Results of conversion surgery after the triple combination chemotherapy of SOXIRI (S-1/oxaliplatin/irinotecan) in patients with unresectable pancreatic cancer.

366 Background: Recent improvements in chemotherapy for initially unresectable pancreatic ductal adenocarcinoma (UPDAC) occasionally show remarkable antitumor effect and lead to conversion surgery (CS). However, the optimal indication and clinical impact of CS remains unknown. We have recently developed a new regimen consisted of biweekly S-1, oxaliplatin, and irinotecan (SOXIRI). In this regimen, we used S-1 in alternate-day administration instead of 5-FU, that can be more feasible than FOLFIRINOX. The aim of this study was to evaluate the clinical impact of CS after SOXILI treatment for initially UPDAC. Methods: We conducted an open-label, single-arm, phase II study that was carried out at Nara Medical University and Kansai Medical University in Japan. Patients with untreated metastatic and locally advanced PDAC were enrolled. They received 80 mg/m2 twice a day of S-1 for 2 weeks in alternate-day administration, 150 mg/m2 of irinotecan on day 1, and 85 mg/m2 of oxaliplatin on day 1 of a 2-week cycle. Results: The 35 enrolled patients received a median of six (range: 2-15) treatment cycles. The RR was 22.8%; median OS, 17.7 months; and median PFS, 7.4 months. Major grade 3 or 4 toxicity included neutropenia (54%), anemia (17%), febrile neutropenia (11%), anorexia (9%), diarrhea (9%), and nausea (9%). Twenty-three out of 35 patients of UR-PDAC were unresectable locally advanced pancreatic cancer (UR-LAPA). Seven out of 23 patients with UR-LAPA underwent CS. Distal pancreatectomy with celiac axis resection was performed in three patients, central pancreatectomy was performed in one patient. Pancreatoduodenectomy (PD) was performed in two patients, and PD with portal vein resection in one patient. Two out of seven patients had postoperative complications. One case had grade B pancreatic fistula, and the other case underwent cholecystectomy due to acute cholecystitis. The median OS in patients who received CS was 31.4 months. Conclusions: SOXIRI regimen has shown promising clinical efficacy with acceptable tolerability in patients with unresectable pancreatic cancer. Furthermore, it may be a potent first-line treatment when considering conversion surgery. Clinical trial information: UMIN000014339.

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Prognostic impact of chemoradiation-related lymphopenia in patients with locally advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.439 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 439-439

Author(s):

Daniel W Kim ◽

Grace Lee ◽

Colin D. Weekes ◽

David P. Ryan ◽

Aparna Raj Parikh ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cox Model ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Pancreatic Head ◽

Locally Advanced Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Prognostic Impact ◽

Entire Cohort ◽

Grade 3

439 Background: Chemoradiation (CRT) induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. The objective of this study was to evaluate the prognostic impact of lymphopenia in patients with nonmetastatic, unresectable pancreatic ductal adenocarcinoma (PDAC) treated by neoadjuvant FOLFIRINOX (5-fluorouracil [5FU]/leucovorin/irinotecan/oxaliplatin) followed by CRT. We hypothesized that severe lymphopenia would correlate with worse survival. Methods: The inclusion criteria for this single-institution retrospective study were: 1) biopsy-proven diagnosis of unresectable PDAC, 2) absence of distant metastasis, 3) receipt of neoadjuvant FOLFIRINOX followed by CRT, and 4) absolute lymphocyte count (ALC) available prior to and two months after initiating CRT. In general, CRT consisted of 5FU or capecitabine and RT with 58.8 Gy over 28 fractions. Lymphopenia was graded according to CTCAE v5.0. The primary variable of interest was lymphopenia at two months, dichotomized by ALC of < 0.5/μl (Grade 3 lymphopenia). The primary endpoint was overall survival (OS). Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results: A total of 138 patients were identified. Median follow-up for the entire cohort was 16 months. Median age was 65. Fifty-six percent were female, 86% were Caucasian, and 97% had ECOG ≤1. Median tumor size was 3.8 cm. Tumor location was pancreatic head in 63%, body in 22%, tail in 8%, and neck in 7%. Median baseline ALC for the entire cohort was 1.5 k/ul. Two months after initiating CRT, 106 (77%) had severe (Grade 3 or worse) lymphopenia. While there were no significant differences in baseline patient or disease characteristics, patients with severe lymphopenia received higher doses of RT with longer duration of treatment compared to those without severe lymphopenia. On multivariable Cox model, severe lymphopenia at two months was significantly associated with increased hazards of death (HR = 4.00 [95% CI 2.03-7.89], p < 0.001). Greater number of neoadjuvant FOLFIRINOX cycles received prior to CRT was associated with lower hazards of death (HR = 0.84 [95% CI 0.77-0.92], p < 0.001). The 12-month OS was 73% vs. 90% in the cohort with vs. without severe lymphopenia, respectively (log-rank p < 0.001). Conclusions: Treatment-related lymphopenia is common and severe lymphopenia may be a prognostic marker of poorer survival in locally advanced pancreatic cancer. Closer observation in high-risk patients and minimization of RT dose and duration are potential approaches to mitigating CRT-related lymphopenia. Our findings also suggest an important role of the host immunity in pancreatic cancer outcomes, supporting the ongoing efforts of immunotherapy trials in pancreatic cancer.

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Conversion Surgery for Advanced Pancreatic Cancer

Journal of Clinical Medicine ◽

10.3390/jcm8111945 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1945

Author(s):

Thomas Hank ◽

Oliver Strobel

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Palliative Therapy ◽

Advanced Pancreatic Cancer ◽

Treatment Strategies ◽

Ductal Adenocarcinoma ◽

Conversion Surgery ◽

Radiological Criteria ◽

Intention To Treat ◽

Conversion Rates

While primarily unresectable locally advanced pancreatic cancer (LAPC) used to be an indication for palliative therapy, a strategy of neoadjuvant therapy (NAT) and conversion surgery is being increasingly used after more effective chemotherapy regimens have become available for pancreatic ductal adenocarcinoma. While high-level evidence from prospective studies is still sparse, several large retrospective studies have recently reported their experience with NAT and conversion surgery for LAPC. This review aims to provide a current overview about different NAT regimens, conversion rates, survival outcomes and determinants of post-resection outcomes, as well as surgical strategies in the context of conversion surgery after NAT. FOLFIRINOX is the predominant regimen used and associated with the highest reported conversion rates. Conversion rates considerably vary between less than 5% and more than half of the study population with heterogeneous long-term outcomes, owing to a lack of intention-to-treat analyses in most studies and a high heterogeneity in resectability criteria, treatment strategies, and reporting among studies. Since radiological criteria of local resectability are no longer applicable after NAT, patients without progressive disease should undergo surgical exploration. Surgery after NAT has to be aimed at local radicality around the peripancreatic vessels and should be performed in expert centers. Future studies in this rapidly evolving field need to be prospective, analyze intention-to-treat populations, report stringent and objective inclusion criteria and criteria for resection. Innovative regimens for NAT in combination with a radical surgical approach hold high promise for patients with LAPC in the future.

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Interim analysis of a phase II study of dose-modified FOLFIRINOX (mFOLFIRINOX) in locally advanced (LAPC) and metastatic pancreatic cancer (MPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.256 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 256-256 ◽

Cited By ~ 4

Author(s):

Edward Samuel James ◽

Xiaopan Yao ◽

Xiangyu Cong ◽

Stacey Stein ◽

Kristin Kaley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Interim Analysis ◽

Historical Data ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Sensory Neuropathy ◽

Open Label ◽

Grade 3 ◽

Ecog Ps

256 Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, we are conducting a prospective phase II open label study to evaluate the efficacy & tolerability of mFOLFIRINOX in pts with advanced pancreatic cancer (PC). Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX with 25% dose reductions of irinotecan & bolus 5-FU given every two wks until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. FDG-PET scans were obtained at baseline & after 2 cycles. CAT scans were obtained after every 4 cycles. Toxicities & response rate (RR) were compared to historical data reported by Conroy. Results: 53 pts with ECOG PS ≤1 have been enrolled to date between 11/11 and 08/13, Pt characteristics: LAPC 22; MPC 31; median age 62 yrs (range 46-86); male 30. Median # of cycles was 8 (range 1-21). Grade 3/4 toxicities were: anemia, febrile neutropenia (FN) & peripheral sensory neuropathy (PSN) – 3.8% each; ALT increased & thromboembolism – 5.7% each; diarrhea 7.5%; fatigue 11.3%; neutropenia 17%; thrombopenia 11.3% & vomiting 1.9%. Anemia ( p< 0.04), FN (p<0.04), PSN (p<0.04) and vomiting (p<0.02) were significantly decreased compared to historical data (Conroy). Response by RECIST (CR+PR) in 26 evaluable pts with MPC was 29% (0 CR, 9 PR, 14 SD, 3 PD) & similar to historical data (31.6%; p 0.85). 6/13 evaluable pts with LAPC underwent resection (46%).13/36 pts evaluable for PET response had a >50% decrease in SUV(max)(36%). Evaluation for OS & PFS is ongoing. Conclusions: Findings from our interim analysis suggests that mFOLFIRINOX, given along with prophylactic pegfilgrastim is associated with a similar RR and improved tolerability compared to full dose FOLFIRINOX in advanced PC. In pts with LAPC, neoadjuvant FOLFIRINOX appears to have substantial activity with 46% of evaluable pts undergoing resection. Accrual will continue to reach a goal of 70 pts. Clinical trial information: NCT01523457.

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A randomized phase III multi-institutional study of TNFerade biologic with 5-FU and radiotherapy for locally advanced pancreatic cancer: Final results

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4055 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4055-4055

Author(s):

Aaron Tyler Wild ◽

Dan Laheru ◽

Hao Wang ◽

Kenneth J. Chang ◽

Gretchen Elizabeth Taylor ◽

...

Keyword(s):

Early Stage ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Systemic Exposure ◽

Adenovirus Vector ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Open Label ◽

Tnf Α ◽

Grade 3

4055 Background: TNFerade biologic (TNF) is a novel means of selective delivery of TNF-α to tumor cells by gene transfer through intratumoral (IT) injection. TNF is a replication deficient adenovirus vector containing TNF-α cDNA ligated downstream from a radiation-inducible Egr-1 promoter, allowing spatiotemporal constraint of TNF-α production to the radiation field. Herein we report the final results of a multi-center, randomized, open-label, controlled phase III trial of TNF with chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with locally advanced PDA were randomized 1:2 to standard of care (SOC; 5-FU/RT followed by GEM) versus TNF + SOC. RT dose was 50.4 Gy in 28 fractions. Concurrent 5-FU (200 mg/m2/day IV) started on day 1 of RT each wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was given until progression or toxicity. Results: Of 277 pts, 187 were randomized to TNF and 90 to SOC. Demographic/baseline characteristics were similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs. 7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95% CI, 7.6-11.2) for SOC (p=0.6). TNF delivery method did not affect OS (9.4 mos for PTA vs. 11.5 for EUS; p=0.7). Baseline CA19-9 > 1000 was found to impart independent risk to TNF pts (HR=1.7; p=0.02). Subgroup analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF compared to SOC (10.9 vs. 9.0 mos, respectively; p=0.04). TNF resulted in more grade 1-2 fever/chills (p<0.001) as well as grade 3 (p<0.001) and 4 (p=0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity rates. Conclusions: TNF + SOC did not prolong OS for locally advanced PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and CA19-9 < 1000. PTA and EUS injection achieved similar rates of efficacy and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-α (pyrexia/hypotension/chills) was common, but grade 3-4 was minimal.

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Combination of gemcitabine, nab-paclitaxel, and S-1(GAS) as the first-line treatment for patients with locally advanced or advanced pancreatic ductal adenocarcinoma: study protocol for an open-label, single-arm phase I study

BMC Cancer ◽

10.1186/s12885-021-08275-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chen Chang ◽

Xiaofen Li ◽

Dan Cao

Keyword(s):

Pancreatic Cancer ◽

Phase I ◽

Pancreatic Ductal Adenocarcinoma ◽

Objective Response ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Chinese Patients ◽

Ductal Adenocarcinoma ◽

Open Label ◽

Systemic Treatments

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is still a highly fatal malignancy among the most common cancers. More powerful treatments are expecting to bring hope for patients. Biweekly gemcitabine/nab-paclitaxel/S-1 (GAS) was proved safe and effective for patients with locally advanced pancreatic cancer in Japan. The objective of this study is to evaluate the feasibility and toxicity of GAS (repeated every 3 weeks) in the treatment of locally advanced or advanced pancreatic cancer and determine the recommended dose of S-1 in this combination. Methods This is an open-label, single-arm, and single-center phase I trial. Patients who have been diagnosed with locally advanced or advanced PDAC pathologically without previous systemic treatments will be enrolled and be treated with GAS chemotherapy every 3 weeks (nab-paclitaxel 125 mg/m 2, ivgtt, day1, 8; gemcitabine 1000 mg/m2, day1, 8; different doses of S-1 within a dose escalation scheme) until the presence of disease progression (PD), intolerable adverse events (AEs), or requirement of patients and researchers. The primary endpoints are maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints include safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Discussion This trial will adjust the administration of GAS to make it more effective for Chinese patients, while exploring the toxicity and feasibility of this adjustment. Trial registration ChiCTR, (ChiCTR1900027833). Registered 30 November 2019.

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Phase I study of oral fluoropyrimidine anticancer agent (S-1) with concurrent external-beam radiotherapy for unresectable pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4109 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4109-4109

Author(s):

H. Shinchi ◽

S. Takao ◽

K. Maemura ◽

H. Noma ◽

T. Aikou

Keyword(s):

Pancreatic Cancer ◽

Anticancer Agent ◽

External Beam Radiotherapy ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

External Beam ◽

Unresectable Pancreatic Cancer ◽

Level 1 ◽

Grade 3 ◽

Level 2

4109 Background: S-1 is an oral fluorouracil anticancer agent that was recently reported to demonstrate a response rate of 21% in 19 patients with advanced pancreatic cancer. Concurrent external-beam radiotherapy (EBRT) and 5-FU has been generally accepted as the standard treatment for locally advanced pancreatic cancer. However, there are no published data regarding the efficacy of combination therapy of S-1 and radiation in patients with pancreatic cancer. Our purpose of this study was to evaluate the safety of S-1 combined with EBRT and determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1 in patients with locally advanced and unresectable pancreatic cancer. Methods: Eligible patients had UICC stage III or IV pancreatic cancer (either advanced unresectable or metastatic), adequate organ function, and no anticancer therapy in the preceding 4 weeks. S-1 was given orally at a dose of 60 mg/m2/day or 80 mg/m2/day in two divided doses after breakfast and supper. External-beam radiotherapy was delivered using a conformal technique in fraction of 1.25 Gy X 2/day, 5 days per week, totaling 50 Gy/40 fraction for 4weeks. S-1 at a dose of 60 mg/m2/day was given on days 1–7 and 15–21 in level 1, on days 1–14 in level 2, on days 1–21 in level 3a, respectively. S-1 at a dose of 80 mg/m2/day was given on days 1–21 in level 3b and on days 1–28 in level 4. DLT was defined as NCI-CTC grade 3/4 toxicity. Results: 18 patients were entered in this phase I trial: level 1 (4 patients), level 2 (5 patients), level 3a (3 patients), level 3b (3 patients), level 4 (3 patients). There were 1 of 5 patients with DLT in level 2: grade 3 vomiting. There were no DLT in levels 1, 3a, and 3b, respectively. Two of 3 patients in level 4 showed DLT: one patient developed grade 3 neutropenia and another patient developed grade 3 diarrhea. Clinical effects by CT scan included one PR, 15 SD and 2 PD. Reduced CA19–9 level less than a half of that at starting time was observed in 6 of 18 patients. Conclusions: S-1 at a dose of 80 mg/m2/day given on days 1–21 is safe and may be recommended for phase II study in patients with locally advanced and unresectable pancreatic cancer. This regimen appears to be a promising and well-tolerated approach with consideration of application to outpatients. No significant financial relationships to disclose.

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A Critical Overview of Systematic Reviews of Chemotherapy for Advanced and Locally Advanced Pancreatic Cancer using both AMSTAR2 and ROBIS as Quality Assessment Tools

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200902111510 ◽

2020 ◽

Vol 15 ◽

Author(s):

Amit Dang ◽

Surendar Chidirala ◽

Prashanth Veeranki ◽

BN Vallish

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Systematic Reviews ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Risk Of Bias ◽

Low Risk ◽

Locally Advanced Pancreatic Cancer ◽

Grade 3 ◽

Critical Overview

Background: We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. Materials and Methods: PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with metaanalysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. Results: Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities, when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had high risk of bias, with only 1/26 SR having low risk of bias. As per AMSTAR2, 25/26 SRs had critically low, and 1/26 SR had low, confidence in the results. The study which scored ‘low’ risk of bias in ROBIS scored ‘low confidence in results’ in AMSTAR2. The inter-rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa=0.649, SEM=0.323, p<0.001. Conclusion: Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.

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Gemcitabine Plus Nab-Paclitaxel as Second-Line Chemotherapy following FOLFIRINOX in Patients with Unresectable Pancreatic Cancer: A Single-Institution, Retrospective Analysis

Chemotherapy ◽

10.1159/000517244 ◽

2021 ◽

pp. 1-7

Author(s):

Kotone Hayuka ◽

Hiroyuki Okuyama ◽

Akitsu Murakami ◽

Yoshihiro Okita ◽

Takamasa Nishiuchi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Adverse Events ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Unresectable Pancreatic Cancer ◽

Line Treatment ◽

Second Line ◽

Free Survival ◽

Common Grade ◽

Grade 3

Introduction: Patients with advanced pancreatic cancer have a poor prognosis. FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) have been established as first-line treatment, but they have not been confirmed as second-line treatment after FFX. The aim of this study was to evaluate the safety and efficacy of GnP as second-line therapy after FFX in patients with unresectable pancreatic cancer. Methods: Twenty-five patients with unresectable pancreatic cancer were enrolled. The patients were treated with GnP after FFX between September 2015 and September 2019. Tumor response, progression-free survival (PFS), overall survival (OS), and incidence of adverse events were evaluated. Results: The response rate, disease control rate, median PFS, and median OS were 12%, 96%, 5.3 months, and 15.6 months, respectively. The common grade 3 or 4 adverse events were neutropenia (76%) and anemia (16%). Conclusions: GnP after FOLFIRINOX is expected to be one of the second-line recommendations for patients with unresectable pancreatic cancer.

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Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

10.2310/7800.16076 ◽

2017 ◽

Author(s):

Gregory C Wilson ◽

Brent T Xia ◽

Syed A Ahmed

Keyword(s):

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Pancreatic Adenocarcinoma ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Advanced Pancreatic Cancer ◽

Treatment Strategies ◽

Ductal Adenocarcinoma ◽

Borderline Resectable

Despite decades of advancement and research into the multimodal care of pancreatic cancer, mortality after the diagnosis of pancreatic ductal adenocarcinoma remains grim. The role of adjuvant therapy following surgical resection has been well established in the literature. However, adjuvant therapy is imperfect, and outside of a clinical trial, there are high rates of omission or delayed initiation of therapy. Neoadjuvant treatment strategies continue to be explored in the management of resectable, borderline-resectable, and locally advanced unresectable pancreatic adenocarcinoma. With improved resection rates and the possibility for tumor downstaging, neoadjuvant therapy has become standard for patients with borderline-resectable and locally advanced unresectable tumors. Additional benefits of neoadjuvant therapy in the treatment of resectable tumors include improved completion rates of systemic therapy and R0 resection rates. Future clinical trials, including the use of novel treatment agents and combination treatment strategies in both neoadjuvant and adjuvant regimens, will add value to the treatment of pancreatic adenocarcinoma. Key words: adjuvant therapy, borderline-resectable pancreatic cancer, locally advanced pancreatic cancer, neoadjuvant therapy, pancreatic adenocarcinoma, resectable disease

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Anlotinib Plus Toripalimab and Nab-Paclitaxel in Patients with Locally Advanced or Metastatic Pancreatic Cancer: Study Protocol for An Open-Label, Non-Randomized, Phase II Study (ATNPA)

10.21203/rs.3.rs-1076724/v1 ◽

2021 ◽

Author(s):

Jingwen Chen ◽

Yiqian Liu ◽

Yizhi Zhu ◽

Shiyun Cui ◽

Chongqi Sun ◽

...

Keyword(s):

Pancreatic Cancer ◽

Maintenance Therapy ◽

Kinase Inhibitor ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Metastatic Pancreatic Cancer ◽

Second Line ◽

First Line ◽

Open Label ◽

Combination Strategy

Abstract Background There have not been standard second-line or maintenance regimens with definite survival benefits so far for patients with pancreatic carcinoma who have lost the opportunity of curable resections or failed first-line chemotherapy. Anlotinib, a potent small-molecule tyrosine kinase inhibitor, exhibits anti-angiogenic and anti-tumour effects by specifically binding to multiple targets such as VEGFR, FGFR, PDGFR, c-Kit and Ret. Toripalimab, a novel anti-PD-1 mAb, has been proved to significantly prolong progression-free survival (PFS) and overall survival (OS) in various solid tumours with manageable toxicities when combining with cytotoxic chemotherapy. We design this study to assess the combination of anlotinib, toripalimab and nab-paclitaxel as a second-line or maintenance therapy for locally advanced pancreatic cancer (LAPC) or metastatic pancreatic cancer (MPC). Patients and Methods: This is an open-label, non-randomized, single-arm phase Ⅱ study, aimed at evaluating the efficacy and safety profile of the above-mentioned combination strategy in first-line therapy-failed LAPC or MPC. Totally 53 patients are to be enrolled and receive anlotinib (12 mg, po. qd.) plus toripalimab (240 mg, ivgtt. q3w.) and nab-paclitaxel (125 mg/m2, ivgtt, d1, d8) every 3 weeks as a cycle until disease progression or intolerable adverse events. The primary endpoint is PFS. Secondary end points include OS, disease control rate (DCR), object response rate (ORR), quality of life (QoL) and safety. Enrollment started in April 2021, and follow-up will be finished in April 2023. Discussion and Significance: Combination of anlotinib, toripalimab and nab-paclitaxel may promote vessel normalization and drug delivery, and activate the immune response, thus exerting synergistic anti-tumour effects and counteracting the immunosuppressive microenvironment of pancreatic cancer. As the first intending to assess this combination in pancreatic cancer, this study will provide comprehensive evidence for second-line or maintenance therapy of LAPC and MPC. Trial registration: ClinicalTrials.gov: ATNPA, NCT04718701. Registered January 22, 2021. (https://clinicaltrials.gov/ct2/show/NCT04718701?term=NCT04718701&draw=2&rank=1)

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