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Updates on adjuvant and neoadjuvant treatment strategies for surgically resectable and borderline resectable pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic cancer is the third leading cause of cancer-related mortality in the US. Outcomes for patients with pancreatic cancer are poor as curative approaches are only available to the minority of patients who have localized tumors for which surgery may be an option. The past decade has established fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as the new standard of care following resection for fit patients with resectable pancreatic tumors. However, most patients will relapse and a large number of patients treated with upfront resection are unable to receive or complete adjuvant chemotherapy. There is therefore considerable interest in neoadjuvant treatment strategies for patients with resectable and borderline resectable pancreatic cancer as a way to provide early systemic treatment of micrometastatic disease, facilitate lymph node downstaging, and increase the likelihood of negative resection margins (R0). This review will focus on key aspects of completed trials evaluating adjuvant therapy in resectable pancreatic cancer and will provide an overview of emerging evidence supporting the use of neoadjuvant treatment strategies for both resectable and borderline resectable pancreatic cancer.

SUBMITTER: Iyengar S

PROVIDER: S-EPMC8450613 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Non-randomized studies have investigated multi-agent gemcitabine-based neo-adjuvant therapies (GEM-NAT) in borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). Treatment sequencing and specific elements of neoadjuvant treatment are still under investigation. The present meta-analysis aims to assess the effectiveness of GEM-NAT on overall survival (OS) in BR-PDAC. Patients and Methods: A meta-analysis of individual participant data (IPD) on GEM-NAT for BR-PDAC were performed. The primary outcome was OS after treatment with GEM-based chemotherapy. In the Individual Patient Data analysis data were reappraised and confirmed as BR-PDAC on provided radiological data. Results: Six studies investigating GEM-NAT were included in the IPD metanalysis. The IPD metanalysis was conducted on 271 patients who received GEM-NAT. Pooled median patient-level OS was 22.2 months (95%CI 19.1-25.2). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Median OS was 27.8 months (95%CI 23.9-31.6) in the patients who received NAT-GEM followed by resection compared to 15.4 months (95%CI 12.3-18.4) for NAT-GEM without resection and 13.0 months (95%CI 7.4-18.5) in the group of patients who received upfront surgery (p < 0.0001). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Overall survival in the R0 group was 29.3 months (95% CI 24.3-34.2) vs. 16.2 months (95% CI 7·9-24.5) in the R1 group (p = 0·001). Conclusions: The present study is the first meta-analysis combining IPD from a number of international centers with BR-PDAC in a cohort that underwent multi-agent gemcitabine neoadjuvant therapy (GEM-NAT) before surgery. GEM-NAT followed by surgical resection improve survival and R0 resection in BR-PDAC. Also, GEM-NAT may result in a good palliative option in non-resected patients because of progressive disease after neoadjuvant treatment. Results from randomized controlled trials (RCTs) are awaited to validate these findings.

Project description:ImportanceChemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat basis are poorly understood.ObjectiveTo investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy.Design, setting, and participantsThis prospective study took place in a national referral center for pancreatic diseases in Italy. Consecutive patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma were enrolled at the time of diagnosis (January 2013 through December 2015) and followed up to June 2018.ExposuresThe chemotherapy regimen, assigned based on multidisciplinary evaluation, was delivered either at a hub center or at spoke centers. By convention, primary chemotherapy was considered completed after 6 months. After restaging, surgical candidates were selected based on radiologic and biochemical response. All surgeries were carried out at the hub center.Main outcomes and measuresRates of receipt and completion of chemotherapy, rates of conversion to surgery, and disease-specific survival.ResultsOf 680 patients, 267 (39.3%) had borderline resectable and 413 (60.7%) had locally advanced pancreatic ductal adenocarcinoma. Overall, 66 patients (9.7%) were lost to follow-up. The rate of chemotherapy receipt was 92.9% (n = 570). The chemotherapeutic regimens most commonly used included FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) (260 [45.6%]) and gemcitabine plus nanoparticle albumin-bound-paclitaxel (123 [21.6%]). Nineteen patients (3.3%) receiving chemotherapy died within 6 months, mainly for disease progression. The treatment completion rate was 71.6% (408 of 570). The overall rate of resection was 15.1% (93 of 614) (borderline resectable, 60 of 249 [24.1%]; locally advanced, 33 of 365 [9%]; resection:exploration ratio, 63.3%). Independent predictors of resection were age, borderline resectable disease, chemotherapy completion, radiologic response, and biochemical response. The median survival for the whole cohort was 12.8 (95% CI, 11.7-13.9) months. Factors independently associated with survival were completion of chemotherapy, receipt of complementary radiation therapy, and resection. In patients who underwent resection, the median survival was 35.4 (95% CI, 27.0-43.7) months for initially borderline resectable and 41.8 (95% CI, 27.5-56.1) months for initially locally advanced disease. No pretreatment and posttreatment factors were associated with survival after pancreatectomy.Conclusions and relevanceThis pragmatic observational cohort study with an intention-to-treat design provides real-world evidence of outcomes associated with the most current primary chemotherapy regimens used for borderline resectable and locally advanced pancreatic ductal adenocarcinoma.

Project description:Only 15-20% of pancreatic ductal adenocarcinoma (PDAC) patients are upfront surgical candidates at presentation, and for this cohort of patients, the 5-year survival is a mere 20% despite adjuvant therapy. Previous data indicate that in clinical practice most of these cases are "borderline-resectable," and there is currently no mature data on perioperative treatment. We performed a retrospective electronic chart review of patients with "borderline-resectable"PDAC treated at an academic comprehensive cancer center, dividing them into groups based on surgery alone, surgery plus neoadjuvant, adjuvant, or neoadjuvant plus adjuvant perioperative treatment groups. The objectives were to determine the median overall survival (mOS), progression-free survival (PFS) and disease-free survival (DFS). Statistical analysis was performed to assess the association of demographic, tumor traits, and interventions with OS, PFS and DFS. Only surgery followed by adjuvant therapy showed an increase in mOS [hazard ratio (HR) 0.22; 95% CI, 0.09-0.51; P<0.001), after adjustment for radiation (yes vs. no), resection margins (R0 vs. R1 or R2), and tumor location (head vs. body or tail). Patients who received adjuvant therapy after surgery had 2.1 times greater odds to be alive at 24 months after diagnosis than those who had surgery alone (P=0.015). PFS and DFS were not statistically significantly different among treatment groups after adjustment. Those whose disease was located in the head of the pancreas had a significantly improved OS (HR =0.27; 95% CI, 0.11-0.64; P=0.003), PFS (HR =0.40; 95% CI, 0.17-0.94; P=0.035), and DFS (HR =0.30; 95% CI, 0.13-0.67; P=0.004). Negative margins led to a significant improvement in PFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001) and DFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001). Those who received radiation had a non-significantly improved OS, PFS, and DFS (P>0.05). Our study corroborated that patients treated with adjuvant therapy after surgical resection had an mOS benefit as reported on prior phase III clinical trials. Patients with "borderline-resectable" pancreatic cancer are encouraged to participate in a clinical trial or clinically be treated with adjuvant therapy until more mature results from the ongoing perioperative prospective study are available.

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Updates on adjuvant and neoadjuvant treatment strategies for surgically resectable and borderline resectable pancreatic ductal adenocarcinoma.

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