MIBG (metaiodobenzylguanidine) theranostics in pediatric and adult malignancies

Abstract

Metaiodobenzylguanidine, a guanithidine analog, labeled with ¹²³I and ¹³¹I, is used for imaging and therapy of neuroblastomas and various neural crest tumors like paragangliomas, pheochromocytomas, medullary cancer of thyroid and carcinoids since the past three to four decades. In this review article, we shall revisit metaiodobenzylguanidine as a radiopharmaceutical and its various applications in neural crest tumors.

Introduction

Metaiodobenzylguanidine (MIBG) was first developed in USA, in Michigan University Medical Centre, in early 1970, for imaging the adrenal medulla and its disease.¹ MIBG, a guanithidine analog, is taken up by an active mechanism into the neuroendocrine cells due to its similarities with nor-epinephrine. It came into clinical practice in 1981 for localization of pheochromocytoma (pheo).² In course of time, MIBG demonstrated its ability to concentrate in tumors of the neural crest origin such as neuroblastoma (NBL),³ carcinoids and medullary carcinoma of the thyroid.^{4, 5} Due to good selective uptake and retention of MIBG by these tumors, its potential was explored for therapy of neuroendocrine tumors (NETs) as well. MIBG is labeled with 123-Iodine (¹²³I) which is exclusively used for imaging and also with 131-Iodine (¹³¹I); which can be used both for imaging and therapy of NBL or other MIBG avid neural crest tumors.

Section I—Metaiodobenzylguanidine (MIBG) in diagnosis and therapy

Part 1—Metaiodobenzylguanidine (MIBG) in diagnosis

MIBG labeled with ¹²³I or ¹³¹I is useful for localization, staging and in follow-up evaluation of NETs like pheo, NBL, ganglioneuroblastoma, paragangliomas (PGLs), medullary carcinoma of thyroid, carcinoid, Merkel cell tumors and MEN (multiple endocrine neoplasia) syndrome and as a prelude to ¹³¹I MIBG therapy. This is a useful tool for confirmation of suspected neural crest tumor. Dosimetric studies and evaluation of treatment response are other indications of MIBG scintigraphy.⁶

Apart from these oncological indications, few non-oncological indications are functional studies for sympathetic innervation of the myocardium and adrenal medullary hyperplasia.⁶

Mechanism of uptake

The uptake of MIBG, an analog of nor-epinephrine, into the neuroendocrine cell is by two mechanisms—active and passive. The active transport or the uptake-1 system is the dominant method of transport of MIBG into the cell. This is an active, sodium and energy dependent amine uptake mechanism in the cell membrane of the sympathomedullary tissues. Within the cell, it is actively transported into the storage granules by an energy dependent transport mechanism via vesicular monoamine transporters 1 and 2. This accumulation of MIBG in these neurosecretory granules forms the basis for imaging and therapy with 123I/131I-labeled MIBG. Small amounts of MIBG is also present in the cytoplasm.⁷ The other mechanism is passive diffusion of MIBG into the cells. The active uptake is more efficient and specific than the passive uptake. Within the body, MIBG is not metabolized and is mainly excreted unaltered by the kidneys by glomerular filtration. Within the first 24 h, about 50% of the injected activity is excreted in urine and about 90% in 4 days after injection, in patients with normal renal function. The highest uptake in tumors is reached after 24–96 h.⁷ A very minimal amount is excreted in feces, sweat and saliva.⁸

Preparation of the patient

Interfering drugs

Many drugs are known to interfere with MIBG uptake and storage, resulting in altered biodistribution, which may interfere with correct interpretation of the study. Common medications such as pseudoephedrine, labetalol, phenothiazines, central nervous system stimulants (cocaine, amphetamine) tricyclic antidepressants, calcium channel blockers, sympathomimetics, antihistaminics, opioid analgesics (Tramadol) and reserpine are known to interfere with MIBG and should be stopped prior to MIBG scan and/or therapy. These should be withheld for 24–72 h.^{6, 9} Few neuroleptics like Haloperidol, Flupentixol and Fluphenazine need a withdrawal period of 24 h to 1 month.⁶ Food containing vanillin and catecholamine, chocolate and blue-veined cheese are also known to interfere with MIBG uptake and should be avoided prior to MIBG scan.

Thyroid blockade

Oral potassium iodide (KI) in dosage of 100mg per day in adults and 2 mg per kg body weight in children is used for blocking the thyroid. KI should be started 24 h prior to the injection and continued for 3–5 days for ¹³¹I-MIBG and 2 days for ¹²³I-MIBG. This is to prevent irradiation of the thyroid due to the presence of 3–5% free radioiodine in the preparation.^{9, 10} Oral potassium perchlorate may be substituted in patients who are allergic to iodine at a dose of 8 mg kg^–1 in children and 400 mg in adults.

Procedure

Dose—18.5–74 MBq (0.5–2 mCi) of ¹³¹I -MIBG (specific activity >74 MBq mg^–1) or 185–370 MBq (5–10 mCi) of ¹²³I-MIBG (specific activity >300 MBq mg^–1) is administered intravenously over 1–5 min to avoid side-effects like hypertensive crisis or tachycardia. There is no distinction between children and adult dosage. The correct amount of tracer to be injected is not based on any scientific basis, but dosages have been suggested from the available literature and current experience.¹¹ The exact dosing for children is not available. However, the minimum activity that should be injected in children is 20 MBq for ¹²³I-MIBG and 35 MBq for ¹³¹I -MIBG, the maximum dosage being 400 MBq for ¹²³I-MIBG and 80 MBq for ¹³¹I-MIBG.^{11, 12}

Image acquisition

The environment should be adapted for children with a friendly and caring attitude. The parents should be well-informed about the entire process and the technologists should be well-trained in pediatric procedures. All this will help in having a co-operative child for scanning and in building a good rapport with the patients. Sedation, if necessary may be given in small infants or in uncooperative children.¹¹

Imaging with ¹²³I/¹³¹I-MIBG

¹²³I is most suited for imaging due to its short half-life of 13h, γ emission of 159 keV γ photons, which is ideal for imaging with gamma camera and lack of β emission. The image quality of ¹²³I-MIBG is superior with lower radiation burden. However, due to lack of availability of ¹²³I-MIBG in few underdeveloped and developing countries, ¹³¹I-MIBG is used for both imaging and therapy. ¹³¹I has a half-life of 8.02days, γ emission of 364 keV and β of 606 keV.

Whole body imaging is performed 24h after injection of ¹²³I-MIBG and 24–48 h after injection of ¹³¹I-MIBG. Delayed imaging may be useful to resolve doubtful uptake in the bowel or kidneys. Additional spot views may be acquired for selected regions if needed. Single photon emission computed tomography (SPECT) or SPECT/CT may be performed with ¹²³I-MIBG for better delineation and cross-sectional imaging of the tumor and metastatic sites.

Normal biodistribution

Knowledge of normal physiological patterns of uptake avoids misinterpretation of images and false-positive results. Physiologic uptake of MIBG includes salivary glands, myocardium (due to sympathetic innervation), large intestine, urinary bladder (due to excretion of tracer through these routes) and liver. Other areas of physiological localization are nasal mucosa, gall bladder, colon, uterus. Occasionally, diffuse uptake may be noted in the lungs (Figure 1)^{9, 11,13} Usually the normal adrenals are not seen; but faint visualization may be seen 48–72 h after injection in 15% of patients with ¹³¹I-MIBG.^{6, 11} The normal adrenals are commonly seen with ¹²³I-MIBG in upto 75% of patients.⁶

Figure 1.

¹³¹I-MIBG scan showing physiological tracer uptake in SG, H, L, B and diffuse uptake in Lu. B, bowel; H, heart; L, liver; Lu, lungs; SG, salivary glands.

Normal variant

^123/131I-MIBG uptake may be seen in brown adipose tissue, usually in bilateral supraclavicular and axillary regions due to sympathetic innervation of brown adipose tissue^{14, 15}

Pitfalls

False-positive uptake of MIBG is rare, but few false-negatives have been reported in NBL.^{16, 17} Commonest cause for false-negative study is drug interference.¹⁸ Other causes of error include small lesions which are below the resolution of the gamma camera, improper patient preparation (tiny lesions in the pelvis may be missed in a patient with a full bladder), lesions close to areas of high pathological or physiological uptake, lesions which are MIBG negative due to necrosis and changes in differentiation. Patient motion particularly in children, physiological uptakes in urinary tract and bowel; uptake in thyroid if not adequately blocked; urinary contamination, muscle uptake and supraclavicular brown fat uptake may also pose a problem in reporting.⁶ PGL, in particular non-functioning tumors and tumors associated with SDH-B gene mutations may also be negative on MIBG study.¹⁹

Image interpretation

Intense tracer uptake is usually visualized in the diseased areas. Any tracer uptake beyond the normal physiological uptake should be taken into consideration and reported as abnormal. MIBG uptake in the skeletal system should be considered abnormal.

New MIBG tracer for imaging

¹²⁴I-MIBG is a relatively new positron emission tomography (PET) tracer for imaging NETs. As compared to other positron emitters, ¹²⁴I has a long half-life of 4.2days. It is produced in a cyclotron by using various reactions depending on the particles and energies available for irradiation. It is mainly produced by using enriched tellurium-124 as the target using ¹²⁴Te (d,2n) ¹²⁴I reaction or ¹²⁴Te (p,n) ¹²⁴I reaction. The later reaction is superior due to low levels of impurity.^{20 124}I-labeled MIBG provides high quality images and accurate tumor volume estimation and helps in better and appropriate dose planning with ¹³¹I-MIBG therapy.^{21 124}I-MIBG is a better agent as compared to ^123/131I-MIBG, due to its higher spatial resolution and provides additional information regarding the extent of the lesion and the overall disease extent. This information helps in appropriate management of the patient by triaging to surgical or medical management.²² Its current use is limited by its non-availability at many centers.²¹

Part II—therapy with ¹³¹I-MIBG

Being a γ and β emitter, ¹³¹I-MIBG can be used for both imaging and therapy. The β rays emitted from ¹³¹I have a cytocidal effect on the tumor cells. ¹³¹I-MIBG was first used in treatment of patients of pheo.²³ Subsequently in 1986, NBL was treated with ¹³¹I-MIBG.²⁴ Since then MIBG has been for treatment for NETs. Being a systemic agent coupled with the effective β emissions from ¹³¹I; this agent achieves a higher therapeutic efficiency to multiple sites in one sitting, when compared to external beam radiation therapy.

Indications for ¹³¹I- MIBG therapy

The pre-treatment MIBG scan should show avid concentration of the radiotracer in the primary and/or the metastatic sites to contemplate MIBG therapy. The indications are inoperable pheo, inoperable or Stage III/IV NBL, other inoperable neural crest tumors, and recurrent of metastatic medullary carcinoma thyroid (MTC).²⁵

Prerequisites for ¹³¹I- MIBG therapy

• Histopathologically proven NET with positive MIBG scintigraphy.

• Adequate thyroidal blockade as discussed in the previous (imaging) section.

• Drugs known to interfere with MIBG uptake should be withdrawn.

Contraindication for ¹³¹I- MIBG therapy

The contraindications can be absolute and relative.

The absolute contraindications are:

1. Pregnancy

2. Breast feeding

3. Renal insufficiency

4. Life expectancy of<3 months.

The relative contraindications are:

• (i) Glomerular filtration rate of <30 ml min^–1. (ii) Myelosuppression (Total white cell count <3 × 10⁹ l^–1; platelets <100 × 10⁹ l^–1). (iii) Progressive renal or haematological toxicity. (iv) Unfit for isolation.

• In case of myelosuppression and renal impairment, the dose of the administered activity should be reduced.²⁵

Patient instructions and preparation prior to MIBG therapy

• Patients should receive both written and verbal information regarding the entire therapy procedure. Informed consent form may be obtained if necessary.

• Prophylactic antiemetics should be started 72 h prior to therapy.

• Proper hygiene to avoid urinary contamination and soiling of clothes.

• The toilet should be flushed twice after use and hands should be washed thoroughly.

• Incontinent patients should be catheterized.

Planning and execution

A successful MIBG therapy program needs a multidisciplinary team effort. Pediatric oncologists, Nuclear Medicine Physicians, medical physicists, nuclear medicine technologists, radiopharmacists, Radiation Safety Officer and well-trained nursing staff are necessary for implementation and execution of MIBG therapy programme. Well-planned isolation therapy unit with an appropriate lead-lined isolation therapy room as well as hot lab with regulatory compliance is mandatory. The requirements of this facility depend on the individual national regulatory policy and should be abided. The facility should be well-equipped with adequate and appropriate personnel, radiation safety equipment, and proper procedures for waste management.²⁵ The isolation therapy room should be a private room with en-suite facilities and should not be shared by other patients or care-givers to minimize the radiation dose to others. Radiation safety precautions that should be taken during the therapy and after discharge from the hospital should be well-informed to the care-givers, family members and also to the patient. The radiation exposure to the care-givers should be as low as reasonably achievable and should be within the established regulatory limits.²⁶

Special care for needs to be taken while treating children with MIBG. To reduce the exposure time for the health personnel and parents’/care-givers, the time spend in patient room should be minimized. Ideally, the parent/care-giver should stay in a room adjacent the therapy room with a lead lined glass window so as to observe the child through the window and also to comfort the child. In case this is not available, a video-monitoring system should be in place.²⁶ Age-appropriate play materials can be given to the child to decrease the apprehension associated with admission into an isolation unit. Care should be taken to avoid contamination of these objects. To reduce the radiation exposure to the care-givers, it is best if two parents /care-givers are involved in the child’s care and take turns to take care of the child. They should be monitored with personal dosimeters and should receive extensive basic training regarding the use of protective clothing, handling and disposal of body fluids; prior to MIBG treatment.²⁶ This training can be done by the use of proper written material with the use of cartoons on these topics, use of power point presentations and proper explanation by healthcare personnel and nursing staff.²⁶

24–48 h prior to the therapy, thyroid protectors like KI or potassium perchlorate are started and continued for 3weeks after treatment.

¹³¹I-MIBG is transported and stored in frozen form and should be thawed prior to administration. All quality control tests should be done prior to injection to ensure that the amount of free iodide in the radiopharmaceutical preparation is <10%. Carrier- free ¹³¹I with high specific activity (upto 1.48 GBq mg^–1) labeled with MIBG is preferred. The prescribed dose [typically in the range of 3.7–11.2 GBq (100–300 mCi)] ¹³¹I-MIBG is administered as an infusion after securing a patent intravenous line, by the nuclear medicine personnel. The infusion continues for 90–120 min. Blood pressure and heart rate should be monitored. ¹³¹I-MIBG therapy may have cardiovascular effects due to changes in sympathetic activity; this makes cardiac and blood pressure monitoring mandatory. α or β blockers should always be available for any emergency/inadvertent situation. The patient is hospitalized for 3–5 days after ¹³¹I-MIBG therapy and discharged after radiation levels are well-within the discharge limits. Prior to discharge, a post-therapy whole-body scan is done to assess the areas of ¹³¹I-MIBG uptake.

Side-effects

There are no major toxicities and the therapy is well tolerated.

Early side effects

<10% of patients experience hypertension and tachycardia within few hours after the treatment, even after slow intravenous administration of ¹³¹I-MIBG over 1–3h. Nausea and vomiting may occur due to acute radiation gastritis in 10–25% of patients in first few hours or 1–2 days after the treatment. This can be reduced by the use of antiemetics given 24 h prior to treatment and continued for 2 days. Hematopoietic toxicity can also occur with ¹³¹I-MIBG therapy. Myelosuppression is seen 2–4 weeks after the therapy. Thrombocytopenia is common in patients of NBL receiving >15 mCi kg^–1. This requires treatment with stem cell rescue.^26–28

Late side-effects

There is a possibility of few late side-effects due to ¹³¹I therapy in general. Hypothyroidism may occur secondary to inadequate blockade of thyroid during ^13II-MIBG therapy. Rarely myelosuppression may occur. Rare possibility of developing second primary like leukemia of solid tumors due to use of radionuclide therapy in conjunction with chemotherapy.^{25, 29}

New MIBG tracer for therapy

New tracer for therapy of neural crest tumors is ²¹¹At meta-astatobenzylguanidine (MABG), which is an α emitter. α-particle is a method of targeted radionuclide therapy that destroys cells by simple cytotoxic mechanism by DNA damage. Due to its high linear energy transfer and limited range in the tissue (<100 micron m), this form of therapy has strong therapeutic effects with minimal side-effects. In a recent study, Ohshima et al have shown strong tumor volume-reducing effect with this agent in mouse-pheo model. Moreover, there no severe adverse effects like weight reduction and reduction in number of myeloid cells in the bone marrow.³⁰ In the future, ²¹¹At-MABG might prove to be an effective treatment option for neural crest tumors.

Section II

Specific role of iodine-labeled MIBG in various tumors

Role of MIBG in neural crest tumors

Neuroblastoma

NBL is a common childhood malignancy and the most common extracranial tumor seen in infancy and young children. It arises from primitive neural crest cells of the sympathetic nervous system. This tumor expresses nor-adrenaline transporter molecule and therefore,>90% of cases demonstrate uptake of MIBG.³¹

NBL can be found anywhere from the neck to the pelvis along the sympathetic chain, but the commonest location is in the abdomen (65–70%), with adrenal gland being the commonest organ of involvement.^{32, 33} The patient might be asymptomatic or may present with distention of the abdomen, abdominal pain, constipation and sometimes hypertension. NBL is seen in the thorax in 20% of patients.³² These manifest with respiratory symptoms and features of Horner’s syndrome, i.e. ptosis, myosis and anhydrosis.

Distant metastases are very common in NBL. About 50% of patients present with distant metastases at initial presentation. The commonest sites of metastases are bone, lymph nodes and liver.³⁴ 5–15% of patients present with intraspinal extension of tumor, which may result in compression of the spinal cord, resulting in paraplegia.^{33, 35} 2–3% of children present with opsoclonus myoclonus ataxia syndrome, which is associated with random eye movements and myoclonic jerks with associated ataxia in few. These children usually have a favorable outcome.³⁶

Staging and prognosis in NBL

NBL is conventionally staged by the International Neuroblastoma Staging System (Table 1). This is based on resectability and histopathological assessment of the locoregional nodal involvement.³⁷ A more recent staging system is the International Neuroblastoma Risk Group Staging System; which is a pre-treatment staging system based on image defined risk factors.³⁸ This differentiates tumors that invade the adjacent organs, blood vessels and the nerves from those tumors that do not.

Table 1.

INSS (Source – Monclairet al. 2008)

Tumor stage	Description
1
2A
2B
3
4S (Special)
4

Age at diagnosis is an important prognostic factor in children with metastatic disease. Infants younger than 12 months of age have a favorable prognosis even with metastatic disease; as compared to children of more than 12 months of age.^{39, 40} Older children with metastatic disease are refractory to both chemotherapy and radiotherapy with overall survival of <40%.⁴¹ The median age at diagnosis is 17 months⁴⁰ and it is rarely diagnosed beyond 10 years of age. Age >18 months, advanced disease stage, poorly or undifferentiated histology, diploid DNA and amplification of MYCN oncogene are poor prognostic factors. Patients are risk stratified into low, intermediate and high risk by the Children’s Oncology Group based on these factors.

Role of MIBG imaging in NBL

¹²³I/¹³¹I-MIBG scintigraphy is a well-established imaging tool for diagnosis and staging of NBL (Figure 2). It is also used for restaging and detection of relapses.³⁷ More than 90% of NBLs are MIBG avid. The reported sensitivity of MIBG scintigraphy for NBL is 85–96% and the specificity is 95–99%.⁴² MIBG scintigraphy documents MIBG avid disease and justifies the feasibility of MIBG therapy; because we treat what we see on the diagnostic MIBG scan. For assessment of response of bone marrow disease MIBG (Figure 3) is superior to ¹⁸F-fluorodeoxyglucose (FDG) PET/CT and MRI because it is not affected by post-treatment changes.⁴³ Due to hyperstimulation of marrow post-chemotherapy, FDG PET/CT shows diffuse FDG uptake in the marrow which may interfere which interpretation of the scan; but unlike FDG, MIBG scintigraphy is not affected by these post-treatment changes. MIBG has a sensitivity of 94% for detection of skeletal relapse, whereas FDG has a detection rate of only 43%.⁴⁴

Figure 2.

¹³¹I-MIBG scan of a 9-year-old female child showing MIBG avid large left suprarenal mass (arrow) with multiple sites of MIBG avid marrow lesions (arrow head). The scan was done for diagnosis and staging. Scan findings suggest left suprarenal Neuroblastoma with skeletal metastases. This was later confirmed by biopsy. MIBG, metaiodobenzylguanidine.

Figure 3.

¹³¹I-MIBG scan of the same 9-year-old female child with left suprarenal neuroblastoma and skeletal metastases done for response assessment post COJEC chemotherapy. The image on the right shows significant reduction in the primary mass as well as the metastatic skeletal lesions. COJEC, Cisplatin (C), Vincristine (O), Carboplatin (J), Etoposide (E) and Cyclophosphamide (C); MIBG, metaiodobenzylguanidine.

¹⁸F-FDG PET/CT is complimentary to MIBG scintigraphy in MIBG-negative tumors. A study comparing ¹⁸F-FDG and ¹²³I-MIBG showed that MIBG is superior to ¹⁸F-FDG PET/CT in Stage IV NBL due to better delineation of skeletal disease and ¹⁸F-FDG PET/CT was more superior in stages I and II.⁴⁵

Scoring system in NBL

Semi-quantitative scoring methods have been proposed to assess the extent of metastatic involvement and also to assess the response to chemotherapy in NBL. Of all the scoring systems, the Curie score and the SIOPEN (International Society of Pediatric Oncology Europe Neuroblastoma) score are the most commonly used^{46, 47} (Table 2). Both the systems take into account the findings of planar MIBG imaging. Findings of SPECT or SPECT/CT are not considered.⁴¹ These scoring systems are helpful in describing the extent of metastatic disease and bring about an objective dimension to reporting. The scoring systems are also excellent prognostic surrogates.⁴⁴ Both the Curie and the SIOPEN scoring systems are equally reliable and predictive with good inter observer reliability. A Curie score of <2 and a SIOPEN score <4 at initial staging have better event-free and overall survival.⁴⁸ MIBG scoring can also define patients with poor outcomes. Curie score >2 or SIOPEN score >3 at the end of induction chemotherapy have shown to have poorer outcomes.⁴⁹

Table 2.

Curie and SIOPEN scoring systems [Source—Sucet al. (1996) and Decarolis et al. (2013) reference]^{47, 48}

	Curie (COG) scoring	SIOPEN scoring
No of segments	10 (9 skeletal+1soft tissue)	12
Soft tissue accounted	Yes	no
Score in each segment	0–3	0–6
Maximum score (sum)	30	72
Skeletal score	1=one distinct lesion 2=two distinct lesions 3=>50% of segment	1=one distinct lesion 2=two distinct lesions 3=three distinct lesions 4=>3or<50% diffuse involvement 5=50–95%diffuse involvement 6=100% diffuse involvement.
Soft tissue score	1=1 MIBG avid soft tissue lesion 2=>1 MIBG avid soft tissue lesion 3=>50% of the region is involved (chest or abdomen/pelvis)

COG, Children’s Oncology Group; SIOPEN, International Society of Pediatric Oncology Europe Neuroblastoma;

¹³¹I-MIBG therapy in NBL

Surgery is the preferred treatment option for localized NBL with favorable tumor biology. In patients with locally advanced disease with favorable tumor biology, surgery with chemotherapy is preferred. Children with metastatic disease or with unfavorable tumor histology and/or biological features are at high-risk and need aggressive multimodality treatment with chemotherapy, surgery, radiotherapy, high-dose chemotherapy with autologous bone marrow transplantation.^{50, 51} High-risk NBL patients initially respond to first-line treatment, but relapses are seen in 50–60%and the prognosis is often dismal. To our knowledge, there are no curative salvage treatments available, till date. It is in this scenario that ¹³¹I-MIBG has been widely investigated as a potential therapeutic radiopharmaceutical.

¹³¹I-MIBG therapy is reserved for relapsed or refractory NBLs, where there is disease progression after initial chemotherapy or in patients who fail to respond to induction chemotherapy.^{52, 53}>90% of NBL concentrate MIBG in primary tumors as well as metastases. This high avidity of MIBG for NBL makes it an ideal radiopharmaceutical for therapy as well as imaging.⁵⁴ Few studies have shown the use of MIBG as “induction therapy”—where MIBG has been used as first-line of treatment in newly diagnosed patients.⁵⁵ MIBG has also been given in conjunction with myeloablative chemotherapy after response with initial chemotherapy—in this setting, it is termed as “consolidation therapy”.⁵⁶ Response rates of MIBG vary widely in different studies, a recent systematic review has quoted median response rates of 30% in relapsed and refractory NBL.⁵⁷ For refractory NBL, ¹³¹I-MIBG has been used in escalating doses ranging from 111 to 666 MBq kg⁻¹ (3–18 mCi kg⁻¹) in a Phase 1 study.⁵⁸ The adverse effects reported were mild nausea and vomiting seen within the first few days of the treatment. Significant hematologic toxicity in terms of thrombocytopenia can occur and is dose dependent. In this Phase 1 study, no patient who received 444 Mbq kg⁻¹ (12 mCi kg⁻¹) or less of ¹³¹I-MIBG needed an autologous stem cell rescue. The overall response rate was 37%.⁵⁸ In a Phase 2 study, comprising of 164 patients of relapsed or refractory NBL, the objective response rate was 37% for 147 patients who were treated with 666 MBq kg⁻¹ (18 mCi kg⁻¹) ¹³¹I-MIBG and 25% for 16 patients treated with 444 Mbq kg⁻¹ (12 mCi kg⁻¹). Disease stabilization was seen in 39%.⁵⁹

Higher dose intensification with cumulative dosing ranging from 814–1887 Mbq kg⁻¹ (22–51 mCi kg⁻¹) followed by stem cell rescue was investigated in New approaches to Neuroblastoma therapy Phase I study.^{60 131}I-MIBG has also been used in combination with other agents such as cisplatin, irinotecan and topotecan. These are mainly feasibility studies with combination therapies and have been reported to be well-tolerated.^61–64

Clinical data have also shown that pre-treatment with chemotherapeutic agents like cisplatin, doxorubicin and topotecan with ¹³¹I-MIBG therapy, helps to significantly increase the MIBG uptake in tumor cells.^65–67 This is likely due to increase in nor-epinephrine transporter gene and thus, increase in norepinephrine receptor expression.⁶⁶

Paraganglioma/Pheochromocytoma

PGLs arising from the chromaffin cells in adrenal medulla are called as pheo. Tumors arising from chromaffin cells located at extra-adrenal sites are referred to as PGL.⁶⁸ They are located in paravertebral and para-aortic areas in the abdomen. Rarely small PGLs may be found in the viscera like the urinary bladder and gall bladder. The clinical manifestations are mainly due to catecholamine hypersecretion and manifest as headache, palpitations and sweating. Hypertension though a common finding is often non-specific.⁶⁹ Prognosis of these masses depends on the malignant status. Currently, there are no validated histological criteria for determining malignancy. The diagnosis of malignant PGL is established only by the detection of metastasis. Metastases are typically seen in lymph nodes, lung, liver and bone.^{70, 71}

PGLs found in the head and neck and anterior mediastinum are related to the parasympathetic nervous system and are chromaffin negative tumors. In head and neck, the parasympathetic PGL usually occur in carotid body, jugular foramen and middle ear. In the anterior mediastinum, the location is in the aortopulmonary window. These tumors rarely produce significant amount of catecholamines and are non-functional. They usually present as painless masses. Only 1% of head and neck PGLs may be functional. Being non-functional, these are usually negative on MIBG. These masses are usually imaged by ¹⁸F-FDG PET/CT or by somatostatin receptor (SSTR) tracer ⁶⁸Ga-DOTA PET/CT or octreotide based SPECT scintigraphy. Somatostatin receptor scintigraphy (SRS) has better sensitivity of 89–93% as compared to 42–44% of ¹²³I-MIBG.⁷² PET tracers like ¹⁸F-fluodihydroxyphenylalanine (DOPA) and ¹⁸F-fluodopamine (FDA) have excellent sensitivity for detection of these tumors but are limited by their lack of availability.⁷³

PGL can be sporadic or hereditary. Sporadic PGL presents in older age group in the fourth-fifth decade. Those with genetic predisposition present at a younger age group in the second or third decade and are often multiple and bilateral. These are often associated with hereditary syndromes like MEN 2 (MEN Type 2), neurofibromatosis Type 1, von Hippel-Lindau disease (VHL) and hereditary PGLs. These syndromes are caused by mutations in rearranged during transfection (RET), neurofibromatosis Type 1, VHL, succinate dehydrogenase (SDH)-B, C and D genes. SDH-related tumors are generally extra-adrenal. SDH-B gene mutation is the commonest, associated with aggressive tumors with high risk of malignancy and poor prognosis.⁷⁴

Both CT and MRI have high sensitivity for detection of pheo and PGLs. CT has a sensitivity of 93–100% for detection of pheo and about 90% for detection of PGLs.⁷⁵ MRI has better sensitivity as compared to CT. The specificity of CT/MRI varies from 50 to 90% because of multiple false-negative studies.^{76, 77} Previous interventions like surgery may hamper the results of CT/MRI in the recurrent setting; when functional imaging becomes the most important imaging tool to detect recurrence and residual disease.⁷⁸

MIBG imaging in PGL/pheo

The advantage of performing nuclear medicine imaging over anatomical imaging is better specificity and advantage of doing a whole-body imaging, which is helpful in detecting the presence of multiple tumors as well as metastases. ¹³¹I-MIBG has a sensitivity of 77–90%and specificity of 95–100% in detection of abdominal PGL/pheo (Figure 4).⁷⁹ Reported sensitivity of ¹²³I-MIBG is slightly higher at 83–100%, the specificity being the same.⁸⁰ In a prospective study including 140 patients, the sensitivity and specificity of ¹²³I-MIBG for detection of pheo has been reported as 88and70%. The same study reported a sensitivity of 75% and specificity of 100% for detection of PGL and sensitivity for detection of metastatic disease was 83%.⁸¹ Also, the role of SPECT/CT in detection of PGL cannot be undermined. Addition of SPECT CT to planar imaging results in improved sensitivity due to precise localization of the lesion and better specificity due to better characterization of the lesions.⁸² Timmers et al, in a prospective study have compared ¹⁸F-fluoDOPA, ¹⁸F-FDG and ¹⁸F-FDA PET/CT and ¹²³I-MIBG for localization of pheo and PGL and have stated that ¹⁸F-FDA PET/CT is the best modality for localizing primary PGL and for ruling out metastasis. Next best with similar sensitivities are ¹⁸F-DOPA and ¹²³I-MIBG.⁸³ MIBG scintigraphy has low sensitivity in patients with malignant pheo/PGL, dedifferentiated tumor, mutation-associated (SDHB, VHL) pheo/PGL due to lower nor-adrenaline transporter expression.^{84, 85} In such cases alternate imaging modalities like ¹⁸F-FDG and ⁶⁸Ga DOTATATE PET/CT are found to be useful. In patients with SDH-B-associated pheo/PGL ¹⁸F-FDG PET is superior to ^123/131I-MIBG, ¹¹¹In-pentreotide and 18F-FDA PET detection of metastatic lesions with sensitivity reaching upto 100%.^{86 68}Ga DOTA-peptide PET/CT imaging which targets SSTRs present on the cell membrane of these tumors has also shown promising results. ⁶⁸Ga DOTA-peptide PET/CT has high sensitivity for detection of pheo/PGL which are negative on MIBG scintigraphy and particularly in small head and neck PGLs which are non-functional and thus not visualized on MIBG scan.^{87, 88} In a study comparing SRS and MIBG scintigraphy in patients with SDH-X related syndromes; Michalowska et al have shown high sensitivity of 77 and 91.4% for SRS scintigraphy for benign and head and neck PGL respectively. The sensitivity of ¹²³I-MIBG in the same group was found to be very poor—22% for benign tumors and 3.7% for head and neck PGL.⁸⁹

Figure 4.

¹³¹I- MIBG scan in a 23-year-old male patient who presented with hypertension and palpitations. The clinical suspicion was of pheochromocytoma. The scan shows MIBG avid left suprarenal mass (arrow) suggestive of pheochromocytoma. The patient underwent surgery and diagnosis of pheo was confirmed. MIBG, metaiodobenzylguanidine.

B¹³¹I-MIBG therapy in pheo and PGL

Surgery is the only curative option for patients with pheo/PGL.⁹⁰ External beam radiotherapy has limited role in these tumors.^{71 131}I-MIBG is a good treatment option for pheo/PGL (Figure 5) in whom the diagnostic scan is positive done either with ¹²³I/¹³¹I-MIBG. ¹³¹I-MIBG therapy dose ranges from 3.7 to11.1 GBq (100–300 mCi) and can be repeated after 3 months.⁹¹ A retrospective study with 116 patients documented tumor response in 30%, biochemical response in 45% and improvement of symptoms in 75% of patients with cumulative doses ranging from 3.55 to 85.91 GBq (96–2322 mCi).⁹² The responses seen with MIBG therapy are mostly stabilization of the disease or partial response. Complete response is rare with MIBG treatment. In a systematic review with 243 patients, 52% showed stable disease, 27% showed partial response and only 3% showed complete response.⁹³ Reductions in symptoms is also noted after MIBG therapy.

Figure 5.

30-year-old male, a case of left para-aortic paraganglioma (arrow) with multiple metastases (arrow head). The patient was treated with 180 mCi of ¹³¹I-MIBG. The post-therapy scan demonstrates the MIBG avid lesions. MIBG, metaiodobenzylguanidine.

The presence of SSTRs in pheo/PGL has facilitated the treatment of these tumors with Yttrium-90- DOTA-peptides (⁹⁰Y-DOTA) and Lutetium-177-DOTA peptides (¹⁷⁷Lu-DOTA), in patients who are negative on MIBG scintigraphy. The results with this therapy are encouraging in terms of tumor stabilization, regression and symptomatic relief.⁹⁴

Medullary carcinoma thyroid

MTC is a NET arising from the parafollicular C cells of thyroid. It is a relatively rare tumor of thyroid comprising 5–10% of all thyroid cancers. It releases calcitonin and carcinoembryonic antigen primarily and also chromogranin, serotonin, somatostatin and gastrin releasing peptide. MTC exists in a more common sporadic form (approx. 70–80%) and a less common inherited form (approx. 20–30%), as an autosomal dominant trait due to RET proto-oncogene mutation. The hereditary form can occur as a component of MEN 2 syndrome. MEN 2A is associated with pheo, hyperparathyroidism and MTC. MEN 2B with pheo, MTC, ganglioneuromatosis, and marfanoid habitus.⁹⁵ MTC with disease confined to the thyroid have better 10 year survival rate of 95% as compared to those with distant metastases where the 10year survival decreases to 40%.⁹⁶ MTC commonly metastasizes to cervical lymph nodes, mediastinum, lungs, liver and bone.

Imaging modalities in MTC include CT/MRI, ultrasound and bone scan. Many nuclear medicine studies with different radiopharmaceuticals have been used for imaging and therapy of MTC. ^99mTc(V) DMSA, ¹³¹I MIBG, ¹⁸F-FDG, ¹⁸F-DOPA, and more recently, ⁶⁸Ga-DOTATOC have been used for imaging MTC. Therapy with ¹³¹I-MIBG, ¹⁷⁷Lu- DOTATOC and ⁹⁰Y-DOTATOC have been attempted. MIBG has a poor diagnostic accuracy in MTC with very low sensitivity of 25–30%, but with high specificity of 95%.^{97, 98} In most cases of MTC, the uptake of MIBG is very low and good therapeutic benefit cannot be expected. The reported response rates with MIBG therapy are 30% partial response and 30% stable disease.⁹⁹ Symptom relief is reported in 60% of patients.^{100 177}Lu/90Y-DOTA offers good treatment opportunity in MTC. ¹³¹I-MIBG therapy can be contemplated in cases which are not DOTA avid or do not respond to any other form of treatment.

Carcinoids

Carcinoids are tumors derived from the cells of neuroendocrine system, present in the bronchial epithelium, gastrointestinal tract and the urogenital system. Carcinoids can arise from lung, thymus, stomach and duodenum (foregut tumors), distal ileum and proximal colon (midgut), distal colon and rectum (hindgut) and also from endocrine pancreas which may be divided based on hormone secretion into insulinomas, gastrinomas, VIPomas, glucagonomas. About 15–30% of pancreatic NETs are non-functional. Radiolabeled MIBG has a limited role in evaluation of carcinoids. The detection rate of carcinoids with MIBG varies from 40 to 85% in various studies. Compared to MIBG, SSTR imaging has much better sensitivity of >80% in detection of primary as well as metastatic lesion.^101–105

¹³¹I MIBG therapy is for treatment of metastatic carcinoids offers good palliation of symptoms and effective disease stabilization. This can be used as an adjunct or alternative therapy regime in addition to the existing treatment modalities that are currently available.¹⁰⁶

Conclusion

^123/131I-labelled MIBG imaging for neural crest tumors is unique because of its specific uptake mechanism due to its similarity with nor-epinephrine. This makes it an ideal imaging and a targeted therapeutic agent for imaging and treatment of these tumors. New agent ²¹¹At-MABG, an α emitter has lesser bone marrow toxicity and strong therapeutic effect due to high linear energy transfer. It remains to be seen whether the use of ²¹¹At-MABG in patients with neural crest tumors gives better therapeutic effect than ¹³¹I-MIBG. At present, ¹³¹I -MIBG remains the best targeted therapy option for these tumors.