Commentary: Neoadjuvant treatment of resectable pancreatic cancer: Lack of level III evidence

The outcome of pancreatic cancer is poor, with a 9% 5-year survival rate. Current treatment recommendations in the 10%–20% of patients who present with resectable disease support upfront resection followed by adjuvant therapy. Until now, only early complete surgical (R0) resection and adjuvant chemotherapy (AC) with either FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or nab-paclitaxel plus gemcitabine have been shown to prolong the survival. However, up to 30% of patients do not receive adjuvant therapy because of the development of early recurrence, postoperative complications, comorbidities, and reduced performance status. The aims of neoadjuvant chemotherapy (NAC) are to identify rapidly progressing patients to avoid futile surgery, eliminate micrometastases, increase the feasibility of R0 resection, and ensure the completion of multimodal treatment. Neoadjuvant treatments are effective, but there is no consensus on their use in resectable pancreatic cancer (RPC) because of its lack of a survival benefit over adjuvant therapy. In this review, we analyze the advantages and disadvantages of the two therapeutic approaches in RPC. We need studies that compare the two approaches and can identify the appropriate sequence of adjuvant therapy after neoadjuvant treatment and surgery.

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Overall survival with preoperative biliary drainage in patients with resectable pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.314 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 314-314

Author(s):

Tobin Joel Crill Strom ◽

Sarah E. Hoffe ◽

Shivakumar Vignesh ◽

Jason Klapman ◽

Cynthia L. Harris ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Tumor Size ◽

Biliary Drainage ◽

Cox Regression ◽

Neoadjuvant Treatment ◽

Preoperative Biliary Drainage ◽

Resectable Pancreatic Cancer ◽

Pathologic Features

314 Background: Resectable pancreatic cancer patients often present with obstructive jaundice necessitating the placement of biliary stents or percutaneouse drainage catheters. We sought to evaluate whether preoperative biliary drainage affects recurrence and survival. Methods: An IRB-approved study was conducted on our institutional tumor registry to identify pancreatic cancer patients who were treated with upfront surgery between 2000 and 2012. Patients were then stratified by preoperative use of endoscopically placed stents (ERCP), percutaneous catheters (PTC), or no biliary drainage (NBD). The primary endpoint was overall survival (OS). Survival curves were calculated using the Kaplan-Meier method and the log-rank test. Multivariate analysis (MVA) was performed with a Cox regression model. Results: We identified 202 patients for the study (21 PTC; 89 ERCP; 92 NBD). Key differences between the 3 groups were mean pathologic tumor size (p=0.005), pathologic T3/4 (p =0.01), and pathologic N1 (p=0.007) status, with more aggressive pathologic features in PTC patients. PTC patients had a non-significant increase in rate of hepatic recurrences compared with ERCP and NBD patients (47.4% vs. 26.6% vs. 28.7%, respectively; p=0.20). PTC patients also had worse median and 3 year survival (21 months and 16%) compared to ERCP (23.3 months and 39%) and NBD patients (29 months and 45%, p=0.02). MVA revealed that PTC was an independent predictor of worse overall survival (HR 2.3[95% CI 1.3-4.0], p=0.005), along with pathologic tumor size (HR 1.1[1.0-1.3], p=0.008), nodes positive (HR 1.1[1.1-1.2], p=0.001), and post-operative CA19-9 >90 (HR 2.6[1.5-4.4], p=0.001). Conclusions: Patients with resectable pancreatic cancer who require a pre-operative PTC drain had a non-significant increase in hepatic recurrence rate and worse overall survival than patients who either had an ERCP stent placed or no biliary decompression prior to surgery. Given their worse prognosis, patients who require PTC placement might also benefit from neoadjuvant treatment with restaging prior to surgery.

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Preliminary safety data from a randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4125 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4125-4125 ◽

Cited By ~ 4

Author(s):

Matthew H. G. Katz ◽

Gauri R. Varadhachary ◽

Todd W. Bauer ◽

Nicolas Acquavella ◽

Nipun B. Merchant ◽

...

Keyword(s):

Pancreatic Cancer ◽

Neoadjuvant Treatment ◽

Safety Data ◽

Neoadjuvant Chemoradiation ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Resectable Disease ◽

Post Surgery ◽

Grade 3 ◽

To Receive

4125 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy.Tumor-infiltrating lymphocytes (TILs) do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of TILs in the PC microenvironment. We hypothesized that combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC have been randomized 2:1 to the investigational treatment (Arm A) to receive pembrolizumab 200mg IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday-Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. Restaging CT scan or MRI is performed at 4-6 weeks after completion of neoadjuvant treatment, and patients with resectable disease will undergo surgical resection. Here we report the preliminary safety data based on 22 enrolled patients. Results: As of February 3-2017,22 patients have been enrolled (14 Arm A and 8 Arm B). 50% of the patients had resectable disease (7 arm A; 4 arm B) and the other 50% had borderline resectable disease (7 Arm A; 4 arm B). Post-neoadjuvant therapy, 6 patients had unresectable disease (3 on each arm), and 14 patients underwent surgery (10 arm A and 4 arm B). There were 7 grade 3 treatment-related toxicities in Arm A (5 patients): 2 grade 3 diarrhea attributed to CRT; 4 grade 3 lymphopenias attributed to pembrolizumab, CRT or the combination; and one patient had elevated alkaline phosphatase probably related to the combination that met the definition of DLT and resolved after holding the treatment and receiving steroids. There was only one grade 3 toxicity on Arm B: lymphopenia attributed to CRT. No grade 4 toxicities have been reported on either arm. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizuamb is safe based on the presented data. Clinical trial information: NCT02305186.

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NEONAX trial: Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer, a phase II study of the AIO pancreatic cancer group (AIO-PAK-0313)—Safety interim analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4128 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4128-4128 ◽

Cited By ~ 2

Author(s):

Waldemar Uhl ◽

Thomas Jens Ettrich ◽

Anke C. Reinacher-Schick ◽

Hana Algül ◽

Helmut Friess ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Interim Analysis ◽

Phase Ii Study ◽

Neoadjuvant Treatment ◽

Postoperative Mortality ◽

Preoperative Imaging ◽

Resectable Pancreatic Cancer ◽

Perioperative Treatment ◽

Grade 3

4128 Background: Survival in pancreatic cancer (PDAC) is still poor even after curatively intended resection. Perioperative treatment approaches improve outcome in various tumor entities. Data on perioperative treatment in resectable PDAC are limited and there is a debate whether neoadjuvant treatment might impair subsequent surgery by adding perioperative morbidity or mortality. Methods: NEONAX is a randomized phase II study (planned 166 patients) of perioperative gemcitabine/nab-paclitaxel (Arm A: 2 pre- and 4 post-operative cycles, Arm B: 6 cycles adjuvant) for patients with primarily resectable PDAC. Primary objective is DFS at 18 months after randomization. Secondary objectives are 3-year OS-rate and DFS-rate, progression during neoadjuvant therapy, R0/R1 resection rate and QoL. Results: NEONAX was initiated in March 2015 in 26 centers for PDAC surgery in Germany. The data represent the safety interim analysis (IA) of the first 48 patients. 25 patients were randomized to Arm A and 23 to Arm B. Patients’ median age was 65.3 years (56.3% males, 43.8% females, 85.4% ECOG 0). Out of 25 patients in Arm A 20 patients (80%) underwent surgery, compared to 21 of 23 patients (91.3%) in Arm B with upfront surgery. Reasons for no resection were intraoperatively determined small liver metastases (2 cases, Arm A), withdrawal of informed consent (2 cases in each arm) and 1 patient with uncontrolled cholestasis (arm A). Postoperative complications occurred in 45% of arm A and 42.8% of arm B. (pancreatic fistula: 15% in arm A and 9.5% in arm B, infections: 10% in arm A and 9.5% in arm B) All resected patients were alive 60 days after surgery. At least 1 adverse event (AE) NCI-CTCAE ≥ grade 3 occurred in 60% of the perioperative and 39.1% of adjuvant treatment arm. Most common AEs were neutropenia (16.7%), fatigue (10.4%) and infections (10.4%). Conclusions: There was an increase in NCI-CTCAE ≥ grade 3 events in the perioperative arm, but this was manageable and did not result in increased peri- or postoperative mortality. 8% of patients in the perioperative arm did not get resected due metastases detectable during surgery, but not on preoperative imaging immediately prior to surgery. Therefore, it cannot be determined whether these metastases were preexistent or developed during neoadjuvant treatment. In conclusion, the first interim analysis of the NEONAX trial shows that this protocol can be safely applied to patients with resectable PDAC in a perioperative setting. Clinical trial information: NCT02047513.

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Landmark Series: Neoadjuvant Treatment in Borderline Resectable Pancreatic Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-020-09535-x ◽

2021 ◽

Author(s):

Jin He ◽

Richard D. Schulick ◽

Marco Del Chiaro

Keyword(s):

Pancreatic Cancer ◽

Neoadjuvant Treatment ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Borderline Resectable Pancreatic Cancer

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Neoadjuvant Therapy in Pancreatic Cancer: An Emerging Strategy

Gastroenterology Research and Practice ◽

10.1155/2014/183852 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 23

Author(s):

Alessandro Bittoni ◽

Matteo Santoni ◽

Andrea Lanese ◽

Chiara Pellei ◽

Kalliopi Andrikou ◽

...

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Case Series ◽

Tumour Response ◽

Tumour Regression ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Future Directions ◽

Tumour Implantation

Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths among men and women, being responsible for 6% of all cancer-related deaths. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. In recent years, increasing evidences support the use of neoadjuvant strategies in pancreatic cancer in patients with resectable pancreatic cancer as well as in patients with borderline resectable or locally advanced PDAC in order to allow early treatment of micrometastatic disease, tumour regression, and reduced risk of peritoneal tumour implantation during surgery. Furthermore, neoadjuvant treatment allows evaluation of tumour response and increases patient’s compliance. However, most evidences in this setting come from retrospective analysis or small case series and in many studies chemotherapy or chemoradiation therapies used were suboptimal. Currently, prospective randomized trials using the most active chemotherapy regimens available are trying to define the real benefit of neoadjuvant strategies compared to conventional adjuvant strategies. In this review, the authors examined available data on neoadjuvant treatment in patients with resectable pancreatic cancer as well as in patients with borderline resectable or locally advanced PDAC and the future directions in this peculiar setting.

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