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Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

AIM: Although anti-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (RTKIs) have been tested in patients with neuroendocrine tumours (NETs) over the last two decades, no study to date has benchmarked efficacy and toxicity of these drugs in this patient population. METHODS: All phase II and phase III studies of anti-VEGF RTKIs in patients with NETs, published between January 1, 2000 andJuly 31, 2021, across major trial databases, were searched in August 2021 for relevant studies. The primary objectives of the meta-analysis were to compare objective response rate (ORR) and progression-free survival (PFS) between patients with pancreatic NETs (pNETs) and extra-pancreatic NETs (epNETs), and the incidence rate ratio (IRR) of adverse events between patients receiving anti-VEGF RTKIs and control. RESULTS: 1611 patients were available for the meta-analysis; 1194 received anti-VEGF RTKIs. ORR in pNETs was 18% (95% confidence interval (CI) 13-25%), while ORR in epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.38, p

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.

BackgroundWe assessed treatment patterns and outcomes of patients with advanced gastrointestinal (GI) neuroendocrine tumors (NET) at four large tertiary referral centers in the U.S.Patients and methodsWe performed a retrospective chart review of patients aged ≥18 years at advanced GI NET diagnosis, treated between July 2011 and December 2014. Index date was the histologically confirmed diagnosis date of locally advanced/metastatic GI NET. Data included baseline characteristics, treatment patterns, progression, death, and GI NET-related health care resource utilization from index date through last contact or death. Time-to-event analyses, including treatment discontinuation, progression, and overall survival (OS), were performed using Kaplan-Meier analysis.ResultsWe identified 273 patients; 156 (57%) had primary ileum NET, and 174 (64%) had functional NET. First-line treatments included somatostatin analog (SSA) alone (89%) or in combination (2%), liver-directed therapy (LDT; 8%), and cytotoxic chemotherapy or interferon (2%). One hundred fifty-five patients continued with second-line therapy, including SSA alone (17%) or in combination (75%, with 3% combined with peptide receptor radionuclide therapy), LDT (4%), and other treatments (3%). Median time (months) to first-line discontinuation was 154.0 for SSAs and 3.8 for cytotoxic chemotherapy. Overall median time to investigator-assessed progression following treatment initiation was 30.3 months. Median OS (months) following first-line initiation was 151.8 for all patients and 178.9 for first-line SSA.ConclusionOur study illustrates the common use of SSAs in both first-line and subsequent treatment of patients with GI NETs, as well as the relatively long survival durations and multiple additional treatments received by patients with this condition. Treatment pattern assessment at later times, following approval of newer treatments, is warranted.Implications for practiceThis study, assessing treatment patterns over a period of up to 30 years, showed that SSAs, LDT, cytotoxic chemotherapy, and interferon are common treatments for advanced GI NETs. SSAs alone or in combination with other treatments were the most frequent therapy in first and subsequent lines. Patients in this study remained on SSAs long-term, with median treatment duration of 12.8 years in first line. Treatment patterns should be assessed beyond this study's time period, given recent U.S. Food and Drug Administration approvals for additional treatments for GI NET, which will likely be incorporated in the continuum of care of patients.

BackgroundUsing data from four tertiary referral centers in the U.S., we assessed real-world treatment patterns and clinical outcomes of patients with advanced lung neuroendocrine tumors (NETs).Subjects, materials, and methodsWe performed a retrospective chart review of adult patients with locally advanced/metastatic (typical/atypical) lung NETs treated between July 2011 and December 2014. Index date was histologically confirmed typical/atypical carcinoid tumor diagnosis date. Data included baseline characteristics, treatment patterns, progression, death, and lung NET-related health care resource use from index date through last contact/death. Time to treatment discontinuation and first progression, time from first to second progression, and overall survival (OS) were estimated using Kaplan-Meier analysis.ResultsWe identified 83 patients; 19 (23%) had functional NET. First-line treatments included somatostatin analogs (SSAs) alone (56%) or in combination with other therapies (6%), cytotoxic chemotherapy (20%), external beam radiation therapy (EBRT) (9%), liver-directed therapy (LDT) (4%), and everolimus/other (5%). Sixty patients had second-line therapy including SSA alone (18%) or in combination (40%), cytotoxic chemotherapy (17%), everolimus (12%), LDT (7%), EBRT (3%), and other treatments (3%). Median time (months) to first-line discontinuation were as follows: SSAs, 43.3; cytotoxic chemotherapy, 3.6. Overall median time (months) to investigator-assessed progression following treatment initiation was 12.4. Median OS (months) following treatment initiation was 66.4 for all patients and 81.5 for patients receiving SSAs.ConclusionSSAs, alone and in combination, are common treatments for advanced lung NETs. Patients have additional treatment options and relatively long survival compared with patients with other advanced cancers. Treatment pattern assessment following approval of newer treatments is needed.Implications for practiceSomatostatin analogs (SSAs), cytotoxic chemotherapy, EBRT, liver-directed therapy, and targeted therapies are common treatments for locally advanced/metastatic (typical/atypical) lung neuroendocrine tumors (NETs). SSAs alone or in combination with other treatment modalities were the most common first- and second-line therapy, followed by cytotoxic chemotherapy. Patients continued treatment with SSAs long-term with median treatment duration of 43 months. Median overall survival was 66 months following initiation of first-line therapy for all patients. Treatment pattern assessment beyond the time period of this study is needed given recent U.S. Food and Drug Administration approvals for additional treatments for lung NETs that will likely be incorporated in the treatment landscape.

Background: The identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) aside from N1c lymph node designation. The objective of this study was to determine the prognostic impact, beyond American Joint Committee on Cancer N1c designation, of TDs among patients with primary CRC. Methods: Patients who had resected stage I–III primary CRC diagnosed between 2010 and 2019 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer‐specific survival (CSS) stratified by TD status and lymph node (N) status was calculated using the Kaplan–Meier method and multivariable Cox proportional hazards regression analyses. Results: In total, 147,783 patients with primary CRC were identified. TDs were present in 15,444 patients (10.5%). The presence of TDs was significantly associated with adverse tumor characteristics, including advanced pathologic stage, nodal status, and metastasis status. The presence of TDs was associated with worse CSS (hazard ratio [HR], 3.12; 95% confidence interval [CI], 3.02–3.22), as it was for each given N category (e.g., N2a and TD‐negative [HR, 2.50; 95% CI, 2.37–2.64] vs. N2a and TD‐positive [HR, 3.75; 95% CI, 3.49–4.03]). The presence of multiple TDs was also associated with decreased CSS for each given N category compared with a single TD (e.g. N2a with one TD [HR, 3.09; 95% CI, 2.65–3.61] vs. N2a with two or more TDs [HR, 4.32; 95% CI, 3.87–4.82]). Conclusions: TDs were identified as an independent predictor of a worse outcome in patients with CRC. The presence of TDs confers distinctly different CSS and provides important prognostic information among patients with CRC and warrants further investigation as a unique variable in future iterations of CRC staging. The presence of tumor deposits confers distinctly different cancer‐specific survival beyond lymph node categories and provides important added prognostic information among patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP‐NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP‐NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP‐NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP‐NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix. [ABSTRACT FROM AUTHOR]