Messersmith, Wells A.

Abstract Background The increased use of superior mesenteric artery (SMA) divestment has been a driver behind the increased resection rate for locally advanced pancreatic cancer following preoperative therapy. This has also resulted in an increase in the rate of postoperative neurogenic diarrhoea, but knowledge about postoperative neurogenic diarrhoea is lacking. The aims of this study were to determine the incidence, risk factors, management, and outcomes of neurogenic diarrhoea after SMA divestment/resection for pancreatic adenocarcinoma. Methods This multicentre retrospective study included consecutive patients undergoing pancreatic adenocarcinoma resection, including SMA divestment/resection, after preoperative chemotherapy with or without radiotherapy between 2016 and 2022. Primary endpoints were the incidence of postoperative neurogenic diarrhoea, associated factors, treatment strategies, and outcomes. Secondary endpoints were the rate of adjuvant chemotherapy and the impact of neurogenic diarrhoea on overall survival (OS). Results Overall, 291 patients who underwent pancreatic resection with concomitant SMA divestment (240, 82%) or resection (51, 18%) were included in the study. Postoperative neurogenic diarrhoea was diagnosed in 193 patients. The adjusted risk of developing neurogenic diarrhoea was 59% (95% confidence interval (c.i.) 46 to 73) after ≤ 180° SMA divestment, 80% (95% c.i. 67 to 93) after > 180° SMA divestment, and 77% (95% c.i. 66 to 88) after SMA resection. Postoperative neurogenic diarrhoea was treated with non-opioid drugs (29, 15%), non-opium opioids (140, 73%), opium tincture (69, 36%), and/or octreotide (49, 25%), and normalized in 51% of patients. After adjusting for confounders, neurogenic diarrhoea was not significantly associated with OS (hazard ratio 0.83; 95% c.i. 0.55 to 1.25). Conclusion Neurogenic diarrhoea occurred in two-thirds of patients following resection of pancreatic adenocarcinoma with concomitant SMA divestment/resection, particularly after > 180° SMA divestment or SMA resection. Although challenging to manage, neurogenic diarrhoea is not associated with impaired OS. Evidence-based treatment strategies are needed for adequate management.

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

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a “watch-and-wait” nonoperative management approach for clinical complete responders to neoadjuvant therapy.

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 .

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a “watch-and-wait” nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org , covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

Background This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor). Methods Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100–400 mg once a day) plus epacadostat (50–300 mg two times per day; group A), or itacitinib (100–400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3–10 mg once a day; group B). Results A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8+ T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8+ T cell infiltration. Conclusion Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment. Trial registration number NCT02559492.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation–positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org . Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.