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Systemic Therapy for Advanced Pancreatic Neuroendocrine Tumors: An Update

Diane L. Reidy-Lagunes

Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (pancNETs). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors appear to be far less sensitive to therapeutic agents than pancNETs, and recent advances approved for pancNETs have not been submitted for FDA approval in patients with carcinoid tumors. Treatment options for patients with advanced pancNETs are multidisciplinary and include surgical resection, liver-directed therapies, and systemic therapies. Cytotoxic therapies, such as temozolomide, fluorouracil, oxaliplatin, and streptozocin-based chemotherapy regimens, are active against some pancNETs, and can play a role in the palliation of patients with advanced disease and symptoms related to tumor bulk. Two therapies were recently approved for progressive well-differentiated pancNETs: sunitinib and everolimus. Both agents showed improved progression-free survival in patients with progressive pancNETs, but can also result in nontrivial toxicities, and therefore should only be considered in patients with progressing and advanced or symptomatic disease. This article discusses these recent trials and provides an update of systemic treatment options in patients with well-differentiated pancNETs.

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Targeted Strategies in the Treatment of Metastatic Colon Cancer

Diane Reidy and Leonard Saltz

Advances in the understanding of tumor biology have led to the identification of important cellular processes involved in the pathogenesis of colon cancer. Drugs that interfere with these critical pathways are known as targeted agents. The goal of these therapies is to selectively interrupt the signal transduction pathways responsible for tumor growth and survival. Some of these targeted agents have made important, albeit modest, contributions to the treatment of patients with metastatic colorectal cancer. However, the activity levels with the currently available targeted therapies are far lower than experts had hoped, and toxicities are often nontrivial. This article reviews the available therapies, the data that justify their use, and the challenges of optimizing targeted therapies through combinations with cytotoxic chemotherapies and other targeted agents. Finally, some newer drugs and strategies currently being tested in clinical trials are discussed.

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Metastatic Insulinoma: Current Molecular and Cytotoxic Therapeutic Approaches for Metastatic Well-Differentiated panNETs

Iulia Giuroiu and Diane Reidy-Lagunes

Pancreatic neuroendocrine tumors (panNETs) are a type of neuroendocrine tumor with 5-year overall survival rates of approximately 50% when metastasis is present at diagnosis. Tumor grade, as defined by Ki-67 proliferation index, influences overall survival, with low-grade tumors portending a better outcome than intermediate- and high-grade tumors. This case report follows the clinical course and management of a patient with an insulin-secreting metastatic panNET who died 10 years after diagnosis after a treatment course with regional therapy and multiple forms of cytotoxic and molecularly targeted agents. This report presents the various treatment options available for patients with insulin-secreting metastatic panNETs.

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Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance

Agata A. Bielska, Walid K. Chatila, Henry Walch, Nikolaus Schultz, Zsofia K. Stadler, Jinru Shia, Diane Reidy-Lagunes, and Rona Yaeger

Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.

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False-Positive Elevations of Carcinoembryonic Antigen in Patients With a History of Resected Colorectal Cancer

Anya Litvak, Andrea Cercek, Neil Segal, Diane Reidy-Lagunes, Zsofia K. Stadler, Rona D. Yaeger, Nancy E. Kemeny, Martin R. Weiser, Melissa S. Pessin, and Leonard Saltz

Routine monitoring of carcinoembryonic antigen (CEA) levels is standard in patients with resected colorectal cancer (CRC). The incidence of false-positives and the upper limits of false-positive elevations have not been previously well characterized. A search of medical records at Memorial Sloan-Kettering Cancer Center identified 728 patients who underwent an R0 resection of locoregional CRC between January 2003 and December 2012 and who had an increase in CEA level above the normal range after a normal perioperative CEA level. Of these, 358 had a false-positive elevation of CEA level, 335 had a true-positive elevation indicative of recurrent CRC, and 35 had a true-positive elevation indicative of the development of a new, non-CRC malignancy. Of those with false elevations, 111 had a single isolated CEA level elevation (median highest CEA level of 5.5 ng/mL) with no further abnormal measurements, whereas 247 had elevations on 2 or more readings, with a median highest level of 6.7 ng/mL. Of these 247 patients with confirmed false-positive CEA level elevations, only 5 (2%) had measurements greater than 15 ng/mL, and no confirmed elevation greater than 35 ng/mL was a false-positive. False-positive CEA test results in the range of 5 to 15 ng/mL are common. Confirmation of CEA elevation in this range before initiating imaging studies may be appropriate. False-positive results greater than 15 ng/mL are rare, and all confirmed CEA levels greater than 35 ng/mL were associated with cancer recurrence.

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Neoadjuvant Chemotherapy First, Followed by Chemoradiation and Then Surgery, in the Management of Locally Advanced Rectal Cancer

Andrea Cercek, Karyn A. Goodman, Carla Hajj, Emily Weisberger, Neil H. Segal, Diane L. Reidy-Lagunes, Zsofia K. Stadler, Abraham J. Wu, Martin R. Weiser, Philip B. Paty, Jose G. Guillem, Garrett M. Nash, Larissa K. Temple, Julio Garcia-Aguilar, and Leonard B. Saltz

Standard therapy for locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy and postoperative chemotherapy. At Memorial Sloan-Kettering Cancer Center (MSKCC) the authors began offering FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as initial treatment for patients with high-risk LARC to target micrometastases while treating the primary tumor. The purpose of this study is to report the safety and efficacy of initial FOLFOX given before chemoradiotherapy on tumor downsizing and pathologic complete response (pathCR) in LARC. The records of patients with stage II/III rectal cancer treated at MSKCC between 2007 and 2012 were reviewed. Of approximately 300 patients with LARC treated at MSKCC, 61 received FOLFOX as initial therapy. Of these 61 patients, 57 received induction FOLFOX (median 7 cycles) followed by chemoradiation, and 4 experienced an excellent response, declined chemoradiation, and underwent total mesorectal excision (TME). Twelve of the 61 patients did not undergo TME: 9 had a complete clinical response (CCR), 1 declined despite persistent tumor, 1 declined because of comorbidities, and 1 developed metastatic disease. Among the 61 patients receiving initial FOLFOX, 22 (36%) had either a pathCR (n=13) or a CCR (n=9). Of the 49 patients who underwent TME, all had R0 resections and 23 (47%) had tumor response greater than 90%, including 13 (27%) who experienced a pathCR. Of the 28 patients who received all 8 cycles of FOLFOX, 8 experienced a pathCR (29%) and 3 a CCR (11%). No serious adverse events occurred that required a delay in treatment during FOLFOX or chemoradiation. FOLFOX and chemoradiation before planned TME results in tumor regression, a high rate of delivery of planned therapy, and a substantial rate of pathCRs, and offers a good platform for nonoperative management in select patients.

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Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

Manisha H. Shah, Whitney S. Goldner, Al B. Benson III, Emily Bergsland, Lawrence S. Blaszkowsky, Pamela Brock, Jennifer Chan, Satya Das, Paxton V. Dickson, Paul Fanta, Thomas Giordano, Thorvardur R. Halfdanarson, Daniel Halperin, Jin He, Anthony Heaney, Martin J. Heslin, Fouad Kandeel, Arash Kardan, Sajid A. Khan, Boris W. Kuvshinoff II, Christopher Lieu, Kimberly Miller, Venu G. Pillarisetty, Diane Reidy, Sarimar Agosto Salgado, Shagufta Shaheen, Heloisa P. Soares, Michael C. Soulen, Jonathan R. Strosberg, Craig R. Sussman, Nikolaos A. Trikalinos, Nataliya A. Uboha, Namrata Vijayvergia, Terence Wong, Beth Lynn, and Cindy Hochstetler

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.