPC).However,the diagnostic performance of computed tomography(CT)imaging to evaluate the residual tumour burden at restaging after neoadjuvant therapy is low due to the difficulty in distinguishing neoplastic tissue from fibrous scar or inflammation.In this context,radiomics has gained popularity over conventional imaging as a complementary clinical tool capable of providing additional,unprecedented information regarding the intratumor heterogeneity and the residual neoplastic tissue,potentially serving in the therapeutic decision-making process.AIM To assess the capability of radiomic features to predict surgical resection in LAPC treated with neoadjuvant chemotherapy and radiotherapy.METHODS Patients with LAPC treated with intensive chemotherapy followed by ablative radiation therapy were retrospectively reviewed.One thousand six hundred and fifty-five radiomic features were extracted from planning CT inside the gross tumour volume.Both extracted features and clinical data contribute to create and validate the predictive model of resectability status.Patients were repeatedly divided into training and validation sets.The discriminating performance of each model,obtained applying a LASSO regression analysis,was assessed with the area under the receiver operating characteristic curve(AUC).The validated model was applied to the entire dataset to obtain the most significant features.RESULTS Seventy-one patients were included in the analysis.Median age was 65 years and 57.8%of patients were male.All patients underwent induction chemotherapy followed by ablative radiotherapy,and 19(26.8%)ultimately received surgical resection.After the first step of variable selections,a predictive model of resectability was developed with a median AUC for training and validation sets of 0.862(95%CI:0.792-0.921)and 0.853(95%CI:0.706-0.960),respectively.The validated model was applied to the entire dataset and 4 features were selected to build the model with predictive performance as measured using AUC of 0.944(95%CI:0.892-0.996).CONCLUSION The present radiomic model could help predict resectability in LAPC after neoadjuvant chemotherapy and radiotherapy,potentially integrating clinical and morphological parameters in predicting surgical resection.

Nine-year survival of a 60-year-old woman with locally advanced pancreatic cancer under repeated open approach radiofrequency ablation:A case report

BACKGROUND Radiofrequency ablation(RFA)is gaining popularity as an additional therapy for pancreatic ductal adenocarcinoma.RFA appears to be an attractive treatment option for patients with unresectable,locally advanced and nonmetastatic pancreatic cancer.CASE SUMMARY A 60-year-old woman with 2 mo intermittent upper abdominal pains was admitted to hospital.She had undergone radical gastrectomy(Billroth II)for gastric antral cancer.Contrast-enhanced computed tomography(CECT)and abdominal ultrasound displayed a primary tumor in the neck of the pancreas.Pathological examination showed that the lesion was a pancreatic ductal adenocarcinoma.According to the results of the imaging,open approach RFA was selected to treat the primary tumor.Eight months later,CECT follow-up revealed local recurrence of the tumor,and another open RFA was performed.Although there is evidence that RFA for recurrence of other cancers such as hepatocellular carcinoma may prolong patient survival,it remains unclear whether repeat RFA for local recurrence of pancreatic cancer is feasible.The patient continued to enjoy 9 years of life following the first RFA.CONCLUSION RFA of locally advanced,nonresectable,nonmetastatic,pancreatic tumor is characterized by feasibility-based treatment giving rise to tumor reduction based on improvement of quality of life.

Modulated electro-hyperthermia in stage III and IV pancreatic cancer:Results of an observational study on 158 patients

BACKGROUND An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy(CHT)and radiotherapy for the treatment of pancreatic cancer;in particular,the use of modulated electrohyperthermia(mEHT)results in increased survival and tumor response.AIM To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer.METHODS This was an observational retrospective study;data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019.A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals;58(37%)of these received CHT+mEHT and 100(63%)CHT.CHT was mainly gemcitabine-based regimens in both groups.RESULTS Overall(19.5 mo vs 11.02 mo,P<0.001)and progression-free(12 mo vs 3 mo,P<0.001)survival were better for the CHT+mEHT group compared to the CHT group.The association of mEHT resulted also in an improvement of tumor response with disease control rate 95%vs 58%(P<0.001)at 3 mo.Toxicity was comparable in the two study groups,and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns.CONCLUSION The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity.

A Single-institution Experience with Open Irreversible Electroporation for Locally Advanced Pancreatic Carcinoma

Background： Locally advanced pancreatic carcinoma （LAPC） is characterized by poor prognosis despite recommended concurrent chemoradiotherapy. Irreversible electroporation （IRE） has emerged as a potential option for the management of unresectable pancreatic cancer. This study was conducted to evaluate the safety and short-term efficacy of open IRE for the treatment of LAPC. Methods： Retrospective data of 25 consecutive patients receiving IRE for T3 lesions from July 2015 to June 2016 at a single center were analyzed. The perioperative and long-term IRE-related complications were reviewed to evaluate the safety of the procedure. The tumor reduction and biological response were analyzed through computed tomography/magnetic resonance imaging; the serum level of CA19-9 was measured as a secondary endpoint to evaluate the short-term efficacy of IRE. Results： All patients were successfully treated; the median tumor size was 4.2 cm and the median IRE time was 36 min. Four intraoperative procedure-related complications were observed （16%）： two transient hypertensive episodes, one hypotension case, and one transient supraventricular tachycardia case. Nine postoperative complications were described, including three Grade A pancreatic fistulas, three delayed gastric emptying, one acute pancreatitis, one upper gastrointestinal hemorrhage, and one portal vein thrombosis. The overall rate of stable disease was 28%, 36% achieved partial response, and lower serum CA19-9 levels were recorded in all patients at discharge. Conclusions： IRE is feasible for the treatment of LAPC and is a reasonable intervention strategy owing to its combined attributes of safety and efficacy.