Diagnosis and Management of Gastric Neuroendocrine Neoplasms
Somatostatin analogues: These compounds inhibit gastrin secretion from the G-cells and thus can ameliorate its effect on ECL-cells. Treatment with somatostatin analogues (SSAs) should always be administered to the rare patients with functioning tumours. Following successful treatment with subcutaneous octreotide in a patient with MEN1 and GNEN2, long-acting SSAs (octreotide and lanreotide) have been shown to be effective in decreasing the number and size of GNEN1/2. This is achieved by reducing gastrin levels and thus the effect of gastrin on GNEN1 and ECL-cell hyperplasia and/or a direct effect on ECL-cells. Using these compounds, tumour disappearance rates of up to 73% have been described, along with improvement in the remaining GNEN1 and ECL-cell hyperplastic/dysplastic lesions. The combination of octreotide and α-interferon has also shown activity in a patient with metastatic hepatic disease. Treatment with SSAs presents a reasonable alternative for patients with multiple and highly recurrent tumours not amenable to surgical treatment. However, the precise indications and duration of such treatment have not been defined, and rebound tumour growth following treatment cessation usually occurs. In addition, this treatment is hampered by the lack of controlled trials and relatively high cost.
Gastrin (CCK-B) antagonists: Gastrin plays a major role in ECL-cell proliferation, with gastrin-17 (G17) as its more active form; gastrin also mediates angiogenesis and may also act in an autocrine or paracrine manner to promote carcinogenesis. Therefore, its inhibition may be of therapeutic significance. Netazepide is an orally administered peripheral CCK-B inhibitor that has rapid onset and prolonged duration, leading to gastric acid output suppression. In a series of eight patients with multiple GNEN1 who received netazepide for 12 weeks, CgA levels normalized within 3 weeks and this was associated with a substantial tumoral reduction, although ECL-cell hyperplasia was not affected. However, similarly to treatment with SSAs, discontinuation of treatment was associated with biochemical relapse. G17-diptheria toxin immunogen (G17DT) acts as a B cell epitope and is an antigastrin vaccination element. Administration of GD17DT in three patients with autoimmune CAG and GNEN1 resulted in a sharp rise in gastrin and GD17 followed by a subsequent decrease in and regression of the ECL-cell lesions in two-thirds of patients; this effect lasted for some years without appearance or exacerbation of an autoimmune process. These data suggest that the administration of the vaccine is able to produce inhibition of the ECL-cell growth and an active generalized immune response, but needs to be confirmed by larger studies.
In rare cases of patients with GNEN1 and advanced disease, recent findings have suggested that treatment with SSAs is associated with more prolonged progression-free survival (PFS) compared to placebo. As GNEN1 seems to have a better prognosis than other GI-NENs even in the presence of extensive disease, treatment with these agents seems an appropriate first-line approach. For patients with progressive disease despite treatment with SSAs, further therapeutic modalities such as the administration of molecular targeted therapies and radiopharmaceuticals could be employed. Although traditionally GI-NENs other than pancreatic NENs are not considered to be chemosensitive, recent data have suggested that they may also respond to temozolomide-based chemotherapy. However, as the sequence of application of these treatments has not as yet been defined and may possibly apply to only a small minority of GNEN1, further discussion is beyond the scope of this review.
Medical Therapies
Patients With Localized Disease
Somatostatin analogues: These compounds inhibit gastrin secretion from the G-cells and thus can ameliorate its effect on ECL-cells. Treatment with somatostatin analogues (SSAs) should always be administered to the rare patients with functioning tumours. Following successful treatment with subcutaneous octreotide in a patient with MEN1 and GNEN2, long-acting SSAs (octreotide and lanreotide) have been shown to be effective in decreasing the number and size of GNEN1/2. This is achieved by reducing gastrin levels and thus the effect of gastrin on GNEN1 and ECL-cell hyperplasia and/or a direct effect on ECL-cells. Using these compounds, tumour disappearance rates of up to 73% have been described, along with improvement in the remaining GNEN1 and ECL-cell hyperplastic/dysplastic lesions. The combination of octreotide and α-interferon has also shown activity in a patient with metastatic hepatic disease. Treatment with SSAs presents a reasonable alternative for patients with multiple and highly recurrent tumours not amenable to surgical treatment. However, the precise indications and duration of such treatment have not been defined, and rebound tumour growth following treatment cessation usually occurs. In addition, this treatment is hampered by the lack of controlled trials and relatively high cost.
Gastrin (CCK-B) antagonists: Gastrin plays a major role in ECL-cell proliferation, with gastrin-17 (G17) as its more active form; gastrin also mediates angiogenesis and may also act in an autocrine or paracrine manner to promote carcinogenesis. Therefore, its inhibition may be of therapeutic significance. Netazepide is an orally administered peripheral CCK-B inhibitor that has rapid onset and prolonged duration, leading to gastric acid output suppression. In a series of eight patients with multiple GNEN1 who received netazepide for 12 weeks, CgA levels normalized within 3 weeks and this was associated with a substantial tumoral reduction, although ECL-cell hyperplasia was not affected. However, similarly to treatment with SSAs, discontinuation of treatment was associated with biochemical relapse. G17-diptheria toxin immunogen (G17DT) acts as a B cell epitope and is an antigastrin vaccination element. Administration of GD17DT in three patients with autoimmune CAG and GNEN1 resulted in a sharp rise in gastrin and GD17 followed by a subsequent decrease in and regression of the ECL-cell lesions in two-thirds of patients; this effect lasted for some years without appearance or exacerbation of an autoimmune process. These data suggest that the administration of the vaccine is able to produce inhibition of the ECL-cell growth and an active generalized immune response, but needs to be confirmed by larger studies.
Patients With Advanced Disease
In rare cases of patients with GNEN1 and advanced disease, recent findings have suggested that treatment with SSAs is associated with more prolonged progression-free survival (PFS) compared to placebo. As GNEN1 seems to have a better prognosis than other GI-NENs even in the presence of extensive disease, treatment with these agents seems an appropriate first-line approach. For patients with progressive disease despite treatment with SSAs, further therapeutic modalities such as the administration of molecular targeted therapies and radiopharmaceuticals could be employed. Although traditionally GI-NENs other than pancreatic NENs are not considered to be chemosensitive, recent data have suggested that they may also respond to temozolomide-based chemotherapy. However, as the sequence of application of these treatments has not as yet been defined and may possibly apply to only a small minority of GNEN1, further discussion is beyond the scope of this review.
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