Phase I trial of gene-mediated cytotoxic immunotherapy in combination with chemoradiation for locally advanced pancreatic cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 195-195 ◽  
Author(s):  
M. Bloomston ◽  
C. Marsh ◽  
J. Walker ◽  
W. Coyle ◽  
H. Marx ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Tumor Vaccine ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Kinase Gene ◽  
Early Results ◽  
Cell Immunity ◽  
Dose Levels

195 Background: More than 80% of patients with pancreatic cancer present with locally advanced or metastatic disease and have a median survival of only 6 months. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) is an approach that generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug and synergy with chemoradiation. The mechanisms of action involve tumor cytotoxicity, activation of antigen presenting cells and stimulation of systemic anti-tumor T-cell immunity. Safety with potential efficacy has been demonstrated in multiple clinical studies. This is the first application of GMCI in pancreatic cancer. Methods: This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into locally advanced tumors via EUS or CT-guidance before and during week 3 of standard 5-FU-chemoradiation. Valacyclovir (Valtrex, GSK) prodrug was given for 14 days after each of 2 AdV-tk injections. Results: The study completed accrual with 13 patients enrolled and 12 completing therapy with 3 at each of the 4 dose levels. One patient refused further participation during course 1 after recovering from azotemia. Median age was 64 years (range 55-81) and median baseline CA19-9 was 1634 U/ml. No dose limiting toxicities and no injection related complications occurred. Possibly related grade 3-4 toxicities, all of which were transient, included dehydration, azotemia and worsening elevation of bilirubin and AST. Kaplan-Meier estimated median survival is 12.2 months with 6 patients still alive at 8-20 months. Two patients achieved a partial response by RECIST criteria. One occurred in week 6 despite discontinuing 5-FU/radiation during week 1. The other had gradual decrease of a 7 cm tumor over 11 months. Serum CA19-9 levels decreased in 8/8 evaluable patients by 32-91% at 3 months after treatment initiation. Conclusions: AdV-tk can be safely injected into pancreatic tumors and combined with standard chemoradiation. Early results are highly encouraging and justify further evaluation in a phase II study. [Table: see text]

Phase I trial of gene-mediated cytotoxic immunotherapy combined with resection for pancreatic adenocarcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 241-241
Author(s):  
Lawrence Andrew Shirley ◽  
Christopher Marsh ◽  
Jon Walker ◽  
Walter Coyle ◽  
Sanaa Tahiri ◽  
...  
Keyword(s):  
Adverse Events ◽  
Pancreatic Adenocarcinoma ◽  
Tumor Vaccine ◽  
Locally Advanced ◽  
Pancreatic Tumors ◽  
Kinase Gene ◽  
Term Survival ◽  
Early Results ◽  
Grade 3 ◽  
Dose Levels

241 Background: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival is still poor. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug administration. This is the first application of GMCI in pancreatic cancer. Methods: This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into pancreatic tumors via EUS 2 weeks before resection. Patients then underwent attempt at resection. If resection was undertaken, AdV-tk was injected into the resection bed. If resection was not possible, AdV-tk was injected into the primary tumor. The prodrug, Valacyclovir, was given for 14 days after each injection. Postoperative therapy was not protocol-driven. Results: The study accrued 14 patients with 12 completing therapy: 3 at each of the 4 planned dose levels. One patient died of an unrelated myocardial infarction 2 days after initial injection and one patient dropped out mid-treatment after metastases were found at surgery. Median age was 67 years (range 40-81). Of 12 patients explored, 4 were not resected due to distant metastases (N=3) or locally advanced disease (N=1). Three patients had Grade 3 possibly-related adverse events: 2 abdominal pain and one dehydration with renal insufficiency. There were no dose limiting toxicities and no grade 4 clinical adverse events. Grade 3-4 laboratory abnormalities were AST/ALT, bilirubin, alkaline phosphatase and lipase, all in patients with obstructive jaundice. Post-operative complications included 2 patients who developed abscesses requiring drainage. Six of 12 patients are alive 5-34 months after start of treatment including 5 resected patients and one unresected. Conclusions: AdV-tk can be safely injected into potentially resectable pancreatic tumors prior to planned resection. Early results are encouraging and justify further evaluation in a Phase 2 study.

Safety and tolerability of combined gemcitabine (G) and erlotinib (E) plus sorafenib (S) in the first-line treatment of metastatic pancreatic cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15594-e15594 ◽  
Author(s):  
D. J. Cohen ◽  
T. Ryan ◽  
T. Moskovits ◽  
N. Cazeau ◽  
E. Newman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Kinase Inhibitor ◽  
Bowel Perforation ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Median Number ◽  
Metastatic Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Disease Stabilization ◽  
Ecog Ps

e15594 Background: The addition of E to G results in improved survival for patients(pts) with locally advanced and metastatic pancreatic cancer. Many pancreatic tumors have constitutively activated ras/raf pathways and overexpress VEGF. Sorafenib, a multitargeted tyrosine kinase inhibitor which targets VEGR 1–3, PDGFR-α and β and the RAF/MEK/ERK pathway, when combined with G and E may synergize with these agents resulting in a more complete blockade of the signal transduction cascade in pancreatic cancer growth and progression and therefore improve outcome. Methods: Pts with previously untreated, histologically confirmed, unresectable pancreatic adenocarcinoma, ECOG PS 0–1, and adequate organ function were eligible and received G 1,000 mg/m2 over 30 min weekly × 3 every 4 weeks. E 150 mg PO daily and S 400 mg PO bid were given continuously. CT scans were performed every 2 cycles (8 weeks). Endpoints included safety and tolerability of the novel combination, PFS at 4 months, response rate, and OS. Results: Between 9/07–12/08 19 pts were enrolled with a median age 59 (range 45- 75), M/F 13/6, PS (0/1) 14/5. All 19 had metastatic disease. 17 pts are evaluable for toxicity and efficacy. The median number of cycles on treatment was 2 (range 1–10). The most common grade (gr) 3 toxicities were thrombocytopenia (24%), venous thrombosis (12%), and hyperbilirubinemia (12%). The most common gr 4 toxicity was infection (12%). 1 pt each experienced gr 3 HFSR, gr 3 diarrhea, gr 3 bleeding (epistaxis) and 1 had a non-fatal bowel perforation. There was 1 PR and 6 SD for an overall RR of 6% and a DCR of 41%. Conclusions: The combination of G and E plus S in the treatment of advanced pancreatic cancer is a well tolerated regimen without significant increased toxicity as compared to gemcitabine alone, except for very manageable cutaneous reactions. Further follow up is required to determine the combination's efficacy, though some patients have achieved prolonged disease stabilization. Supported in part by grants from Bayer Healthcare Pharmaceuticals/Onyx and OSI. [Table: see text]

FOLFIRINOX for patients with borderline and never-resectable locally advanced pancreatic cancer, with the addition of chemoradiotherapy for potentially resectable patients: A phase II study.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 408-408
Author(s):  
Jon Kroll Bjerregaard ◽  
Morten Ladekarl ◽  
Anna-Lene Fromm ◽  
Per Pfeiffer
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Observation Time ◽  
Stage Ii ◽  
Locally Advanced Pancreatic Cancer

408 Background: Locally advanced pancreatic cancer (LAPC) is often a mix of borderline and never-resectable tumors. Multimodality treatment might downstage these tumors to allow a potential radical resection, especially the borderline group. In this ongoing phase II study we examined the feasibility of FOLFIRINOX with or without CRT followed by surgery for both borderline and never-resectable tumors (NCT-01397019). Methods: Patients in performance status 0-1, with initially non-resectable stage II/III pancreatic cancer were offered FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2+ 2400 mg/m2) every 14 days. Every 4th series the patients were evaluated and offered CRT (50.4 Gy/27F & capecitabine) if deemed potentially resectable. Resections were performed if deemed possible by the MDT. Results: Between August 2012 and present, 58 patients have been recruited with a median observation time of 14.5 months. Median age was 65(range 38-75) years, with 47%/53% stage II/III distribution. Median CA19-9 was 299(range 2-13,432). Two-hundred-seventy-four courses of FOLFIRINOX have been given, with a median of 6.5 per patient, with a median of 2 without dose modifications. Presently twenty-one patients have been treated with CRT. Twelve patients have been resected, of which 7 received prior CRT. Median survival for all patients was 15.6 months (11-NR) with a 1-year survival of 70% (49-84). For patients not resected the median survival was 12.8 months (9-16) for resected the median survival has not yet been reached. The FOLFIRINOX was associated with adverse events similar to what is expected in metastatic patients. Conclusions: FOLFIRINOX with or without CRT in patients with LAPC shows promising efficacy in patients with both borderline and never-resectable tumors. Unmodified FOLFIRINOX had acceptable toxicity, however dose reductions are often needed. CRT following initial FOLFIRINOX was feasible and without unexpected toxicity. Clinical trial information: NCT-01397019.

Phase I trial of radiotherapy with concurrent bevacizumab, erlotinib, and capecitabine for locally advanced pancreatic cancer (LAPC).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 254-254
Author(s):  
Heath Devin Skinner ◽  
Milind M. Javle ◽  
Robert A. Wolff ◽  
Marilyn V. Clemons ◽  
Mark F. Munsell ◽  
...  
Keyword(s):  
Median Survival ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
High Rate ◽  
Viable Tumor ◽  
Grade 3 ◽  
Dose Levels

254 Background: The addition of bevacizumab to capecitabine-based chemoradiotherapy (CRT) for LAPC has been shown to be safe. The aim of this study was to determine the safety, tolerability and maximum tolerated dose (MTD) of the addition of erlotinib to this treatment regimen. Methods: Seventeen patients with CT-staged biopsy-proven non-metastatic unresectable LAPC were enrolled between March 2008 and October 2010. Prior chemotherapy was permitted. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose was escalated using a continual reassessment method. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. Bevacizumab was escalated from 5mg/Kg every two weeks (DLs 1-4) to 10mg/Kg (DL 5); erlotinib from 100 mg/day (DLs 1-2) to 150 mg/day (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 600mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. Results: With a median follow-up of 10 months (range 3-23), no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrheas and 1 rash). No grade 4 or 5 toxicities were seen. DL 4, with a posterior probability of 0.122 of dose limiting toxicity, was selected as the MTD. Median survival was 19.4 months and time to distant progression was 9.8 months. Patients treated at DLs 4 and 5 had a median survival of 24 months. Of 5 patients who underwent margin-negative resections, 4 were originally deemed unresectable and 1 was borderline; 4 were treated at DLs 4 or 5 (36% of patients treated at these DLs); 3 patients had excellent pathological responses (complete response, 5% viable tumor, and 20% viable tumor) at pancreatectomy and are alive at 13, 21 and 22 months respectively with no local or distant failures. Conclusions: The combination of erlotinib, bevacizumab and capecitabine with radiotherapy for LAPC is safe and tolerable. Both the promising survival and the high rate of resectability at the higher dose levels suggest that this strategy of dual inhibition of growth factor receptor pathways during CRT warrants continued evaluation.

18F-fluorothymidine (FLT) PET-CT for early response assessment in advanced pancreatic cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21093-e21093
Author(s):  
Amarnath Challapalli ◽  
Harpreet S Wasan ◽  
Adil Al-Nahhas ◽  
Eric Aboagye ◽  
Charles Coombes ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Standardized Uptake Value ◽  
Response To Therapy ◽  
Pancreatic Tumors ◽  
Metastatic Tumors ◽  
Flt Pet ◽  
Pet Ct ◽  
The Mean

e21093 Background: Advanced pancreatic cancer has a poor prognosis with a median survival of 6-10 months. There is a need for early non-invasive assessment of treatment response. We evaluated FLT PET-CT combined with a kinetic spatial filtering method (FLT-PETKSF) for detecting response to gemcitabine-based chemotherapy in advanced pancreatic cancer. Methods: Dynamic FLT PET-CT data were collected from patients with confirmed locally advanced or metastatic pancreatic cancer before and 2 weeks after the first cycle of chemotherapy. Changes in tumor FLT-PET variables with treatment were determined. Standardized uptake value (SUV) reduction of 18% was taken as cut-off for response. Voxel quantification of each tumor volume was performed on the filtered data. Each voxel-intensity was normalised by injected dose, body weight and decay corrected to obtain the SUV for the voxel. Changes in high intensity voxels (HiVox: SUV ≥ 2) - were computed. Results: Results of the first 5 patients are discussed. There were 4 primary and 9 metastatic tumors. FLT-PETKSF improved tumor-to-background ratio and enabled visualisation of all the primary and metastatic tumors. The mean (± SD) average and maximum SUV at 60 min (SUV60, av & SUV60, max) of the primary lesions was 2.10 (±0.38) & 4.85 (±1.55) and that of the metastatic lesions was 3.74 (±1.49) & 6.90 (±2.05) respectively. The mean (± SD) percentage reduction in the SUV60, av & SUV60, max, HIVox was 26 (±44), 18 (±38) and 23 (±50) respectively. The changes in the voxel occurrences correlated strongly with the changes in both SUV60, av & SUV60, max (Pearson r-0.9, p=0.001) .Overall, there were 2 partial responders and 3 with stable disease. These responses concurred with response evaluation on mid-treatment CT scan. Conclusions: FLT-PET and FLT-PETKSF enables visualisation of the pancreatic tumors and the liver metastases, and could be used to monitor response to therapy.

scholarly journals Complete Responses after Hyperthermic Ablation by Ultrasound Guided High Intensity Focused Ultrasound Plus Systemic Chemotherapy for Locally Advanced Pancreatic Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Joan Vidal-Jove ◽  
Marta Garcia-Bernal ◽  
Eloi Perich ◽  
Manuel Alvarez del Castillo
Keyword(s):  
Pancreatic Cancer ◽  
Systemic Chemotherapy ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Stage Iv ◽  
High Intensity Focused Ultrasound ◽  
Stage Iii ◽  
Pancreatic Tumors ◽  
Clinical Responses

We describe results in unresectable pancreatic tumors treated with USgHIFU hyperthermia ablation plus adjuvant chemotherapy. Materials and Methods. Thirty two cases of nonresectable pancreatic tumors were treated from March 2010 to March 2012, and all of them underwent systemic chemotherapy. Clinical responses (thermal ablation achieved) were measured by image techniques. There were 23 stage III cases and 9 stage IV cases. Complications were also analyzed. Results. Clinical responses (ablation obtained) were 82% in all cases, sustained at 8 weeks of the procedure. We obtained 8 complete responses (25%) at the end of the combined treatment, 7 from stage III patients and 1 from stage IV. Major complications included (1) severe pancreatitis with GI bleeding and (2) skin burning grade III that required plastic surgery. No deaths were registered. Median survival was 12.5 month (6 months–2.5 year). Conclusion. HIFU plus SC is a potentially effective and safe modality for the treatment of unresectable pancreatic cancer.

scholarly journals CT Findings of Patients Treated with Irreversible Electroporation for Locally Advanced Pancreatic Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Olaguoke Akinwande ◽  
Shakeeb S. Ahmad ◽  
Tracy Van Meter ◽  
Brittany Schulz ◽  
Robert C. G. Martin
Keyword(s):  
Pancreatic Cancer ◽  
Imaging Modality ◽  
Locally Advanced ◽  
Irreversible Electroporation ◽  
Advanced Pancreatic Cancer ◽  
Mass Effect ◽  
Ct Imaging ◽  
Locally Advanced Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Before And After

Introduction. In patients with locally advanced pancreatic cancer (LAPC), IRE has been shown to be safe for local disease control and palliation. As IRE continues to gain acceptance it is important to characterize the expected imaging findings.Materials and Methods. A review of our prospective soft tissue ablation registry from July 2010 to June 2013 was performed on patients who had undergone IRE for LAPC. Five masses treated with intraoperative IRE ablation for pancreatic tumors that underwent CT imaging before and after ablation were reviewed.Results and Discussion. Following IRE, the postablation bed is larger than the original ablated tumor. This ablation zone may get smaller in size (due to decreased edema and hyperemia) in the following months and more importantly remains stable provided there is no recurrence. In cases of recurrent disease there is increased size of the ablation bed, mass effect, and new or worsening vascular encasement or occlusion.Conclusion. CT imaging remains the best current imaging modality to assess post-IRE ablation changes. Serial imaging over at least 2–6 months must be employed to detect recurrence by comparing with prior studies in conjunction with clinical and serum studies. Larger imaging studies are underway to evaluate a more ideal imaging modality for this unique patient population.

scholarly journals Cryoablation for locally advanced pancreatic cancer

2018 ◽  
Vol 23 (2) ◽  
pp. 37-49
Author(s):  
D. A. Ionkin ◽  
N. A. Karelskaya ◽  
Yu. A. Stepanova ◽  
V. M. Zemskov ◽  
M. N. Kozlova ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pain Syndrome ◽  
Locally Advanced Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Complete Regression ◽  
Early Postoperative Complications ◽  
Additional Chemotherapy

Aim. To improve quality and duration of life in patients with locally advanced pancreatic cancer. Material and methods. Cryosurgery through laparotomy has been performed in 36 patients with locally advanced pancreatic cancer since 2012. There were 14 (38.9%) men and 22 (61.1%) women (mean age 58 ± 6.8 years). Dimensions of pancreatic tumors were from 4 to 10 cm. Domestic devices “CRYO-MT”, “CRYO-01”, “ELAMED” and cryoapplicators with a diameter 2–5 cm were applied. Target temperature was about 186 °С, time of exposure – 3–5 min. There were 1–5 sessions of cryoablation (mean 2.4) and their number depended on tumor dimensions. Local cryodestruction was supplemented by bypass anastomoses in 18 patients (50%). All patients subsequently underwent adjuvant chemotherapy with additional regional chemoembolization in 10 of them. Results. There were no lethal outcomes during cryodestruction and in postoperative period. Early postoperative complications occurred in 14 (38.8%) patients, severe complications – in 13.6%. Cryodestruction was followed by complete regression (39.2%) or significant improvement (41.6%) of pain syndrome. 6-, 12-, 24- and 36-month survival was 92%, 84%, 48% and 14%, respectively. Median survival was 18.2 months. Conclusion. Cryodestruction is able to improve patients’ quality of life due to reduced pain syndrome in case of locally advanced pancreatic cancer. Certain increase of survival was observed in additional chemotherapy.

scholarly journals Factors Associated With Long-Term Survival in Gemcitabine-Concurrent Proton Radiotherapy For Non-Metastatic Locally Advanced Pancreatic Cancer: a Single-Center Retrospective Study

2021 ◽  
Author(s):  
Yuta Ogura ◽  
Kazuki Terashima ◽  
Yoshihide Nanno ◽  
SungChul Park ◽  
Masaki Suga ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Proton Radiotherapy ◽  
Term Survival ◽  
Long Term Survival ◽  
Factors Associated ◽  
Pancreatic Body

Abstract Background: Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy (GPT) for non-metastatic locally advanced pancreatic cancer (LAPC) remain unclear. This study aimed to determine the factors associated with long-term survival in GPT for non-metastatic LAPC.Methods: The medical records of 123 patients with LAPC treated with GPT between February 2009 and December 2019 at Hyogo Ion Beam Medical Center were retrospectively reviewed to assess the factors associated with long-term survival outcomes.Results: The median survival time of the total cohort treated with GPT was 18.7 months. The 1- and 2-year overall, local progression-free, and progression-free survival rates were 70.4% and 35.7%, 78.2% and 59.0%, and 38.6% and 20.8%, respectively. Multivariate analysis revealed that LAPCs at the pancreatic body-tail and those without anterior peripancreatic invasion were independently associated with longer overall survival (P = 0.040 and P = 0.015, respectively). The median survival times of patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion were 24.1 and 28.1 months, respectively. LAPCs at the pancreatic body-tail had a higher volume ratio irradiated over 60 Gy equivalents at gross tumor volume than those at the pancreatic head (P < 0.001). LAPCs with anterior peripancreatic invasion had more peritoneal recurrence within 6 months than those without anterior peripancreatic invasion (P = 0.039).Conclusions: GPT is a promising treatment option for patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion.

Head-to-head comparison of first-line FOLFIRINOX versus gemcitabine plus nabpaclitaxel (GN) in advanced pancreatic cancer (APC): A target trial emulation using Canadian real-world data.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18713-e18713
Author(s):  
Devon J. Boyne ◽  
Darren Brenner ◽  
Alind Gupta ◽  
Eric Mackay ◽  
Paul Arora ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Median Survival ◽  
Real World ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Medical Decision ◽  
Target Trial ◽  
Real World Data ◽  
World Data

e18713 Background: When randomized trials are not available, observational real-world data can be used to emulate a (hypothetical) target trial. The procedure starts with the specification of the protocol of the target trial, whose components are then explicitly emulated using observational data. This approach prevents biases that are common when using more conventional methods for real-world data. Advanced pancreatic cancer represents an opportunity for trial emulation since two main frontline therapies, FOLFIRINOX and GN, have never been directly compared in a randomized fashion. The choice between the two regimens is largely based on physician discretion and patient preference rather than direct comparison of effectiveness. Methods: We emulated a target trial using linked data from the provincial cancer registry, electronic health records and various administrative databases from Alberta, Canada. Eligible individuals had locally advanced or metastatic pancreatic cancer diagnosed between Jan. 2015- Dec. 2018, no prior treatment, and adequate hematologic and serum creatinine values. They were followed from diagnosis until March 2020, death, or date of last known contact with the healthcare system. We estimated the effect of initiating FOLFIRINOX vs. GN within 8 weeks of diagnosis on overall survival. Cloning, artificial censoring, and inverse probability weighting were used to address unknown treatment assignment at baseline, non-adherence, and confounding. Adjusted Kaplan-Meier survival curves and hazard ratios were estimated. Results: Of 298 eligible individuals, 70 adhered to the FOLFIRINOX strategy and 147 to the GN strategy. The mean age was 65 years, 173 (58%) were male, and 247 (83%) had metastatic disease. The adjusted median survival, 1-year survival, and 2-year survival for FOLFIRNOX was 8.2 months (95% CI: 5.3 to 9.4), 36.9% (22.2 to 55.8), and 14.1% (4.8 to 32.2), respectively; and for GN was 4.8 months (3.3 to 5.3), 22.2% (13.6 to 35.9), and 4.7% (1.7 to 13.0), respectively. The adjusted difference in median survival was 3.4 months (0.6 to 11.1) and the adjusted hazard ratio was 0.79 (0.56 to 1.05). Conclusions: Target trial emulations can help to inform medical decision making in situations where head-to-head randomized trial data are unavailable or unfeasible. Findings from this real-world trial emulation suggest improved overall survival with FOLFIRINOX over GN.

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