Imaging to Monitor Treatment Response in Patients With Advanced Neuroendocrine Tumors
Image-based monitoring for patients with advanced neuroendocrine tumors (NETs) can be individualized based on the NET site and tumor characteristics. Emerging strategies may add to existing monitoring capabilities.
Professor of Oncology
“Tumor grade and location play a role with respect to planning the follow-up imaging intervals after treatment. For a grade 1 small-bowel NET, imaging every 6 to 9 months may be feasible. Pancreatic NETs are more aggressive and may call for scanning every 2 to 6 months, depending on tumor grade and differentiation.”
For patients with small-bowel NETs, a diagnosis of either metastatic or seemingly localized NETs should start with adequate contrast-enhanced, multiphasic, cross-sectional imaging and should include nuclear medicine imaging to confirm the expression of somatostatin receptors (SSTRs) on the tumor cells and to determine the stage of the disease. Conventional cross-sectional imaging alone may miss small-volume peritoneal disease, bone metastases, and metastases at unusual sites (eg, orbital metastases).
SSTR positron emission tomography (PET) imaging using labeled gallium-68 dotatate or copper-64 dotatate is coupled with the anatomical imaging (eg, PET/computed tomography [CT] or PET/magnetic resonance imaging [MRI]). The vast majority of patients with well-differentiated, small-bowel NETs and many patients with pancreatic NETs will have tumor SSTR expression that lights up on PET. The target needs to be present if we are considering somatostatin analogue (SSA) therapy or peptide receptor radionuclide therapy.
After an initial PET/CT, some patients with metastatic gastroenteropathic NETs, or even lung NETs, may not need another PET/CT scan for a while (eg, if you are seeing stable disease). Subsequently, if something unusual arises, including some changes or new symptoms, a new SSTR PET scan may be warranted.
Combined dotatate PET and fluorine-18-fluorodeoxyglucose (18F-FDG) PET might be used in some scenarios, although insurance coverage may be a barrier to using both SSTR and FDG PET. FDG imaging is currently a hot topic, as, even within grades 1 and 2, a positive FDG PET will predict more aggressive disease. When both SSTR and FDG PET can be performed, a NETPET score can be assigned. This new scoring system nicely separates patients into groups according to progression-free survival.
For advanced small-bowel NET treatment response assessment, anatomic imaging allows for a more precise measurement of the tumor, whether by contrast-enhanced CT or by MRI with hepatobiliary contrast, for example. However, conventional Response Evaluation Criteria in Solid Tumors (also known as RECIST criteria) may not apply well to all NETs, and disease stability is very common. For example, among patients in the phase 3 NETTER-1 study, the response rate was only 18% per RECIST; however, many of these patients benefited enormously from having stable disease and improved symptoms. Tumor grade and location play a role with respect to planning the follow-up imaging intervals after treatment. For a grade 1 small-bowel NET, imaging every 6 to 9 months may be feasible. Pancreatic NETs are more aggressive and may call for scanning every 2 to 6 months, depending on tumor grade and differentiation.
For patients without residual disease after surgery, monitoring for up to 15 years (or even longer) may be appropriate, as the cumulative risk of recurrence for pancreatic and grades 1 to 2 small-bowel tumors is approximately 50% at 10 years and as high as 69% at 15 years. Conversely, for small, node-negative, low-grade pancreatic NETs under 2 cm, the 10-year risk of recurrence may be less than 20%. So, there is definitely variability, even at the same primary site.
For those with resectable NETs, we perform postoperative SSTR PET imaging 6 to 9 months after surgery to obtain a new baseline. Then, if it is not a high grade 2 or a well-differentiated grade 3 tumor, we do annual imaging with CT or MRI for 5 years and biennial imaging for another 10 years. For higher-grade tumors or for patients with more aggressive disease, imaging every 6 to 9 months for several years may be appropriate.
These intervals may change due to the use of postoperative NET transcriptomic blood tests that look for minimal residual disease, such as the neuroendocrine neoplasms test (NETest). Some data suggest that if you have a positive NETest 30 days or more after surgery, the 2- to 3-year risk of recurrence may be as high as 60% to 70%, while the risk of recurrence after a negative NETest may be less than 10%. This is not yet a standard part of clinical practice, but I believe that it is a promising technology that may allow for more individualized monitoring.
Alevroudis E, Spei M-E, Chatziioannou SN, et al. Clinical utility of 18F-FDG PET in neuroendocrine tumors prior to peptide receptor radionuclide therapy: a systematic review and meta-analysis. Cancers (Basel). 2021;13(8):1813. doi:10.3390/cancers13081813
Chan DL, Hayes AR, Karfis I, et al. Dual [68GA]DOTATATE and [18F]FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms: a multicentre validation of the NETPET score. Br J Cancer. 2023;128(4):549-555. doi:10.1038/s41416-022-02061-5
Fernandez CJ, Agarwal M, Pottakkat B, Haroon NN, George AS, Pappachan JM. Gastroenteropancreatic neuroendocrine neoplasms: a clinical snapshot. World J Gastrointest Surg. 2021;13(3):231-255. doi:10.4240/wjgs.v13.i3.231
Hayes AR, O’Mahony LF, Quigley A-M, et al. The combined interpretation of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in metastatic gastroenteropancreatic neuroendocrine tumors: a classification system with prognostic impact. Clin Nucl Med. 2022;47(1):26-35. doi:10.1097/RLU.0000000000003937
Loft M, Carlsen EA, Johnbeck CB, et al. 64Cu-DOTATATE PET in patients with neuroendocrine neoplasms: prospective, head-to-head comparison of imaging at 1 hour and 3 hours after injection. J Nucl Med. 2021;62(1):73-80. doi:10.2967/jnumed.120.244509
Modlin IM, Kidd M, Malczewska A, et al. The NETest: the clinical utility of multigene blood analysis in the diagnosis and management of neuroendocrine tumors. Endocrinol Metab Clin North Am. 2018;47(3):485-504. doi:10.1016/j.ecl.2018.05.002
Navin PJ, Ehman EC, Liu JB, et al. Imaging of small-bowel neuroendocrine neoplasms: AJR Expert Panel Narrative Review. AJR Am J Roentgenol. 2023 Feb 8. doi:10.2214/AJR.22.28877
Rajamohan N, Khasawneh H, Singh A, et al. PET/CT and PET/MRI in neuroendocrine neoplasms. Abdom Radiol (NY). 2022;47(12):4058-4072. doi:10.1007/s00261-022-03516-2
Singh S, Chan DL, Moody L, et al. Recurrence in resected gastroenteropancreatic neuroendocrine tumors. JAMA Oncol. 2018;4(4):583-585. doi:10.1001/jamaoncol.2018.0024
Strosberg J, El-Haddad G, Wolin E, et al; NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi:10.1056/NEJMoa1607427
Vellani SD, Nigro A, Varatharajan S, Dworkin LD, Creeden JF. Emerging immunotherapeutic and diagnostic modalities in carcinoid tumors. Molecules. 2023;28(5):2047. doi:10.3390/molecules28052047