Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2–3 trial

Reni, Michele; Balzano, Gianpaolo; Zanon, Silvia; Zerbi, Alessandro; Rimassa, Lorenza; Castoldi, R.; Pinelli, D.; Mosconi, S.; Doglioni, Claudio; Chiaravalli, Marta; Pircher, Chiara; Arcidiacono, Paolo Giorgio; Torri, Valter; Maggiora, Paola; Ceraulo, Domenica; Falconi, Massimo; Gianni, Luca

doi:10.1016/s2468-1253(18)30081-5

Cited by 184 publications

(158 citation statements)

References 31 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…Among 1586 articles identified, 24 were selected for full-text review, and 6 RCTs comparing SF to NT for PDAC were included ( Figure 1) [21,22,[34][35][36][37]. The characteristics of the included trials are reported in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, Reni et al performed a three-arm RCT comparing immediate surgery and two different adjuvant chemotherapy regimens to neoadjuvant chemotherapy followed by surgery and adjuvant therapy for patients with resectable PDAC. Based on the observed improved OS, the planned phase III component was not continued [34]. These first four RCTs highlight not only the challenges in designing, conducting, accruing, and completing trials in PDAC, but also the strong desire for novel treatment options with stronger evidence for this aggressive cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Early trials primarily focused on preoperative CRT [40][41][42]; however, as the chemotherapy options for PDAC have improved, increasingly chemotherapy alone is being used prior to surgery, especially for patients with PR disease [43]. Nevertheless, the best chemotherapy regimen has not been established, and it is unlikely that the chemotherapy regimens used in the PACT-15 (Cisplatin, Epirubicin, Gemcitabine, Capecitabine) or Prep-02/JSAP-05 (gemcitabine, S-1) will be widely adopted [34,35]. Given that most patients currently receive either gemcitabine/nab-paclitaxel or mFOLFIRINOX, the ongoing NEONAX [44], NEPAFOX [45], NORPACT-1 [46], PANACHE01-PRODIGE48 [47], PREOPANC-2 [48], ESPAC-5 [49], and SWOG S1505 [50] trials as well as the upcoming Alliance A021806 trial, which incorporate one of these regimens, should improve our understanding of the preferred preoperative regimen.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

Cloyd

Heh

Pawlik

et al. 2020

JCM

View full text Add to dashboard Cite

The efficacy of neoadjuvant therapy (NT) versus surgery first (SF) for pancreatic ductal adenocarcinoma (PDAC) remains controversial. A random-effects meta-analysis of only prospective randomized controlled trials (RCTs) comparing NT versus SF for potentially resectable (PR) or borderline resectable (BR) PDAC was performed. Among six RCTs including 850 patients, 411 (48.3%) received NT and 439 (51.6%) SF. In all included trials, NT was gemcitabine-based: four using chemoradiation and two chemotherapy alone. Based on an intention-to-treat analysis, NT resulted in improved overall survival (OS) compared to SF (HR 0.73, 95% CI 0.61-0.86). This effect was independent of anatomic classification (PR: hazard ratio (HR) 0.73, 95% CI 0.59-0.91; BR: HR 0.51 95% CI 0.28-0.93) or NT type (chemoradiation: HR 0.77, 95% CI 0.61-0.98; chemotherapy alone: HR 0.68, 95% CI 0.54-0.87). Overall resection rate was similar (risk ratio (RR) 0.93, 95% CI 0.82-1.04, I 2 = 39.0%) but NT increased the likelihood of a margin-negative (R0) resection (RR 1.51, 95% CI 1.18-1.93, I 2 = 0%) and having negative lymph nodes (RR 2.07, 95% CI 1.47-2.91, I 2 = 12.3%). In this meta-analysis of prospective RCTs, NT significantly improved OS in an intention-to-treat fashion, compared with SF for localized PDAC. Randomized controlled trials using contemporary multi-agent chemotherapy will be needed to confirm these findings and to define the optimal NT regimen.been associated with improved rates of margin-negative resection and a decreased incidence of lymph node metastases [10,11]. NT also offers several other theoretical benefits, including early treatment of presumed micro-metastatic disease, enhanced selection of patients with appropriate tumor biology for surgery, and the ability to histologically measure the response to therapy [12,13]. Evidence of improved survival has also been suggested based on data from cancer databases [10], meta-analyses of retrospective studies [14], and Markov decision models [15]. In turn, NT has become the preferred approach for borderline resectable (BR) PDAC, while guidelines support the use of either SF or NT for potentially resectable (PR) PDAC [16][17][18].Despite the theoretical and empirical advantages of NT, its use in the United States has remained relatively low [19,20], potentially driven by the lack of level I evidence for its efficacy. Until recently, only two small randomized controlled trials (RCTs) had been performed comparing SF to NT, and both were terminated early due to poor accrual [21,22]. Previous systematic reviews and meta-analyses that have purported a survival benefit with NT included non-randomized prospective and retrospective studies, which are limited due to their inherent selection biases [14,[23][24][25][26]. As several larger RCTs have recently been completed, albeit with older neoadjuvant regimens, the purpose of the current study was to perform a meta-analysis limited to only RCTs evaluating SF vs. NT for PDAC.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

Cloyd

Heh

Pawlik

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…In the recent years, there is a growing enthusiasm for neoadjuvant therapy in patients with radiologically resectable carcinoma of the head of the pancreas because of the emerging consensus that pancreatic cancer is a systemic disease from the earliest stages. In addition, few randomized controlled phase 2 trials have provided evidence of the efficacy of neoadjuvant therapy in the resectable pancreatic ductal adenocarcinoma [30,31]. As a result, these days, in most of the tertiary care centers from the Western world, the majority of pancreatic ductal adenocarcinoma patients with jaundice undergo PBD as they are going to receive chemotherapy or chemoradiotherapy upfront.…”

Section: Discussionmentioning

confidence: 99%

Upfront pancreaticoduodenectomy in severely jaundiced patients: is it safe?

Pamecha

Patil

Kumar

et al. 2019

J Hepato Biliary Pancreat

View full text Add to dashboard Cite

Aim The aim of this study was to evaluate the outcomes following upfront pancreaticoduodenectomy (PD) in severely jaundiced (serum bilirubin level ≥15 mg/dl) patients with malignant distal common bile duct (CBD) obstruction. Background Recent studies have failed to show the benefits of preoperative biliary drainage (PBD) before PD. In addition, there is limited data on the impact of upfront PD on perioperative outcomes in severely jaundiced patients. Methods We reviewed the prospectively collected data of 177 patients who had undergone PD for the malignant distal CBD obstruction from May 2009 to May 2018. Study subjects were divided into Group A (severely jaundiced patients with upfront PD; n = 20), Group B (patients with serum bilirubin <15 mg/dl and no PBD; n = 88) and Group C (PBD prior to PD; n = 69). Overall morbidity, in-hospital mortality, and postoperative hospital stay were compared. Results No significant differences were noted between the three groups regarding sex, tumor size and stage, comorbidities, and surgical technique. The intra-operative blood loss was more in severely jaundiced patients as compared to Groups B and C (605 vs. 300 vs. 350 ml, P = 0.0001), but similar operative times, blood transfusions, and rates of post-pancreatectomy leak and hemorrhage.The infective complications were significantly less with upfront surgery. The overall morbidity, in-hospital mortality, and hospital stay were comparable between the three groups. Multiple logistic regression analysis failed to identify both the presence of preoperative jaundice and hyperbilirubinemia ≥15 mg/dl as independent risk factors for post-PD major morbidity. Conclusion Upfront PD can be performed safely in the selected severely jaundiced patients and is associated with significantly lower infective complications.

show abstract

“…Only 8% of patients diagnosed with pancreatic cancer today survive longer than 5 years despite aggressive interventions 1 . Although surgery can provide a clear therapeutic benefit for eligible patients, especially when combined with radiation and chemotherapy [2][3][4] , a sustained clinical response is rarely achieved in the majority of patients.…”

Section: Introductionmentioning

confidence: 99%

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Baxter

Souza

Tai

et al. 2020

Preprint

View full text Add to dashboard Cite

Background:Although surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations. Materials and Methods:Surgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass. Results:As expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery. Conclusion:This represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.3

show abstract

Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2–3 trial

Cited by 184 publications

References 31 publications

Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

Upfront pancreaticoduodenectomy in severely jaundiced patients: is it safe?

An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

Contact Info

Product

Resources

About