Klimstra, David S.

4020 Background: High grade (G3) GEPNENs are a rare and heterogeneous disease entity for which there is little prospective treatment data. EP chemotherapy is the treatment standard but this may not be appropriate for all G3 GEPNEN pts. CAPTEM has demonstrated activity in G3 GEPNENs and may be a promising alternative. EA2142 aimed to determine if CAPTEM was superior to EP in pts with G3 GEPNENs. Methods: This was a multicenter, randomized (1:1) phase II trial for pts with a locally advanced and unresectable or metastatic well differentiated G3 neuroendocrine tumor (NET) or a poorly differentiated, non-small cell G3 neuroendocrine carcinoma (NEC) of suspected gastrointestinal origin and an ECOG PS of 0-2. Pathology must have demonstrated a Ki-67 of 20-100% or at least 10 mitoses/10 high powered field. Pts were randomized to receive capecitabine 750 mg/m2 orally every 12 hours on days 1-14 and temozolomide 200 mg/m2 orally once daily on days 10-14 of a 28-day treatment cycle (Arm A) or etoposide 100 mg/m2 daily on days 1-3 with either cisplatin 25 mg/m2 daily on days 1-3 or carboplatin AUC 5 on day 1 of a 21-day treatment cycle (Arm B). Restaging scans were performed every 8 weeks and toxicity monitored per CTCAEv4. Final statistical plan was to accrue 80 pts to detect a 67% improvement in progression free survival (PFS) (primary endpoint) with CAPTEM as compared to EP, 80% power and one-sided significance level of 0.10. A planned interim analysis for efficacy and futility was conducted. Results: A total of 67 pts were enrolled (Arm A, n=32; Arm B, n=35). Male 58%, African American 4%, Asian 3%. Mean age 61. Among 63 eligible pts, primary tumor site pancreatic 56%, non-pancreatic 43%. Poorly differentiated 57%, well differentiated 33%, unknown 10%. Mean Ki-67 48% (Arm A), 60% (Arm B). The study was closed prior to full accrual due to futility at 57.7% information time. In the interim analysis, among 62 eligible pts, PFS, overall survival and response rate with CAPTEM were 2.43 months (mos) (95% CI 2.04, 7.72), 12.6 mos, 9% respectively vs 5.36 mos (95% CI 2.14, 7.23), 13.6 mos and 10% with EP. Toxicity was evaluable in 57 pts with Grade (G) 3/4 events occurring in 29% of pts on Arm A, 66% of pts on Arm B. G3/4 events occurring in more than 5% of pts on Arm A—febrile neutropenia (n=2); abdominal pain (n=2); diarrhea (n=2); nausea (n=2); neutropenia (n=2); dehydration (n=2) and on Arm B—anemia (n=8); febrile neutropenia (n=2); fatigue (n=2); lymphopenia (n=2); neutropenia (n=12); thrombocytopenia (n=4); leukopenia (n=6). There was one G5 event on Arm A due to sepsis. Conclusions: CAPTEM does not appear to be superior to EP chemotherapy as front-line treatment for pts with G3 NENs but does demonstrate a more favorable toxicity profile. Studies assessing G3 NET independently of G3 NEC are needed. Clinical trial information: NCT02595424.

Currently, there are no internationally accepted consensus guidelines for pathologic evaluation of posttherapy pancreatectomy specimens. The Neoadjuvant Therapy Working Group of Pancreatobiliary Pathology Society was formed in 2018 to review grossing protocols, literature, and major issues and to develop recommendations for pathologic evaluation of posttherapy pancreatectomy specimens. The working group generated the following recommendations: (1) Systematic and standardized grossing and sampling protocols should be adopted for pancreatectomy specimens for treated pancreatic ductal adenocarcinoma (PDAC). (2) Consecutive mapping sections along the largest gross tumor dimension are recommended to validate tumor size by histology as required by the College of American Pathologists (CAP) cancer protocol. (3) Tumor size of treated PDACs should be measured microscopically as the largest dimension of tumor outer limits that is bound by viable tumor cells, including intervening stroma. (4) The MD Anderson grading system for tumor response has a better correlation with prognosis and better interobserver concordance among pathologists than does the CAP system. (5) A case should not be classified as a complete response unless the entire pancreas, peripancreatic tissues, ampulla of Vater, common bile duct, and duodenum adjacent to the pancreas are submitted for microscopic examination. (6) Future studies on tumor response of lymph node metastases, molecular and/or immunohistochemical markers, as well as application of artificial intelligence in grading tumor response of treated PDAC are needed. In summary, systematic, standardized pathologic evaluation, accurate tumor size measurement, and reproducible tumor response grading to neoadjuvant therapy are needed for optimal patient care. The criteria and discussions provided here may provide guidance towards these goals.

AbstractThe WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.