Management of Neuroendocrine Tumors: Current and Future Therapies

Kjell E Öberg

Disclosures

Expert Rev Endocrinol Metab. 2011;6(1):49-62. 

In This Article

New Therapeutic Strategies

mTOR Inhibitors

mTOR is a central regulator of protein synthesis important in cancer, including cell growth and proliferation, angiogenesis and cell metabolism. Several genetic syndromes associated with NETs involve signaling through the mTOR pathway (Figure 4).[70] Everolimus, or RAD001 (Afinitor®, Novartis), is a new oral, once-daily mTOR inhibitor that blocks the mTOR pathway by binding to its intracellular receptor, FKBP-12. In preclinical studies, everolimus inhibited tumor growth in a variety of human solid tumors, both in vitro and in vivo.[71,72] Everolimus has synergistic anti-tumor effects when used in combination with other anticancer agents[73,74] and may have a similar effect when used in combination with a somatostatin analogue.[54] A study of 60 patients with metastatic low- to intermediate-grade NETs (30 with primitive NETs and 30 with nonprimitive NETs) assessed the antiproliferative effect of combining everolimus with octreotide.[75] Promising anti-tumor activity and PFS was observed in those who received a higher dose of everolimus (10 vs 5 mg/day) had slightly better partial response and PFS rates.[76] A Phase II trial of everolimus with or without octreotide LAR in patients with advanced pancreatic NETs following chemotherapy failure (RADIANT-1) found that in those receiving everolimus monotherapy, median PFS was 9.7 months, and 89 patients (77.4%) experienced a stabilization or decrease in tumor size.[10] By contrast, patients receiving everolimus 10 mg/day plus octreotide 30 mg/month achieved a median PFS of 16.7 months, and 38 patients (84.4%) had tumor stabilization or shrinkage (Figure 5).[10] A Phase III trial in advanced midgut carcinoid tumors (n = 429), the RADIANT-2 study, compared everolimus 10 mg/day plus octreotide LAR 30 mg every 28 days with placebo and octreotide LAR every 28 days. Patients treated with a combination of everolimus and octreotide demonstrated a median PFS of 16.4 vs 11.3 months for the control arm (p = 0.026). This did not meet a prespecified significance level by central review (p = 0.024). However, by an investigator review the median PFS was 12.0 months for the combination arm and 8.6 months for the control arm (p = 0.018). Further analyses of this trial are ongoing, but at the moment it is not easy to indicate the precise role of everolimus in midgut carcinoid tumors (abstract presented at ESMO 2010).[77]

Figure 4.

mTOR signaling and mechanisms of action of mTOR inhibitors.
LAR: Long-acting repeatable; NET: Neuroendocrine tumor.

Figure 5.

Kaplan–Meier analysis of progression-free survival. Patients were treated with (A) everolimus and (B) everolimus plus octreotide [10].
NA: Not available; PFS: Progression-free survival.
Adapted with permission from [10].

In the RADIANT-3 study, a Phase III trial in advanced pancreatic neuroendocrine tumors, 410 patients were randomized either to everolimus 10 mg/day plus best supportive care or placebo plus best supported care. The majority of the patients presented well-differentiated or moderately differentiated tumors. Half of the patients in each arm had previously been treated with chemotherapy and 50% of the patients in each arm also received somatostatin analogs. Median PFS in the treatment arm was 11.4 vs 4.6 months in the placebo arm (HR: 0.35; p < 0.0001). The most common side effects in all the RADIANT trials are stomatitis followed by infections and pneumonitis. However, grade 3/4 adverse events only occurred in approximately 5% of patients and therefore everolimus should be considered a safe and well tolerated treatment in patients with neuroendocrine tumors (abstract presented at ESMO 2010).[77]

Tyrosine Kinase Inhibitors

Sunitinib (Sutent®, Pfizer) an oral multi-targeted tyrosine kinase inhibitor was applied in a Phase III randomized, double-blind trial in patients with pancreatic neuroendocrine tumors. A total of 171 patients were randomized either to sunitinib 37.5 mg/day orally or placebo. They had well-differentiated malignant pancreatic neuroendocrine tumors with disease progression in the past 12 months. Initially, 340 patients were planned but an interim analysis closed the study early. A Kaplan–Meier analysis of PFS showed in the sunitinib arm a median PFS of 11.4 months versus 5.5 months in the placebo arm (HR: 0.418; p = 0.0001)(Figure 6). The objective response rate was 9.3 months in the sunitinib arm and 0 months in the placebo arm. Median duration of response was 18.1 months. The most frequently reported all grade adverse events with sunitinib were diarrhea (59%), nausea (45%), asthenia (34%) and fatigue (33%). Most common grade 3 or 4 adverse events included neutropenia and hypotension hand/foot syndrome. The drug seems to be well tolerated (ASCO abstract 2010).[78,79]

Figure 6.

Kaplan–Meier analogs of progression-free survival in patients treated with sunitinib versus placebo.
HR: Hazard ratio; PFS: Progression-free survival.
Adapted with permission from [77].

Chemotherapy

Single chemotherapeutic agents in midgut carcinoid tumors such as fluorouracil, dacarbazine, doxorubicin and streptozotocin were initially evaluated with little beneficial effect.[80] As such, combination chemotherapy trials were conducted to try to improve on these results. However, there is no evidence that multiagent regimens are any more effective; no regimen has demonstrated a response rate greater than 15% using the criterion of a 50% decrease in bidimensionally measurable disease.[11] Combination of chemotherapy and IFN-α therapy does not appear to improve on the results of monotherapy.[81,82] However, in patients with pancreatic endocrine tumors, response rates of approximately 40% have been reported for streptozotocin in combination with other agents such as 5-fluorouracil, cisplatin or doxorubicin.[31,83] Furthermore, temozolomide has demonstrated promising anti-tumor effects in pancreatic NETs.[84,85] A study combining temozolomide and thalidomide in 29 patients with metastatic carcinoid, pheochromocytoma or pancreatic NETs observed an objective biochemical (CgA) response rate of 40%, and a radiologic response rate of 25%; this was 45, 33 and 7% in patients with pancreatic NETs, pheochromocytomas and carcinoid tumors, respectively.[85] The median duration of response was 13.5 months, 1-year survival was 79% and 2-year survival was 61%. The response rate seems to be related to the expression of 06-methylguanine DNA methyltransferase (MGMT). Low expression gives a higher response rate (40%) versus high expression (0%).[84] A recent Phase II study in naive pancreatic neuroendocrine tumors treated with a combination of temozolomide plus capecitabine presented a PFS of 18 months and partial response (RECIST) in 67% of the patients.[86]

Radionuclide Therapy

Although the response rate of NETs to external beam radiation is limited, the introduction of systemic receptor-targeted therapy (peptide receptor radiotherapy [PRRT]) has provided beneficial effects in patients with unresectable somatostatin receptor-positive NETs.[87,88] Current data suggest objective response rates of 30–40% with disease stabilization in 40% of patients.[89] One study assessing PRRT with the radiolabeled somatostatin analog 9177Lu-DOTA0, Tyr30 octreotate in 310 patients with NETs observed complete and partial tumor remissions in 2 and 28%, respectively.[90] Minor tumor response (decrease in size >25 to <50%) occurred in 16% of patients. Compared with historical controls, there was a survival benefit of 40–72 months from diagnosis.

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