Long-term efficacy of low activity meta-[131I]iodobenzylguanidine therapy in patients with disseminated neuroendocrine tumours depends on initial response.

BACKGROUND: meta-[131I]Iodobenzylguanidine (131I-MIBG) has been used to treat patients with disseminated neuroendocrine tumours (NET). However, so far there is limited information related to the efficacy of this agent beyond the normal 6-month assessment period. Before we can assume that such treatment would be beneficial to patients with these tumours the outcome of the patients over a longer time course should be determined. In many centres financial or radiation protection constraints mean that lower activities of 131I-MIBG have to be used at each administration, therefore instead of giving a single administration of a higher activity 131I-MIBG a series of multiple lower activity administrations are used. METHODS: The case records of 25 patients who had received 131I-MIBG over a 4-year period, from 1 June 1997 to 30 June 2001, were reviewed. Overall time of clinical follow-up range from 1 to 60 months, with a mean of 16 months). There were 16 female and nine male patients (mean age 55.6 years; range, 30-79 years). Most of patients had carcinoid (17), two had phaeochromocytoma, two gastrinoma and two an undifferentiated NET, one had malignant paraganglioma and one had medullary cell carcinoma of the thyroid. All had avid uptake for 123I-MIBG on diagnostic scanning. The minimum number of treatments received was 1 in 4 patients (with activities of 2.0 to 3.4 GBq); the maximum was 11 treatments (with cumulative activities as high as 29.1 GBq). Treatment was given using an infusion pump and was normally repeated at 12- to 16-week intervals (mean number of treatments per patient, 4). Response to therapy was determined by changes in the size of the tumour on computed tomography and/or magnetic resonance imaging using the response evaluation criteria in solid tumours (RECIST). Toxicity was measured using blood and urine tests of renal, hepatic, thyroid and bone marrow function. The median time from the last treatment to progression of disease and death (if applicable) was also calculated. RESULTS: No significant or long-lasting toxicity was encountered. At 6 months after the patient's last treatment, 18 patients (72%) had no evidence for progression. Twelve months after their last treatment 12 (48%) patients had no evidence for progression. At 18 months after the patient's last treatment, only seven patients (28%) had no progression of their disease. Overall, the median progression-free survival was 15 months. In those patients with stability or response at 6 months there was a prolonged progression-free survival and overall survival. In those with progression of disease at 6 months, at the 6-month assessment point, there had been four deaths (16%), at 12 months, there were three additional cancer deaths and finally at 18 months, there were a further five deaths. The median survival was 18 months. In those patients who died the mean time interval between disease progression and death was 4.6 months (range 0-12 months). CONCLUSION: Of the patients treated with low-activity 131I-MIBG 68% had significant benefit for at least 6 months post-treatment. In these patients with progressive and extensive disease this technique provided prolonged progression-free and overall survival with minimal side effects especially if an initial response to treatment was seen.

Toxicity of high-activity 111In-Octreotide therapy in patients with disseminated neuroendocrine tumours.

Disseminated neuroendocrine tumours are difficult to treat and are generally not responsive to radiotherapy or chemotherapy. Nuclear medicine techniques using a radiolabelled somatostatin analogue, 111In-Octreotide, have been used for the diagnosis of neuroendocrine tumours. It has been suggested that high activities of such an agent may have a therapeutic effect. The aims of this study were to assess toxicity and to determine if there had been evidence of efficacy. Eight patients with known disseminated neuroendocrine tumours were enrolled in the study; six had carcinoid tumours, one had a medullary cell carcinoma of the thyroid and one patient had a malignant gastrinoma. Between 1.3 and 4.6 GBq of 111In-Octreotide were administered to each patient for up to five administrations over 12 months. A total of 23 administrations were given. Tests of vital signs, renal, liver and endocrine function as well as haematological markers were taken before and after treatment. The treatment was well tolerated with only one patient suffering from a sensation of flushing during the infusion but no changes in vital sings. There was a transient (up to 48 h) drop in circulating lymphocytes in four patients and platelets in two patients; no supportive therapy was needed. One patient with severe renal impairment had a slight reduction in glomerular filtration rate. We conclude that high-activity 111In-Octreotide is well tolerated with low toxicity and can be considered for use in patients with disseminated neuroendocrine tumours. Further work is now being performed to assess efficacy.

[Carcinoid tumors of the intestines: developments in the Netherlands for diagnosis and palliative treatment]. / Carcinoïde tumoren van de darm: ontwikkelingen binnen Nederland in diagnostiek en palliatieve behandeling.

Carcinoid tumours in the intestine are slowly growing neuroendocrine tumours. Patients as a rule report symptoms of the carcinoid syndrome: attacks of diarrhoea and of flushing. When the earliest symptoms manifest themselves, metastases are already present, virtually always localized in the liver. At a late stage, heart failure may occur, difficult to treat and caused by fibrosis of the tricuspid valve in the presence of protractedly raised blood serotonin levels. To diagnose carcinoid tumours, use is made of radioactive substances binding to hormone receptors such as 131I-MIBG and 111-In-octreotide. When multiple metastases exist, only palliative treatment is possible. The drugs used are the somatostatin analog octreotide, interferon alpha, radioactive MIBG and non-radioactive MIBG; these drugs may also be used in combination. The therapies mentioned have approximately the same effect: symptoms improve in 60-80%, while 30-50% show a biochemical response, i.e. decrease of the number of breakdown products in the urine of the hormones produced by the tumour; tumour size decreases in 0-12%.

[Radionuclide therapy of Sipple syndrome using iodine-131 metaiodobenzylguanidine].

A 40-year-old female who had lung and liver metastases from malignant pheochromocytoma was treated with 3.7 GBq 131I-MIBG (metaiodobenzylguanidine). After the treatment, 131I-MIBG showed increased uptake in the metastatic lesions of the lung and liver. The size of tumor was no significant change on CT and MRI, but the intensity of liver metastases decreased gradually on MRI. Prior to the treatment, the levels of adrenaline and noradrenaline were high. One to three days after treatment, the level of these laboratory data further increased, but they gradually decreased in 1 to 3 months. These changes may be due to necrosis of tumor tissue.

Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy.

A retrospective study of 202 patients with medullary thyroid carcinoma (MTC) diagnosed between 1943 and 1987 was done to compare the prognosis of patients with sporadic disease and those with the familial form of multiple endocrine neoplasia type II and to study the effect of radiotherapy. Patients with multiple endocrine neoplasia type II had a significantly higher survival rate than did patients with the sporadic variety (P less than 0.005), but most patients with sporadic tumors were older and had more advanced disease. No differences in survival rates were found when patients from these 2 groups were matched for age and involvement of the thyroid gland only (P greater than 0.3), involvement of the thyroid gland plus cervical nodes (P greater than 0.3), and involvement of the thyroid gland, cervical nodes, and soft tissue (P greater than 0.7). When patients with MTC who received radiotherapy were matched for age, extent of disease, and surgery with patients who had had no radiotherapy, the latter group was found to live significantly longer (P less than 0.05). We conclude that 1) the apparently poor prognosis of patients with the sporadic variety of MTC may be related to the patients' older age at detection rather than to inherent differences in the two forms of disease, and 2) radiotherapy has little effect on MTC.

Adenomatosis endocrina multiple tipo IIb / Endocrine multiple adenomatosis type IIb

Se revisa el sindrome de Adenomatosis Endocrina Multiple Tipo IIb, el cual esta constituido por carcinoma medular del tiroides, neuromas mucosos multiples, feocromocitoma y un habito marfanoide caracreristico. Este sindrome al igual que el Tipo I y el Tipo IIa son considerados actualmente como apudomas. El diagnostico se hace por las caracteristicas clinicas marfanoides descritas, por la dosificacion de calcitonina y por los hallazgos histopatologicos que muestran carcinoma medular, neuromas y feocromocitoma. El tratamiento es quirurgico y consiste en la tiroidectomia total y en la extirpacion de los feocromocitomas, cuando estos existen. El pronostico es sombrio y los pacientes invariablemente fallecen, considerandose el tratamiento quirurgico como de tipo paliativo; la radioterapia y la quimioterapia no evitan las metastasis ni las recurrencias. Se presenta un caso clinico con este curioso pero letal sindrome