Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

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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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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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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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Sequential neoadjuvant chemotherpy with nab-paclitaxel plus gemcitabine and FOLFIRINOX in locally advanced pancreatic cancer (LAPC): A PILOT study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15193 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15193-e15193 ◽

Cited By ~ 2

Author(s):

Volker Kunzmann ◽

Ingo Hartlapp ◽

Michael Scheurlen ◽

Hermann Einsele ◽

Justus Mueller ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pilot Study ◽

Neoadjuvant Chemotherapy ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Sensory Neuropathy ◽

Disease Stage ◽

Ductal Adenocarcinoma ◽

Hematological Toxicity ◽

Highly Active

e15193 Background: Nab-Paclitaxel (nab-P) + Gemcitabin (G) and FOLFIRINOX have both shown promising activity in metastatic pancreatic cancer (mPC). Our group has developed sequential usage of both regimens in order to exploit the stromal depletion effects of nab-P and increase global efficacy of chemotherapy in the neoadjuvant setting of LAPC. Methods: This pilot study evaluated patients with cytological/histological confirmed diagnosis of locally advanced pancreatic ductal adenocarcinoma without evidence of metastatic disease (stage III). nab-P+G was administered for 2 cycles (nab-P 125 mg/m2, G 1000 mg/ 2; on days 1, 8, 15; every 28 days) followed by 2 cycles of FOLFIRINOX (as reported by Conroy et al., NEJM 2011). Results: We report the preliminary analysis of 8 pts treated in our institution. Patients characteristics were M/F: 5/3; median age 63 (46-79); PS 0/1: 6/2. 3 pts (37%) had a biliary stent before starting treatment. All pts received the planned 4 cycles of neoadjuvant chemotherapy without dose reductions. There were no treatment-related deaths and none of pts stopped treatment due to toxicity. Grade 3-4 toxicities were neutropenia (50 %), nausea (12%), diarrhea (12%) and thrombopenia (25%). Grade 2-3 sensory neuropathy occured in 25% of pts. Prior nab-P+G did not result in increased hematological or non-hematological toxicity of FOLFIRINOX. Among the 8 patients evaluable so far, 5 partial responses (63%) and 3 stable disease (37%) have been observed, resulting in a disease control rate of 100%. After sequential chemotherapy 3 pts (37%) underwent radical surgical resection. Of note, all resected patients pts showed regression of the tumor (Evans Regression Score 2-4) with 1 patient fullfilling the criteria of a complete pathological remission (pCR). 4 pts received concomitant chemo-radiotherapy and 1 pt underwent an explorative laparotomy with evidence of occult (micronodular) peritoneal metastasis. Conclusions: Sequential neoadjuvant chemotherapy with nab-P+G and FOLFIRINOX seems to be highly active with manageable toxicity profile and may allow to achieve pCR in LAPC. These results are encouraging to test this approach in a prospective phase II trial.

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.366 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 366-366

Author(s):

Naoya Ikeda ◽

Takahiro Akahori ◽

Sohei Satoi ◽

Hiroaki Yanagimoto ◽

Minako Nagai ◽

...

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Clinical Impact ◽

Ductal Adenocarcinoma ◽

Unresectable Pancreatic Cancer ◽

Conversion Surgery ◽

Open Label ◽

Grade 3 ◽

Medical University

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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Local Ablative Strategies for Ductal Pancreatic Cancer (Radiofrequency Ablation, Irreversible Electroporation): A Review

Gastroenterology Research and Practice ◽

10.1155/2016/4508376 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 28

Author(s):

Salvatore Paiella ◽

Roberto Salvia ◽

Marco Ramera ◽

Roberto Girelli ◽

Isabella Frigerio ◽

...

Keyword(s):

Pancreatic Cancer ◽

Radiofrequency Ablation ◽

Therapeutic Option ◽

Treatment Options ◽

Locally Advanced ◽

Irreversible Electroporation ◽

Advanced Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Dismal Prognosis ◽

Ablative Techniques

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Locally advanced pancreatic cancer (LAPC) accounts for the 40% of the new diagnoses. Current treatment options are based on chemo- and radiotherapy regimens. Local ablative techniques seem to be the future therapeutic option for stage-III patients with PDAC. Radiofrequency Ablation (RFA) and Irreversible Electroporation (IRE) are actually the most emerging local ablative techniques used on LAPC. Initial clinical studies on the use of these techniques have already demonstrated encouraging results in terms of safety and feasibility. Unfortunately, few studies on their efficacy are currently available. Even though some reports on the overall survival are encouraging, randomized studies are still required to corroborate these findings. This study provides an up-to-date overview and a thematic summary of the current available evidence on the application of RFA and IRE on PDAC, together with a comparison of the two procedures.

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Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

10.2310/cgso.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

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Outcomes with FOLFIRINOX for locally advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.256 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 256-256

Author(s):

Brian A. Boone ◽

Jennifer Steve ◽

Alyssa M. Krasinskas ◽

Amer H. Zureikat ◽

Barry C. Lembersky ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Advanced Pancreatic Cancer ◽

Response Rates ◽

Biologically Active ◽

Ductal Adenocarcinoma ◽

R0 Resection ◽

Borderline Resectable

256 Background: Trials examining the use of FOLFIRINOX in metastatic pancreatic ductal adenocarcinoma demonstrate significantly higher response rates compared to gemcitabine-based regimens. These high response rates may be particularly important for patients with locally advanced pancreatic ductal adenocarcinoma (LAPD), in which there is currently limited experience with FOLFIRINOX. We examined the outcomes of patients with LAPD treated with neoadjuvant FOLFIRINOX at our high volume clinic. Methods: Retrospective review of a prospectively maintained pancreatic cancer database was used to identify patients who were recommended neoadjuvant treatment with FOLFIRINOX. Clinical outcomes were reviewed. Resectability was determined using SSO criteria. Results: Between 2/2011 and 9/2012 FOLFIRINOX was recommended for 25 patients with LAPD, 13 (52%) unresectable (UR) and 12 (48%) borderline resectable (BR). Median age was 59. 4 patients (16%) either refused treatment or were lost to follow up. 21 patients (84%) were treated with a median of 4.7 cycles (Range: 2-8). 5 patients (24%) required dose reductions secondary to toxicity. 2 patients (9%) were unable to tolerate treatment and 3 patients (14%) had disease progression on treatment. Of the remaining 16 patients, 13 patients (62%) displayed a radiologic response allowing for surgical exploration, 4 (31%) of which were initially unresectable. 6 of these patients (29%) received additional chemotherapy and/or radiation therapy prior to surgery. Peritoneal metastases were discovered at surgery in 2 (8%) patients. Of the patients who were BR, 7/8 (88%) had a R0 resection. Of the 10 UR patients, 3 (33%) underwent surgical resection, with 2 (20%) R0 resections. Overall R0 resection rate was 43%. A total of 4 patients (19%) demonstrated a major pathologic response (2 complete responses and 2 near complete responses) and 8 other patients (73%) had some pathological response. Conclusions: FOLFIRINOX alone or as part of multimodality approach is a biologically active regimen in LAPD with encouraging R0 resection rates, especially in BR LAPD. Further research is needed to determine the utility of additional chemoradiotherapy with FOLFIRINOX and to identify predictors of response in UR patients.

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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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Locally Advanced Pancreatic Cancer: Percutaneous Management Using Ablation, Brachytherapy, Intra-arterial Chemotherapy, and Intra-tumoral Immunotherapy

Current Oncology Reports ◽

10.1007/s11912-021-01057-3 ◽

2021 ◽

Vol 23 (6) ◽

Author(s):

Florentine E.F. Timmer ◽

Bart Geboers ◽

Sanne Nieuwenhuizen ◽

Evelien A.C. Schouten ◽

Madelon Dijkstra ◽

...

Keyword(s):

Pancreatic Cancer ◽

Palliative Chemotherapy ◽

Treatment Approach ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Multimodality Treatment ◽

Locally Advanced Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Interventional Techniques ◽

Randomized Controlled

Abstract Purpose of Review Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasms, bearing a terrible prognosis. Stage III tumors, also known as locally advanced pancreatic cancer (LAPC), are unresectable, and current palliative chemotherapy regimens have only modestly improved survival in these patients. At this stage of disease, interventional techniques may be of value and further prolong life. The aim of this review was to explore current literature on locoregional percutaneous management for LAPC. Recent Findings Locoregional percutaneous interventional techniques such as ablation, brachytherapy, and intra-arterial chemotherapy possess cytoreductive abilities and have the potential to increase survival. In addition, recent research demonstrates the immunomodulatory capacities of these treatments. This immune response may be leveraged by combining the interventional techniques with intra-tumoral immunotherapy, possibly creating a durable anti-tumor effect. This multimodality treatment approach is currently being examined in several ongoing clinical trials. Summary The use of certain interventional techniques appears to improve survival in LAPC patients and may work synergistically when combined with immunotherapy. However, definitive conclusions can only be made when large prospective (randomized controlled) trials confirm these results.

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