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Neuroendocrine Tumors: Therapy with 131I-MIBG

  • Jorge A. CarrasquilloEmail author
  • Clara C. Chen
Living reference work entry

Abstract

Metaiodobenzylguanidine (MIBG) is an analog of guanethidine which has been used for imaging a variety of neuroendocrine tumors (NETs). While 131I-MIBG is approved by the FDA for imaging, it is not yet approved for therapy, whereas it is approved for therapy by the EMA. Thus, in the United States 131I-MIBG used for therapy trials is either made in accordance with USP regulations or used under an investigational new drug application (IND).

Procedure guidelines for the use of 131I-MIBG in therapy have been published. 131I-MIBG is used mostly to treat pheochromocytoma/paraganglioma (PHEO/PARA), carcinoid tumors, and neuroblastoma. Preparation of patients prior to treatment with 131I-MIBG includes discontinuing therapy with drugs known to interfere with uptake of MIBG by tumor cells and blocking thyroid uptake of radioiodine. Because patients may have nausea and vomiting after administration of MIBG, antiemetics are often administered prior to therapy and in the first 3 days post-administration. To minimize the bladder dose, hydration is encouraged. Candidates for 131I-MIBG therapy should have a reasonable performance status and a life expectancy of at least 3 months. Acceptable hematopoietic parameters are required prior to MIBG therapy. There are no uniform guidelines for selecting or excluding patients from consideration for 131I-MIBG therapy. Most investigators require tumor localization on a diagnostic MIBG scan. Other selection criteria often include evidence of disease progression or symptoms.

131I-MIBG is administered i.v. by pump through a plastic indwelling catheter or central line. Slow administration is a precaution to minimize pharmacologic effects from the unlabeled MIBG. There is no standard activity for therapy. Most studies use fixed activities based on empirical evidence of limited toxicity. Others have used fixed activities adjusted to body weight based on dose escalation studies. Some studies use estimates of dose to radiosensitive organs to define a safe upper limit.

Response assessment may be performed as early as 2 months, but more frequently at 3–6-month intervals unless the patient is known to have fast-growing disease. Follow-up typically involves anatomic and functional imaging with 123I-MIBG or [18F]FDG. The frequency of retreatment is variable, ranging from every 4 weeks to every 6 months.

PHEO/PARA are tumors that originate in the chromaffin tissue of the adrenal medulla and sympathetic nervous system and often secrete catecholamines. Some PHEO/PARA are related to genetic defects and are associated with an increased incidence of malignant and/or extra-adrenal disease. The lymph nodes, bone, liver, and lung are the most common sites of metastases.

The optimal therapy for PHEO/PARA consists of surgical resection when feasible. In patients in whom a surgical cure is not possible, chemotherapy regimens have been developed. However, given the often suboptimal response to chemotherapy, other therapeutic modalities such as 131I-MIBG are now being applied. Although many patients benefit from 131I-MIBG treatment, complete response rates are low. It appears that the response of soft tissue disease to MIBG therapy is superior to that of bone and that patients with smaller volume disease are more likely to respond than those with high-volume disease. Biochemical catecholamine response has often been reported after treatment. Responses vary in duration, with reported 5-year survivals between 45% and 85%. Low-, medium-, or high-dose activities of 131I-MIBG have been used in PHEO/PARA, but there have been no systematic comparisons between these groups. However, there is some evidence that higher activities >500 mCi or myeloablative regimens are associated with higher response rates. The use of high specific activity 131I-MIBG for therapy seems to reduce acute side effects. Few data have been published regarding combined chemotherapy with 131I-MIBG therapy in this patient group.

Carcinoids are slow-growing NETs that often secrete substances leading to hormonal syndromes. The most frequent sites for carcinoids are the gastrointestinal tract (73.7%) and the bronchopulmonary system (25.1%).

Initial staging and follow-up relies on CT and MRI to evaluate for nodal and metastatic liver disease. Imaging with 111In-pentetreotide or, more recently, with 68Ga-somatostatin analogs is performed. Scintigraphy with 123I-/131I-MIBG is also often performed and a published review reported a sensitivity of 70%. At presentation, the best management is surgical resection, or in cases with metastatic disease, debulking for palliation. Unfortunately, metastatic disease at presentation is frequent, and no consistently effective therapeutic strategies are available. Symptomatic tumor response is often seen following therapy with cold octreotide analogs, whereas objective tumor regression is rare. Interferon may also result in symptomatic improvement. Multiple chemotherapy regimens have been utilized with none showing objective tumor responses greater than 15%. The uptake of 131I-MIBG in carcinoid led to the use of this radiopharmaceutical therapeutically. Recently, radiolabeled octreotide analogs have recently been utilized and shown a higher overall accumulation in carcinoids than MIBG.

Although carcinoid patients rarely have a complete response to 131I-MIBG therapy, objective response rates of 11–27.5% and symptomatic response rates ranging from 38% to 92% have been reported. Biochemical responses are less common. Median 5-year survivals of 42–78% have been reported after 131I-MIBG therapy in carcinoid. Initial single activities of >14.8 GBq (400 mCi) have been recommended to improve survival and symptomatic improvement. Studies combining 131I-MIBG with chemotherapy or biologic therapy are rare.

Neuroblastoma is a tumor that arises from primordial neural crest cells and is almost exclusively found in infants and young children. It is the most common tumor of childhood. Therapy relies on induction chemotherapy, surgery, and radiotherapy (given that this is a radiosensitive tumor), followed by consolidation of remission with autologous stem cell transplant (ASCT) or cis-retinoic acid with or without antibody immunotherapy. High-risk patients often relapse and are resistant to conventional therapy. 131I-MIBG therapy has been utilized as first-line therapy, combined with chemotherapy or biologic therapy for consolidation, and as palliative therapy for patients with multiple relapses. Several 131I-MIBG dosing strategies have been pursued. Most 131I-MIBG trials have selected patients with advanced disease that have failed first-line therapy, while others have incorporated 131I-MIBG into multiprong treatment strategies. Several trials demonstrated that repeated doses of 131I-MIBG could be administered safely. Partial objective responses have been reported in up to 40% of patients, but complete response rates are usually much lower (seldom over 10%). Because many trials were not prospective, reporting criteria in terms of outcome were variable, and the parameters measured in terms of duration of response have been inconsistent and include survival, overall response, and event-free survival (EFS).

The most significant toxicity associated with 131I-MIBG therapy in both children and adults is hematologic. Nadirs in children have been reported to occur approximately 28 days after a single 131I-MIBG administration (range 9–42). When chemotherapy is combined with 131I-MIBG therapy, this nadir may occur earlier and is felt to be predominantly driven by the chemotherapy. Patients treated with high activities of 131I-MIBG (≥444–666 MBq/kg (12–18 mCi/kg)) may require bone marrow transplant because of significant and prolonged marrow toxicity, particularly in heavily pretreated subjects. Because higher doses induce considerable neutropenia, significant infections are occasionally encountered.

Myelodysplasia (MDS)/acute myelocytic leukemia have been reported in patients who have received both chemotherapy and large amounts of 131I-MIBG. Secondary malignancies have been also reported. The occurrence of secondary malignancies and bone marrow disorders indicates that these patients require close follow-up, especially those with prolonged survival. Hypothyroidism can also occur. Common systemic/constitutional toxicity associated with large doses of 131I-MIBG includes asthenia, nausea, and vomiting. Although 131I-MIBG localizes in normal organs such as the heart, lung, kidney, liver, and adrenals, complications related to cardiac, renal, liver, or adrenal insufficiency have been very limited. Pulmonary complications are most frequently related to infectious disorders.

Keywords

131I-MIBG therapy Metaiodobenzylguanidine Pheochromocytoma Paraganglioma Carcinoids Neuroblastoma 

Glossary

[18F]FDG

2-deoxy-2-[18F]fluoro-D-glucose

18F-DOPA

2-18F-Fluoro-l-3,4-dihydroxyphenylalanine

ARDS

Acute respiratory distress syndrome

ASCT

Autologous stem cell transplantation

BOOP

Bronchiolitis obliterans organizing pneumonia

CISP

Cis platinum

CR

Complete response

CT

X-ray computed tomography

CTX

Cytoxan

CVD

Chemotherapy regimen based on Cyclophosphamide, vincristine, and dacarbazine

DOTATATE

1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid -(Tyr3)-octreotate

DOTATOC

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid0-Phe1-Tyr3)octreotide

EANM

European Association of Nuclear Medicine

EFS

Event-free survival

eGFR

Estimated glomerular filtration rate

EMA

European Medicines Agency

FDA

United States Food and Drug Administration

FH

Gene encoding for a member of the pseudo-hypoxic pathway family

G-CSF

Granulocyte colony stimulating factor

GEP

Gastroenteropancreatic

GFR

Glomerular filtration rate

GI

Gastrointestinal

Gy

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

HIF2A

Gene encoding for a member of the pseudo-hypoxic pathway family

ID

Injected dose

IND

Investigational new drug

KI

Potassium iodide

MAX

Gene encoding for a member of the tyrosine kinase signaling pathway family

MDS

Myelodisplastic syndrome

MEN

Gene encoding for a member of the tyrosine kinase signaling pathway family

MEN

Multiple endocrine neoplasia

MIBG

Metaiodobenzylguanidine

MIRD

Medical Internal Radiation Dose

MRI

Magnetic resonance imaging

MSKCC

Memorial Sloan-Kettering Cancer Center

MYCN

Gene encoding for a member of the MYC family of transcription factors

NA

Not available

NB

Neuroblastoma

NET

Neuroendocrine tumor

NF1

Gene encoding for a member of the tyrosine kinase signaling pathway family

NRC

Nuclear Regulatory Commission

NRC

Nuclear regulatory commission

OS

Overall survival

PARA

Paraganglioma

PD

Progressive disease

PFS

Progression-free survival

PHEO

Pheochromocytoma

PR

Partial response

RET

Gene encoding for a member of the tyrosine kinase signaling pathway family

RFA

Radiofrequency ablation

SD

Stable disease

SDHAF2

Gene encoding for a member of the pseudo-hypoxic pathway family

SDHB

Gene encoding for one of four subunits of the succinate dehydrogenase (SDH) enzyme

SDHx

Gene encoding for a member of the pseudo-hypoxic pathway family

SSKI

Saturated solution of potassium iodide

SUV

Standardized uptake value

T3

3-5-3’-Triiodothyronine, a thyroid hormone

TMEM127

Gene encoding for a member of the tyrosine kinase signaling pathway family

TSH

Thyroid stimulating hormone

TTP

Time to progression

UCSF

University of San Francisco

USP

United States Pharmacopeia

VHL

Von Hippel Lindau

VNC

Vincristine

VP-16

Etoposide

WBC

White blood cell

WHO

World Health Organization

Metaiodobenzylguanidine (MIBG) , also known as iobenguane, was developed at the University of Michigan by Wieland et al. [202]. As an analog of guanethidine, MIBG shares structural features with norepinephrine, binds to the norepinephrine transporter, and is internalized. Having entered the cell, MIBG is transported to secretory granules via vesicular monoamine transporters [101] or, in some cells without many granules, localizes in the cytoplasm [106, 171, 177]. For imaging purposes, MIBG is labeled with 131I or 123I. For diagnostic imaging, 123I is superior to 131I [57], and imaging methods are described in imaging guidelines [15].

Radiolabeled MIBG has been used for imaging a variety of neuroendocrine tumors (NETs) and other disorders [26, 156]. The sensitivity for tumor detection of pheochromocytoma/paraganglioma (PHEO/PARA) and neuroblastoma (NB) tends to be higher than for other NETs. Given the excellent localization often seen with radioiodinated MIBG (Fig. 1a), therapy with 131I-MIBG has been evaluated. In this chapter, we focus on the therapeutic use of MIBG in the three most frequently treated tumors: PHEO/PARA, carcinoid, and neuroblastoma.
Fig. 1

(a) Serial 123I-MIBG posterior whole-body images from a patient with unresectable primary PHEO of the right adrenal (upper arrows) and metastatic disease to retroperitoneal nodes (lower arrows), spine, pelvis, ribs, and bilateral lung metastases are also present. He received four treatments consisting of 204, 211, 215, and 243 mCi of 131I-MIBG over a 14-month period. The initial posttreatment scan 1 showed some decrease in retroperitoneal nodes and disappearance of some lung and bone lesions. Posttreatment 4, all lung and bone lesions had disappeared, and retroperitoneal nodes had resolved or improved markedly. The adrenal mass had decreased in size and intensity and was resected for palliative reasons. (b) Anterior [18F]FDG PET/CT MIP images of the same patient as in Fig. 1a, showing extensive [18F]FDG avid PHEO uptake in the primary adrenal tumor (arrow) and retroperitoneal, bone, and lung metastases. After four treatments (cumulative activity of 873 mCi 131I-MIBG) (middle panel), residual [18F]FDG activity was only seen in the right adrenal bed and retroperitoneal nodes (two lower arrows). The adrenal mass had shrunk considerably and become largely necrotic. Because persistent mild elevation of normetanephrines was observed and this was the site of largest disease, this residual adrenal mass was resected. [18F]FDG PET 6 months postsurgery (right panel) showed small residual uptake in the surgical bed and two small hypermetabolic nodes in the abdomen (not clearly seen in this MIP image). Note that the activity in the right upper quadrant (arrowhead) represents kidney, not tumor. (c) Biochemical parameters may be used to track response in PHEO. This is the same patient shown in Fig. 1a and b who had elevated chromogranin and normetanephrine levels pretreatment. The arrows represent the four 131I-MIBG treatments, totaling 873 mCi. Although chromogranins started to improve after the first treatment, it was not until after the second treatment that metanephrines started to improve. Chromogranin levels were in the normal range at the time of the fourth treatment, but normetanephrine levels did not normalize until after surgery (arrowhead)

131I-MIBG Preparation

Procedure guidelines for the use of 131I-MIBG in therapy have been published [65]. The specific activity of the 131I-MIBG used for imaging typically is low (123 MBq/mg, or 3.33 mCi/mg), while the specific activity of the 131I-MIBG used for therapy is higher, ranging from 1.11 to 1.85 GBq/mg (30–50 mCi/mg) [41, 51, 70, 85, 118, 170]. At these specific activities, approximately 1 in every 2,000 molecules of MIBG will be labeled with 131I. Therefore, for an activity of 18.5 GBq (500 mCi), a total of 10–17 mg of MIBG is administered. Even higher specific activity 131I-MIBG has been developed, in the range of 92.5 GBq/mg (2,500 mCi/mg) [80, 112, 113]. Theoretical and preclinical studies in small animals have shown that higher specific activity results in greater tumor uptake and higher tumor to normal tissue ratios than lower specific activity reagents [112, 114]. However, a study with high specific activity MIBG resulted in higher activity in heart but not in tumor xenografts [189]. Limited studies in humans using high specific activity 131I-MIBG have also failed to show higher tumor targeting [145], including phase I clinical trials with high specific activity 131I-MIBG, and have not clearly confirmed an advantage in terms of tumor targeting, although its safety has been documented [36]. Even if high specific activity 131I-MIBG does not have a clear advantage over low specific activity material in terms of tumor targeting, administration of lower mass amounts of MIBG over a shorter period of time with a lower incidence of nausea, vomiting, and hypertension may be possible [6]. It should be noted that while 131I-MIBG was approved by the FDA for imaging, it has yet to be approved for therapy in the USA. Thus, for therapy trials in the United States, 131I-MIBG is either made in accordance with USP regulations or used under an investigational new drug application (IND). Whereas, the use of 131I-MIBG for therapy has been approved by the EMA as well as by regulatory authorities in other countries.

Logistical Issues

At present, there are few centers performing 131I-MIBG therapy. One major impediment is that the radiopharmaceutical is not yet FDA approved for therapeutic use, as previously described above. Other impediments relate to the safe handling of large amounts of therapeutic materials. In establishing an 131I-MIBG therapy program, there needs to be adequately trained staff to carry out the treatment safely and within regulatory compliance with NRC mandates, and a significant institutional commitment is necessary [167]. In addition to radiation safety-related issues, a dedicated multimodality group of physicians that deal with the relevant diseases are necessary to provide optimal patient care. High-activity administration in the range of 18 mCi/kg, as is often used in patients with neuroblastoma, has its own safety challenges that must be appropriately addressed, especially when dealing with small children [32].

Patient Preparation

Proper preparation of patients is required prior to treatment with 131I-MIBG. A variety of drugs are known to interfere with uptake of MIBG by tumor cells and should be discontinued prior to therapy, including labetalol, tricyclic antidepressants, reserpine, and some sympathomimetics (Table 1) [5, 76, 97, 133, 172]. A detailed list of drugs that may interfere has been compiled [172] and recommendations of which to avoid have been proposed [87]. When possible, these drugs are eliminated or substituted prior to therapy with 131I-MIBG. The amount of time necessary for withdrawal is related to their half-life [172]. In PHEO/PARA patients, hypertension can usually be controlled with oral phenoxybenzamine and atenolol as they do not block 131I-MIBG uptake in vivo. In addition, nifedipine can be added to antihypertensive regimens since interference has not been observed [11]. As a practical matter, patients generally undergo a diagnostic 123I-MIBG study on their current drug regimen to assess targeting of MIBG prior to considering therapy [209].
Table 1

Drugs that interfere with MIBG uptakea

 

Documented in patients

Documented in vitro

Antihypertensives

Labetalol [97, 133], phenoxybenzamine [172]b

Propranolol but not other beta-blocker [5], guanethidine, reserpine, nifedipine, verapamil

Opioids

Cocaine [209]

 

Tricyclic antidepressants

Imipramine [139]

Amitriptyline derivatives

Sympathomimetics

 

Phenylpropanolamine, amphetamines, pseudoephedrine, phenylephrine

Antipsychotic

 

Phenothiazines, haloperidol

aFor detailed list of drugs that have the potential to interfere, see Solanski et al. [172] and Giammarile et al. [65]

bPhenoxybenzamine at low doses does not interfere; i.v. administration at high doses is reported to interfere

Thyroid Blockade

Although USP release criteria require >95% 131I bound to MIBG, 131I-MIBG preparations all contain a small amount of free radioiodine. In the interval between manufacture and dose administration, there is a time-dependent breakdown, with the release of free iodine [197] into solution. In addition, a small amount of free iodide may be generated in vivo from metabolism [115]. Therefore, blocking the thyroid is necessary to prevent thyroid damage from radioiodine. A variety of regimens using potassium iodide (KI), saturated solution of potassium iodide (SSKI), or Lugol’s solution have been used for this purpose. Several studies have shown the efficacy and timing of cold iodine administration to block thyroid uptake of radiolabeled iodine [176, 208]. The dose of KI recommended by the FDA for use during radiation emergencies is 130 mg of KI (100 mg iodine) per day for adults and is scaled down for children (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm080542.pdf). This regimen is in line with what others have suggested for blockade prior to diagnostic MIBG scanning [173]. Typically, the dose of KI prior to 131I-MIBG therapy is higher than 130 mg. Thyroid blockade usually starts 1 day prior to administration of the 131I-MIBG [150, 183, 205], although some protocols start up to 5–7 days prior [59, 61]. However, this appears to be unnecessary [176, 208]. The amount of KI has ranged from 120 to 200 mg/day with smaller amounts for children [13, 64, 65, 104, 148, 166]. The length of blockade has ranged from 7 to 45 days [17, 41, 59, 61, 64, 153, 183, 206]. Some have used more intensive regimens including thyroid suppression with thyroid hormone, in order to decrease TSH [37, 52, 61]. In pediatric populations, some regimens add potassium perchlorate and T3 to lower the TSH [81]. A report analyzing various phase I and II studies in children utilized an oral loading dose of 6 mg/kg of KI solution 8–12 h prior to 131I-MIBG infusion, then 1 mg/kg every 4 h on days 0–6, and 1 mg/kg/day through day 45 post-infusion. Potassium perchlorate was also given as an additional oral blocking agent for 5 days post-infusion with a loading dose of 8 mg/kg and then 2 mg/kg every 6 h on days 0–4, beginning 4 h after the start of 131I-MIBG infusion.

The EANM guidelines suggest starting iodide blockade 24–48 h prior to treatment and continuing for 10–15 days and do not recommend thyroxine administration [65]. Pharmacokinetic studies of radioiodinated 131I-MIBG have shown that there is less than 10% in blood at 1 h post-administration [122] and that >80% of radiolabeled MIBG is released from the body over 4–5 days [36, 198, 199]. MIBG clears from the body with a terminal effective half-life of 37 h [45]. Therefore, it is reasonable to stop administering iodide for thyroid blockade 14 days after treatment. In spite of these blocking measures, it is not unusual to see some uptake of 131I in the normal thyroid with some series showing that only 52% of subjects had no visualization of the thyroid posttreatment [17, 153].

SSKI and Lugol’s are well tolerated. Infrequent side effects include sialadenitis, gastrointestinal disturbances, allergic-like reactions, and minor rashes. Thyroidal side effects include iodine-induced thyrotoxicosis, which is more common in older people and in iodine-deficient areas, and hypothyroidism, particularly in iodine-sufficient areas.

Additional Precautions

Because patients may have nausea and vomiting after administration of 131I-MIBG, antiemetics such as ondansetron are often administered prior to therapy and in the first 3 days post-administration. Since the major route of 131I-MIBG excretion is renal, the bladder is exposed to high concentrations of radioactivity. To minimize the radiation dose to the bladder, hydration is encouraged. Some investigators administer 3 L/m2 or 150 mL/h for several days [68, 107]. In small children, urinary catheterization is often performed to decrease both the radiation dose and the potential for contamination [82, 107, 205].

Patient Eligibility

Candidates for 131I-MIBG therapy should have a reasonable performance status (Karnofsky >60) and a life expectancy of at least 3 months, unless they have intractable bone pain. Reasonable hematopoietic parameters (WBC >3,000/μL, platelets >100 K/μL) are required prior to 131I-MIBG therapy, especially when stem cells are not available [65]. The degree of acceptable liver function required has not been well established, although some have used bilirubin ≤2.5 and liver enzymes ≤2.5 times the upper limit of normal as criteria [70]. Kidney glomerular filtration rate >30 mL/min or serum creatinine ≤2.5 the upper limit of normal are also desirable [65, 70]. Recently, it has been found that patients with nephrotic syndrome receiving large activities of 131I-MIBG may be prone to bronchiolitis obliterans organizing pneumonia (BOOP) or acute distress respiratory distress syndrome (ARDS), and a recommendation has been made to limit the cumulative activity in these patients to less than 800 mCi of 131I-MIBG [70].

131I-MIBG is administered by pump i.v. through an indwelling catheter or central line. A variety of infusion times have been used, ranging from 1 to 2 h [164, 161, 150, 148, 23]. Six and even 24 h infusions have also been evaluated [81, 99, 181]. Slow administration is a precaution to minimize pharmacologic effects from the unlabeled MIBG, although some have administered the therapy over 30–60 min without sequela [14, 148, 23]. Our practice at MSKCC is to administer the drug over ~45 min. When high specific activity material is given, the infusion rate has been shortened to 15–30 min, since the total mass of MIBG is reduced [89, 36]. Monitoring of vital signs during the administration is recommended since patients may develop a hypertensive response. This can be particularly significant in PHEO/PARA patients and requires slowing of the infusion or pharmacologic intervention.

Administering therapy on an inpatient versus outpatient basis depends on multiple considerations. In many countries, there are policies or regulations that define the limits of administered activity for outpatient treatment. In the USA, patients must be given oral and written instructions to ensure that there is less than 500 mrem exposure to caregivers or other household members when they return home. Several groups have confirmed that this exposure rate to caregivers can be achieved. Caregiver exposures of 30–125 mrem with activities up to 5.55 GBq (150 mCi) were observed by Hoefnagel et al., and a median exposure of 60 mrem/3.7 GBq (60 mrem/100 mCi) was reported [61, 77]. With a higher median activity of 16.2 GBq (437.8 mCi), radiation exposure to caregivers was within regulatory range with median dose to them of 302 mrem [58]. At MSKCC, we perform most adult MIBG therapy as outpatients, although internal policies require that patients receiving >9.25 GBq (>250 mCi) 131I-MIBG be inpatients. In children, most groups are more conservative and will hospitalize for ease of treatment, monitoring, and radiation safety considerations. Furthermore, in order to reduce bladder radiation, a Foley catheter is often placed for 3 days to minimize bladder dose and avoid contamination.

Patient Selection Criteria

There are no uniform guidelines for selecting or excluding patients from consideration for 131I-MIBG therapy. Most investigators require demonstration of tumor localization on a diagnostic MIBG scan, although it is not always stated whether all known lesions were MIBG avid [70, 141, 148, 150, 165, 180]. Criteria for deciding how much tumor localization is required range from >20 cGy/37 MBq (>20 cGy/mCi) [165], 5 Gy/3.7 GBq (5 Gy/100 mCi) [104], visual localization above background, higher than two times background [70], and >1% of ID in tumor [13, 137]. Requiring a positive diagnostic MIBG scan is required since not all tumors take up MIBG. Furthermore, this also helps to avoid the presence of interfering medication.

Other selection criteria often include evidence of disease progression or symptoms [141, 148]. Patients need to follow radiation safety precautions; thus, a Karnofsky performance status of greater than 60% is advisable. Patients must not be pregnant or breast-feeding and must agree to birth control, although it is not known for exactly how long. Sperm banking or ovum harvest may be considered in younger patients.

Activity/Dose Selection

Various approaches have been utilized to select the dose for 131I-MIBG therapy. Most studies have used fixed activities based on empirical evidence of limited toxicity [28, 37, 40, 61, 64, 72, 77, 81, 85, 110, 117, 120, 161, 164, 186]. Others have used fixed activities adjusted to body weight based on dose escalation studies [63, 70, 82, 94, 99, 121, 124, 126, 155]. Yet others have performed dosimetry analysis using a diagnostic scan and have calculated activities to deliver less than 2–4 Gy to blood or whole body [50, 62, 107].

There is also no standardized practice in terms of frequency of 131I-MIBG therapy administration. If the patient responds to treatment or is stable and has no dose-limiting toxicity, the therapy is usually repeated. The frequency of retreatment is variable, ranging from a minimum of every 4 weeks to 6 months and requiring adequate recovery from toxicity [13, 40, 64, 72, 77, 92, 110]. Some investigators tailor the frequency based on tumor growth rate, with fast-growing tumors treated every 2.5–3 months and slower-growing tumors every 6 months [23]. Others perform three treatments and then reassess whether to proceed [23, 148]. High-activity therapy often requires longer intervals between treatments to allow marrow recovery; lower activities are much better tolerated. High-activity regimens delivering 18 mCi/kg on two occasions have shown the feasibility of stem cell rescue with 50–71% of patients achieving platelet transfusion independence [82, 91].

Thus, there are no predefined limits in terms of repeated treatments. In patients with PHEO/PARA (Table 2), patients have received 1–11 treatments with 131I-MIBG [14, 64, 104]. Krempf et al. observed that 1–8 treatments were needed before a response was observed and no patient had a complete biochemical response until at least three treatments were given [104]. Similarly, Sisson et al. reported variable responses in patients (n = 5) receiving 2–4 treatments and suggested a minimum tumor dose of 150 Gy (15,000 rad) [168]. Those utilizing very large doses have found that continued response may be seen many months after treatment and sometimes wait a year before considering retreatment [68].
Table 2

PHEO/PARA : treatment schema (administered activities are listed here in mCi; multiply by 37 for conversion to MBq)

Author

# patients

Single administration (mCi)

Cumulative (mCi)

# Doses

Shapiro et al. [164]

28

97–301 (mean 181)

111–916 (mean 479)

1–6

Fischer [52]

14

64–210

200–1,135 (median 559)

1–6

Bestagno et al. [10]

6

100–200

147–1,022

1–6

Krempf et al. [104]

15

78.4–250 (mean 127)

300–2,322 (mean 624)

2–11 (median 3.5)

Lumbroso et al. [110], Schlumberger et al. [161]

11

100–200

100–711 (mean 200)

1–6 (median 2)

Loh et al. [109]

116a

96–300 (mean 158)

96–2,322 (mean 490)

1–11 (mean 3.3)

Hartley et al. [72]

6

200

200–1,200 (mean 640)

1–6 (median 2.5)

Mukherjee et al. [137]

15

100–300 (mean 188)

200–1,592 (592 median)

1–7 (mean 3.4)

Safford et al. [158]

33

391 mean

70–1,223 (mean 549)

1–6 (median 1)

Bomanji et al. [14]

6

220–357 (mean 304)

342–987 (mean 910)

1–3

Rose et al. [155]

12

5.6–18.3 mCi/kg (median 11.5 mCi/kg and 800)

386–1,717 (median 1,015)

1–3 (median 1.5)

Gedik et al. [64]

19

100–700 (median 200)

183–2,200 median (800)

1–10 (median 3)

Gonias et al. [70]

50

6–19 mCi/kg (492–1,160), 500 if no stem cells (median 818)

492–3,191

1–3 (median 1)

Castellani et al. [28]

12

124–149 (median 149)

149–1,800 (median 1,065)

Up to 10 (median 7)

16

200–350 (median 268)

249–1,546 (median 651)

Up to 6 (median 2)

Shilkrut et al. [166]

10

150 (mean 145)

100–600 (mean 310)

1–4 (median 2.1)

Rachh et al. [154]

12

NAb

199–513 (mean 319)

1–5(median 2)

Sze et al. [179]

14

Around 195

Mean 576

Median 2

Wakabayashi et al. [200]

26

1.9–5.8 mCi/kg (median 200)

NA

1–6 (median 2)

Yoshinaga et al. [207]

48

100–300 (median 3.5 mCi/kg)

NA

1–4 (median 2)

Rutherford et al. [157]

22

135–305 (mean 270)

270–1,369 (mean 544)

1–5 (median 2)

aCombination of several series from different institutions

bNot available

The cumulative activity administered has ranged up to 118.1 GBq (3,191 mCi) in PHEO/PARA (Table 2), 78.1 GBq (2,112 mCi) in carcinoids (Table 4), and 89.3 GBq (2,414 mCi) or 31.325 GBq/kg (35.8 mCi/kg) in neuroblastoma (Tables 6 and 7).

Dosimetry

Several studies have reviewed the pharmacokinetics of 131I-MIBG. The pharmacokinetics of carrier-free 131I-MIBG in adults has been reported [36] – with alpha T1/2 of 3 h and beta T1/2 of 38.3 h. In adults, the mean urinary excretion was 27.4% in the first 6 h, 49.8% in 24 h, and 80.3% in 120 h. Detailed pharmacokinetics in children with neuroblastoma has been published [100, 198, 199]. A terminal biologic T1/2 in serum of 45.8 h is reported. In addition, at 24 h there was a cumulative urinary excretion of 32%, 71% at 48 h, and 65% at 6 days. MIRD dosimetry of 131I-MIBG [88, 185] identifies the main target organs as the liver, myocardium, and gonads. Dosimetry of no-carrier added 131I-MIBG is somewhat different, with higher radiation dose per mCi to most normal organs than those described in the package insert for low specific activity 131I-MIBG [36]. While some of these dosimetry differences can be related to the specific activity, differences in methodology where self-irradiation is not considered likely plays a large role; dosimetry estimates performed from diagnostic scans in NB patients are often significantly different from those estimated from the therapy dose. Fielding et al. found that estimates from the diagnostic scan would have resulted in under dosing 65% of the patients. Nonetheless, this was more reproducible than weight-based dosing [21, 50]. Using dosimetry from diagnostic scans, Lashford et al. predicted therapy doses to within −20–30% of that seen with the therapeutic dose [107]. It is not known what the required doses are to obtain biochemical or tumor responses. Estimates of radiation-absorbed dose to tumor vary considerably between patients and diseases. For instance, tumor dose estimates of 10–40 cGy/37 MBq (10–40 cGy/mCi) have been reported [36, 164], with cumulative doses ranging from 10 to 198 Gy [77, 104, 109, 168] in patients with PHEO/PARA. The impression has been that cumulative doses 60–100 Gy are beneficial [104, 168]. Other studies suggested that doses of 150 Gy were necessary to obtain tumor response [168]. Because there is large variability in determining tumor dose due to inherent problems in quantification of single-photon emitters, many studies use estimates of dose to whole body as a safe upper limit [50, 164]. Whole-body doses ranged from 50 to 231 cGy [85, 164]. New methods to evaluate the biodistribution and residence time of 131I-MIBG are now feasible using the surrogate positron emitting reagent 124I-MIBG [73, 84, 144].

Evaluation of Response

Response assessment may be performed as early as 2 months [14] but more frequently at 3–6-month intervals unless the patient is known to have fast-growing disease [64, 70, 166, 205]. Follow-up typically involves anatomic imaging such as CT or MRI to evaluate changes in lesion size. Functional imaging is performed using 123I-MIBG [43] and, in known [18F]FDG avid lesions (Fig. 1b), changes in SUV may be an indication of response, although limited studies have been reported [149]. In hormone-secreting tumors, biochemical parameters can be used to assess response (Fig. 1c).

Following therapy, response is usually evaluated at 8–24 weeks. As in many cancers, response is determined using size measurement criteria, most often using WHO criteria [27, 141, 148, 181]. WHO criteria for complete response include the disappearance of all lesions and negative 123I-MIBG scans; partial response is a 50% or greater reduction of all measurable disease; and progression is the appearance of new lesions or an increase of 25% or more in tumor size. In PHEO/PARA, because most patients have elevated catecholamines, levels of these and their metabolites are also used to gauge response. Biochemical CR is defined as complete normalization of biochemical markers, partial response typically by ≥50% drop but not normalization, and progression by ≥20% increase in these levels (Fig. 1c).

In neuroblastoma , posttreatment diagnostic 123I-MIBG scintigraphy is routinely used to assess response (Fig. 2) [43, 91]. Interestingly, Johnson et al. noted that in four patients with CR based on negative 123I-MIBG imaging following their initial treatment, a post-therapy 131I-MIBG scan performed after a second treatment showed residual disease [91]; this is probably related to the higher sensitivity of tumor detection on post-therapy scans that have shown to be more sensitive for tumor detection [204]. These authors suggest that 131I-MIBG therapy could be used to consolidate first remission in patients with newly diagnosed high-risk neuroblastoma. Patients undergoing high-dose therapy invariably have significant hematologic toxicity, and stem cell harvesting is routinely performed in these patients [91]. The parameter that determines if the patient needs stem cell transplant is the duration and resistance of the hematologic toxicity to respond to supportive treatment. When transplantation is required, it is usually not performed for at least 3 weeks post- 131I-MIBG treatment [82, 124, 205].
Fig. 2

A 26-year-old woman with neuroblastoma. 123I-MIBG diagnostic scan (left panel) pre-therapy shows extensive bone disease (arrows) and left adrenal mass (arrowhead). After receiving 27.6 GBq (746 mCi) 131I-MIBG , she was imaged at 4 days (middle panel). This showed excellent targeting of sites of disease. A follow-up 123I-MIBG scan (right panel) showed that in spite of excellent tumor targeting, there was little response with only minor decreases in uptake in the left scapula and humerus compared to baseline

Pheochromocytoma/Paraganglioma

PHEO/PARA are tumors that originate in chromaffin tissue of the adrenal medulla or sympathetic nervous system. The incidence of PHEO/PARA is estimated to be ~1–2 per million [9, 49], although in autopsy series an incidence of 1 in 2,031 cases has been reported [125]. These tumors are most often found in the adrenal and in this location are referred to as PHEO. If they occur outside of the adrenal they are referred to as PARA. Three percent of adrenal “incidentalomas” are PHEO [95]. These tumors often secrete catecholamines, and consequently, patients present with hypertension and other symptoms of adrenergic excess. In some instances, however, these tumors are nonfunctional and presentation is related to mass effect or incidental discovery.

Traditionally, PHEO/PARA were known as the “10% tumor” due to the thought that they were 10% bilateral, 10% metastatic, 10% extra-adrenal, 10% non-hypertensive, and 10% inherited. However, in the last decade, it has become increasingly clear that this rule no longer holds, as was explicitly pointed out by Elder et al. in 2005 [46]. While the majority of PHEO/PARA are still thought to be sporadic, up to 35–40% of PHEO/PARA are now estimated to be related to genetic defects, and 15% or more with somatic mutations [39, 116, 147]. With ever expanding genetic testing, mutations are now frequently found in patients with apparently sporadic disease, no family history, and a non-syndromic presentation [1, 140]. Since 2002, when SDHx mutations were first associated with PHEO/PARA [3, 8], at least 17 genetic mutations have been identified to date, as well as somatic mutations occurring in the same susceptibility genes as the genetic ones [22, 147]. Depending on the mutation, two major pathways have been recognized: a pseudo hypoxic pathway referred to as Cluster 1 (including SDHx, SDHAF2 VHL, HIF2A, and FH) and a tyrosine kinase signaling pathway (including MEN, RET, NF1, MAX, and TMEM127) referred to as Cluster 2 [39].

While most PHEO/PARA are benign, up to 26% or more are malignant [152, 210], with higher rates in certain inherited forms of disease [39, 116, 147]. In addition, extra-adrenal tumors which are also more prevalent in certain inherited PHEO/PARA are often malignant [1, 7, 140, 210]. In particular, SDHB related PHEO/PARA are known to have a high risk for metastases [66]. Pathologically it is difficult to differentiate benign from malignant tumors because of lack of robust morphological and histological criteria [182]. Therefore, in order to classify PHEO/PARA as malignant, one must find disease in sites where this tissue is not normally present [33]. The most common sites of metastatic disease include lymph nodes, bone, liver, and lung [18].

The most sensitive tests to confirm the diagnosis of PHEO/PARA are plasma-free metanephrines or urinary fractionated metanephrines, with sensitivities of 97% and 99%, respectively [30, 108]. The diagnostic imaging modalities most often used for staging are CT and MRI; functional imaging ­modalities are also useful, including radiolabeled MIBG (Fig. 1a), 18F-fluorodopamine PET, 18F-DOPA PET, [18F]FDG PET (Fig. 1b), 111In-pentetreotide scintigraphy [26, 146, 213], and 68Ga-DOTA-somatostatin analog-scans (REF below). 68Ga-DOTATATE has recently been approved by the FDA.

The optimal therapy for PHEO/PARA consists of surgical resection when feasible. Even in patients with metastatic disease, surgical debulking is often used with palliative intent, although no controlled studies have been performed to show an effect on survival. Patients with benign disease have normal overall survival after complete surgical resection, whereas patients with malignant disease typically have an overall 5-year survival of less than 50% [31, 90, 160]. Nonetheless, it is recognized that there is a subset of patients with malignant disease who have a more indolent course and may live >20 years with limited therapy [135]. Patients that are asymptomatic and have slow growth rates may opt for observation until symptoms require therapy.

Averbuch et al. evaluated the use of cyclophosphamide, vincristine, and dacarbazine (CVD) for metastatic disease [4]. In 14 patients with malignant PARA, they observed a complete or partial response in 57%, with median duration of 21 months. A second analysis of this data expanded to 18 patients was performed with long-term follow-up of 22 years [83]. A CR was present in 11% of the patients, 44% had a partial response, and 72% had a biochemical response with a median duration of 20 months. Nonetheless, 16 of the 18 patients died of their disease and one was lost to follow-up. Patients that responded had a median survival of 3.8 years compared to 1.8 years for nonresponders. The common toxicities were myelosuppression, peripheral neuropathy, and gastrointestinal toxicity. Overall, the treatment was well tolerated as evidenced by the ability to administer a median of 23 cycles. These authors conclude that the treatment is not for all patients with metastatic disease but can be considered when patients are symptomatic or tumor shrinkage is desirable. Results in other small series or case reports have shown similar findings, with remissions typically lasting less than 2 years [162]. CVD have become the most often used first-line chemotherapy regimen for metastatic disease, although other regimens have also been utilized [60, 175]. Given the suboptimal response to chemotherapy, newer therapeutic modalities such as 131I-MIBG therapy are being applied in patients with PHEO/PARA, and guidelines have been published [65], but others believe 60–100 Gy is adequate [104, 186]. Patients with disease limited to the liver have also been treated successfully with RFA ablation [192]. In patients with rapidly progressive disease, chemotherapy with the CVD regimen is often used first.

There has not been a systematic evaluation comparing regimens using low, mid, or high doses of 131I-MIBG in PHEO/PARA. Initial reports, first by Vetter et al. [193] and followed shortly by a report of treatment of five patients at the University of Michigan [168] appeared in the early 1980s. In the latter report, five patients were treated with total activities ranging from 9.99 to 17.91 GBq (270–484 mCi), resulting in 35–180 Gy to tumor [168]. A significant reduction in tumor size was observed in a few patients. Since then, a variety of dose ranges have been used. Individual doses ranging from low activity (2.96–7.4 GBq or 80–200 mCi), intermediate (up to 18.5 GBq, or 500 mCi), to high activities that are often weight based (444–666 GBq/kg, or 12–18 mCi/kg) have been used (Table 2). Strategies using low-intermediate activity rely on repeat treatment, with which cumulative doses as high as 85.1 GBq (2.3 Ci) have been achieved, although median cumulative activities are generally in the 18.5–37 GBq (500–1,000 mCi) range (Table 2). Even higher total doses have been achieved using high activities doses The UCSF group has been a proponent of high doses with stem cell support, based on a phase I dose escalation trial [54, 70, 155]. Activities >12 mCi/kg usually require having stem cells available for transplantation.

A meta-analysis of publications from 1983 to 1997 on 116 patients treated with 131I-MIBG has been reported [109]. These studies used a mean single activity of 5.85 GBq (range 3.55–11.1 GBq) or mean 158 mCi (range 96–300 mCi) with a mean of 3.3 (1–11) repeated treatments, resulting in cumulative activities of 3.55–85.9 GBq (mean of 18.1 GBq) and 96–2,322 mCi (mean of 490 mCi). Although these retrospective studies had different methodologies, clear therapeutic results were observed using what are now regarded as relatively low activities. Of the 116 patients, 4% had an objective CR and 26% had partial response (PR). Biochemical catecholamine response demonstrated complete normalization in 13% of 96 patients, 32% had >50% improvement, and 76% of 99 patients had improvement in symptoms.

Other reports describe results with low (median below 7.4 GBq or 200 mCi) [28, 64, 166], intermediate (median above ≥7.4 GBq or above 200 mCi) [14, 28, 72, 158], and high activities (>44.4 MBq/kg or >12 mCi/kg) (Table 3) [70, 155]. A retrospective review of the Duke experience in 33 patients treated with 131I-MIBG with cumulative activities ranging from 2.59 to 45.3 GBq or 70–1,223 mCi (mean individual activity 14.47 GBq or 391 mCi) demonstrated an objective response rate of 38%, a symptomatic response rate of 86%, and a biochemical response rate of 60%. Responders had a median survival of 4.7 years compared to 1.7 years for nonresponders. Patients receiving high-activity therapy (>18.5 GBq or 500 mCi) had a survival advantage with median survival of 3.8 years versus 2.6 years for the low-activity group [158].
Table 3

PHEO/PARA: response

Author

# patients

Objective CR (%)

Objective CR/PR (%)

Biochemical CR (%)

Biochemical CR/PR (%)

Symptomatic CR (%)

Symptomatic CR/PR (%)

Duration of response or survival

Shapiro et al. [164]

28

0

7

0

18

NA

NA

Median PFS 18 months

Fischer [52]

14

0

14

NA

NA

NA

100

NA

Krempf et al. [104]

15

0

33

27

47

NA

NA

Median TTP 36 months

Lumbroso et al. [110], Schlumberger et al. [161]

20

0

15

0

15

0

71

Median OS 16 months

Bomanji et al. [13]

5

0

60

75

75

80

80

Median OS > 50 months

Loh et al. [109]

116a

4

30

13

45

NA

76

Median PFS 19 months

Mukherjee et al. [137]

15

0

62

22

89

7

93

5-year survival 85%

Hartley et al. [72]

6

0

0

25

50

NA

NA

Median TTP 12 months

Safford et al. [158]

33

NA

38

NA

60

NA

86

Median survival 4.7 years

5-year survival 45%

Median OS 56 months

Bomanji et al. [14]

6

0

83

25

 

50

83

Median OS > 30.5 months

Rose et al. [155]

12

18

36

22

56

50

90

15 months PFS

Median symptomatic improvement 43 months

Gedik et al. [64]

19

0

47

17

67

62

89

Median PFS 24 months

Median OS 42 months

Gonias et al. [70]a After first treatment

50

9b

17c

27b

50c

19

35

NA

NA

64% 5-year OS

47% 5 EFS

Castellani et al. [28]

Group 1 12/28

Group 2 16/28

8.3

12.5

33

25

33

29

89

67

NA

NA

Group 1 median response duration 1.9 years

Group 2 median response duration 2.3 years

Shilkrut et al. [166]

10

0

30

NA

50

NA

50

Median PFS 17.5 months

Sze et al. [179]

14

0

NA

NA

NA

NA

 

5 years survival 68%

Wakabayashi et al. [200]

26

0

0

0

24

0

52

5 years survival 50%

Yoshinaga et al. [207]

48

0

2

NA

NA

NA

NA

NA

Rutherford et al. [157]

22

5

19

5

10

5

23%

Median survival from date of first treatment was 11.1 years

CR complete response, PR partial response, OS overall survival, PFS progression-free survival, EFS event-free survival, TTP time to progression

aReview of the literature from multiple centers

bAfter first treatment

cAfter second treatment combination of several series from different institutions

A prospective study using high-dose therapy, median individual activity of 30.27 GBq (818 mCi), showed a CR of 8% and objective response in 36%. In this group, the majority of the patients only received a single administration, with a small proportion receiving two or three treatments. Because of the expected myelotoxicity, peripheral stem cells were harvested, although some patients recovered adequate marrow function and did not require stem cell infusion [70].

The use of high specific activity 131I-MIBG for therapy was recently evaluated in a phase I clinical trial [36]. In a group of 11 patients receiving no-carrier added 131I-MIBG, no side effects were observed related to the injection. Estimated tumor doses ranged from 11 to 40 rad/37 MBq (11–40 rad/mCi). In this phase I study, activities ranged from 222 to 333 MBq/kg (6–9 mCi/kg) with a maximum activity of 24.98 GBq (675 mCi).

When comparing objective responses in different studies where patients received median activity of approximately 7.4, 14.47, or 30.27 GBq (200, 391, or 818 mCi), the observed response rates overlap, in the range of 20–40% (Table 3) [64, 70, 158]. Within a single institution, Castellani et al. reviewed patients treated with a median activity of 5.51 GBq (149 mCi) versus 9.92 GBq (268 mCi). Their conclusion was that in these ranges, higher activities could deliver the desired dose faster, with a modest increase in toxicity and similar overall response rates [28].

Several protocols have combined chemotherapy with 131I-MIBG therapy in neuroblastoma, but there has been only one such prospective report in patients with PHEO [170]. In this small series, six patients underwent dosimetry and were scheduled to receive three 131I-MIBG treatments at 3-month intervals with activities estimated to deliver 85–90 cGy to the whole body per single administration. The patients would then start the CVD chemotherapy regimen [4]. Three of the six patients had improvement in tumor following 131I-MIBG therapy. Two patients completed 9 months of sequential chemotherapy with further improvement and were considered to have partial response. Toxicity from 131I-MIBG was minimal but forced reduction of chemotherapy doses in some patients.

The most frequent sites of metastatic disease include the lymph nodes, bone, lung, and liver [18]. There is suggestion that soft tissue disease response to 131I-MIBG therapy is superior to that of the bone [69, 104, 168]. It also appears that patients with smaller volume disease following surgical resection are more likely to respond.

In summary, high-quality data on the use of 131I-MIBG therapy in PHEO/PARA is limited, with few prospective trials, and there is currently no consensus on an optimal dosing strategy. Differences in patient selection and follow-up may account for differences in response rates and survival. It is clear that many patients will benefit from treatment, and objective responses are often observed, but complete response rates are low, ranging from 0% to 18%. The duration of responses is also variable, with 5-year survivals between 45% and 85% [137, 158]. There is some suggestion that higher activities >18.5 GBq (500 mCi) or myeloablative regimens may be associated with higher response rates. However, there are no direct comparisons to determine if fractionated smaller activities, that are associated with lesser toxicity, result in different overall survival. Nonetheless, the ease of performing this therapy, the evidence of objective responses, symptomatic improvement, biochemical improvement, and the limited toxicity and few late effects compared to other chemotherapy and external beam regimens make this an acceptable strategy in patients with metastatic PHEO/PARA

Carcinoid

131I-MIBG is used most frequently to treat neuroblastoma and PHEO/PARA. The third largest experience is with carcinoid tumors (Tables 4 and 5) [148, 23]. Carcinoids are slow-growing NETs that often secrete substances leading to hormonal syndromes. These tumors are rare, with incidence in the range of two cases per 100,000 [67, 132]. The most frequent sites for carcinoids are the gastrointestinal (GI) tract (73.7%) and the bronchopulmonary system (25.1%). Within the GI tract, most occur in the small bowel (28.7%), appendix (18.9%), rectum (12.6%), and stomach (6%). Although 45% exhibit metastases at the time of diagnosis, the overall 5-year survival is 50–67% [131, 132]. Higher incidences of carcinoids are found in patients with MEN1, VHL, and neurofibromatosis. In 2000, recognizing the heterogeneity of presentation, prognosis, and outcome, the WHO developed a classification system for NET reflecting a better understanding of cell biology, therapeutic implications, and pathology [174]. Three types of NET were defined: (1) well-differentiated NET (benign behavior, low grade), (2) well-differentiated neuroendocrine carcinoma (low-grade malignant), and (3) poorly differentiated neuroendocrine carcinoma (high-grade malignant). However, this classification is relatively new, and most reports of 131I-MIBG therapy in carcinoid have not incorporated this classification.
Table 4

Carcinoid: treatment schema (administered activities are listed here in mCi; multiply by 37 for conversion to MBq)

Author

# patients

Single administration (median) (mCi)

Cumulative (mCi)

# doses

Taal et al. [180]

30

200

200–600

1–3 (mean 1.8)

Pathirana et al. [150]

12

200 Initial single dose

 

1

Mukherjee et al. [137]

18

70–220 (median 190)

200–1,592 (median 600)

1–8 (median 3.2)

Sywak et al. [178]

58

2.5 mCi/kg capped at 150

Median 182

Mean 2.8

Nguyen et al. [141]

32a

157–554 (median 381)

157–554 (median 381)

1

Pasieka et al. [148]

13a

2.5 mCi/kg (median 149)

85–2,112 (median 594)

1–7

Safford et al. [159]

98

77–500 (median 306)

77–1,076 (median 401)

1–3 (mean 1.2)

Buscombe et al. [23]

25a

54–91

54–635 (median 300)

1–11

Nwosu et al. [143]

48a

200 Each cycle

200–800 (mean ∼362)

1–4 (mean 1.8)

Ezziddin et al. [47]

31a

300

300–1,200 (median 600)

1–4 (median 2)

aIncluded some non-carcinoids

Table 5

Carcinoid: response

Author

# Patients

Objective CR (%)

Objective CR/PR (%)

Biochemical CR (%)

Biochemical CR/PR (%)

Symptomatic CR (%)

Symptomatic CR/PR (%)

Duration of response or survival

Hoefnagel [74]

52a

4

15

NA

NA

NA

65

NA

Taal et al. [180]

30

0

0

0

13

0

60

3-year survival 22%

Median OS 29 months

Median symptom response 8 months

Pathirana et al. [150]

12

0

17

NA

NA

58

83

Mean symptom response 15.4 months

Pasieka et al. [148]

13b

8

15

0

15

0

92

Mean symptom response 17 months

Safford et al. [159]

98

0

15

6

37

NA

49

5-year survival 22%

Median OS 2.3 years

Sywak et al. [178]

58

NA

NA

NA

NA

NA

NA

5-year survival 63%

Median OS 8.3 years

Buscombe et al. [23]

25c

0

35

NA

NA

NA

NA

Median PFS 14.5 months

Median OS 18 months

Nwosu et al. [143]

48d

0

28

NA

37

NA

56

Median survival of symptomatic responder 59 months

Nonresponder 22 months

Ezziddin et al. [47]

31e

NA

10

NA

NA

27

82

PFS 34 month, median OS 47 month, 5 year survival 31%

CR complete response, PR partial response, OS overall survival, PFS progression-free survival, NA not available

aWorldwide experience summary up to 1994

bIncluded 4 non-carcinoid

c17 With carcinoid, 8 non-carcinoids

dIncluded 30 GEP, 6 pulmonary NET, 12 unknown primary

e20 carcinoids, 11 other tumors survival data for carcinoids

Initial staging and follow-up relies on conventional imaging, such as CT and MRI, to evaluate for nodal or metastatic liver disease. Because these tumors often express somatostatin receptors, functional imaging with 111In-pentetreotide or, more recently, with 68Ga-somatostatin analogs is performed [26]. Before 111In-pentetreotide was available, 131I/123I-MIBG scintigraphy was often performed following an initial report by Fischer et al. [53]. These tumors also express norepinephrine transporters, as do PHEO/PARA. Reports have shown that 131I-MIBG has a lower sensitivity for the detection of carcinoid than for pheochromocytoma [26]. A review of 275 carcinoid patients demonstrated a sensitivity of 70% for tumor detection with 131I-MIBG [74].

At presentation, the best management is surgical removal for curative intent, or in cases with metastatic disease, debulking for palliation. Unfortunately, metastatic disease at presentation is frequent, and no consistently effective therapeutic strategies are available. Symptomatic tumor response is often seen following therapy with octreotide analogs [2], whereas objective tumor regression is rare [130]. Interferon may also result in symptomatic improvement in 58–65% of patients [130]. Multiple single and multi-agent chemotherapy regimens have been utilized, with none showing objective tumor response greater than 15%, and newer molecularly targeted reagents are now being evaluated [130]. Because liver metastases are commonly present, interventional radiology techniques including embolization and ablation with radiofrequency or cryoablation are often utilized [105, 130].

The uptake and accumulation of 131I-MIBG in carcinoid raised the possibility of using the radiopharmaceutical for treating these tumors [78]. More recently, 111In-, 90Y-, and 177Lu-octreotide or other somatostatin analogs have been utilized since somatostatin reagents have higher overall accumulation in carcinoid and gastroenteropancreatic tumors [93]. In this chapter, we focus on the use of 131I-MIBG therapy of carcinoid, since radiolabeled somatostatin analog therapy is discussed in the chapter “ Neuroendocrine Tumors” by Dr. Bodi of this book.

Hoefnagel et al. treated five patients with 131I-MIBG which produced some symptomatic responses [78]. Numerous additional reports have since followed (Table 4). Activities have ranged from ∼2 to 20.5 GBq (54–554 mCi), with most series having median single activity <7.4 GBq (<200 mCi). As in PHEO/PARA, patients are often treated repetitively (1–11 treatments, median 1.2–3 treatments) until toxicity or lack of response is seen. Cumulative activities have ranged from 2 to 78.14 GBq (54–2,112 mCi), with median activities between 6.73 and 21.98 GBq (182–594 mCi). In contrast to neuroblastoma and PHEO/PARA, no series have included marrow ablative doses and stem cell transplant in carcinoid patients.

Although carcinoid patients rarely have a complete response to 131I-MIBG therapy, measurable objective response rates of 11–27.5% have been reported (Table 5). The cumulative experience in 52 patients treated up to 1994 reported a 15% objective response rate and 65% symptomatic response. Multiple publications suggest that symptomatic response rates range from 38% to 92%, with partial symptomatic improvement more common than complete relief [137, 150, 159]. Patients whose symptomatic disease is resistant to octreotide or chemotherapy may benefit from 131I-MIBG [159]. Biochemical responses are seen less commonly than symptomatic responses and range from 13% to 73% (Table 5), with complete biochemical normalization being infrequent [137, 148, 159]. For instance, Taal et al. observed that 60% of patients had symptomatic improvement, whereas only 13% had decreases in biochemical markers [180]. It is not well understood why only some patients with symptomatic response also show biochemical response [148, 180]. Symptomatic responses last a median of 8–17 months [148, 150, 180].

Because evaluation and outcome reporting is not standardized, the exact advantage in terms of survival is difficult to gauge from the literature. Median 5-year survivals of 42–78% have been reported [137, 159]. This is in the same overall survival range for carcinoid patients undergoing other, non-131I-MIBG treatments [131, 132]. The largest series of 98 patients was reported by Duke University [159]. Their median initial activity was 11.32 GBq (306 mCi), although over time, this increased, and they now recommend initial single activities of >14.8 GBq (>400 mCi). Patients receiving >14.8 GBq (>400 mCi) survived an average of 4.69 years compared to 1.86 years for those receiving <14.8 GBq (<400 mCi). Most of these patients received only a single treatment. The authors also noted that patients that had symptomatic improvement had a 5.76-year survival compared to 2.09 years for those that did not. Interestingly, in those with biochemical improvement, survival was not significantly different from those without biochemical response (4.11 years versus 3.42 years). In this study, 49% of progressive metastatic carcinoid patients had improvement in symptoms. Similarly, others have also reported high rates ranging from 56% to 92% (Table 5). Nwosu et al. also found that patients with symptomatic improvement had a longer survival of 59 months compared to 22 months in those without improvement [143].

Few studies have directly compared 131I-MIBG treatment to untreated controls or patients undergoing other therapies. Sywak et al. reported a 5-year survival of 63% in patients treated with 131I-MIBG compared to 47% for those not receiving it [178]. In these patients, further deaths occurred over time, with a 10-year survival of 38% in the 131I-MIBG treatment group versus 33% in the no treatment control. In a separate report, Taal et al. compared 131I-MIBG therapy to nonradioactive MIBG therapy and the median survival times were similar, approximately 28 months from start of treatment. Interestingly, they found a symptomatic response rate in both groups of 60%, although responses lasted longer with 131I-MIBG than with nonradioactive MIBG (8 months versus 4–5 months) [180].

Studies combining 131I-MIBG with chemotherapy or biologic therapy are rare. Zuetenhorst et al. evaluated whether interferon or cold MIBG increased the uptake of 131I-MIBG in carcinoid tumors [212]. They found a 10% increase in 131I-MIBG uptake in 19% of the patients receiving interferon and a 10% increase in 83% receiving cold MIBG. Unfortunately, no objective responses or synergistic effect from combined treatments with 131I-MIBG were observed.

Another approach that may result in improved response is direct intra-arterial injection of the radiopharmaceutical. This approach delivered a 69% higher dose of 131I-MIBG to the targeted tumor [20], but the therapeutic consequences of this approach are still to be determined.

With the advent of improved somatostatin analogs that exhibit better targeting of carcinoids than MIBG, the role of 131I-MIBG therapy in this disease has diminished. 90Y- and 177Lu-labeled DOTATOC and DOTATATE have already demonstrated promising results [24, 190]. Nonetheless, in octreotide negative patients or those with borderline renal function, 131I-MIBG remains a useful palliative option.

Case reports and smaller series have been reported on therapy of other NETs (non-PHEO/PARA carcinoid and neuroblastoma). For example, in a review article, the experience in 52 patients with medullary thyroid carcinoma was presented. There was a 38% objective response rated and palliation in 22% of the patients [74]. Treatment of 38 patients with gastroenteropancreatic tumors with a median of 6.8 GBq (range 1.6–10.57 GBq) of 131I-MIBG has been reported. At 3–6 month following single treatment, 75%, 67%, and 63% of patients showed either a partial response (PR) or stable disease (SD) on radiological, biochemical, and symptomatic criteria, respectively. Overall survival from the date of the first therapy was 4 years ± 0.69 years, with 29% of patients alive at 10 years [138].

In summary, this modality is safe in patients with carcinoid, and there is evidence of objective, symptomatic, and biochemical benefit, although rarely complete responses are reported. There is a lack of prospective well-designed trials to compare with other modalities. Many carcinoid patients failing surgical resection or local ablation procedures are treated with radiolabeled somatostatin rather than 131I-MIBG because of better targeting with somatostatin analogs. Nonetheless, in patients in whom radiolabeled somatostatin may be contraindicated (e.g., poor renal function) or not available, 131I-MIBG is a reasonable strategy for symptomatic palliation.

Neuroblastoma

Neuroblastoma is a tumor that arises from primordial neural crest cells and is almost exclusively found in infants and young children. It is the most common tumor of childhood with an incidence rate of 9.5 per million [71]. Prognostic markers include age, stage at presentation, and MYCN amplification status [127]. The 5-year survival is 83% for infants, 55% for children 1–4 years, and 40% for older children [71]. Children less than 1 year may present with a self-limited disease with spontaneous remission (stage 4S). These children have an excellent long-term prognosis with 70–97% survival [142]. Stage 4 disease consists of dissemination to the distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs. In patients younger than 18 months and without MYCN amplification, these tumors have more favorable prognosis and are usually treated with intermediate dose chemotherapy without autologous stem cell transplant (ASCT). Patients at high risk are those >18 months old with stage 4 disease and those with MYCN amplification. Therapy for these patients usually relies on induction chemotherapy, surgery, and radiotherapy (given that this is a radiosensitive tumor) followed by consolidation of remission with ASCT or cis-retinoic acid with or without antibody immunotherapy [127]. High-risk patients often relapse and are resistant to conventional therapy. Newer strategies include immunotherapy such as anti-GD2 antibodies [127]. 131I-MIBG therapy has also been utilized, and several retrospective studies and a few phase I and II studies have been reported. 131I-MIBG applications have included palliative therapy for patients with multiple relapses, first-line therapy, localized symptomatic inoperable disease, and combined therapy with chemotherapy or biologic therapy for consolidation.

Patient preparation for 131I-MIBG therapy is simple and similar to that described above, where patients are taken off drugs that may interfere with uptake or release of MIBG [172]. The patient’s thyroid is blocked with an age-appropriate dose of KI. A diagnostic 123I-MIBG scan is obtained to document MIBG uptake, which is typically seen in 93–97% of neuroblastoma patients [86, 194].

Several 131I-MIBG dosing strategies have been pursued in patients with neuroblastoma (Tables 6 and 7). Fixed activities are most commonly used, usually consisting of single 3.7–7.4 GBq (100–200 mCi) administrations that are repeated at a similar activity. Treatment regimens such as this that are not weight based have been repeated up to seven times with cumulative activities of up to 1.1 Ci. Another strategy is based on activity per body weight where phase I dose escalation trials have been performed using single activities of 96–666 MBq/kg (2.6–18 mCi/kg), number of doses ranging from 1 to 7 [61, 77, 94, 99, 121]. Typically, activities above 444 MBq/kg (12 mCi/kg) require preharvesting of stem cells because of marked hematologic toxicity. Other groups have based dosing on a delivered whole-body radiation dose, where the goal is to deliver 1–4 Gy to the whole body based on a dosimetric study or on an initial 131I-MIBG therapy study [62, 81, 107]. Using these strategies, whole-body doses of 2 Gy can be administered without bone marrow support. Typically, the large myeloablative strategies utilize high doses, delivering 666 MBq/kg (∼18 mCi/kg) [124] or large whole-body radiation doses, >4 Gy [21, 62]. A high-dose study that allowed up to 8 Gy fractionated marrow dose recommended a maximum cumulative activity of 1.33 GBq/kg (36 mCi/kg) [123]. In addition, some have utilized a combination of strategies coupled to the concomitant administration of chemotherapy (Table 7).
Table 6

131I-MIBG therapy in neuroblastoma (administered activities are listed here in mCi; multiply by 37 for conversion to MBq)

Study

# Patients

Stage

Single treatment (mCi)

Number of treatments

Cumulative dose (mCi)

PR

CR

Measurement of response duration

Treuner et al. [184]

6

3–4

35–210 (median 85)

2–5 (median 3)

150–590 (median 234)

33%

17%

Median PFS 5.1

Troncone et al. [186]

7

3–4

70–184 (median 122)

1–4 (median 2)

80–296 (median 178)

43%

14%

NA

Hoefnagel et al. [77]

16a

High risk/4

40.5–200

1–6 (median 3)

59–1,100 (median 300)

42%

17%

NA

Klingebiel et al. [99]

47

3–4

1.7–30 mCi/kg (8.9 mCi/kg)

1–6

88–1,033

Stage 3 36%

Stage 4 25%

Stage 3 39%

Stage 4 22%

Stage 3: survival at 28 months 32%

Stage 4: survival at 28 months 12%

Garaventa et al. [61]

31

Resistant/recurrent

68–162 based on body weight

1–5 (median 3)

76–646

13%

6%

23% biochemistry

Median TTP 4–9 months

Hor [81]

15

3–4

To deliver 1 Gy

1–6 (median 3)

8.8 mCi/kg

13%

0%

Median survival ∼12 months

Hoefnagel et al. [79]

53

Stage 3 and 4

100–200

1

100–200

43%

13%

Response lasted 2–38 months

Lumbroso et al. [110]

26

3–4

30–108 (median 70)

1–5

NA

0

0

NA

Lashford et al. [107]

25

3–4

64–327 (based on 1,2, 2.5 Gy whole body)

1

64–327

33%

0

Median survival 12 months

Hutchinson et al. [85]

14

3–4

60–220 (median 154)

1–3 (median 1)

60–293 (median 210)

0%

0%

Median survival 5.65 months

De Kraker et al. [40] Cfirst line

33

2,3,4

200 with repeat 100

2–7 (median 3)

NA

54%

3%

NA

Matthay et al. [121]

30

3–4

90–803

2.6–18.2 mCi/kg

1

90–803

30%

3%

Median survival 6 months

Garaventa et al. [59]

43

3–4

68–149 (median 100) based on body weight

1–5 (median 3)

NA

28%

2%

Stage 3: 5-year EFS 92%

Stage 4: 5-year EFS 40%

Kang et al. [94]

20

2–4

3.8–14.1 mCi/kg (9.5 mCi/kg)

1–3

27.6–30.5 mCi/kg

31%

0%

Pain relief 1–3 months

Howard et al. [82]

28

4

Median 17.3 (2.6–19.3 mCi/kg)

1–4 (median 2)

346–2,414 (median 860 or 35.8 mCi/kg)

36%

4%

Median survival 12 months

Matthay et al. [124] Phase II

164

Progressive/relapsed/refractory

12 mCi/kg or 18 mCi/kg if stem cells

1

NA

19%

29%

6%

8%

OS at 2 years 29%

EFS at 1 year 18%

de Kraker et al. [41] First line

44

High risk

200 initial with repeat 100–150

1–5 (median 3)

350–950 (median 500)

63%

2%

Median EFS 10 months

OS15 month

5 year OS 14.6%

Matthay et al. [123] Phase I

21

Refractory/relapsed

Dose escalation-based 4,6, 8 Gy red marrow

2

Double dose (day 0 and 14) 22–51 mCi/kg (4–8 Gy marrow)

10%

0%

OS at 18 months 48% PFS 0.55 year

Johnson et al. [91]

76

Relapsed

Intent 18 mCi/kg × 2

1–2

Double dose 36 mCi/kg

First treatment 23.7%

Second treatment 17.1%

First treatment 6.6%

Second treatment 12.2%

OS 60% at median 18 month

OS for those with CR 22 month

Polishchuk et al. [151]

39 (10–17 years)

16 pts. >18

Recurrent or refractory

11.9 mCi/kg (range,2.6–18.8 mCi/kg)

1–4 (median 1)

10–17y/o

17.8 mCi/kg

>18 y/o

16.9 mCi/kg (range, 9.0–43.0 mCi/kg),

10–17 y/o

39%

>18 y/o

44%

10–17 y/o

0%

>18 y/o

13%

5 years OS 14.6%

Schoot et al. [163]

21b

Stage 1–3

First 5.8–20.6 mCi/kg(median 13.4 mCi/kg

Second 5.9–16.3 mCi/kg(median 12.4 mCi/kg)

1–7 (median 2)

NA

4

16

10 years OS 90.5%

CR complete response, PR partial response, OS overall survival, PFS progression-free survival, EFS event-free survival, TTP time to progression

aInclude neuroblastoma only

bIn some patients combined with chemo and or surgery

Table 7

131I-MIBG therapy plus chemotherapy in neuroblastoma (administered activities are listed here in mCi; multiply by 37 for conversion to MBq)

Study

# patients

Stage

Single treatment (mCi)

Number of treatments

Cumulative dose (mCi)

PR

CR

Measurement of response duration

Chemotherapy

Corbett et al. [38]

5

Advanced/relapsed

200–303

1

200–303

NA

NA

NA

Carboplatin, melphalan or etoposide, vincristine

Mastrangelo et al. [118]

4

4

100–120

2

200–250

25%

50%

Two only lasted <3.5 months and one at least 5 months

CISP, CTX

Voute et al. [196]

No O2: 36 hyperbaric O2:27

4

200 mCi followed by 100 mCi

2–7 (median 3)

2–12 (median 3)

NA

NA

NA

No O2: survival at 28 months—12%

O 2: survival at 28 months–32%

No chemo, hyperbaric

Gaze et al. [63]

5

4

2 Gy whole body (179–277)

1

179–277

20

80%

OS 23 months

Melphalan, whole-body XRT(12.6–14.4 Gy), and stem cells

Klingebiel et al. [98]

11

4

7.8–22 mCi/kg (median 15.7 mCi/kg) 195–302

1

195–302 (median 297)

18%

36%

Mean PFS 2.15 years

Melphalan, carboplatin etoposide, and anti-GD2 mAb after MIBG

Miano et al. [126]

17

3–4

4.1–11.1 mCi/kg (median 7 mCi/kg)

1

NA

35

12

NA

Busulfan and melphalan

Mastrangelo et al. [120]

21 (16 with MIBG)

3–4

200

1

200

75%

0%

PFS median 12 months

CISP, VP16 VNC. CTX then MIBG

Yanik et al. [205]

12

Metastatic or localized

132–484 (median 212 or 12 mCi/kg)

1

132–484

17%

50%

Median survival 12.8 months

Carboplatin, etoposide, melphalan

Gaze et al. [62]

8

4

12 mCi/kg (median 243)

Second dose to deliver total 4 Gy

2

318–609 (median 431)

NA

NA

NA

Topotecan

Mastrangelo et al. [119]

Group 1 = 5

Group 2 = 8

Stage 4 and 3

Group 1

168–200 (mean 178)

Group 2,109–200 (mean164)

1

Same

Group 1

80%

Group 2

75%

 

Group 1 20%

Group 2 13%

Both group;

Carboplatinum,cyclophosphamide, etoposide, doxorubicin, vincristine

Group 2 additional busulfan, mephalan, and G-CSF

DuBois et al. [42]

24

Relapse or refractory

Dose escalation 8,12,15,18 mCi/kg (median 16.5)

1–3 (Median 1)

8–36 mCi/kg

17

9

NA

Vincristine and irinotecan

Kraal et al. [103]

16

High risk

First 10.6 (6.9–12.6) mCi/kg

Second 10.6 (6.9–12.6) mCi/kg

2

25 (14.3–29.4)mCi/kg

56

0

10 year OS

Topotecana

DuBois et al. [43]

27

Relapse or refractory

8,12,15 and 18 mCi/kg

1–2

Same

12

 

NA

Vorinostat

Yanik et al. [206]

50

Cohort 1 refractory and relapse

Cohort 2 partial responder

8–12 mCi/kg based on GFR

1

8–12 mCi/kg

2.4%

12.5%

7.3%

25%

3 years (EFS) 20% ± 7%

OS 62% ± 8%

Carboplatin, etoposide, mephalan,local XRT

Modak et al. [129]

19

Recurrent or refractory

12–18.7

(median 18)

1

Same

0

0

Median OS 23.7 ± 9.1

Median time to progression 6.5 ± 2

Arsenic trioxide

CR complete response, PR partial response, OS overall survival, PFS progression-free survival, EFS event-free survival

aAfter MIBG and topotecan therapy pts. underwent standard induction treatment surgery or ASCT

Response criteria have been developed for the objective assessment in patients with neuroblastoma [19]. Most 131I-MIBG trials have selected patients with advanced disease that have failed first-line therapy, while others have incorporated 131I-MIBG into a multiprong dosing strategy (Tables 6 and 7). Initial trials were focused on feasibility and toxicity and represented single center, poorly controlled trials [61, 81, 184, 186]. Nonetheless, these trials demonstrated that repeated administrations of 131I-MIBG could be given safely in patients with advanced disease who had failed conventional therapy. Overall, evidence of objective response was often observed (Table 6) with several trials reporting partial responses of up to ∼40% in patients who had failed other treatments. The incidence of objective complete response was usually much lower and seldom over 10%. In Tables 6 and 7, objective response rates are utilized although it is recognized that symptomatic or biochemical improvements are also important outcome measures [61, 94, 110, 184, 187]. Because many of these trials were not prospective, reporting criteria in terms of outcome were variable, and the parameters measured in terms of duration of response are inconsistent and include survival, overall response, and event-free survival (EFS).

Early studies such as those of Garaventa et al. reported their experience in patients with stage 3 or 4 neuroblastoma who had not achieved a complete response following conventional therapy. These patients received 1–5 treatments of 2.52–5.51 GBq (68–149 mCi) 131I-MIBG and had a 30% objective response rate with 2% achieving a CR. The 5-year EFS was 40% for stage 4 and 92% for stage 3 [61]. In a retrospective review, Kang et al. treated 20 patients, the majority of whom had residual or recurrent disease, with submyeloablative doses (median single activity of 131I-MIBG 351 MBq/kg (9.5 mCi/kg) and cumulative activities of 1.02–1.13 GBq/kg, or 27.6–30.5 mCi/kg) [94]. These patients experienced a 31% objective partial response rate and effective symptomatic relief.

A formal phase I study was reported by Matthay et al. in patients with stage 3–4 relapsed neuroblastoma receiving escalating activities of 111–666 MBq/kg (3–18 mCi/kg) [121]. In patients receiving >444 MBq/kg (>12 mCi/kg), stem cells were harvested because of the significant bone marrow toxicity that was expected. Dose-limiting toxicity requiring stem cell transplant was observed in patients receiving 555 and 666 MBq/kg (15–18 mCi/kg). After transplant, a significant proportion of the patients did not achieve platelet independence before death (49–150 days posttransplant), although neutrophils recovered. Thirty-seven percent of patients had objective responses, 3% achieved CR, and median survival for all patients was 6 months.

In a phase I trial, Lashford et al. treated patients with advanced chemoresistant neuroblastoma using escalating whole-body doses of 1, 2, or 2.5 Gy based on a diagnostic scan [107]. Overall, the activity ranged from 2.37 to 12.1 GBq (64–327 mCi) with activities >5.29–9.18 GBq (143–248 mCi) required to deliver 2.5 Gy to the whole body. In this study, 56% of the measured post-therapy whole-body doses were a median of 10% lower than the prescribed dose. Whole-body doses of 1 Gy were well tolerated. However, 31% of patients receiving 2 Gy developed grade 3 or 4 thrombocytopenia, and at 2.5 Gy, 80% developed grade 3 or 4 thrombocytopenia and 40% developed grade 3 or 4 neutropenia. A 33% objective response was seen, similar to the range of results seen by Matthay et al. [124].

While most studies have administered more than one therapeutic dose of 131I-MIBG (Table 6), there have been several studies using a single administration [79, 107, 121, 124]. The response rates reported in these trials are in the range of 25–46% (Table 6). Although single large amounts of 131I-MIBG may target sites of disease well, this does not guarantee response to treatment (Fig. 2). Several studies have also repeated large doses of 131I-MIBG. Howard et al. delivered high-cumulative doses of 131I-MIBG by administering a median of 1.325 GBq/kg (35.8 mCi/kg). This was delivered in a median of two sessions (range 1–4) [82]. These treatments resulted in a response rate of ∼40% with median overall survival of 12 months. Matthay et al. used two sequential administrations of 131I-MIBG totaling 0.81–1.89 GBq/kg (22–51 mCi/kg) delivered over 14 days, with a response rate of 10% and overall survival of 48% at 18 months [123]. A compassionate use report in 53 subjects with relapsed neuroblastoma administered tandem doses of 18 mCi/kg to 41 patients with the second dose administered at 6 weeks (within 100 days). In these patients, stem cell support was available. Response rates are shown in Table 6 [91]. In these patients, 30% response rate was seen to initial treatment with a further 29% response on repeat treatment. While one report suggests that the greatest benefit occurs after the first of multiple treatments [82], this has not been adequately studied. A report using 131I-MIBG in conjunction with chemotherapy concluded that two administrations were optimal, whereas reports in patients with pheochromocytoma have indicated that it may take more than one treatment before objective responses are noted.

Most studies have used 131I-MIBG therapy in the setting of resistant or recurrent disease at the time of relapse or in conjunction with chemotherapy regimens. One group used it as first-line therapy with intent to obtain better results at time of tumor surgery with less toxicity than that of conventional approaches. Hoefnagel et al. treated 31 patients with stages 3 and 4 disease with an initial activity of 7.4 GBq (200 mCi) followed by 2–6 treatments with 3.7 GBq (100 mCi) treatments [75]. This regimen was well tolerated and resulted in an overall 71% response rate in primary tumors and 81% in metastatic lesions. Initial 131I-MIBG resulted in successful surgical resection of >95% of tumor in 70% of the patients. Furthermore, they observed a greater than 50% drop in catecholamines in 70% of patients. The same group reported on their expanded experience in 41 patients treated with frontline 131I-MIBG using the same regimen of 7.4 GBq (200 mCi) followed by 3.7 GBq (100 mCi) every 4 weeks, with cumulative total doses of 12.95–35.15 GBq (350–950 mCi). In this study, an objective partial response rate of 63% was observed along with a 2% complete response rate [41]. Their conclusion was that the optimal response appeared to occur after two treatments. This was part of a planned therapy regimen that was to be followed by surgery and chemotherapy, and the overall response rate after surgery was 73%.

A retrospective study focused on patients with stage 1–3 with localized inoperable disease causing compromised organ dysfunction or respiratory effects [163]. These patients received a regimen previously described by the group consisting of a fixed dose of 5.5–7.4 GBq (200 or 150 mCi) followed by a second dose of 3.7–5.5 GBq (150 or 100 mCi), with adjustments based on weight. That study concluded that 131I-MIBG therapy is an effective treatment modality for unresectable localized neuroblastoma causing or in danger of causing organ or respiratory dysfunction and offers a good alternative to chemotherapy if urgent treatment is needed. Toxicity was mainly hematologic and mostly well tolerated.

There is some data to suggest that older patients with NB have improved response rates compared to younger patients [55, 96]. Neuroblastoma is predominantly seen in young children. In a retrospective study a total of 39 patients were treated with median large cumulative doses of 720 mCi (17.8 mCi/kg) 131I-MIBG for those 10–17 years old and 857 mCi (16.9 mCi/kg) for those ≥18 years old. The overall response rate was 39% for those 10–17 years old and 56% for those ≥18 years old. Overall survival rates at 3 years were 32.8% and 43.2%, respectively.

In a retrospective analysis of 218 patients, 72 had refractory disease and 146 patients had relapsed disease. These patients were then treated with 6.3–20.9 mCi/kg 131I-MIBG. Less favorable outcomes were seen in patients with relapsed disease, with 24% of relapsed patients having progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients. Among all patients, the 24-month OS was 47.0%. The 24-month OS for refractory patients was significantly higher at 65.3%, compared to 38.7% for relapsed patients (p < 0.001) [211].

Sixteen patients with high-risk neuroblastoma were treated with two upfront courses of 131I-MIBG combined with topotecan. An overall response rate of 57% was noted with a response in 94% of primary tumors but only 34% of bone marrow disease. Further treatment with induction chemotherapy, surgery, or ASCT resulted in additional responses [103].

Because of the response rate to 131I-MIBG as a single agent in relapsed or refractory neuroblastoma, several investigators have used 131I-MIBG prior to chemotherapy, attempting to improve the remission status prior to myeloablative chemotherapy and ASCT. In one such study, eight refractory NB patients were administered 131I-MIBG treatment at doses of 16–19 mCi/kg i.v. followed by autologous stem cell transplant approximately 2 weeks later. Some patients received local radiation to primary tumors and/or residual sites of disease. After 6–8 weeks, the patients received myeloablative treatment with busulfan and mephalan followed by ASCT [56]. Seven of the eight patients were alive 10 months after ASCT, demonstrating that combined therapy was possible and engraftment was achieved. One patient died of sinusoidal obstructive syndrome at day 50. Two patients had PR and three had CR. Other investigators have aimed to combine 131I-MIBG with arsenic, based on preclinical studies that have shown a radiosensitizing effect. A group of 19 recurrent or refractory NB patients were treated with 131I-MIBG and arsenic. By international research criteria, 12 patients had no response while 7 had progressive disease (PD), including six out of eight who entered the study with PD. Objective improvements in semiquantitative MIBG scores were observed in six patients. Five-year overall survival for NB was 37 ± 11%. The adverse drug-related side effects were similar to those for 131I-MIBG alone [129]. Overall, the addition of arsenic had no additional effect on toxicity.

Full courses of irinotecan and vincristine have been administered with high-dose 131I-MIBG with stem cell transplant in the setting of a dose escalation phase I [42]. Significant responses were observed in 26% when a combination of MIBG, CT, and bone marrow was used for assessment. Furthermore, responses were seen in 43% of seven patients receiving more than one therapy cycle.

Other pharmaceuticals that may enhance the therapeutic effect of 131I-MIBG have been combined, taking advantage of potentially synergistic mechanisms and pathways. Vorinostat, a histone deacetylase inhibitor and radiosensitizer [136], also increases density of norepinephrine receptors [134]. Based on these preclinical studies, 131I-MIBG has been combined with vorinostat in a dose escalation trial. This combination resulted in an overall 12% response rate and 17% response rate at the highest dose level [43].

There is no consensus on how to best incorporate 131I-MIBG in the treatment of high-risk patients. It is clear that 131I-MIBG has efficacy in advanced neuroblastoma, but research continues as to how best to incorporate its use as part of a multimodal approach to therapy, taking advantage of synergies of mechanism of actions and to some extent non-overlapping toxicities. There is also ongoing work using improved reagents with 131I-MIBG at high specific activity [36] and work using 211At-MIBG [188]. Furthermore, future imaging may be used to select candidates that may benefit from the combination of 131I-MIBG and peptide receptor radionuclide therapy such as 177Lu-/90Y-labeled somatostatin analogs [25].

Toxicity

The most significant toxicity associated with 131I-MIBG therapy in both children and adults is hematologic. There is a larger drop in platelets than white blood cells, likely related to binding of MIBG to platelets [48]. These drops in counts are dependent on the administered activity and are minor when activities in the range of 7.4 GBq (200 mCi) are used [47], whereas doses >444 MBq/kg (12 mCi/kg) cause hematologic toxicity. Grade 3 or 4 thrombocytopenia is observed in 80–87% of patients, requiring platelet transfusion and/or growth factors [70, 91, 124]. After whole-body doses up to 2.5 Gy in children with neuroblastoma, grade 3 or 4 thrombocytopenia was seen in 80% [107]. The nadir in children has been reported to occur at approximately 28 days after a single administration (range 9–42) [107]. When chemotherapy is combined with 131I-MIBG therapy, nadirs may occur earlier and are felt to be predominantly driven by the chemotherapy [120].

In patients with upfront 131I-MIBG treatment receiving median activities of 441 MBq/kg as a first dose and a repeated median dose of 328 MBq/kg, the main toxicity was also hematologic with grade 4 thrombocytopenia in 1% of patients after first treatment and 3% after the second [12]. This is lower than that seen in patients with multiple prior treatments. Other predictors of increased marrow toxicity include whole-body or marrow absorbed dose, extensive marrow/bone involvement, and prior stem cell transplantation [12, 44, 59, 169].

Children and adults treated with activity ≥444–666 MBq/kg (12–18 mCi/kg) may require bone marrow transplant because of significant and prolonged marrow toxicity [44, 91]. Howard et al. reported thrombocytopenia requiring platelet transfusion in 78% and 82% of patients after the first and second infusion, respectively, while only 50% had grade 4 neutropenia that was usually transient. Ten patients required stem cell transplant. Nonetheless, in this and other trials, there are patients who fail to engraft adequately at these high levels of activity [44, 82]. In this and other trials, stem cells are transplanted when severe neutropenia is present, requiring growth factors, or when the patient requires platelet transfusion more than 2 times a week [82, 124]. In other cases, stem cells are routinely transplanted at 21 days post high-dose 131I-MIBG [206]. With tandem therapy of 18 mCi/kg, 85% of patients receiving two treatments required stem cell support, which typically was administered a median of 15 days after the second therapy dose [91]. Gaze et al. used dosimetry to deliver 4 Gy to the whole body [62]. These doses often required transplant that was performed 14 days post last 131I-MIBG treatment and when the estimated whole-body retention of 131I was less than 0.8 mCi. In patients receiving 131I-MIBG and myeloablative chemotherapy, the stem cells were infused 21 days after MIBG and 7 days after the chemotherapy [205]. At a mean activity of 381 mCi, Safford et al. reported that 12% of patients had enough hematopoietic depression to required hospitalization [158]. Because neutropenia is infrequent with low activity, the incidence of infections is low. As expected with higher activity that induces considerable neutropenia, significant infections are occasionally encountered [107, 124, 205]. In addition, when high-dose 131I-MIBG is given with myeloablative chemotherapy, a high incidence of febrile neutropenia was observed in 70% of treated patients [206]. With tandem high-dose treatment, 29% of patients remained thrombocytopenic and transfusion dependent in spite of stem cell transplant. Toxicity was similar for adult patients, young adolescent receiving high-dose therapy compared to younger patients [151]. Combined chemotherapy and high-dose 131I-MIBG results in hematotoxicity similar to when 131I-MIBG is given alone, but other toxicities are new/more prominent when combined with chemotherapy; for example, when irinotecan, vincristine, and MIBG therapy were combined, diarrhea was frequently seen [42].

Myelodysplasia (MDS)/acute myelocytic leukemia have been reported in patients who have received both chemotherapy and large amounts of 131I-MIBG. In adult PHEO patients, a ~4% incidence was reported with high-dose therapy [42, 70]. MDS has also been reported after therapy in patients with medullary thyroid carcinoma and carcinoid tumors [29]. MDS in children receiving 131I-MIBG is also reported [59, 79]. The timeline for MDS after 131I-MIBG is typically >2 years [28, 70]. The UCSF group reviewed their experience in 95 patients with neuroblastoma as well as a review of the literature. In their patients, the cumulative incidence of MDS was 3.9% at 60-month post-therapy [201]. A further review of the literature only yielded three additional patients out of 500 treated with 131I-MIBG. The authors felt that alkylating chemotherapy agents played a significant role. Garaventa et al. reviewed 119 patients treated with a mean of two therapy regimens using activity estimated at ~240 MBq/kg (6.5 mCi/kg) where whole-body doses were usually less than 200 cGy. At follow-up, 78 patients had died and five secondary malignancies were reported at a median of 3 years (1–15 years) including acute monolymphoblastic leukemia, chronic myelomonocytic leukemia, angiomatoid malignant fibrous histiocytoma, malignant schwannoma, and rhabdomyosarcoma [60]. This occurrence of secondary malignancy and bone marrow disorders indicates that these patients require close follow-up, especially in patients with prolonged survival.

The thyroid is routinely protected with iodine-containing solutions (see above). Nonetheless, hypothyroidism has been reported. The incidence of hypothyroidism has ranged from 11% to 32% [41, 61, 164, 166, 205]. One investigator reported that 48% of treated patients developed hypothyroidism [59]. In children receiving high-dose 131I-MIBG (~18 mCi/kg), there was a high baseline incidence of elevated TSH in 24% of patients [153]. In the latter report, the 2-year cumulative incidence rates of hypothyroidism was 35 ± 14% in those with baseline thyroid dysfunction and 10 +/± 5% in those without baseline abnormal thyroid function, possibly attributed to the KI and potassium perchlorate regimen. In patients with neuroblastoma, the incidence of non-visualization of the thyroid in post-therapy images ranges from 52% to 59% [35, 153]. In adults, the incidence of hypothyroidism is lower [150, 190]. There have also been reports of thyroid cancer attributed to 131I-MIBG [191].

Common systemic/constitutional toxicity associated with large doses of radiation from 131I-MIBG is often observed (6–67% of patients) including asthenia, nausea, and vomiting. Nausea and/or vomiting may start as early as 8–12 h and last a week; this appears to be more frequent in patients with larger liver metastatic burdens [64, 104, 109, 158, 164]. While some have reported a low incidence [47, 61, 109, 158], other have encountered it more frequently, sometimes in >40% of the patients [12, 164]. In our institution, ondansetron is administered prophylactically starting immediately before treatment and continued for several days. This regimen minimizes the incidence of nausea and vomiting due to therapy. Salivary gland tenderness and short-term dysfunction have been reported [128].

Although 131I-MIBG localizes in normal organs such as the heart, lung, liver, and adrenal, there have been very limited complications related to cardiac, renal, liver, or adrenal insufficiency. Pulmonary toxicity is most frequently related to infectious disorders. Nonetheless, infrequent reports of ARDS, bronchiolitis obliterans, and other serious pulmonary disorders have been described [12, 70, 82, 126]. Mild changes in liver function have been encountered [41, 137, 150], but severe hepatic dysfunction is rare [13, 16, 107]. Sinusoidal obstructive syndrome has been reported when 131I-MIBG is combined with chemotherapy, that was though to be mainly related to the chemotherapy component [206]. In children receiving a median dose of 18.2 mCi/kg 131I-MIBG, there were 20 patients who developed grade 3 or 4 liver toxicity, although there suggestion of causality with 131I MIBG in only eight cases [153]. Changes in glomerular filtration rate have been documented, but the induction of renal failure is unlikely [41]. Drops in hormone levels such as corticosteroids and testosterone have been reported, as well as primary ovarian failure [34, 195].

Hypertension can occur and cases of hypertensive crises have been reported in PHEO patients [72, 154]. Hypertension can also occur following administration of 131I-MIBG therapy in patients with neuroblastoma [102, 111]. Hypertension was reported in 5% of 50 patients receiving 110 infusions of 131I-MIBG, more commonly in those with pre-existing hypertension, including hypertensive crises with seizure [102]. In this report, a >15 mm Hg rise was seen in 12% of the patients. Most adverse hypertensive events occur between 20 and 25 h post-administration [12, 102, 203]. Risk factors for a hypertensive response not only include pre-existing hypertension but also younger age and eGFR prior to treatment [203]. When therapy is administered, antihypertensive medication should be available, particularly in patients with PHEO [54], and observation over 48 h has been suggested. In 218 administrations of 131I-MIBG, the administration of antihypertensive medication (nifedipine) was only required in 2.8% of patients [203].

Summary

Therapeutic 131I-MIBG is safe and well tolerated in both children and adults with few side effects, when used in low-to-moderate doses in patients with PHEO/PARA, carcinoid, and neuroblastoma. Myeloablative doses are associated with more toxicity but are still relatively well tolerated. The role of 131I-MIBG has been best characterized in patients with PHEO/PARA where symptomatic and biochemical improvements are frequently observed. In patients with carcinoid, studies have also shown that, in selected patients, good palliative results can be obtained. In both carcinoid and PHEO/PARA, objective partial responses are often seen and can be long lasting. In neuroblastoma, good responses, albeit often temporary, have also been obtained with 131I-MIBG. In neuroblastoma, most studies have been used with therapeutic rather than palliative intent. It is clear that new, combined approaches must be developed if 131I-MIBG is to find more general use and to have greater impact on quality of life or survival in neuroblastoma, PHEO/PARA, and carcinoid.

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Copyright information

© Springer International Publishing Switzerland (outside the USA) 2016

Authors and Affiliations

  1. 1.Molecular Imaging and Therapy ServiceMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Division of Nuclear Medicine, Department of Radiology and Imaging Sciences, Clinical CenterNational Institutes of HealthBethesdaUSA

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