Weekes, Colin D.

Abstract Background Surgical resection without visible or residual microscopic disease (R0 resection) is known as the optimal path to cure localized pancreatic cancer (PDAC). Neoadjuvant therapy (NAT) is used to improve R0 resection rates; however, the optimal regimen is unclear. We assessed the safety and efficacy of peri-operative gemcitabine/nab-paclitaxel (GEM/NAB) and pre-operative stereotactic body radiotherapy (SBRT) in patients with resectable (R-PDAC) and borderline resectable PDAC (BR-PDAC). Patients and Methods This was a prospective, multicenter single arm phase 2 study in patients with R-PDAC and BR-PDAC. Patients received three cycles of GEM/NAB prior to SBRT followed by surgery and three cycles of adjuvant GEM/NAB. Primary endpoint was R0 surgical resection rate in each cohort. Secondary endpoints included safety and overall survival (OS). Results Eighty-six patients consented and following radiologic screening, 49 were enrolled into two cohorts: R-PDAC (n = 20) and BR-PDAC (n = 29) between June 2016 and April 2021. Seventy percent of R-PDAC (14/20) and 55.2% of BR-PDAC patients (16/29) completed all NAT. Eleven R-PDAC (55.0%) and 11 BR-PDAC patients (37.9%) underwent surgical resection. Nine R-PDAC (45.0%) and 9 BR-PDAC patients (31.0%) had R0 resections. The median OS for R-PDAC and BR-PDAC patients with R0 resections was 22 months (95% CI: 17.7 months-NA) and 39 months (95%CI: 13.21 months-NA), respectively. Conclusion While the trial failed to meet one of its primary objectives as only 45% of R-PDAC patients had an R0 resection, the objective of 30% R0 resection for the BR-PDAC group was met. NAT should be part of current therapeutic strategies for BR-PDAC; however, our trial does not answer what is the best NAT for BR-PDAC. Trial Registration NCT02723331

4175 Background: Patients (pts) with pancreatic adenocarcinoma (PDAC) who are candidates for surgery are anatomically segregated into two groups: those with resectable tumors (R-PDAC), and those with borderline resectable tumors (BR-PDAC). For each group, complete surgical resection with no visible or microscopic disease left behind (R0 resection) is generally accepted as the path to cure. Neoadjuvant therapy (NAT) has been used to improve the R0 resection rate. However, the optimal role and type of NAT that will improve R0 resection rate and overall survival (OS) remains controversial. The Academic Gastrointestinal Cancer Consortium (AGICC) evaluated a perioperative strategy with combination chemotherapy and preoperative stereotactic radiation therapy (SBRT) to improve the R0 resection rate. Methods: This prospective, multicenter open label, single arm phase 2 clinical trial conducted among 5 member AGICC institutions enrolled pts with R-PDAC and BR-PDAC. Treatment included 3 cycles of gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) (GEM/NAB) on days 1, 8 and 15 of a 28-day cycle prior to SBRT (33Gy: 6.6Gy daily x 5) followed by surgery and 3 cycles of adjuvant GEM/NAB. Accrual goal was 20 R-PDAC and 30 BR-PDAC pts selected by central radiology review. Primary objective was to estimate the R0 resection rate for each cohort. Secondary objectives included safety and tolerability of neoadjuvant treatment and OS. Results: Eighty-six pts signed consent and after radiologic screening, 20 R-PDAC patients and 29 BR-PDAC patients were found eligible to begin treatment. One R-PDAC and two BR-PDAC pts did not initiate therapy. 14 (70%) and 19 (66%) R-PDAC and BR-PDAC pts, respectively, completed all neoadjuvant chemotherapy.14 R-PDAC (70%) and 17 BR-PDAC (59%) pts completed SBRT. 11 R-PDAC pts (55%) and 11 (38%) BR-PDAC, underwent surgery. 8 R-PDAC pts (40%) had an R0 resection. One R-PDAC pt had a complete pathologic response (pCR). 8 BR-PDAC pts (28%) had an R0 resection. 19% (3/16) pts undergoing an R0 resection are alive (47-73+ mos). 16 pts (32%) had at least one grade ≥ 3 non-hematologic adverse event (AE); 25 patients (51%) had at least one grade ≥ 3 hematologic AE. 8 pts, 4 R-PDAC and 4 BR-PDAC were hospitalized prior to surgery. One pt (2%) died during NAT. There were no deaths due to surgery. Conclusions: R0 resection rates and survival in R-PDAC and BR-PDAC were low despite a perioperative approach of systemic therapy and SBRT. The lack of survival benefit of GEM/NAB as an adjuvant regimen, as well as SBRT pre-operatively (both shown in studies subsequent to this one) may explain the disappointing results. While an R0 resection for localized PDAC is recognized as essential, our results demonstrate that an R0 resection is not sufficient to cure the majority of PDAC pts who receive NAT with GEM/NAB + SBRT. Future NAT therapy trials should aim to markedly improve the pCR rates associated with R0 resection. Clinical trial information: NCT02723331 .

Objectives We evaluated the outcomes of metastatic pancreatic cancer (MPC) patients who underwent liver metastases (LMs)–directed ablative radiotherapy (RT) and sought to characterize patients with more favorable prognosis. Methods A retrospective analysis of 76 MPC patients who underwent ablative RT (median dose, 50 Gy) to LM at 3 academic centers between 2008 and 2018 was performed. Endpoints were local control (LC), progression-free survival, and overall survival (OS) since RT. Results Median follow-up was 10.9 months. Liver metastases were metachronous in 68%. Before RT, LM was responsive/stable on chemotherapy (CTX) in 36% whereas progressive in 43%. Median carbohydrate antigen 19-9 (CA 19-9) at RT was 334 U/mL. After RT, 32% had ≥6 months of CTX break. Twelve-month outcomes were: LC, 66%; progression-free survival, 7%; and OS, 38%. On multivariable analysis, Eastern Cooperative Oncology Group 2–3 (hazard ratio [HR], 13.49; P < 0.01), progressive LM on CTX (HR, 3.26; P < 0.01), and higher CA 19-9 (log 10 scale; HR, 1.39; P < 0.01) at RT predicted worse OS. Conclusions Ablative RT to LM in setting of MPC may offer LC of systemic disease and thus quality time off CTX. Selected patients with good performance status, stable/responsive LM on CTX, and lower CA 19-9 have more favorable prognosis.

Most health care professionals spend a substantial amount of their time at the workplace. Our interactions with team members can define our daily experiences, impact our work performance, and influence our overall job satisfaction. Over the last years, how we interact with colleagues and patients has changed with the introduction of social media, a tenser political climate, and an evolving health care system. In oncology, a team can be composed of medical students, clinicians, and support and administrative staff within a heavy emotional environment where some of our patients are facing the risk of early mortality and most are dealing with the unmeasurable burden of cancer. Many of these factors can increase the risk for professionalism lapses. We discuss common challenges faced in the practice of cancer care, including the generational gap between medical trainees and senior members, gender disparities, and microaggressions. Microaggressions represent verbal, behavioral, and environmental indignities that communicate hostile, derogatory, and negative slights that insult a target person or group. Microaggressions should not be accepted as the norm in the workplace. It is essential to recognize these negative behaviors and manage them effectively to reduce or even prevent the long-term toxicities that these behaviors can bring to the workplace environment. Ultimately, we must acknowledge that these issues exist and remember that education and collaboration are the pillars of an inclusive workplace. We owe such efforts to our patients who deserve good care, to our partners in the care of patients so that they feel supported and included, and to ourselves.

Abstract DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2–2.8 mg/kg; q3w) or weekly (0.8–1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer. Mol Cancer Ther; 15(3); 439–47. ©2016 AACR.

Abstract Background. nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. Materials and Methods. Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. Results. Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. Conclusion. The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.