[131I] metaiodobenzylguanidine

Radiopharmaceutical: [¹³¹I]metaiodobenzylguanidine ([¹³¹I]-mIBG)

Nuclide: Iodine-131

Activity: The first administration in children and young adults for the treatment of neuroblastoma is delivered according to a body mass-based prescription of 444 MBq/kg [132]. Unlike those for neuroblastoma treatment, administered activities for treatment of neuroendocrine tumours in adults are usually not based on patient mass, and single or multiple activities ranging between 3.7 GBq and 18.5 GBq are delivered.

Administration: i.v.

6.2.1 Mechanism of uptake / drug biology

[¹³¹I]-mIBG is an aralkyl-guanidine which structurally resembles norepinephrine (also called noradrenaline), a monoamine secreted by the adrenal medulla. Therefore, tumours expressing the norepinephrine transporter show [¹³¹I]mIBG uptake capacity.

6.2.2 Patient selection

The indications are tumours showing adequate uptake and retention of radiolabelled [¹³¹I]mIBG on the basis of a pretherapy tracer study [45,133]. Because there is no clear agreement on what should be considered as an adequate uptake, the final decision must be based on imaging and clinical considerations:

• Inoperable pheochromocytoma;
• Inoperable paraganglioma;
• Inoperable carcinoid tumour;
• Stage III or IV neuroblastoma [133].
• Metastatic or recurrent medullary thyroid cancer.

6.2.3 Exclusion criteria

The following are absolute contra-indications:

• Pregnancy, breastfeeding;
• Life expectancy less than 3 months, unless in case of intractable bone pain;
• Renal insufficiency requiring dialysis on short term.

The following are relative contra-indications:

• Unacceptable medical risk for isolation;
• Unmanageable urinary incontinence;
• Rapidly deteriorating renal function-glomerular filtration rate less than 30 mL/min;
• Progressive haematological and/or renal toxicity because of prior treatment;
• Myelosuppression:
  • Total white cell counts less than 3.0×10⁹/L;
  • Platelets less than 100×10⁹/L.

In case of low white blood cell counts, low platelet counts, massive bone marrow invasion and/or impaired renal function the administered activity should be reduced, and close follow-up is recommended to anticipate toxicity.

6.2.4 Procedure

Patients should have a proven, inoperable neuro-endocrine tumour and have undergone conventional staging investigations including [¹²³I]mIBG scintigraphy, anatomical imaging (CT, MRI, ultrasound) and biochemical assessment to identify objective tumour markers.

Children undergoing [¹³¹I]mIBG therapy should be managed jointly by teams including the specialist paediatric staff [134].

Eligible patients will have mIBG-positive tumours as documented by tracer scintigraphy using [¹²³I]mIBG (in adults, [¹³¹I]mIBG can also be used for tumour imaging).

Thyroidal uptake of free iodide-131 is prevented using per os stable iodine (Table 2) Capsules of oral iodine are more suitable for children due to their neutral taste. The treatment should begin 48-24 h before the planned [¹³¹I]mIBG administration and continued for 10-15 days posttherapy. Potassium perchlorate, normally used alone before [¹²³I]mIBG scintigraphy, is generally used in combination with stable iodine to facilitate the wash-out of the radio-iodine from the thyroid. Hormonal treatment with thyroxine or neomercazole is generally not indicated.

Many classes of medicines may theoretically interfere with [¹³¹I]mIBG uptake and storage (Table 3) [135]. Ideally, drugs likely to interfere with the uptake and/or retention of [¹³¹I]mIBG should be withdrawn before treatment, and patients should be stabilized on alternative medication. However, patients with metabolically active catecholamine- secreting tumours (i.e., pheochromocytoma, paraganglioma) are often alpha and beta blocked by medical treatment before [¹³¹I]mIBG administration. A considerable number of such patients with catecholamine-secreting tumours are at risk for developing symptoms after withdrawal of their medication. Furthermore, hypertension induced by [¹³¹I]mIBG is always possible, even if rare, in children [136]. Therefore, we recommend that in these patients, diagnostic scintigraphy and therapeutic administration of [¹³¹I]mIBG are conducted without changing the medication taken, although using beta blockers or calcium channels blockers could impair the efficacy of procedure. In the other patients, a slow administration of [¹³¹I]mIBG is recommended, but administration should be stopped if hypertension occurs.

Monitoring of vital signs is essential as [¹³¹I]mIBG administration may result in unstable blood pressure. Vital signs should be checked before and after the infusion and at least twice daily afterwards. More frequent monitoring is recommended in the case of catecholamine-secreting tumours. Short-acting alpha or beta blockers should be available for emergency use in the event of catecholamine surge during or immediately after [¹³¹I]mIBG administration. In practice, unstable hypertension can be managed by reducing or temporarily stopping the [¹³¹I]mIBG infusion. In some cases, additional alpha or beta blockers are essential.

Prophylactic anti-emetics are advised, commencing on the day of treatment and continued for 72 h. To avoid possible drug interaction, Ondansetron is the anti-emetic of choice. During this period, patients should also be encouraged to drink extra fluids to limit extra-tumoural radiation burden, especially to the bladder.

Urinary [¹³¹I]mIBG excretion is of particular concern during the first 5 days post-administration. Patients should be advised to observe rigorous hygiene to avoid contaminating persons using the same toilet facility. Patients should be warned to avoid soiling underclothing or areas around toilet bowls for 1-week post-injection. Significantly soiled clothing should be washed separately. A double toilet flush is recommended after urination. Patients should wash their hands after urination.

Incontinent patients should be catheterized before [¹³¹I]mIBG administration. The catheter should remain in place for 3 to 4 days. Catheter bags should be emptied frequently. Gloves should be worn by staff caring for catheterized patients (or for any procedure involving contact).

Haematological monitoring is essential post-therapy to anticipate significant myelosuppression and to plan subsequent treatment cycles. Quantitative post-therapy scintigraphy may be of value to clarify tumour extent and perform dosimetry calculations.

After treatment, patients should avoid pregnancy for at least 6 months. Male patients should consider sperm banking before therapy and respect the same 6-month duration before conceiving a child.

Table 2. Thyroid blockade

Compound	Adults	Children (15-50 kg)	Children (5-15 kg)	Children (<5 kg)
Capsules	mg/daily
Potassium iodate (KIO3)	170	80	40	20
Potassium iodide (KI)	130	65	32	16
Lugol solution 1%	1 drop/kg per day with a maximum of 40 (20 drops twice daily)
Potassium perchlorate (KCIO4)	400	300	200	100

Table 3. Drug interactions with [¹³¹I]mIBG

Drug group	Approved name	Recommended withdrawal time	Mechanism of actiona
Cardiovascular and sympathomimetic drugs
Anti-arrhythmics for ventricular arrhythmias	Amiodarone	Not practical to withdraw	1, 3
Combined alpha and beta blocker	Labetalol	72 h	1, 3
Adrenergic neuron blockers	Bretylium	48 h	2, 3
	Guanethidine	48 h	2, 3
	Reserpine	48 h	2, 3
Alfa blockers	Phenoxybenzamine (IV doses only)	15 days	5
Calcium channel blockers	Amlodipine	48 h	4, 5
	Diltiazem	24 h	4, 5
	Felodipine	48 h	4, 5
	Isradipine	48 h	4, 5
	Lacidipine	48 h	4, 5
	Lercanidipine	48 h	4, 5
	Nicardipine	48 h	4, 5
	Nifedipine	24 h	4, 5
	Nimodipine	24 h	4, 5
	Nisoldipine	48 h	4, 5
	Verapamil	48 h	4, 5
Inotropic sympatho- mimetics	Dobutamine	24 h	3
	Dopamine	24 h	3
	Dopexamine	24 h	3
Vasoconstrictor sympathomimetics	Ephedrine	24 h	1
	Metaraminol	24 h	3
	Norepinephrine	24 h	3
	Phenylephrine	24 h	3
Beta2 stimulants (sympathomimetics)	Salbutamol	24 h	3
	Terbutaline	24 h	3
	Eformoterol	24 h	3
	Bambuterol	24 h	3
	Fenoterol	24 h	3
	Salmeterol	24 h	3
Other adrenoreceptor stimulants	Orciprenaline	24 h	3
Systematic and local nasal decongestants, compound cough and cold preparations	Pseudoephedrine	48 h	3
	Phenylephrine	48 h	3
	Ephedrine	24 h	1
	Xylometazoline	24 h	3
	Oxymetazoline	24 h	3
Sympathomimetics for glaucoma	Brimonidine	48 h	3
	Dipivefrine	48 h	3
Neurological drugs
Antipsychotics (neuroleptics)	Chlorpromazine	24 h	1
	Benperidol	48 h	1
	Flupentixol	48 h or 1 month for depot	1
	Fluphenazine	24 h or 1 month for depot	1
	Haloperidol	8 h or 1 month for depot	1
	Levomepromazine	72 h	1
	Pericyazine	48 h	1
	Perphenazine	24 h	1
	Pimozide	72 h	1
	Pipotiazine	1 month for depot	1
	Prochlorperazine	24 h	1
	Promazine	24 h	1
	Sulpiride	48 h	1
	Thioridazine	24 h	1
	Trifluoperazine	48 h	1
	Zuclopenthixol	48 h or 1 month for depot	1
	Amisulpride	72 h	1
	Clozapine	7 days	1
	Olanzapine	7-10 days	1
	Quetiapine	48 h	1
	Risperidone	5 days or 1 month for depot	1
	Sertindole	15 days	1
	Zotepine	5 days	1
Sedating antihistamines	Promethazine	24 h	1
Opioid analgesics	Tramadol	24 h	1
Tricyclic anti- depressants	Amitriptyline	48 h	1
	Amoxapine	48 h	1
	Clomipramine	24 h	1
	Dosulepin (Dothiepin)	24 h	1
	Doxepin	24 h	1
	Imipramine	24 h	1
	Lofepramine	48 h	1
	Nortriptyline	24 h	1
	Trimipramine	48 h	1
Tricyclic-related anti- depressants	Maprotiline	48 h	1
	Mianserin	48 h	1
	Trazolone	48 h	1
	Venlaflaxine	48 h	1
	Mirtazepine	8 days	1
	Reboxetine	3 days	1
CNS Stimulants	Amphetamines, e.g. Dexamfetamine	48 h	3
	Atomoxetine	5 days	1
	Methylphenidate	48 h	5
	Modafinil	72 h	5
	Cocaine	24 h	1
	Caffeine	24 h	5
a Mechanisms of interaction Inhibition of sodium-dependent uptake system i.e. uptake-one inhibition (1) Transport interference-inhibition of uptake by active transport into vesicles, i.e., inhibition of granular uptake, and competition for transport into vesicles, i.e., competition for granular uptake (2) Depletion of content from storage vesicles/granules (3) Calcium mediated (4) Other, possible, unknown mechanisms (5) (Adapted from the Radiopharmacy Protocol of the Nuclear Medicine Department, Queen Elizabeth Hospital, Birmingham, UK). Theoretical mechanism of interaction in italic, high significance mechanism of interaction in bold, probable mechanism of interaction in standard font.

6.2.5 Dosimetry

Tumour dosimetry has been performed with both SPECT and planar imaging, and, as in the case of neuroblastoma, a wide range of absorbed doses have been reported ranging from <5 Gy to >300 Gy [137–140]. Guidelines with recommended dosimetry procedures for ¹³¹I mIBG therapy of neuroendocrine tumours are available [37]. Treatments are often prescribed according to a whole-body absorbed dose. An increasingly common protocol is to deliver a whole-body absorbed dose of 4 Gy in two administrations of radioactivity separated by 2 weeks followed by a stem cell rescue. The first administration is delivered according to a body mass-based prescription of 444 MBq/kg [132]. If there is no stem cell rescue available, a [¹³¹I]mIBG tracer study may be performed to deliver a given red-marrow or whole-body absorbed dose. To date, there are no prescription values for the tumour absorbed dose.

Considering an absorbed-dose limit of 2 Gy for the red marrow, a dosimetric study with a tracer could be performed to determine the red marrow absorbed dose per administered activity. Using this value, the activity of [¹³¹I]mIBG can be prescribed so as not to exceed the red marrow toxicity. Alternatively, the treatment can be fractionated, and the activity in subsequent administrations determined from the biokinetics of the first administration [141].

A correlation between tumour absorbed dose and response to treatment has been reported, where progressive disease was seen only in those patients whose tumours received less than 17 Gy, and partial response was much higher in patients who received >70 Gy [142]. One study showed that an absorbed dose higher than 150 Gy was necessary to cause beneficial effects in the treatment of pheochromocytoma [139]. Moreover, better response has been observed with higher administered activities, which might be explained under the assumption that higher tumour absorbed doses were delivered [140]. With regard to toxicity, a correlation between the whole-body absorbed dose and neutropenia has been shown [143].

6.2.6 Effectiveness

The effectiveness of [¹³¹I]mIBG in the treatment of neuroendocrine tumours in adults has been reported in several studies. In the case of pheochromocytoma and paraganglioma, response rates between 30% and 47% for morphologic response and 75-90% for symptomatic response have been reported. Approximately 30% of the metastases demonstrated objective response to therapy and in 40% of the cases tumours remained stable. In the case of medullary thyroid carcinoma, an objective response of 30% has been reported, and in the case of carcinoid tumours symptomatic responses in the range of 50-75% [133].

Therapy with [¹³¹I]mIBG is usually delivered to children with more advanced stages of neuroblastoma, and its effectiveness has been studied. For instance, similar results to those of chemotherapy in stage Ill and stage IV patients were found in a phase I/II study [144]. More recently, a response rate of 58% after individualized [¹³¹I]mIBG therapy was reported [137].

6.2.7 Side Effects

Early side effects include:

• Temporary nausea and vomiting may occur during the first 2 days after administration.
• Temporary myelosuppression which typically occurs 4-6 weeks post-therapy. Haematological effects are common in children with neuroblastoma after chemotherapy (60%), predominantly as an isolated thrombocytopenia, but are less frequent in adults.
  • Bone marrow depression is likely in patients who have bone marrow involvement at the time of [¹³¹I]mIBG therapy and, because of a high whole-body radiation dose, in patients with delayed renal [¹³¹I]mIBG clearance.
  • [¹³¹I]mIBG therapy is associated with significantly less haematological toxicity in chemotherapy naïve patients.
• Rarely, deterioration of renal function is observed in patients whose kidneys have been compromised by intensive pretreatment with cisplatin and ifosfamide.
• Rarely, in adults with pheochromocytoma or paraganglioma and children with neuroblastoma, hypertensive crises requiring alpha blockade might be evoked by release of catecholamines. In patients with carcinoid, flushing might occur because of release of serotonin.

Late possible long-term effects include those known for ¹³¹I therapy in general, such as:

• Hypothyroidism (after inadequate thyroid blockade);
• Persistent haematological effects (thrombocytopenia, myelosuppression);
• There is a sparse evidence for induction of leukaemia or secondary solid tumours, but this is a rare possibility, especially in conjunction with (longstanding) chemotherapy treatment [145].

6.2.8 Status

[¹³¹I] meta-iodobenzylguanidine is approved as a therapeutic agent in inoperable pheochromocytoma, inoperable paraganglioma, inoperable carcinoid tumour, stage III or IV neuroblastoma, and metastatic or recurrent medullary thyroid cancer.