An ASCO guideline has been developed to inform the use of systemic treatments for metastatic, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs).1 The guideline helps fill a knowledge gap among community oncologists in particular, who typically do not see many of these rare and challenging cases and were lacking universal treatment recommendations.
Jaydira Del Rivero, MD
“The management of neuroendocrine tumors is personalized from patient to patient and requires a multidisciplinary approach as well,” said Jaydira Del Rivero, MD, of the National Cancer Institute, and Guideline Co-Chair. “For community oncologists especially, it is increasingly important to have a standardized consensus statement on how experts see the disease.”
Rare and Challenging Cancers
GEP-NETs are a diverse group of tumors with primary involvement in the pancreas, stomach, small intestine, colon, rectum, and appendix. Treatment selection is informed by tumor classification based on numerous factors, including grade, primary tumor location (gastrointestinal vs pancreatic), hormone status, tumor volume, somatostatin receptor (SSTR) positivity, and degree to which the patient is symptomatic. Further complicating the clinical picture is their low incidence, meaning oncologists in community settings are not likely to have had significant experience managing these cancers.
There has been ample progress in expanding the therapeutic options for GEP-NETs in the past decade, thanks to promising results from several clinical trials.2 “The one that was probably the most recent and most significant was the NETTER-1 trial, which evaluated a drug called [lutetium Lu-177 dotatate], which is a radioactive-based therapy,” said Kimberly Perez, MD, of the Dana-Farber Cancer Institute and Guideline Co-Chair. “The positive results from this trial and the U.S. Food and Drug Administration approval of [Lu-177 dotatate] have driven a lot of the clinical trials that are ongoing.”
Kimberly Perez, MD
For instance, the pivotal phase III NETTER-1 trial has led to increased research into other innovative systemic radiotherapies, including alpha-particle therapy and SSTR antagonists, as well as combined approaches with novel antiangiogenic treatments and immunotherapies.2,3 As a result of these exciting advances, said Dr. Perez, community oncologists have been increasingly asking questions about how to integrate new drugs into clinical care, including how to sequence them and when to use them.
Making Informed Treatment Decisions
The Expert Panel included findings from NETTER-1 and seven other clinical trials in forming its recommendations, which focus solely on well-differentiated, grade 1 to 3 NETs in the pancreas and gastrointestinal tract. Because patients often present with late-stage disease, the guideline also only addresses metastatic and advanced GEP-NETs.3
The Panel offered numerous recommendations on general treatment selection as well as specific guidance based on tumor location, grade, and other factors.
“Although there are multiple prospective trials that support the therapies we have, the Expert Panel still had pretty active discussions regarding how to interpret or extrapolate the results from these prospective studies for the different cohorts or different subsets of neuroendocrine tumors,” Dr. Perez said.
The Expert Panel also had in-depth discussions on certain topics on which data are limited or unclear, such as how to treat patients deficient in the DNA repair enzyme methylguanine methyltransferase and whether to routinely test patients for this deficiency.
Although NETs can impinge on patients’ functioning and quality of life, the guideline does not speak to managing specific symptoms of GEP-NETs. However, ASCO is currently developing recommendations on this topic, with publication anticipated in 2024.
The guideline also provides input on treatment sequencing, but the Panel had to support those recommendations using clinical experience given the current absence of definitive clinical trial data about sequencing. However, Dr. Del Rivero expressed confidence that the recommendations will still be useful for patient care.
“This guideline can certainly help a lot of physicians in the community have a better and more standardized way to help these patients, and that hasn’t always been the case,” she said. “Some patients, after one line of therapy, they were being sent into clinical trials when there were other therapies that could have been provided. So, having this information gives [community oncologists] a broader understanding of the tumors as well as which options are available for which patients.”
Closing Knowledge Gaps
Future research in GEP-NETs is needed to clarify safety and efficacy findings from head-to-head drug comparisons, although some initial data have already been shared at the European Society for Medical Oncology Congress 2022. For instance, the SEQTOR study was an open-label comparison of the mTOR inhibitor everolimus followed by chemotherapy with streptozotocin and fluorouracil, vs a reverse sequence of the same treatment, for patients with metastatic pancreatic NETs.4 However, no differences were observed in progression-free survival, and clinical benefit rates were similar, signaling the need for more treatment-sequencing studies.
Combination therapies are also of increasing interest in the field, such as combining Lu-177 dotatate with PARP inhibitors (ClinicalTrials.gov identifier NCT04086485) or other DNA repair inhibitors (NCT04234568), which are in the pipeline. The first adjuvant therapy for high-risk pancreatic NET is also ongoing (NCT05040360). Further, the recent OCLURANDOM trial found increased progression-free survival with Lu-177 dotatate vs sunitinib in progressive SSTR-positive GEP-NETs—an outcome that is considered practice validating.5
Whether these and other innovations advance to the point of being relevant for inclusion in forthcoming guideline updates is still unknown. But the hope is that the current guideline—in addition to the one in progress for symptom management—will help community oncologists feel better prepared to make treatment decisions for both extending patient survival and improving their quality of life.
“I do think for oncologists who may not see this disease regularly, the guideline may help them feel a bit more empowered to take care of these patients,” Dr. Perez said.
REFERENCES
1. Del Rivero J, Perez K, Kennedy EB, et al: Systemic therapy for tumor control in metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: ASCO guideline. J Clin Oncol. September 29, 2023 (early release online).
2. Cives M, Pelle’ E, Strosberg J: Emerging treatment options for gastroenteropancreatic neuroendocrine tumors. J Clin Med 9:3655, 2020.
3. Das S, Dasari A: Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors. Ther Adv Med Oncol 13:17588359211018047, 2021.
4. NECs: Mixed results for second-line therapy after progression. ESMO Daily Reporter. September 12, 2022. Available at https://dailyreporter.esmo.org/esmo-congress-2022/news/necs-mixed-results-for-second-line-therapy-after-progression. Accessed November 3, 2023.
5. Baudin E, Walter TA, Beron A, et al: 887O: First multicentric randomized phase II trial investigating the antitumor efficacy of peptide receptor radionuclide therapy with 177-lutetium–octreotate (OCLU) in unresectable progressive neuroendocrine pancreatic tumor: Results of the OCLURANDOM trial. Ann Oncol 33:S954, 2022.
Originally published in ASCO Daily News © American Society of Clinical Oncology. ASCO Daily News. October 5, 2023. All rights reserved.
