SURGICAL PRINCIPLES FOR MANAGEMENT OF NEUROENDOCRINE TUMORS
nccn NET & NEC GI & Pancreas
- Standard oncologic surgery is appropriate for most resectable, non metastatic pancreatic NETs
- Tumor enucleation should be considered primarily for insulinomas are rarely malignant
- small (<2 cm) low-grade NETs, decisions on surgery versus active surveillance need to be individualized base on tumor size, and tumor and pts caracteritics and // Tumors <1 cm have a lower malignant potential than tumors measuring 1–2
cm.// ◊ Other radiographic characteristics of small tumors (homogeneous, wellcircumscribed) may also correlate with benign behavior. // ◊ Patient characteristics such as age and comorbidities are important when
determining whether surveillance is appropriate. - larger (>2 cm) or malignant-appearing non-functional and functional PanNETs should include total removal of the tumor with negative margins (including adjacent
organs) and regional lymph nodes - gastrointestinal NETs should include adequate regional lymph node resection (including all palpable disease where feasible) and thorough exploration of synchronous primary tumors (15%–30% incidence)
- Resection of recurrent locoregional disease, isolated distant metastases, or a
previously unresectable tumor that has regressed should be considered - metastatic disease, resection of small bowel NET (primary tumor and mesenteric lymph nodes) should be performed when symptoms arise from the primary tumor. In asymptomatic cases, resection should be considered to reduce future obstruction, mesenteric ischemia, bleeding, or perforation
- Cytoreductive surgery of >90% of metastatic disease may provide symptomatic relief, and improve
progression-free survival for patients with functioning tumors, Patients who are symptomatic from hormonal syndromes, such as carcinoid syndrome, typically derive palliation from cytoreductive surgery - Octreotide therapy should be considered parenterally prior to induction of anesthesia in patients with carcinoid syndrome to prevent carcinoid crisis
PRINCIPLES OF LIVER-DIRECTED THERAPY FOR NEUROENDOCRINE TUMOR METASTASES
- Hepatic arterial embolization, including bland transarterial embolization [TAE], chemoembolization [TACE], and radioembolization [TARE]
Percutaneous thermal ablation - Indications for Hepatic Arterial Embolization
- Embolization is recommended for well-differentiated NETs with liver-dominant, unresectable metastases that are:
*Symptomatic on an SSA or following another form of systemic therapy
*Progressive on an SSA or following another form of systemic therapy
*Presenting with bulky liver disease; embolization may be employed as debulking therapy without waiting for progression. - Objective radiologic response rates vary widely in retrospective studies, but average approximately 60%, with symptom palliation in approximately 85% of patients with hormonal syndromes.
- Relative contraindications include significant baseline liver dysfunction (jaundice, ascites) and a liver tumor burden >70%. Prior Whipple surgery or biliary instrumentation (ie, sphincterotomy, stent) increases the risk of liver abscess due to biliary bacterial colonization; infectious complications occur in about 20% of cases following TAE/TACE and 8% after TARE, even with broad-spectrum antibiotic coverage.
Embolization Modalities - TAE and TACE
*There are no completed randomized studies comparing TAE with conventional TACE and both are acceptable.
*Drug-eluting embolics are associated with increased hepatobiliary toxicity in the NET population, and are not recommended.
*In patients with bilobar disease, TAE/TACE is generally performed over at least two procedures, approximately one month apart. Patients with very high liver tumor burden may require three or four embolizations to safely treat the entire liver. Short-acting octreotide should be administered pre-embolization for patients with hormonal syndromes. Overnight observation is typically appropriate to monitor and treat symptoms of post-embolization syndrome such as pain and nausea and exacerbation of hormone-related symptoms. - TARE may be considered particularly in the following scenarios:
*Lobar or segmental (less than lobular) disease distribution.
*Patients with prior Whipple surgery or biliary tract instrumentation (lower risk of hepatobiliary infection than TAE/TACE).
*TARE is better tolerated than TAE/TACE, but late radioembolization-induced chronic hepatotoxicity (RECHT) may occur in long-term survivors, and is particularly a concern among patients undergoing bilobar radioembolization.
*To date there is no evidence for or against the safety of sequencing TARE and PRRT.
Evaluation of Neuroendocrine Tumors of the Gastrointestinal Tract (WellDifferentiated Grade 1/2)
- Biochemical evaluation can also be helpful in the initial diagnostic
evaluation, particularly in patients who have clinical symptoms that are
suggestive of hormone hypersecretion - serotonin secretion, using a 24-hour urine or plasma collection for 5 hydroxyindoleacetic acid (5-HIAA), is generally recommended in patients with metastatic lung or GI NETs, particularly if carcinoid syndrome
- Chromogranin A is sometimes used as a biochemical marker in nonfunctioning tumors. Whereas one meta-analysis calculated the sensitivity and specificity of chromogranin A to be 73% and 95%, respectively, for diagnosis of NETs,78 others have questioned its value, the panel retire in 2021 the test of the algoritm
Management of Locoregional Disease
- Resection is the primary treatment approach for most localized NETs of the GI tract
- Octreotide and lanreotide also may be considered for tumor control in patients with locoregional disease who have SSR-positive imaging
* Gastric Neuroendocrine Tumors
->Type 1 gastric NETs pursue an indolent course, with a rate of metastases of less than 5%. Evidence suggestive of type 1
disease includes a histologic diagnosis of atrophic gastritis on gastric biopsy, elevated gastric pH, vitamin B12 deficiency, and positive antiintrinsic factor antibodies
->Type 2 tumors are rare and occur in the setting of gastrinoma in which elevated gastrin levels produce gastric neuroendocrine hyperplasia and multifocal gastric NETs. A SEER-based analysis of 3523 patients with gastric neuroendocrine neoplasms found a 5-year OS rate of 53.7%
->Endoscopic surveillance and endoscopic resection of prominent tumors is recommended for patients with locoregional type 1 gastric NETs every 2 to 3 years or as clinically indicated
–>locoregional type 2 gastric NETs, the
primary gastrinoma should, in general, be resected, is not resected, endoscopic surveillance and endoscopic resection of prominent gastric NETs should be considered and/or octreotide or lanreotide can be given
–> non-metastatic gastric NETs and
normal gastrin levels (type 3) often have more aggressive tumors and arey treated with radical resection of the tumor and regional lymphadenectomy.
–>For early-stage, smaller tumors, endoscopic or wedge resection can be considered if there is no evidence of regional lymphadenopathy on EUS or other imaging.
—>Endoscopic resection should be reserved for small (<1 cm), superficial, low-grade tumors
Management of Locoregional Advanced and/or Distant Metastatic
Gastrointestinal Tract (Well-Differentiated Grade 1/2) Neuroendocrine
Tumors
Somatostatin Analogs for Control of Symptoms and Tumor Growth Patients who have metastatic NETs and carcinoid syndrome should be treated with octreotide or lanreotide
Standard doses of octreotide LAR are 20 to 30 mg intramuscularly every 4 weeks
The multinational phase III ELECT
trial 4 Patients in the lanreotide arm required less frequent rescue
octreotide than those in the placebo arm (33.7% vs. 48.5%; P = .017). Overall, lanreotide treatment improved symptom control, irrespective of prior octreotide use
If carcinoid syndrome is poorly controlled, telotristat may be considered for persistent symptoms, Telotristat or telotristat ethyl is a smallmolecule tryptophan hydroxylase (TPH) inhibitor, which decreases urinary
5-HIAA levels and the frequency of bowel movements (BMs) in patients with carcinoid syndrome
A study of 250 patients with carcinoid
syndrome showed that patients with 5-HIAA levels of 300 μmol or greater (57 mg) over 24 hours and with 3 or more flushing episodes per day were more likely to have carcinoid heart disease
GI tract primary tumors who have clinically significant tumor burden or progressive disease, initiation of either octreotide LAR or lanreotide is recommended to potentially control tumor growth if they are not already receiving it
Resection of Metastatic Disease
hepatic resection of metastatic NETs showed that long-term survival can be achieved in selected cases: the reported 10-year OS rate was 50.4%
Most patients with resected metastatic disease, however, will eventually experience recurrence
Noncurative debulking surgery can also be considered in select cases, especially if the patient is symptomatic either from tumor bulk or hormone production
Resection of the primary site in the setting of unresectable metastases is generally not indicated if the primary site remains asymptomatic and is relatively stable
Evaluation of Neuroendocrine Tumors of the Pancreas (Well-Differentiated
Grade 1/2)
Chromogranin A levels are elevated in 60% or more of patients with either functioning or nonfunctioning pancreatic endocrine tumors
care should be taken in measuring chromogranin A and interpreting the results, because spuriously elevated levels of chromogranin A have been reported
in patients using PPIs, renal or liver failure,
hypertension, and with chronic gastritis
Gastrinomas: e suspected in patients with severe and refractory gastroduodenal ulcers or symptoms such as dyspepsia, usually accompanied by diarrhea, evaluation must include measurement of serum gastrin levels, most patients who are found to have an elevated level of serum gastrin do not have a gastrinoma but have achlorhydria or are receiving PPIs or antacids. To confirm diagnosis, gastrin levels must be measured after the patient is off PPI therapy for at least 1 week, Approximately 70% of patients with MEN1 and gastrinoma have tumors situated in the duodenum
Insulinomas: hypoglycemia (generally fasting or nocturnal) and a pancreatic mass, . Evaluation with a 72-hour fast, which tests serum insulin, pro-insulin, and C-peptide during concurrent hypoglycemia, is the gold standard, An insulin level greater than 3 mcIU/mL (usually >6 mcIU/mL), C-peptide concentrations of at
least 0.6 ng/mL, and proinsulin levels of greater than or equal to 5 pmol/L when fasting blood glucose is less than 55 mg/dL is suspicious for insulinoma
