R.A. Valdes Olmos, C.A. Hoefnagel, E. Bais, H. Boot, B. Taal, J. de Kraker, P.A. Voûte
The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence:

Mailing address: R.A. Valdes Olmos, MD, PhD Nuclear Medicine Physician The Netherlands Cancer Institute Plesmanlaan 121 1066 CX Amsterdam Telephone: 31-20-5122289 Fax: 31-20-5122290 E-mail: r.valdes@nki.nl

Cita/Reference:
Valdes Olmos, R.A., et al. Nuclear Medicine in the Tretment of Endocrine and Neuroendocrine Tumors. Alasbimn Journal 5(18): October 2002. Article N° AJ18-8.

Summary

Radionuclide therapy plays an important role in the treatment of endocrine and neuroendocrine tumors. Therapy with ¹³¹I is used in patients with papillary and follicular thyroid carcinoma for ablation of thyroid remnants and for treatment of distant metastases. In neck recurrence, ¹³¹I may be used as monotherapy or in combination with surgery. Both radioimmunotherapy and ⁹⁰Y-DOTATOC are being applied in non-¹³¹I-avid thyroid malignancies such as medullary thyroid carcinoma. ¹³¹I-MIBG is currently used in various treatment schedules for recurrences and metastases of neuroblastoma, pheochromocytoma, paraganglioma and carcinoid. In neuroblastoma ¹³¹I-MIBG can be given upfront to reduce large and bulky tumors for subsequent surgery, chemotherapy and autologus bone marrow infusion. In carcinoid and other neuroendocrine tumors therapy with radiolabelled somatostatin analogues appears to be a promising modality. Radiopharmaceutical quality requirements, patient preparation, radiation protection and hospital isolation facilities are important supportive factors to enable adequate radionuclide therapy.

Thyroid Cancer

¹³¹ I therapy of differentiated thyroid carcinoma. Based on its concentration by thyroid cancer cells ¹³¹I is used for therapy in patients with papillary and follicular thyroid carcinoma for both ablation of thyroid remnants and treatment of metastases. For ablation ¹³¹I is usually given in a dosage of 1.85-3.7 GBq (50-100 mCi) 4 to 6 weeks after total or near-total thyroidectomy. For pre-ablation diagnostic ¹³¹I scintigraphy low tracer dosages are recommended in order to avoid thyroid tissue stunning (1). During post-surgery period any thyroid hormone treatment is withheld. Ablation of residual normal thyroid tissue may enable subsequent scintigraphic detection and possibly radionuclide treatment of local or distant metastases, which may not sufficiently concentrate ¹³¹I in the presence of thyroid remnants. For treatment of metastases ¹³¹I is often administered, following TSH stimulation obtained after thyroid hormone withdrawal, in a dosage of 7.4 GBq (200 mCi), which usually may deliver appropriate radiation doses per gram thyroid cancer tissue. Lower dosage is recommended (80-120 mCi) if diffuse lung metastases are present in order to prevent lung fibrosis (2). The efficacy of ¹³¹I therapy (Fig. 1) has principally been documented in terms of survival. Patients treated with surgery and ¹³¹I appear to have a significantly longer survival than patients treated with surgery alone (3). A better prognosis has been found for patients with ¹³¹I-avid metastases (4) and therapy is less effective in bone metastases (5). In the treatment of bone metastases ¹³¹I therapy has been combined with surgery, radiotherapy and more recently with embolization (6). Also the combination with surgery is advocated for the treatment of neck recurrences (1).

Neuroblastoma

¹³¹I-MIBG as first-line. ¹³¹I-MIBG treatment can be given upfront to reduce large and bulky tumors in order to enable surgery to remove the primary tumor. This induction therapy is followed by chemotherapy, ablative chemotherapy and autologus bone marrow infusion. In 54 patients with stage III or IV objective response was observed in 82% after a first dosage of 7.4 GBq followed by 3.7 GBq every four weeks (range 2-5 cycles). Thrombocytopenia was seen in 37%. The condition of the patients improved dramatically, as is expressed by relief of pain within 24 to 48 after first dose, and weight gain of 3-11% (11). Five-year-survival after completion of treatment was 37%. In high-risk neuroblastoma ¹³¹I-MIBG is being combined with other compounds such as Topotecan (12).

Malignant pheochromocytoma and paraganglioma

An objective response rate (including hormonal response) of 75% according to the data of 116 patients treated in various centers was observed for the use of ¹³¹I-MIBG as monotherapy with cumulative doses ranging from 3.6 to 85.9 GBq in malignant pheochromocytoma (Fig. 4). In 76% of the patients subjective improvement of symptoms, lowering of blood pressure, as well as pain relief were achieved (17). Also in malignant paraganglioma (secreting or non-secreting) objective partial remission, pain relief and improved quality of life have been described (18, 19).

Carcinoid and other neuroendocrine tumors

Monotherapy with¹³¹I-MIBG or MIBG. Based on 7.4 GBq (200 mCi) dosages, monotherapy with ¹³¹I-MIBG resulted in relief of symptoms (flushes, diarrhoea, anorexia, pain) in 18/30 carcinoid patients (60%) with a median duration of 8 months (range 2-24 m). Also unlabeled MIBG may lead to a pharmacological effect and dosages of 20-40 mg/m² resulted in symptom relief in 12/20 patients (60%) with a median duration of 4 months (range 1-10 m) (20). An overall 5-year survival rate of 78% was found for a group of 18 carcinoid patients treated with ¹³¹I-MIBG alone (19).

Logistical aspects

Patient preparation. Pregnancy and breast feeding are generally considered absolute contraindications for radionuclide therapy. Severe myelosuppression and severe renal failure are contraindications for ¹³¹I-MIBG therapy. Unstable patient condition not allowing isolation is considered as a relative contraindication.

Four to 6 weeks before ¹³¹I therapy thyroid hormone medication must be discontinued. A low-iodide diet for a period of 4-10 days before ¹³¹I administration is also recommended. Any other iodide-containing preparation (e.g. expectorants, kelp, agar, carrageen, Lugol's solution, potassium iodide solution, topical iodine, radiographic contrast agents) that potentially may affect ¹³¹I uptake must be discontinued or avoided.

With respect to ¹³¹I-MIBG drugs such as labetalol, reserpine, calcium-channel blockers, trycyclic antidepressants, ephinedrine, and adrenergic blocking agents may interfere ¹³¹I-MIBG uptake and must be discontinued before therapy. In order to prevent thyroid uptake of free ¹³¹I 100 (children) to 200 (adults) mg potassium iodide must be daily given from one day before ¹³¹I-MIBG to 2-3 weeks after treatment.

Concerning therapy with radiolabeled somatostatine analogues discontinuation in the administration of somatostatine analogues such as octreotide would be considered.

Radiopharmaceutical administration. Quality control of the used radiopharmaceuticals prior to the administration checking both the radionuclide and radiochemical purity is essential. Impurities will not contribute to the tumor targeting but may add to the side effects of such a treatment. Relatively high doses of radioiodinated pharmaceuticals such as MIBG with a high specific activity may undergo autoradiolysis (depending on the temperature, volume and presence of stabilizers and scavengers in the formulation) and too much free ¹³¹I (> 5%) may result in some radioiodine thyroid uptake despite blocking with potassium iodide.

Therapeutic ¹³¹I can be given in capsule or liquid form or is administered intravenously in patients who are prone to vomit. To increase salivary flow patients would be asked to chew gum or suck citrus sweets during the first 48 hours. Also hydration and at least one bowel movement daily are important to reduce bladder and colon radiation exposure.

For ¹³¹I-MIBG therapy the radiopharmaceutical is administered intravenously over 1 to 4 hours in 50-100 ml saline or glucose solution through a lead-shielding infusion system. Flushing of the line at the end of the infusion is necessary. Hydration of the patient following ¹³¹I-MIBG is important to reduce radiation exposure. Dibeniline and propanolol should be available in case of hypertensive crises in patients with pheochromocytoma. Often these patients are receiving these drugs in the week before ¹³¹I-MIBG therapy. In carcinoid patients octreotide by subcutaneous administration may be used in case of flushing. Anti-emetics not interfering with MIBG such as Motilium (Domperidon) may be used in case of nausea.

For therapy radiolabeled somatostatin analogues have been administered intravenously in infusion volumes of 80-100 ml over a period of 10 to 15 min. Co-infusion of amino acids have been recommended to reduce kidney uptake (29).

Isolation facilities. The availability and licensing of radiation protected isolation as well as the necessity of guidelines for radiation protection are important logistical factors to enable that radionuclide therapy becomes safe both for the patient and for relatives, personnel and the enviroment. An European survey demonstrated that there is considerable variation between countries in radionuclide therapeutic procedures, depending on local legislation and the requirement and availability of isolation facilities (30). Patients must be instructed how to reduce unnecessary radiation exposure to family members and members of the public. Particularly, when children need to be isolated, parents or other relatives are directly involved in child's patient care and need to be instructed for issues of radiation protection during isolation and in the period thereafter.

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