Prognostic nomogram for patients with unresectable pancreatic cancer treated with gemcitabine plus nab–paclitaxel or FOLFIRINOX: A post–hoc analysis of a multicenter retrospective study in Japan (NAPOLEON study)

Background No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab–paclitaxel (GnP) or FOLFIRINOX. Methods This analysis was conducted using clinical data of Japanese patients with unresectable pancreatic cancer undergoing GnP or FOLFIRINOX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6–, 12–, and 18–month survival probabilities was generated, validated by using the concordance index (C–index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points). Results A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19–9. The C–indexes of the nomogram were 0.77, 0.72 and 0.70 for 6–, 12–, and 18–month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the total nomogram points yielded clear separations of the survival curves. The median survival times in the low–, moderate–, and high–risk groups were 15.8, 12.8 and 7.8 months (P<0.05), respectively. Conclusions Our nomogram might be a convenient and inexpensive tool to accurately predict survival in Japanese patients with unresectable pancreatic cancer undergoing treatment with GnP or FOLFIRINOX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

The Effect of Celiac Neurolysis and Splanchnicectomy on Survival in Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Intractable pancreatic pain is one of the most common symptoms of patients with pancreatic ductal adenocarcinoma (PDAC). Celiac neurolysis (CN) and splanchnicectomy were already described as effective methods to manage abdominal pain in unresectable PDAC, but their impact on overall survival (OS) has not yet been established. <b><i>Objective:</i></b> We aimed to investigate the impact of CN and splanchnicectomy on the survival of patients with unresectable pancreatic cancer. <b><i>Methods:</i></b> A systematic review of PubMed and Cochrane Library according to predefined searching terms was conducted in March 2020. Hazard ratios (HR) of OS data were calculated using the Mantel-Haenszel model for random effects or fixed effects. <b><i>Result:</i></b> Four randomized-controlled trials (RCTs) and 2 non-RCTs with a total of 2,507 patients were identified. The overall pooled HR did not reveal any relevant effect of CN and splanchnicectomy on OS (HR: 1.03; 95% CI: 0.81–1.32), which was also underlined by the sensitivity analysis of RCTs (HR: 1.0; 95% CI: 0.72–1.39) and non-RCTs (HR: 1.07; 95% CI: 0.71–1.63). However, subgroup analyses depending on tumor stage revealed that CN or splanchnicectomy was associated with a worsened OS in AJCC (American Joint Committee on Cancer) stage III patients with unresectable PDAC (HR: 1.22; 95% CI: 1.03–1.45), but nor for AJCC stage IV patients (HR: 1.27; 95% CI: 0.9–1.80). <b><i>Conclusion:</i></b> Although only few data are currently available, this systematic review with meta-analysis showed that in unresectable PDAC, CN or splanchnicectomy is associated with a worsened survival in stage III PDAC patients, with no effect on stage IV PDAC patients. These data call for caution in the usage of CN or splanchnicectomy in stage III PDAC and for further studies addressing this observation.

Novel Therapeutic Method for Unresectable Pancreatic Cancer-The Impact of the Long-Term Research in Therapeutic Effect of High-Intensity Focused Ultrasound (HIFU) Therapy

High-intensity focused ultrasound (HIFU) is a novel advanced therapy for unresectable pancreatic cancer (PC). HIFU therapy with chemotherapy is being promoted as a novel method to control local advancement by tumor ablation. We evaluated the therapeutic effects of HIFU therapy in locally advanced and metastatic PC. PC patients were treated with HIFU as an optional local therapy and systemic chemotherapy. The FEP-BY02 (Yuande Bio-Medical Engineering) HIFU device was used under ultrasound guidance. Of 176 PC patients, 89 cases were Stage III and 87 were Stage IV. The rate of complete tumor ablation was 90.3%, while that of symptom relief was 63.8%. The effectiveness on the primary lesions were as follows: complete response (CR): n = 0, partial response (PR): n = 21, stable disease (SD): n = 105, and progressive disease (PD): n = 47; the primary disease control rate was 71.0%. Eight patients underwent surgery. The median survival time (MST) after diagnosis for HIFU with chemotherapy compared to chemotherapy alone (100 patients in our hospital) was 772.3 vs. 346.6 days (p < 0.001). Compared with chemotherapy alone, the combination of HIFU therapy and chemotherapy demonstrated significant prolongation of prognosis. This study suggests that HIFU therapy has the potential to be a novel combination therapy for unresectable PC.

Circulating Tumor Cell Clusters Are Cloaked with Platelets and Correlate with Poor Prognosis in Unresectable Pancreatic Cancer

Circulating tumor cells (CTCs) are known to be heterogeneous and clustered with tumor-associated cells, such as macrophages, neutrophils, fibroblasts, and platelets. However, their molecular profile and clinical significance remain largely unknown. Thus, we aimed to perform a comprehensive gene expression analysis of single CTCs and CTC clusters in patients with pancreatic cancer and to identify their potential clinical relevance to provide personalized medicine. Epitope-independent, rapid (>3 mL of whole blood/min) isolation of single CTCs and CTC clusters was achieved from a prospective cohort of 16 patients with unresectable pancreatic cancer using a centrifugal microfluidic device. Forty-eight mRNA expressions of individual CTCs and CTC clusters were analyzed to identify pancreatic CTC phenotype. CTC clusters had a larger proportion of mesenchymal expression than single CTCs (p = 0.0004). The presence of CTC clusters positively correlated with poor prognosis (progression-free survival, p = 0.0159; overall survival, p = 0.0186). Furthermore, we found that most CTCs in these patients (90.7%) were cloaked with platelets and found the presence of a positive correlation between the increase in CTC clusters and rapid disease progression during follow-ups. Efficient CTC cluster isolation and analysis techniques will enhance the understanding of complex tumor metastasis processes and can facilitate personalized disease management.

An Investigation of Non-Coplanar Volumetric Modulated Radiation Therapy for Locally Advanced Unresectable Pancreatic Cancer Using a Trajectory Optimization Method

PurposeThis study was conducted in order to develop a trajectory optimization algorithm for non-coplanar volumetric modulated arc therapy (VMAT) and investigate the potential of organs at risk (OARs) sparing in locally advanced pancreatic cancer patients using non-coplanar VMAT.Methods and MaterialsFirstly, a cost map that represents the ray–OAR voxel intersections at each source position was generated using a ray-tracing algorithm. A graph search algorithm was then used to determine the least-cost path from the cost map. Lastly, full arcs or partial arcs were selected based on the least-cost path to generate the non-coplanar VMAT (ncVMAT) trajectories. Clinical coplanar VMAT (coVMAT) plans for 11 patients diagnosed with locally advanced unresectable pancreatic cancer (LAPC) receiving 45 to 70 Gy in 25 fractions were replanned using non-coplanar VMAT trajectories. Both coplanar and non-coplanar plans were normalized to cover 95% of the PTV45 Gy volume with a prescription dose of 45 Gy. The conformity index (CI), homogeneity index (HI), PTV coverage, and dose to the OARs were compared between coVMAT and ncVMAT plans.ResultsWith ncVMAT, the mean coverage of PTV50 Gy, PTV54 Gy, PTV60 Gy, and PTV70 Gy increased significantly. The mean conformity index of PTV45 Gy, PTV54 Gy, and PTV70 Gy was also improved in the ncVMAT plans. Compared with coVMAT plans, the ncVMAT plans resulted in significantly lower doses to the spinal cord, bilateral kidneys, stomach, and duodenum. The maximum dose to the spinal cord decreased by 6.11%. The mean dose to the left and right kidneys decreased by an average of 5.52% and 11.71%, respectively. The Dmax, Dmean, and D15% of the stomach were reduced by an average of 7.45%, 15.82%, and 16.79%, separately. The D15% and Dmean of the duodenum decreased 6.38% and 5.64%, respectively.ConclusionA trajectory optimization algorithm was developed for non-coplanar VMAT. Compared with conventional coplanar VMAT, non-coplanar VMAT resulted in improved coverage and conformity to the targets. The sparing of OARs was significantly improved in non-coplanar VMAT compared with coVMAT plans for locally advanced pancreatic cancer.

Efficacy And Safety Of EUS-Guided Multimode Ablation Compared With Conventional Chemotherapy In Unresectable Pancreatic Cancer Patients

Background & Aims: To compare the feasibility and safety between multimode endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) and conventional chemotherapy in unresectable pancreatic ductal adenocarcinoma (PDAC).Methods: All the pathologically confirmed unresectable PDAC located in the head of the pancreas patients who underwent multimode EUS-RFA or conventional chemotherapy were retrospectively enrolled from June 2018 and April 2019. Patients who underwent multimode EUS-RFA (Group A) was performed through HybridTherm probe(HTP). Patients in Group B accepted nab-Paclitaxel plus Gemcitabine or S-1 plus Gemcitabine. The comparison between efficacy and safety of multimode EUS-RFA and conventional chemotherapy were analyzed by T test and MannWhitney test. A multivariate analysis was performed for each prognostic factor using the Cox proportional hazards model.Results: A total of 10 unresectable PDAC patients were retrospectively enrolled in Group A (mean size 9.46±5.94 cm3, range 2.00-21.09 cm3) and 9 patients in Group B (mean size 14.02±5.81cm3, range 4.60–24.62 cm3). The tumor size was significantly reduced before and after undergoing multimode EUS-RFA (P = 0.005), with an average tumor volume reduction of 38.1%.The tumor size was not significantly changed in Group B (P = 0.452). Statistically significant difference was observed in tumor size between Group A and Group B after treatment (P = 0.033). All patients died because of the progress of the tumor. The median lifetime from Group A&B was 9 months ranged 3-18 months VS 7 months ranged 1-7 months (P = 0.001). Overall no severe adverse events occurred in both groups.Conclusion: EUS-guided multimode ablation has the more feasibility in the treatment of unresectable pancreatic cancer than conventional chemotherapy. In this article, the limited data seems to show the trend of tumor shrinkage, pain relief, lifetime prolongation. Further studies are needed, such as expanding the sample size of patients and comparing the feasibility and safety among all the treatment.