Locally Advanced Pancreatic Ductal Adenocarcinoma Research Articles

Total neoadjuvant treatment for pancreatic adenocarcinoma is associated with limited lymph node yield but improved ratio

Presenter: Maitham Moslim MD | Fox Chase Cancer Center Background: The lymph node yield (LNY) and lymph node ratio (LNR) of nodal metastases to total harvested lymph nodes after pancreatoduodenectomy (PD) have been reported as essential parameters for the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). We present the first study comparing LNY and LNR in the setting of different neoadjuvant therapy approaches for PDAC. Understanding the influence of neoadjuvant therapy on LNY may help reassess the minimal requirement of 12 harvested lymph nodes to achieve adequate oncologic staging in PDAC. Methods: 134 patients diagnosed with resectable, borderline-resectable and locally-advanced PDAC who underwent PD between 2010-2019 were identified. Pathology reports were examined to obtain LNY and calculate LNR. Patients were categorized based on first-line treatment as: surgery first (SF), total neoadjuvant therapy (TNT) and non-TNT neoadjuvant therapy (NTNT). Patients who received TNT were stratified in three groups: incomplete TNT, induction TNT (chemotherapy prior to chemoradiotherapy) and consolidation TNT (chemoradiotherapy prior to chemotherapy). Results: 49 patients (36.6%), 38 (28.4%), 12 (9%), 27 (20%) and 8 (6%) underwent SF approach, NTNT, induction TNT, incomplete TNT and consolidation TNT, respectively. Patients who underwent the SF approach were older than the induction TNT group (median: 71 vs. 62 years, respectively; p = 0.0068). There were no statistically significant differences between groups comparing gender and index cancer antigen 19-9 (CA 19-9) levels (p = 0.95 and 0.62, respectively). Preoperative evaluation of sectional imaging declared 8.2% of tumors borderline resectable in the SF group, while this percentage was significantly higher in the NTNT, induction TNT, incomplete TNT and consolidation TNT groups (63,2%, 70.2%, 75% and 75%, respectively; p = < 0.0001). There was no difference in R0 resection and vascular resection between the groups (p = 0.09 and 0.79, respectively). The median counts of LNY on final pathology were 22, 15, 21, 11.5 and 10 for the SF approach, NTNT, incomplete TNT, induction TNT and consolidation TNT, respectively (p<0.0001). The median LNR was 0.16, 0.07, 0.03, 0.02 and 0.02, respectively (p = 0.0002). No significant differences in postoperative CA19-9 levels or recurrence rates between the groups were noted (p = 0.24 and p = 0.81). There was no difference in overall survival (OS) or disease-free survival (DFS) between the treatment groups. Conclusion: PDAC patients who undergo TNT prior to PD exhibits lower LNY and improved LNR compared to the SF approach and non-TNT neoadjuvant therapy groups, although no significant differences were demonstrated in DFS or OS. This is likely explained by the increased treatment response and lymph node obliteration associated with the TNT approach. Our study questions the minimal requirement of 12 harvested lymph nodes in patients who undergo PD for PDAC following TNT.

Multiparametric MRI for prediction of treatment response to neoadjuvant FOLFIRINOX therapy in borderline resectable or locally advanced pancreatic cancer.

To identify multiparametric MRI biomarkers to predict the tumor response to neoadjuvant FOLFIRINOX therapy in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). From May 2016 to March 2018, adult patients with BR or LA PDAC were prospectively enrolled in this study. They received eight cycles of FOLFIRINOX therapy and underwent multiparametric MRI twice (at baseline and after the second cycle). MRI evaluations included dynamic contrast-enhanced MRI, intravoxel incoherent motion diffusion-weighted imaging, and assessment of T2* relaxivity (R2*) and the change in T1 relaxivity (ΔR1, equilibrium phase R1 minus non-enhanced R1) of the tumors. Factors to predict the responders determined by the best overall response during FOLFIRINOX therapy and those to predict progression-free survival (PFS) and overall survival (OS) were evaluated using multivariable logistic regression and the Cox proportional hazard model. Forty-one patients (mean age, 60.3 years ± 9.3; 24 men) were included. Among the clinical and MRI factors, the baseline ΔR1 (adjusted odds ratio, 31.07; p = 0.008) was the only independent predictor for tumor response. The baseline ΔR1 was also an independent predictor for PFS (adjusted hazard ratio, 0.40; p = 0.033) along with R0 resection. The use of a cutoff ΔR1 value of ≥ 1.31 s-1 enabled prognostic stratification (median PFS, 16.0 months vs.10.0 months; p = 0.029; median OS, 34.9 months vs. 16.6 months; p = 0 .023, respectively). The baseline tumor ΔR1 value may be useful to predict tumor response and survival in patients with BR or LA PDAC receiving FOLFIRINOX neoadjuvant therapy. • Baseline ΔR1 was an independent predictor for tumor response (adjusted odds ratio, 31.07; p = 0.008) and progression-free survival (adjusted hazard ratio, 0.40; p = 0.033) in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant FOLFIRINOX therapy. • The criterion of baseline ΔR1 value ≥ 1.31 s-1 allowed for the prediction of favorable tumor response and survival outcome after neoadjuvant FOLFIRINOX therapy.

A Single-Institution Experience of Induction 5-Fluorouracil, Leucovorin, Irinotecan, and Oxaliplatin Followed by Surgery Versus Consolidative Radiation for Borderline and Locally Advanced Unresectable Pancreatic Cancer.

In the 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) era, the benefit of surgery versus definitive radiation for borderline resectable (BR) and locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC) is not well defined. Our primary objective was to identify the survival impact of surgery for BR and LA unresectable PDAC treated with induction FOLFIRINOX. We performed a single-center retrospective review of BR and LA PDAC treated with FOLFIRINOX from 2010 to 2018. The overall survival of surgery and consolidative radiotherapy was estimated in the Kaplan-Meier method and compared via the log-rank test. Subgroup analyses were conducted for BR and LA patients. We identified 101 BR and LA PDAC patients treated with induction FOLFIRINOX (41 surgeries and 60 consolidative radiotherapies). Surgery patients were 68.3% (28/41) BR and 31.7% (13/41) LA, whereas consolidative radiotherapy patients were 30% (18/60) BR and 70% (42/60) LA. The R0 resection rate was 100%, and 46.3% (19/41) received preoperative radiation. Median overall survival of surgery versus consolidative radiotherapy was 42.3 versus 19.6 months, respectively (P < 0.001). On multivariate analysis, surgery associated with improved survival. Surgery after induction FOLFIRINOX is feasible and has a clinically meaningful survival benefit in BR and LA PDAC.

Conversion Surgery for Pancreatic Cancer-The Impact of Neoadjuvant Treatment.

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis, mainly because only 15–20% of all patients present with resectable tumor stages at the time of diagnosis. Due to locally extended tumor growth or distant metastases upfront resection is not reasonable in the majority of patients. Considerably, PDAC will be the 2nd most frequent cause of cancer-related deaths within the next 10 years for both men and women. While there is currently no convincing evidence for the use of neoadjuvant therapy in resectable PDAC, there are controversial results from studies investigating neoadjuvant treatment concepts in borderline resectable PDAC (BR-PDAC). However, the definition of BR-PDAC is a topic of debate. While BR-PDAC has originally been defined on merely anatomical criteria, the International Association of Pancreatology (IAP) has recently suggested a broader definition based on a combination of anatomical (A) findings, biological (B) criteria (which reflect tumor aggressiveness), and conditional (C) aspects (which respect host-related condition). In case of BR-PDAC with venous invasion alone, upfront resection is generally recommended whenever technically possible in patients fit for surgery and without evidence for lymph node metastases. In contrast, in case of arterial invasion neoadjuvant therapy is regarded as the treatment of choice. The same accounts for high CA 19-9 levels, suspected or proven lymph node involvement and poor performance status. In locally advanced PDAC (LA-PDAC), neoadjuvant treatment represents the standard of care resulting in proportionally high rates of secondary resection. This “conversion” surgery offers the chance for improved survival times in an otherwise palliative situation. Herein, we summarize the current evidence of different treatment strategies for pancreatic cancer with a focus on conversion surgery and the impact of neoadjuvant treatment in this setting.

Abstract B05: Paclitaxel protein bound plus gemcitabine plus cisplatin and paricalcitol neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: Localized PDAC management has recently evolved. Due to concerns over micrometastases at diagnosis, the use of neoadjuvant chemotherapy for PDAC has become more common. Typical therapies involve the use of multiagent systemic chemotherapy with or without radiation therapy. Cancer antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A) has shown promising clinical data in a previously reported study in advanced PDAC (J Clin Oncol 2017;35:suppl 4S; abstract 341). We conducted a prospective, phase 2 clinical trial of patients with resectable, BR, and LA PDAC utilizing a regimen combining A + G + C + paricalcitol (P) with the primary endpoint of CA 19-9 normalization (NCT03138720). Methods: Eligibility criteria include patients with histologically confirmed resectable, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2, P at a fixed dose of 25 μg on days 1, 8 of a 21-day cycle (all treatment IV). Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate, and 2-year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date, 21 of the planned 24 patients have been enrolled: 11 male, 10 female; age range 49 to 85 yo. Patient classifications are 7 R; 7 BR; 7 LAPC. Most common drug-related grade (gr) 3-4 adverse events (AEs) are thrombocytopenia gr 3 40%, gr 4 33%, anemia gr 3 60%, and hypophosphatemia 13%. Of the 21, 16 are evaluable for maximum percent decrease in CA 19-9. CA 19-9 normalization occurred in 44% (7/16) who have completed at least 1 cycle of treatment. To date, 9 individuals went to surgery, with 8/9 achieving R0 (no pCR). Overall response rate in measurable patients is 26% (4/15 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with nonmetastatic PDAC, the use of A+G+C+P resulted in a CA 19-9 normalization rate in 44% of individuals. The study is ongoing and OS data are maturing. (Supported by grants from the HonorHealth Foundation and Marley Foundation.) Citation Format: Erkut Borazanci, Gayle Jameson, Courtney Snyder, Frank Tsai, Michael Gordon, Sunil Sharma, Carol Guarnieri, Amar Thosani, Syed Rahmanuddin, Ronald Korn, Steven Sckolnik, Paula Sedivy, Susan Haag, Kevin Gosselin, Daniel Von Hoff, Albert Amini. Paclitaxel protein bound plus gemcitabine plus cisplatin and paricalcitol neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B05.

A Single Institution Experience of Induction FOLFIRINOX Followed by Surgery vs Consolidative Radiation for Borderline and Locally Advanced Unresectable Pancreatic Cancer

Background: Induction FOLFIRINOX is increasingly used for borderline resectable (BR) and locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC), but the benefit of surgery versus consolidative radiation in the FOLFIRINOX era is not well defined. Single institution experiences have included FOLFIRINOX with gemcitabine-based chemotherapy, lack a uniform comparator group to surgery, or are limited to surgical patients after FOLFIRINOX. No prospective clinical trials have assessed surgery versus radiation. Therefore, our primary objective was to identify the long-term survival impact of surgery versus radiation for BR and LA unresectable PDAC treated with induction FOLFIRINOX. Methods: We performed a single center retrospective review of BR and LA PDAC treated with FOLFIRINOX from 2010 - 2018. Patients were divided into two cohorts based on receipt of surgery versus consolidative radiotherapy. Findings: We identified 101 BR and LA PDAC patients treated with induction FOLFIRINOX; 40 underwent surgery and 61 received consolidative radiotherapy. The surgery group was 28/40 (70%) BR and 12/40 (30%) LA, while consolidative radiotherapy was 18/61 (30%) BR and 43/61 (70%) LA. The R0 resection rate was 100% for surgery and 18/40 (45%) received radiation prior to surgery. Median overall survival (OS) for surgery was 42·3 months (95% CI 24·6 - not reached) compared to a median OS of 19·6 months (95% CI 16·3 - 24·6) with consolidative radiotherapy(p = 0·0001). On multivariate analysis, surgery was associated with improved OS (HR 0·35, 95% CI 0·17 - 0·71, p=0·004). Interpretation: Surgery after induction FOLFIRINOX is feasible and has a clinically meaningful survival benefit in BR and LA PDAC compared to induction FOLFIRINOX followed by consolidative radiotherapy. Funding Statement: This research was not supported by any funding. Declaration of Interests: The authors declare no conflicts of interest relevant to this manuscript. Ethics Approval Statement: This study was approved by the Yale University institutional review board.

Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer.

To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT). The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined. We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints. One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) [overall survival (OS)] rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response. Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.

Common Hepatic Artery Abutment or Encasement Is an Adverse Prognostic Factor in Patients with Borderline and Unresectable Pancreatic Cancer

BackgroundLocalized and unresectable pancreatic ductal adenocarcinoma (PDA) comprises one third of new diagnoses and includes borderline resectable (BR) and locally advanced (LA) unresectable disease. In a cohort of patients who were treated and followed at a single institution, we assessed clinical and radiographic predictors of outcome. MethodsThe study included 69 consecutive patients with BR or LA PDA. Serial imaging studies were reviewed by both a pancreatic surgeon and a radiologist for vascular abutment or encasement by cancer, and they were recorded. ResultsThe cohort included 25 patients with BR and 44 patients with LA PDA, with median overall survivals (OS) of 15 and 14 months, respectively (p = 0.802). Fifteen patients were resected (22%), with a median OS of 21 months from diagnosis (HR 2.50, p = 0.006) and 13 months from resection. Median OS from diagnosis was 33 months in patients without lymph node metastases at resection (n = 10), but just 17 months with lymph node metastases (n = 5, HR = 8.95, p = 0.011). There were 12 two-year survivors in the total cohort (17%), and seven of them never underwent resection. First-line treatments consisted of gemcitabine (n = 13), modern first-line combinations (FOLFIRNOX or gemcitabine/nab-paclitaxel, n = 24), or alternative multi-agent therapies (n = 32); there were no statistical differences between treatment subgroups (OS of 10, 13, and 16 months, respectively). Common hepatic artery (CHA) abutment or encasement at diagnosis was associated with poor survival (adjusted hazard ratio, CHA abutment = 2.47 (p = 0.015) and CHA encasement = 2.16 (p = 0.036)). ConclusionIn this cohort, common hepatic arterial abutment or encasement and residual lymph node disease at resection portended a particularly poor outcome in patients with localized, unresectable PDA.

Results of a prospective phase 2 clinical trial of induction gemcitabine/capecitabine followed by stereotactic ablative radiation therapy in borderline resectable or locally advanced pancreatic adenocarcinoma

PurposeStereotactic ablative radiation therapy’s (SABR’s) great conformity and short duration has become an attractive treatment modality. We report a phase 2 clinical trial to evaluate efficacy and safety of induction chemotherapy (ICT) followed by SABR in patient with borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Methods and materialsPatients with biopsy-proven BR or LA PDAC were treated with four 21-day cycles of intravenous gemcitabine and oral capecitabine. Patients were restaged within 4 weeks after ICT by computed tomography and treated by 3-fraction SABR if no metastasis or progressive disease was identified. Patients were restaged 4 weeks following SABR to determine resectability. Tumor response was assessed with carbohydrate antigen 19-9. ResultsThirty-five patients (19 BR/16 LA) were enrolled. The median age was 71.8 years (range, 50.6-81.1). ICT was completed in 91.4% (n = 32) of patients. All patients who completed ICT completed SABR. Of those 32 patients, 34.3% (n = 12: 10 BR, 2 LA) underwent pancreaticoduodenectomy and 11 of 12 (91.7%) received R0 resection. Median overall survival was 18.8, 28.3, and 14.3 months for the entire cohort, BR, and LA, respectively. The 2-year local progression-free survival (LPFS) was 44.9%, 40%, and 52% for the entire cohort, BR, and LA, respectively. For BR patients, multivariate analysis showed surgery was associated with better overall survival and LPFS. One-year LPFS for patients with surgery was 80% and 44% without surgery. Within the 15.4-month follow-up, no grade 3+ toxicity from SABR was observed. No significant quality of life change was observed before and after ICT, SABR, or surgery for BR or LA patients. ConclusionsThis is the first prospective phase 2 study to investigate the feasibility and efficacy of a 12-week gemcitabine/capecitabine ICT followed by SABR for BR or LA PDAC. The results suggest excellent tolerability, high R0 resection rates, and acceptable posttreatment complications.

Outcomes with FOLFIRINOX for locally advanced pancreatic cancer.

256 Background: Trials examining the use of FOLFIRINOX in metastatic pancreatic ductal adenocarcinoma demonstrate significantly higher response rates compared to gemcitabine-based regimens. These high response rates may be particularly important for patients with locally advanced pancreatic ductal adenocarcinoma (LAPD), in which there is currently limited experience with FOLFIRINOX. We examined the outcomes of patients with LAPD treated with neoadjuvant FOLFIRINOX at our high volume clinic. Methods: Retrospective review of a prospectively maintained pancreatic cancer database was used to identify patients who were recommended neoadjuvant treatment with FOLFIRINOX. Clinical outcomes were reviewed. Resectability was determined using SSO criteria. Results: Between 2/2011 and 9/2012 FOLFIRINOX was recommended for 25 patients with LAPD, 13 (52%) unresectable (UR) and 12 (48%) borderline resectable (BR). Median age was 59. 4 patients (16%) either refused treatment or were lost to follow up. 21 patients (84%) were treated with a median of 4.7 cycles (Range: 2-8). 5 patients (24%) required dose reductions secondary to toxicity. 2 patients (9%) were unable to tolerate treatment and 3 patients (14%) had disease progression on treatment. Of the remaining 16 patients, 13 patients (62%) displayed a radiologic response allowing for surgical exploration, 4 (31%) of which were initially unresectable. 6 of these patients (29%) received additional chemotherapy and/or radiation therapy prior to surgery. Peritoneal metastases were discovered at surgery in 2 (8%) patients. Of the patients who were BR, 7/8 (88%) had a R0 resection. Of the 10 UR patients, 3 (33%) underwent surgical resection, with 2 (20%) R0 resections. Overall R0 resection rate was 43%. A total of 4 patients (19%) demonstrated a major pathologic response (2 complete responses and 2 near complete responses) and 8 other patients (73%) had some pathological response. Conclusions: FOLFIRINOX alone or as part of multimodality approach is a biologically active regimen in LAPD with encouraging R0 resection rates, especially in BR LAPD. Further research is needed to determine the utility of additional chemoradiotherapy with FOLFIRINOX and to identify predictors of response in UR patients.