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Description : 20% of pancreatic ductal adenocarcinoma (PDAC) … resectable or borderline resectable

Tags : cancer,surgery,pancreatic cancer

Published on : Apr 30, 2021 | Views : 2011 | Downloads : 6

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Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer (PREOPANC Trial) JCO 22 Feb 2020 1
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Introduction 20% of pancreatic ductal adenocarcinoma (PDAC) … resectable or borderline resectable Standard treatment is resection followed by adjuvant chemotherapy Only half of the patients with surgery receive adjuvant chemotherapy Approximately half of the resections are microscopically incomplete (R1) One quarter of patients will develop disease recurrence within 6 months 2
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Introduction Preoperative chemoradiotherapy, by inducing downstaging of the tumor, might increase the R0 resection rate R0 resection rate is an important prognostic factor, diminishing local and distant recurrence rates, hence improving survival In addition, compliance with preoperative chemoradiotherapy is better compared with postoperative chemotherapy Complicated surgery by radiation toxicity in preoperative treatment 3
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Introduction Most of the studies that advocate preoperative chemoradiotherapy are nonrandomized Surgical radicality after preoperative chemoradiotherapy has never been studied in a multicenter randomized trial A recent meta-analysis of the effect of preoperative chemoradiotherapy in resectable or borderline resectable PDAC showed a prolonged overall survival (OS) (18.8 v 14.8 months) mostly observational 4
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Introduction 11 trials are reported, 4 of which are phase III trials Three trials were completed, of which 2 reported results (1 in abstract only) The Dutch Pancreatic Cancer Group (DPCG) initiated the PREOPANC trial with the aim to investigate whether preoperative chemoradiotherapy provides better OS than immediate surgery in patients with resectable or borderline resectable PDAC 5
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Patients & Methods Phase III 16 high volume pancreatic surgery centers 6
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Patients & Methods Inclusion Criteria Pathologically confirmed resectable or borderline resectable PDAC Resectable : Tumor without arterial involvement and with venous involvement < 90° Borderline resectable : Tumor with arterial involvement < 90° and/or venous involvement 90° - 270° without occlusion WHO performance status of ≤ 1 and adequate hematologic, renal, and hepatic function Exclusion criteria cT1 tumor (< 2 cm, without vascular involvement), history of malignancy within 5 years, and previous radiotherapy or chemotherapy 7
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Patients & Methods 1:1 randomization ARM 1 Staging laparoscopy to rule out metastasis Radiotherapy consisted of 15 fractions of 2.4 Gy in 3 weeks to the pancreatic tumor and suspicious lymph nodes 1,000 mg/m2 gemcitabine on D1, D8, D15 of 4 weeks, preceded and followed by a modified course of gemcitabine (1,000 mg/m2 gemcitabine on D1 and D8 of 3 weeks Explorative laparotomy, with subsequent resection, if possible, was conducted between 14 and 18 weeks after random assignment After resection and confirmation of PDAC, the remaining gemcitabine was administered at 1,000 mg/m2 on D1, D8, and D15 in 4 courses of 4 weeks 8
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Patients & Methods ARM 2 Surgery was to be performed within 4 weeks after random assignment; staging laparoscopy was at the surgeon’s discretion Patients received 6 courses of adjuvant gemcitabine at 1,000 mg/m2 on D1, D8, and D15 of 4 weeks All patients underwent follow-up assessment with CT scans and serum CA19.9 at 6, 12, 18, and 24 m and yearly thereafter 9
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Patient & Methods Primary end point was OS Secondary end points were disease-free survival (DFS), locoregional failure–free interval (LFFI), distant metastasis–free interval (DMFI), resection rate, R0 resection rate, and toxicity of both surgery and pre- and postoperative treatment Subgroup analyses were prespecified for resectable and borderline resectable PDAC separately 10
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Patients & Methods The trial was designed to have 80% power to detect a 6-month difference in median OS by intention-to-treat between both treatment groups (17 months with preoperative chemoradiotherapy and 11 months with immediate surgery) At least 176 events were required to detect Assuming a 10% dropout rate, 122 patients in each treatment arm were required 11
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Results 2013 to 2017,,,, 248 patients from 16 centers 120 in preoperative chemoradiotherapy and 128 to immediate surgery 12
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Results 13
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Results The resection rate was not significantly different between the preoperative chemoradiotherapy and the immediate surgery groups (61% v 72%; P = .058) R0 resection rate was higher in patients treated with preoperative chemoradiotherapy (72% v 40%; P , .001) Fewer patients had pathologic lymph nodes (33% v 78%; P , .001), perineural invasion (39% v 73%; P , .001), or venous invasion (19% v 36%; P = .024) Overall, patients with an R0 resection had a better OS than patients with non-R0 resection (HR, 0.47; 95% CI, 0.31 to 0.72; P < .001) 14
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Results Median follow-up of 27 months, 180 patients (73%) died: 81 (68%) in the preoperative chemoradiotherapy group and 99 (78%) in the immediate surgery group The median OS in the preoperative chemoradiotherapy group was 16.0 months (95% CI, 13.0-20.9 m) and 14.3 months (95% CI, 12.7-17.9 m) in surgery (HR, 0.78; 95% CI, 0.58-1.05; P = .096) 15
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Results DFS, disease-free survival; DMFI, distant metastasis–free interval; HR, hazard ratio; LFFI, locoregional failure–free interval; NR, not reached; OR, odds ratio; OS, overall survival; SAE, serious adverse event 16
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Results 17
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Results 18
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Results 19
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Discussion This is the first completed multicenter, randomized trial on preoperative chemoradiotherapy versus immediate surgery in patients with resectable or borderline resectable PDAC The study did not demonstrate an OS benefit in the ITT population (median, 16.0 v 14.3 months; HR, 0.78; P = .096). Nevertheless, the secondary end points DFS, LFFI, R0 resection rate, and pathologic parameters were superior with preoperative chemoradiotherapy. This suggests a clinically relevant benefit of preoperative chemoradiotherapy in patients with resectable or borderline resectable PDAC 20
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Discussion A comparison of our results with those of published trials of adjuvant gemcitabine and capecitabine (ESPAC-4; median OS, 28 m) or modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX; PRODIGE 24/CCTG PA.6; median OS, 54.4 m) is difficult Adjuvant trials exclude patients with disease progression before surgery, occult metastases, or locally advanced disease detected at exploration as well as patients poorly recovering from surgery To enable observational comparison with these trials, we analyzed data of the 120 patients who underwent resection and started adjuvant chemotherapy This subgroup analysis showed a clinically and statistically relevant OS benefit of preoperative chemoradiotherapy over immediate surgery (35.2 v 19.8 months; P = .029) 21
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Discussion Preoperative FOLFIRINOX might further improve the outcome and is currently being investigated in the PREOPANC-2 trial (Netherlands), the NorPACT-1 trial and the PANACHE01-PRODIGE48 trial The addition of radiotherapy to preoperative FOLFIRINOX could be a next step, as preoperative chemoradiotherapy gives higher R0 rates, less lymph node positivity, and local recurrences compared with preoperative chemotherapy only 22
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Discussion A predefined subgroup analysis showed superior OS after preoperative chemoradiotherapy for borderline resectable PDAC and no significant difference for resectable PDAC The recently presented phase II/III Prep-02/JSAP-05 trial showed a significant benefit of preoperative chemotherapy (gemcitabine and S-1) over immediate surgery for resectable PDAC, with a median OS of 36.7 v 26.6 months 23
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Discussion Limitations The median OS in the immediate surgery group was better than expected (14 instead of 11 months), which probably resulted in an underpowered study. This might be explained by effective lines of salvage therapies in patients with locoregional or distant failure 10 patients had persistent jaundice after biliary drainage, which caused a delay of preoperative treatment. These aspects should be taken into account when considering neoadjuvant therapy in patients with suspected PDAC 14 patients (6%) had other pathology than PDAC; 9 (4%) had a cholangiocarcinoma, which implies a more favorable prognosis than PDAC 24
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Discussion This national, multicenter, randomized, phase III trial of preoperative chemoradiotherapy versus immediate surgery in resectable or borderline resectable PDAC did not show a significant OS benefit of preoperative chemoradiotherapy but it was superior 25
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