Management of Neuroendocrine Tumors: Current and Future Therapies

Kjell E Öberg


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

In This Article

Antiproliferative Effects & Survival


Data from the SEER database demonstrated a dramatic improvement in survival in patients with NETs diagnosed between 1988–2004 compared with those diagnosed earlier;[1] the authors suggested that this may be related to the introduction of octreotide in 1987. The literature appears to support this, as shown in a study reporting 5-year survival rates of 67% in patients receiving somatostatin analogues compared with 18% for historical controls.[45] The survival duration of patients with metastatic midgut tumors, as recorded in the SEER database (representing standard care in the USA) and as observed in a specialty center in Uppsala, Sweden, managing patients with a multidisciplinary team, is shown in Figure 2.

Figure 2.

Survival duration in patients with neuroendocrine tumors during the last four decades: a clinician's view.
SEER: Surveillance, Epidemiology and End Results.

Octreotide may have direct antiproliferative effects on tumors via stimulation of sst2, which mediates cell cycle arrest and apoptosis. It also has various indirect antiproliferative effects such as inhibition of the antiapoptotic hormone IGF-1, inhibition of the release of growth factors and trophic hormones, inhibition of angiogenesis and immune system modulation.[34,54] A number of studies have highlighted the antiproliferative effects of octreotide in patients with NETs and have shown that approximately two-thirds experience stable disease for up to 5 years, although objective tumor responses are uncommon (5% of patients).[31,55–61] The recent double-blind, placebo-controlled, randomized Phase IIIb study (PROMID) of octreotide LAR or placebo in patients with well-differentiated metastatic midgut NETs demonstrated that octreotide LAR 30 mg/month (n = 42) more than doubled the time to tumor progression compared with placebo (n = 43; 14.3 vs 6.0 months, respectively; p =0.000072; Figure 3), in both functioning and nonfunctioning NETs.[60] Overall, 67% of patients treated with octreotide had stable disease compared with 37% of placebo recipients. The PROMID study demonstrated that the benefits of octreotide treatment in NETs are independent of functionality, CgA level, Karnofsky performance status or age.[60] The National Comprehensive Cancer Network has updated its guidelines based on the PROMID data, to include octreotide LAR as a management option for asymptomatic patients with recurrent, unresectable metastatic NETs.

Figure 3.

Time to progression or tumor-related death in patients with well-differentiated, metastatic, functioning or nonfunctioning, midgut neuroendocrine tumors treated with octreotide long-acting repeatable or placebo.
LAR: Long-acting repeatable.
Adapted with permission from [60].

Patients with pancreatic NETs have a less favorable prognosis than those with nonpancreatic NETs and there are few treatment options available. The typical treatment approach for pancreatic NETs is chemotherapy with streptozotocin (as it is currently the only US FDA-approved drug for this indication[62]), either alone or in combination with other chemotherapeutic agents. As such, a small, randomized, Phase III study has compared the antiproliferative activity of octreotide LAR 30 mg/month versus chemotherapy (streptozotocin + 5-fluorouracil) in treatment-naive patients with progressive NETs of the pancreas and bronchial tract.[63] A higher rate of stable disease was observed in the octreotide group, while the time to tumor progression was comparable (19 vs 17 months, respectively).


There are few studies evaluating the antiproliferative effects of lanreotide in patients with NETs, and there are no Phase III data with tumor control as the primary end point. One study evaluated the antiproliferative efficacy of lanreotide in 25 patients; partial tumor remission was seen in one patient and stable disease was observed in seven patients, whereas tumor progression occurred in 14 out of 25 patients.[64] There is an ongoing Phase III study in patients with nonfunctioning NETs comparing lanreotide Autogel with placebo (Clarinet study). No major differences in classical efficacy have been seen between octreotide and lanreotide.[47,65]


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