Chemotherapy In Resectable Pancreatic Adenocarcinoma Research Articles

Barriers to resection following neoadjuvant chemotherapy for resectable pancreatic adenocarcinoma: A national and local perspective.

Neoadjuvant chemotherapy (NAC) use for pancreatic ductal adenocarcinoma (PDAC) has increased, but some patients never get resection following NAC. Data from January 2012 to December 2019 for all clinically resectable patients across two health networks were utilized, as well as data from the ACS NCDB registry. Univariate testing, multivariable logistic regression, and survival analyses were employed to evaluate failure to resection after neo-adjuvant chemotherapy. Of the 10 007 registry patients eligible for resection, the resected group was younger (64.6 vs. 69.5 years; p < 0.001) and had a slightly lower mean comorbidity index (0.41 vs. 0.45; p < 0.001) than the nonsurgical group. The nonsurgical group was composed of a higher percentage of Black and Hispanic patients (17.5 vs. 13.1%; p < 0.001). After adjusting for age and comorbidities, the factors associated with decreased probability of resection after NAC were evaluation at a community hospital (OR 2.4), Black or Hispanic race (OR 1.6), areas of increased high school drop-out rates (OR 1.4), and lack of private health insurance (OR 1.3). The median overall survival for nonsurgery was markedly worse than the surgical cohort (10.6 vs. 26.6 months; p < 0.001). The most frequent reasons for a lack of definitive resection were operative upstaging to unresectable (39.6%), patient preference (14.5%), progression on NAC (13.2%), deconditioning or comorbidity severity (12.5%), and nonreferral to a surgeon (8.8%). Racial, economic, and educational disparities have a considerable influence on the successful completion of a neoadjuvant approach for resectable PDAC. A comprehensive closed or highly collaborative/communicative multidisciplinary neoadjuvant program is optimal for treatment success and completion.

GATA6 Expression as a predictor of response to perioperative chemotherapy in resectable pancreatic adenocarcinoma: A multicenter Canadian phase II study (NeoPancONE).

TPS638 Background: Prospective studies of the benefit of neoadjuvant chemotherapy in resectable pancreatic adenocarcinoma (PDAC) have been reported. The ideal peri-operative regimen is yet to be determined. Adjuvant FOLFIRINOX (mFFX) in resected PDAC has been proven to improve overall survival (OS) relative to adjuvant gemcitabine. An accepted perioperative approach involves delivering the majority of chemotherapy (6-8 cycles) in the pre-operative setting, while the remainder (of 12 cycles) is administered post-operatively. This pre-operative treatment period may allow for chemosensitivity assessment, and better patient selection for surgery, thereby improving R0 resection rates and reducing the frequency of early post-operative recurrence. Data from the COMPASS trial (NCT02750657) has shown that shown that low levels of the transcription factor GATA6 expression is a putative surrogate for the RNA Moffit signature and predictive of a chemoresistant phenotype in advanced PDAC. NeoPancONE will evaluate clinical outcomes and molecular biomarkers including GATA6 and radiomic biomarkers in pts with resectable PDAC treated with perioperative mFFX. Methods: NeoPancONE is a Phase 2, open-label, single arm study in pts with resectable PDAC. Tissue and serum are collected for biomarker testing, including GATA6 by FISH and IHC (1) with expression levels measured by RNAseq, and longitudinal ctDNA analysis. Pts with histologically confirmed, resectable PDAC and ECOG PS 0-1 will be recruited over 2.5 years. Resectability will be determined by central review as per NCCN guidelines. The primary objective is to evaluate disease-free survival in resectable PDAC treated with peri-operative mFFX according to baseline tumor GATA6 expression level. The ratio of GATA6-high to low is expected to be approximately 4:1[1]. Assuming 1-year disease-free survival of 65% in the GATA6-high, compared to 34% in the GATA6-low cohort, this corresponds to a hazard ratio of 2.5. With 80% power and a 5% 2-sided significance level, a total of 84 patients will be enrolled with 67 events expected in the GATA6 high cohort and 17 in GATA6 low. Participants will receive up to 6 cycles of neoadjuvant mFFX. After neoadjuvant chemotherapy, definitive surgical resection will proceed as deemed appropriate by a hepatobiliary surgeon. Post-operatively, pts will receive up to 6 cycles of adjuvant chemotherapy. Secondary objectives include determination of overall response rate, incidence of R0 resection, OS, Moffit gene expression profiling (RNAseq), ctDNA, and radiomic signatures to predict outcomes. Enrolment for NeoPancONE began in October 2020 and is being conducted at 8 sites across Canada. To date, 23 pts have been recruited. The study duration will be five years. Reference: O’Kane G M et al. Clin Can Res Sep 2020. Clinical trial information: NCT04472910.

Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma

Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial. To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA. This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria. Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2). The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review. From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2. This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria. ClinicalTrials.gov Identifier: NCT02562716.

A Qualitative Review of Neoadjuvant Chemotherapy in Resectable Pancreatic Adenocarcinoma.

The aim of this study was to evaluate outcomes of patients with resectable pancreatic adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. The MEDLINE and PubMed databases were searched to identify relevant original articles investigating neoadjuvant therapy in resectable PDAC. Qualitative analyses were performed to investigate patient selection, disease stage, impact on perioperative outcomes, and cost-effectiveness. Forty-three studies met inclusion criteria for this review. Neoadjuvant chemotherapy for upfront resectable PDAC is cost-effective, safe, may result in lower stage disease and has potential survival advantages. With proper patient selection, neoadjuvant chemotherapy is an appropriate approach for upfront resectable PDAC. Nevertheless, the risk for disease progression and losing a curative surgical window highlights the need for appropriate patient identification, further discovery of superior biomarkers or molecular profiles representative of positive treatment response, and additional prospective comparative study.

Racial disparities in the receipt of adjuvant chemotherapy in patients with resected stage I-III pancreatic adenocarcinoma.

357 Background: Adjuvant chemotherapy for resected pancreatic adenocarcinoma is a category 1 NCCN recommendation, however studies have shown that many patients do not go on to receive chemotherapy after definitive surgery. Whether racial disparities exist for receipt of adjuvant chemotherapy is unknown. Methods: The National Cancer Database was used to identify 28,255 patients with non-metastatic pancreatic adenocarcinoma who underwent definitive surgery between 2005-2014. Multivariable logistic regression defined adjusted odds ratio (AOR) and 95% confidence intervals (CI) of receipt of adjuvant chemotherapy by race. Additional variables included in the model were age, sex, stage, node positivity, comorbidity index, facility type and insurance. Among those receiving chemotherapy, multivariable logistic regression assessed odds of treatment with multiagent chemotherapy and among those not receiving chemotherapy, predictors of chemotherapy refusal were assessed. Results: Compared to white patients, black patients were less likely to receive adjuvant chemotherapy (AOR 0.74, 95% CI 0.64-0.85, p &lt; 0.001) and multiagent adjuvant chemotherapy (AOR 0.80, 95% CI 0.72-0.88, p &lt; 0.001). The disparities were limited to patients with comorbidity score of 0 and persisted when analyses were restricted to only academic cancer centers. Among 2,405 patients not treated with chemotherapy, black patients had lower odds of refusing chemotherapy (AOR 0.72, 95% CI 0.55-0.93, p = 0.01). Conclusions: In this nationally representative study, black patients were less likely to receive NCCN-guideline concordant treatment for resected pancreatic adenocarcinoma; this disparity did not appear to be driven by increased refusal of treatment by black patients. Given that differences in quality of care may contribute to disparities in cancer survival, our findings suggest that outcomes for black patients could be improved by increasing the proportion receiving guideline-concordant adjuvant chemotherapy. Further investigation is needed to identify factors leading to the observed differences in this study, such that appropriate interventions can be undertaken to mitigate this disparity.

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

Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. We did this randomised, open-label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m2 on days 1, 8, 15 every 4 weeks for six cycles (arm A), surgery followed by six cycles of adjuvant PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 every 4 weeks and capecitabine 1250 mg/m2 on days 1-28; arm B), or three cycles of PEXG before and three cycles after surgery (arm C). Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary endpoint was the proportion of patients who were event-free at 1 year. The primary endpoint was analysed in the per-protocol population. Safety analysis was done for all patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, number NCT01150630. Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. PERLAVITA ONLUS and MyEverest ONLUS.

A randomized phase II trial on neoadjuvant chemotherapy in resectable pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a remarkable trend to metastasize early. Accordingly, there is a strong rational to investigate neoadjuvant chemotherapy in patients with resectable disease. We conducted a multicenter randomized phase II trial (PACT-15; NCT01150630) to assess the role of combination chemotherapy in perioperative setting.

Randomized phase 2 trial of peri- or post-operative chemotherapy in resectable pancreatic adenocarcinoma

Randomized phase 2 trial of peri- or post-operative chemotherapy in resectable pancreatic adenocarcinoma

736P - Randomized phase 2 trial of peri- or post-operative chemotherapy in resectable pancreatic adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) has a remarkable trend to metastasize early. Accordingly, there is a strong rational to investigate preoperative chemotherapy in patients with resectable disease. We conducted a multicenter randomized phase 2 trial (PACT-15; NCT01150630) to assess the role of combination chemotherapy in perioperative setting. Methods: Treatment-naïve patients with 18-75 yr, KPS>60 and pathologically confirmed stage 1-2 resectable PDAC were randomized to surgery followed by 6 cycles of adjuvant gemcitabine 1000 mg/m21,8,15q4w (arm A), or PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 1,15q4w and capecitabine 1250 mg/m2/day 1-28) (arm B), or to 3 cycles of PEXG before and 3 after surgery (arm C). The primary endpoint was 1-year event-free survival (EFS); the secondary endpoints were EFS, overall survival (OS), and the difference in pathological findings between arm A+B and arm C. With 24 eligible patients in each group (H0 20%, H1 40%, α 10%, β 20%), ≤16 events of 24 would support further evaluation of experimental therapy. Results: Between September 2010 and April 2015, 88 eligible patients were randomized in 9 Italian centers (arm A: 26, B: 30, C: 32). Basal patients and tumor characteristics were well balanced across arms. One-year EFS (A, B, C) was 6/26 (23%), 15/30 (50%), 23/32 (72%). Median EFS was 4.8, 12.4, 18.9 months (A vs C p=0.002). Three-year OS (A,B,C) was 35%, 42%, 55%. Median OS (A,B,C) was 20.4, 25.1, not reached at 33 months (A vs C p = 0.022). Pathological results are summarized in the table. Treatment safety profile was good.Table736P Pathological findingsA+BCEnrolled5632T resection49 (88%)27 (84%)Intraoperative metasteses7/56 (13%)2/32 (6%)Postoperative metastases10/56 (18%)3/32 (9%)Grade 329/49 (59%)6/27 (22%)T12/49 (4%)4/27 (15%)No13/49 (27%)13/27 (48%)Ro16/49 (33%)15/27 (56%)Median size2.5 cm2.0 cm Open table in a new tab Conclusions: Patients receiving perioperative chemotherapy had significant improvement of EFS and OS as compared to those receiving adjuvant treatment. This trial provides the strongest piece of evidence currently available in favor of preoperative chemotherapy in resectable PDAC. Clinical trial identification: NCT01150630 Legal entity responsible for the study: IRCCS San Raffaele Scientific Institute, Milan, Italy Funding: IRCCS San Raffaele Scientific Institute, Milan, Italy Disclosure: M. Reni: Funding from Celgene, Baxalta, Helsinn, and Merck-Serono; consultant or advisor for Celgene, Baxalta, Merck Serono, Boheringer, Lilly, Pfizer, AstraZeneca, Novocure, Genentech, Halozyme, Novartis. G. Balzano: Advisory role for Celgene. M. Falconi: Research funding to institution from Novartis. L. Gianni: Consulting/advisory role for Roche, Pfizer, GlaxoSmithKline, Synthon, Taiho Pharmaceutical, AstraZeneca, Genomic Health, Merck Sharp & Dohme, Boehringer Ingelheim, Tiziana Pharma, Synaffix, Celgene; patents/royalties/intellectual property with Roche. All other authors have declared no conflicts of interest.

Optimal adjuvant chemotherapy for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis.

Adjuvant chemotherapy improves survival in patients with resected pancreatic cancer but the optimal regimen remains unclear. We aim to compare all possible adjuvant chemotherapy in terms of overall survival and toxic effects. Pubmed, Trial registries and Cochrane library databases for randomized controlled trials were searched until November 2016. Thirteen trials were included for network analysis and the hazard ratios (HRs) for survival and odds ratios for toxic effects were assessed via Aggregate Data Drug Information System software. Only S-1 chemotherapy improved 1-year, 3-year and 5-year survival compared with observation (HR (95% CI): 3.94 (1.18–12.34); 4.08 (1.58–8.24) and 5.09 (1.16–29.83) respectively). Although not significant, gemcitabine plus uracil/tegafur was associated with poorer 1-year and 3-year survival compared with observation (HR (95% CI): 0.85 (0.16–4.03) and 0.86 (0.23–2.95)). Adding radiation to chemotherapy has no significant improvement in survival. S-1 and gemcitabine plus capecitabine are currently the most effective adjuvant therapies for pancreatic cancer. While S1 has only been validated in Asian people, higher toxicity is an issue for gemcitabine plus capecitabine.

Does adjuvant therapy improve overall survival for stage IA/B pancreatic adenocarcinoma?

BackgroundCurrent guidelines recommend adjuvant chemotherapy for resected pancreatic adenocarcinoma (PDAC). However, no studies have addressed its survival benefit for stage I patients as they comprise <10% of PDAC. MethodsUsing the NCDB 2006–2012, resected PDAC patients with stage I disease who received adjuvant therapy (chemotherapy or chemoradiation) were analyzed. Factors associated with overall survival (OS) were identified. Results3909 patients with resected stage IA or IB PDAC were identified. Median OS was 60.3 months (mo) for stage IA and 36.9 mo for IB. 45.5% received adjuvant chemotherapy; 19.9% received adjuvant chemoradiation. There was OS benefit for both stage IA/IB patients with adjuvant chemotherapy (HR = 0.73 and 0.76 for IA and IB, respectively, p = 0.002 and <0.001). For patients with Stage IA disease (n = 1,477, 37.8%), age ≥70 (p < 0.001), higher grade (p < 0.001), ≤10 lymph nodes examined (p = 0.008), positive margins (p < 0.001), and receipt of adjuvant chemoradiation (p = 0.002) were associated with worse OS. For stage IB patients (n = 2,432, 62.2%), similar associations were observed with the exception of adjuvant chemoradiation whereby there was no significant association (p = 0.35). ConclusionAdjuvant chemotherapy was associated with an OS benefit for patients with stage I PDAC; adjuvant chemoradiation was either of no benefit or associated with worse OS.

Is adjuvant radiation plus chemotherapy for resectable pancreatic adenocarcinoma associated with improved survival? The Cleveland Clinic experience

15528 Background: A large single-institution series of pts who recently underwent pancreaticoduodenectomy for resectable pancreatic cancer was analyzed to determine prognostic factors for overall survival (OS), including the impact of adjuvant radiation (XRT) and chemo (CT). Methods: Medical records were reviewed for 179 consecutive pts tx'd at The Cleveland Clinic w/ pancreaticoduodenectomy for resectable pancreatic adenoca. from 10/1999 to 12/2006. Clinical data was collected, Kaplan Meier method was used to estimate OS, and univariate/multivariate analysis was performed. Results: 179 pts with T1–3N0–1M0 pancreatic cancer met the above criteria. Median age at surgery was 67 (range 35–93) and median length of post-op hospital stay was 10 days. Peri-op mortality rate was 0.6%. 77% pts were R0 and 31% N0. Median OS for R0 pts = 20 mths [vs 16.3 mths for R1 (p=.86)]. Median OS for pts tx'd w/ XRT + CT was 28.1 mths [vs. 10.9 mths for pts receiving no adj. tx (p=.001)] (see table). In pts who relapse, the liver is the most common site (>50%). On univariate analysis, poor prognostic factors for OS were: poorly diff. histology (p=.002), >1 positive lymph node (p=.02), elevated AlkPhos (p=.01), elevated total bilirubin (p=.02), elevated AST (p=.05), age at dx >70 (p=.05), and high T-stage (p=.06). On multivariate analysis, poorly diff. histology, age >70, and elevated LFT's (AlkPhos or bilirubin or AST) were independent predictors of OS. Conclusions: In the 21st century, curative-intent surgery for pancreatic cancer at large academic institutions can have very low mortality rates. Pts who receive adj. XRT + CT appear to live longer than pts who receive no adjuvant therapy in this retrospective analysis. Pathology findings are valuable prognostic markers in resected pancreatic cancer. Few studies have examined the prognostic value of pre-op LFT's; our analysis indicates they may have predictive value - this should be confirmed in other series. Adj. Tx % pts Median OS (mths) XRT/CT + CT 22 23.3 XRT/CT 40 28.1 CT only 12 >28 No adj. tx 26 10.9 All pts - 19.6 No significant financial relationships to disclose.