Distinct Indications for Adjuvant Therapy in Resected Invasive Mucinous Cystic Neoplasms of the Pancreas Compared with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN. PATIENTS AND METHODS: The National Cancer Database (2004-2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed. RESULTS: For 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47-11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02-6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47-5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28-12.27; p < 0.001), and stage III disease (HR 12.46, 95% CI 1.40-111.05; p = 0.024) were associated with worse OS. Receipt of adjuvant systemic therapy was independently associated with decreased risk of mortality in node positive patients (HR 0.23, 95% CI 0.10-0.69; p = 0.002). Survival was not associated with adjuvant therapy in patients with negative lymph nodes or margin negative status. CONCLUSION: In contrast to pancreatic ductal adenocarcinoma (PDAC), where adjuvant therapy improves OS for every tumor stage, surgery alone for invasive MCN is not associated with improved OS compared with surgery plus adjuvant therapy in node-negative patients. Surgery alone is likely sufficient for a subset of invasive MCN.

Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.

BACKGROUND: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.

PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

Long-Term Survival Outcomes After Minimally Invasive Surgery for Ileal Neuroendocrine Tumors.

BACKGROUND: Ileal neuroendocrine tumors (i-NETs) are characterized by their multifocality and bulky mesenteric mass. Having shown that minimally invasive surgery (MIS) utilizing a hand-access port device has favorable short-term outcomes and achieves the goals of surgery for i-NETs, we sought to analyze long-term survival outcomes of MIS. METHODS: One hundred and sixty-eight patients who underwent resection of primary i-NETs at a single institution between January 2007 and February 2023 were retrospectively studied. Patients were categorized into the MIS or open surgery cohorts on an intention-to-treat basis. Open surgery was selected mainly based on the need for hepatectomy or bulky mesenteric mass resection. Overall survival was analyzed using log-rank tests with propensity score matching (PSM) and Cox proportional hazards regression. PSM was performed to reduce standardized mean differences of the variables to <0.2. RESULTS: Overall, 129 (77%) patients underwent MIS and 39 (23%) underwent open surgery. Twenty-seven MIS patients were converted to an open procedure. The median follow-up time was 49 months (interquartile range 23-87 months). In the PSM cohorts, overall survival did not differ significantly between the MIS and open surgery cohorts {median 99 months (95% confidence interval [CI] 91-not applicable [NA]) vs. 103 months (95% CI 86-NA), p = 0.77; hazard ratio 0.87 (95% CI 0.33-2.2), p = 0.77}. CONCLUSIONS: MIS is an alternative to open surgery for i-NETs, achieving similar short- and long-term oncological outcomes. Bulky mesenteric mass and a plan for concurrent liver resection are potential criteria for open surgery.

Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.

BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Baseline tumor growth rate highlights the heterogeneity of well differentiated gastroenteropancreatic neuroendocrine tumors and predicts for increases in Ki67 index over time.

Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1-2) GEP-NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1-3 GEP-NET, we calculated baseline TGR (TGR0 ) from radiological images of metastases acquired prior to first-line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1-3 tumors combined was 5% (range = 0.1%-52%) and median TGR0 was 4.8%/month (m) (range = 0%-45.9%/m). TGR0 correlated with pretreatment Ki67 across G1-3 pooled and within G3 GEP-NET. Patients with higher TGR0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p = .03) and shorter overall survival (median, 4.1 years vs. not reached; p = .003). Independent of therapies given, higher TGR0 GEP-NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p = .02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p = .04) upon serial biopsy. Importantly, TGR0 , but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP-NETs, future clinical trials may benefit from stratification for TGR0 , particularly in G1-2 tumors, in which TGR0 does not correlate with Ki67. TGR0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR0 in larger and more homogeneously treated cohorts, and to ascertain if post-treatment TGR has value in previously treated patients starting a new line of therapy.

Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.

BACKGROUND: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN. METHODS: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups. RESULTS: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively). CONCLUSIONS: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.

Outcomes after high-dose radiation in the management of neuroendocrine neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. MATERIALS AND METHODS: We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/ß = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. RESULTS: 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. CONCLUSIONS: These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.

Recurrence Patterns After Surgical Resection of Gastroenteropancreatic Neuroendocrine Tumors: Analysis From the National Comprehensive Cancer Network Oncology Outcomes Database.

OBJECTIVE: Current National Comprehensive Cancer Network guidelines for gastroenteropancreatic neuroendocrine tumors (GEPNETs) recommend complete (R0) surgical resection of the primary tumor and metastases, if feasible. However, large multicenter studies of recurrence patterns of GEPNETs after resection have not been performed. METHODS: Patients 18 years or older who presented to 7 participating National Comprehensive Cancer Network institutions between 2004 and 2008 with a new diagnosis of a small bowel, pancreas, or colon/rectum neuroendocrine tumor (NET) and underwent R0 resection of the primary tumor, and synchronous metastases, if present, were included in this analysis. Descriptive statistics and Kaplan-Meier estimates were used to calculate recurrence rates and time-associated end points, respectively. RESULTS: Of 294 patients with GEPNETs, 50% were male, 88% were White, and 99% had Eastern Cooperative Oncology Group performance status 0 to 1. The median age was 55 years (range, 20-90). The median follow-up time from R0 resection was 62.1 months. Recurrence rates were 18% in small bowel NETs (n = 110), 26% in pancreatic NETs (n = 141), and 10% in colon/rectum NETs (n = 50). The frequency of surveillance imaging was highly variable. CONCLUSIONS: R0 resection was associated with variable risk of recurrence across subtypes. Further research to inform refinement of guidelines for the appropriate duration of surveillance after R0 resection is needed.

Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.