Pancreatic cancer is one of the most lethal solid organ tumors. Due to the rising incidence, late diagnosis, and limited treatment options, it is expected to be the second leading cause of cancer deaths in high income countries in the next decade. The multidisciplinary treatment of this disease depends on the stage of cancer at diagnosis (resectable, borderline, locally advanced, and metastatic disease), and combines surgery, chemotherapy, chemoradiotherapy, and supportive care. The landscape of multidisciplinary pancreatic cancer treatment is changing rapidly, especially in locally advanced disease, and the number of treatment options in metastatic disease, including personalized medicine, innovative targets, immunotherapy, therapeutic vaccines, adoptive T-cell transfer, or stemness inhibitors, will probably expand in the near future. This review summarizes the current literature and provides an overview of how new therapies or new therapeutic strategies (neoadjuvant therapies, conversion surgery) will guide multidisciplinary disease management, future clinical trials, and, hopefully, will increase overall survival.

https://journals.sagepub.com/doi/pdf/10.1177/1758835919875568

An update on treatment options for pancreatic adenocarcinoma.

Importance The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. Objective To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. Design, Setting, and Participants This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. Exposures The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. Results We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28;P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75];P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10;P = .73). Conclusions and Relevance These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment

Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. Primary registry and trial identifying number: EudraCT: 2017–002036-17
 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register – NL7094
 , NL61961.078.17, MEC-2018-004.

/pdf/total-neoadjuvant-folfirinox-versus-neoadjuvant-gemcitabine-2tat71lgwr.pdf

Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial

Approximately 20% of pancreatic ductal adenocarcinoma (PDAC) patients have (borderline) resectable pancreatic cancer [(B)RPC] at diagnosis. Upfront resection with adjuvant chemotherapy has long been the standard of care for these patients. However, although surgical quality has improved, still about 50% of patients never receive adjuvant treatment. Therefore, recent developments have focused on a neoadjuvant approach. Directly comparing results from neoadjuvant and adjuvant regimens is challenging due to differences in patient populations that influence outcomes. Neoadjuvant trials include all patients who have (B)RPC on imaging, while adjuvant-only trials include patients who underwent a complete resection and recovered to a good performance status without any evidence of residual disease. Guidelines recommend neoadjuvant treatment for BRPC patients mainly to improve negative resection margin (R0) rates. For resectable PDAC, upfront resection is still considered the standard of care. However, theoretical advantages of neoadjuvant treatment, including the increased R0 resection rate, early delivery of systemic therapy to all patients, directly addressing occult metastatic disease, and improved patient selection for resection, may also apply to these patients. A systematic review by intention-to-treat showed a superior median overall survival (OS) for any neoadjuvant approach (19 months) compared to upfront surgery (15 months) in (B)RPC patients. A neoadjuvant approach was recently supported by three randomized controlled trials (RCTs). For resectable PDAC, neoadjuvant treatment was superior in a Japanese RCT of neoadjuvant gemcitabine with S-1 vs. upfront surgery, with adjuvant S-1 in both arms (median OS: 37 vs. 27 months, p = 0.015). A Korean trial of neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront resection in BRPC patients was terminated early due to superiority of the neoadjuvant group (median OS: 21 vs. 12 months, p = 0.028; R0 resection: 52 vs. 26%, p = 0.004). The PREOPANC-1 trial for (B)RPC patients also showed favorable outcome for neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront surgery (median OS: 17 vs. 14 months, p = 0.07; R0 resection: 63 vs. 31%, p < 0.001). FOLFIRINOX is likely a better neoadjuvant regimen, because of superiority compared to gemcitabine in both the metastatic and adjuvant setting. Currently, five RCTs evaluating neoadjuvant modified or fulldose FOLFIRINOX are accruing patients.

/pdf/neoadjuvant-treatment-in-patients-with-resectable-and-4zjljt5t4y.pdf

Neoadjuvant Treatment in Patients With Resectable and Borderline Resectable Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.

/pdf/the-current-treatment-paradigm-for-pancreatic-ductal-j0ce4ritgx.pdf

The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy.

Background: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant
FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.
Methods: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with
BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary
endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate,
and grade III–IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.
Results: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with
FOLFIRINOX. Most studies (n ¼ 20) presented intention-to-treat results. The median number of administered neoadjuvant
FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] ¼ 60.1% to 74.6%), and the
R0-resection rate was 83.9% (95% CI ¼ 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patientlevel survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months
(95% CI ¼ 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI ¼ 14.5 to 21.5
months). Pooled event rates for grade III–IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI ¼
10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI ¼ 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI ¼ 8.1 to 14.2).
No deaths were attributed to FOLFIRINOX. Conclusions: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable
median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

/pdf/neoadjuvant-folfirinox-in-patients-with-borderline-3fuoh0jh06.pdf

Kyu Pyo Kim

Papers

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis