Making Sense of a Complex Disease

A Practical Approach to Managing Neuroendocrine Tumors

Janie Y. Zhang, MD; Pamela L. Kunz, MD

Disclosures

J Oncol Pract. 2022;18(4):258-264. 

In This Article

Systemic Therapies

In patients with well-differentiated, advanced or metastatic NETs, systemic therapies offer symptom control and a survival benefit. However, an important point is that not all patients with unresectable NETs need systemic therapy. Observation, with tumor marker assessment and multiphasic cross-sectional abdominal and pelvic imaging every 3–12 months, may be appropriate for patients with low-burden, asymptomatic, and stable disease.[9] The observed pace of tumor growth will inform the frequency of imaging. Monitoring of therapy response should be performed with cross-sectional imaging every 3 months, although for patients with relatively stable disease on SSA alone, imaging may be done as infrequently as every 6 months.[9]

Somatostatin Analogs

SSAs are typically the first-line therapy to control the growth of well-differentiated NETs. PROMID, a placebo-controlled trial of 85 patients with low-grade, metastatic midgut NETs, demonstrated median time to tumor progression of 14.3 versus 6.0 months in the octreotide LAR versus placebo groups.[24] The CLARINET study, which randomly assigned 204 patients with locally advanced or metastatic nonfunctioning pancreatic and intestinal NETs to lanreotide or placebo, yielded median progression-free survival (PFS) of 32.8 months versus 18 months in these groups.[25,26] Lanreotide is FDA-approved for tumor control for NETs, whereas octreotide is only FDA-approved for hormone control. In practice, they are very similar in mechanism of action and are used interchangeably.[27] The two commercially available LAR formulations of SSAs are octreotide LAR, with a standard dose of 20–30 mg intramuscularly every 4 weeks, and lanreotide, dosed at 120 mg every 4 weeks as a deep subcutaneous injection.[24,27] Short-acting octreotide, dosed at 150–250 μg subcutaneously three times a day, is available for rapid relief of symptoms and breakthrough symptoms.[27] Dose increase of LAR SSA for suboptimal tumor control is controversial but may be considered in practice. Evidence in support of this comes from a single-arm phase II study, CLARINET FORTE, which treated patients with progression on standard (once every 28 days) lanreotide dosing v once every 14 days dosing and demonstrated promising PFS (median 5.6 months in pNETs; 8.3 months in midgut NETs).[28] Common adverse effects of SSAs include nausea, abdominal cramping, diarrhea, steatorrhea, flatulence, hyperglycemia, and biliary sludging for which patients may benefit from a prophylactic cholecystectomy if other abdominal surgeries are planned.[29]

Peptide Receptor Radionuclide Therapy

For patients with SSTR-positive GEP-NETs, PRRT using 177Lu-DOTATATE has been shown to offer disease control and a survival benefit. NETTER-1 was a phase III clinical trial that randomly assigned 229 patients with advanced midgut NETs to 177Lu-DOTATATE or high-dose octreotide. Median PFS was not reached versus 8.4 months in the treatment and control groups, respectively, with hazard ratio (HR) for progression or death of 0.21 (P < .001).[30] Final survival analysis showed median OS of 48.0 months in the 177Lu-DOTATATE arm and 36.3 months in the control arm (HR 0.84, P = .30), although a high rate of patient crossover (36%) may have affected ability to achieve statistical significance.[31] A retrospective analysis of patients with GEP and bronchial NETs treated with 177Lu-DOTATATE at a Dutch institution showed a median PFS of 29 months and a median OS of 63 months. Among 133 patients with pNETs assessed, median PFS was 30 months and median OS was 71 months.[32] Since 2018, 177Lu-DOTATATE has been FDA-approved for unresectable, low- or intermediate-grade GEP-NETs. It is not FDA-approved for bronchial NETs, but off-label use can be considered and is being evaluated in a trial of 177Lu-DOTATATE versus everolimus in advanced, SSTR-positive bronchial NETs (Alliance A021901; NCT04665739). The dosing of 177Lu-DOTATATE is 200 mCi every 8 weeks for four treatments. Relative contraindications include glomerular filtration rate < 30 and presence of liver disease. Adverse effects include myelosuppression, nephrotoxicity, hepatotoxicity, nausea and vomiting, carcinoid crisis, fetal toxicity, infertility, and rarely development of myelodysplastic syndrome or leukemia.[32]177Lu-DOTATATE is administered with an amino acid infusion, usually arginine and lysine, to provide nephroprotection.[30] Since many patients being considered for 177Lu-DOTATATE are being actively treated with SSAs, the continuation and timing of SSAs after initiation of 177Lu-DOTATATE is important. LAR SSAs should be avoided in the 4–6 weeks before each 177Lu-DOTATATE treatment, and short-acting SSAs should not be administered in the 24 hours before each treatment. LAR and short-acting SSAs may be restarted as needed 4–24 hours after the treatment.[30] Concurrent with 177Lu-DOTATATE, SSAs should be continued for symptom control of functional NETs, but the clinician may choose to stop LAR SSAs for nonfunctional NETs.

Ongoing randomized clinical trials of PRRT include the COMPETE study (NCT03049189), a phase III trial comparing 177Lu-Edotreotide with everolimus in G1 or G2 GEP-NETs that are inoperable, progressive, and SSTR-positive. NETTER-2 (NCT03972488) is a phase III trial of 177Lu-DOTATATE plus LAR SSA versus high-dose SSA as a first-line treatment for patients with unresectable, SSTR-positive, high-proliferation (G2 or G3, Ki-67 10%-55%) NETs.

Tyrosine Kinase Inhibitors

Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), remains the only FDA-approved TKI for advanced pNETs, on the basis of a phase III study that randomly assigned171 patients to sunitinib versus placebo. The primary endpoint, median PFS, was 11.4 months versus 5.5 months in the sunitinib and placebo groups (P < .001).[33] Overall response rate (ORR) of sunitinib was 9.3% versus 0% in the placebo arm. Sunitinib was given at a dose of 37.5 mg daily in this study; adverse events included nausea, vomiting, diarrhea, asthenia, fatigue, and congestive heart failure. Long-term treatment (median 87.1 weeks) did not alter the safety profile.[34] No TKIs are currently FDA-approved for use in epNETs.

Surufatinib and cabozantinib are currently under investigation for the treatment of both pNETs and epNETs. SANET-p was a phase III study conducted in China that randomly assigned 172 patients with advanced, well-differentiated pNETs to surufatinib versus placebo. The primary endpoint, median PFS, was 10.9 months versus 3.7 months in the surufatinib and placebo groups (P = .0011); ORR was 19%.[35] In its sister study, SANET-ep, 289 patients with advanced, well-differentiated epNETs were randomly assigned to surufatinib versus placebo. Median PFS was 9.2 months versus 3.8 months in the treatment and control arms (P < .001); ORR was 10%.[36] Subsequently, a phase I/II study of surufatinib was conducted in the United States to confirm safety and efficacy, and the new drug application of surufatinib is under FDA review.[37] Cabozantinib is currently under evaluation in CABINET (Alliance A021601; NCT03375320), a phase III study of cabozantinib versus placebo in patients with GEP and bronchial NETs who have progressed on at least one line of therapy other than SSAs.

Everolimus

Everolimus has been studied in multiple prospective clinical trials for pNETs and epNETs and is FDA-approved for treatment of progressive, well-differentiated bronchopulmonary and GI NETs.[38–41] RADIANT-3 randomly assigned 410 patients with advanced, progressive pNETs to everolimus versus placebo. Median PFS was 11.0 versus 4.6 months, respectively (HR 0.35, P < .001), although median OS was not significantly different between the groups (44.0 months in everolimus arm v 37.7 months in placebo arm, HR 0.94, P = .30), possibly because of the confounding effect of patient crossover.[40,42] RADIANT-4 randomly assigned 302 patients with progressive, nonfunctional lung or GI NETs to everolimus versus placebo. Median PFS was 11.0 versus 3.9 months, respectively (HR 0.48, P < .001).[41] Everolimus is given at a dose of 10 mg daily. Adverse effects include stomatitis, rash, fatigue, diarrhea, anemia, infections, and hyperglycemia, although everolimus may help with glucose stabilization in insulinomas.

Cytotoxic Chemotherapy for Well-differentiated NETs

In the subset of NETs that are high-risk because of high proliferation index, FDG-PET avidity, high burden of disease, rapid progression, or symptomatic presentation, cytotoxic chemotherapy is often used to achieve a tumor response. The first (and only) alkylator approved by the FDA as an antitumor agent for pNETs was streptozocin in 1982, although it is rarely used now because of drug shortages and toxicity.[43] There is no consensus on the optimal regimen, although temozolomide, an oral alkylating agent, is most commonly used today for the treatment of pNETs. To date, there is no clinical trial evidence supporting the use of alkylators in NETs of other sites.

Temozolomide in combination with capecitabine has been shown in a retrospective series to have an ORR of 70% and median PFS of 18 months.[44] In the randomized, phase II trial (ECOG 2211; NCT01824875) of temozolomide versus temozolomide plus capecitabine (CAPTEM) in progressive, unresectable G1-G2 pNETs, median PFS was 22.7 months in the CAPTEM arm versus 14.4 months in the temozolomide arm (HR 0.58, P = .023). ORR was 33.3% in the CAPTEM arm and 27.8% in the temozolomide arm (not statistically significant).[45] We recommend the combination of capecitabine and temozolomide in advanced pNETs for which cytotoxic agents are indicated. Other cytotoxic chemotherapies can be considered for epNETs in the absence of strong evidence, including fluorouracil, capecitabine, and oxaliplatin.[9] For clinically aggressive G3 NETs, we would consider a combination of platinum and etoposide, similar to the regimen used for NECs.

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