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. Author manuscript; available in PMC: 2013 Aug 27.
Published in final edited form as: J Nucl Med. 2010 Sep 16;51(10):1524–1531. doi: 10.2967/jnumed.110.075226

Phase I Trial of 90Y-DOTA0-Tyr3-Octreotide Therapy in Children and Young Adults with Refractory Solid Tumors That Express Somatostatin Receptors

Yusuf Menda 1,2, M Sue O’Dorisio 2,3, Simon Kao 1,2, Geetika Khanna 4, Stacy Michael 3, Mary Connolly 5, John Babich 6, Thomas O’Dorisio 2,7, David Bushnell 1,8, Mark Madsen 1
PMCID: PMC3753801  NIHMSID: NIHMS495708  PMID: 20847174

Abstract

Purpose

Conduct a Phase I trial of 90Y-DOTA0-Tyr3-octreotide to determine the dose/toxicity profile in children and young adults with somatostatin receptor positive tumors.

Methods

A 3×3 design was utilized to determine the highest tolerable dose of 90Y-DOTA0-Tyr3-octreotide with administered activities of 1.11, 1.48 and 1.85 GBq/m2/cycle given in 3 cycles at 6-week intervals. An amino acid infusion was co-administered with the radiopharmaceutical for renal protection. Eligibility criteria included age 2–25 years, progressive disease, positive lesion on 111In-DTPA-D-Phe1-octreotide scan, glomerular filtration rate ≥ 80 ml/min/1.73m2, bone marrow cellularity ≥40% or stored autologous hematopoietic stem cells, Lansky Play Scale ≥ 60 %, and informed consent.

Results

Seventeen subjects, ages 2 to 24 years, received at least one dose of 90Y-DOTA0-Tyr3-octreotide; diagnoses included neuroblastoma, embryonal and astrocytic brain tumors, paraganglioma, MEN IIB, and neuroendocrine tumors. There were no dose limiting toxicities and no individual dose reductions due to renal or hematologic toxicity. There were no complete responses; 2 subjects experienced partial response (PR), 5 had minor responses (MR), 6 experienced stable disease (SD), 2 had progressive disease (PD) and 2 subjects withdrew.

Conclusions

Peptide receptor radionuclide therapy (PRRT) with 90Y-DOTA0-Tyr3-octreotide is safe in children and young adults and demonstrated a 12% PR plus 29% MR rate in patients with somatostatin receptor positive tumors. No dose limiting toxicities were observed. The recommended Phase II dosing is three cycles of 1.85GBq/m2/dose 90Y-DOTA0-Tyr3-octreotide co-administered with amino acids.

Keywords: Radiolabeled peptide, somatostatin, therapy, children

INTRODUCTION

Somatostatin receptor expression has been demonstrated in several embryonal tumors in children, including more than 90% of neuroblastoma and medulloblastomas as well as 35% of Ewing’s sarcomas (1, 2). Similarly, bronchopulmonary, intestinal and pancreatic neuroendocrine tumors are known to express somatostatin receptors both in vitro (3) and in vivo (4). Early observations were made on excised tumor tissue using immunohistochemistry or in vitro receptor binding studies and have since been shown to correlate very closely with in vivo nuclear imaging techniques using 111In-DTPA-D-Phe1-octreotide which primarily targets somatostatin receptor type 2 (sst2) (5–7). These advances led to the development of somatostatin analogs labeled with beta-emitting radionuclides that can be used for peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (8). The radiopharmaceuticals most commonly employed in PRRT are 90Y-DOTA0-Tyr3-octreotide and 177Lutetium-DOTA0-Tyr3-Thre8-octreotide (9). The present Phase I trial in pediatric patient population used 90Y-DOTA0-Tyr3-octreotide. 90Y is a pure β-emitter with a maximum energy of 2.3 MeV, a maximum range of 12 mm, and a 64 hr half-life. The relatively long range of the β particle allows for a bystander effect in heterogeneous tumors in which some cells may be sst2 negative.

Both neuroblastoma and medulloblastoma are known to be responsive to external beam and to targeted radiotherapies (10–13); thus, these tumors should be responsive to PRRT as well. On the other hand, neuroendocrine tumors are minimally responsive to conventional radiation therapy (14); yet, their response to PRRT has been promising with Phase I/II trials in adults demonstrating 25–30% partial response rates (9, 15). Early dose-finding clinical trials in adults established the kidneys as the critical organ of toxicity followed by bone marrow toxicity at very high doses (16). Renal failure was observed in subjects who received up to 7.4 GBq/m2 in the absence of kidney protection with infusion of cationic amino acids (17). Current practice in adults now includes infusion of amino acid solution beginning 30 minutes prior to and continuing 90 min following administration of the 90Y-DOTA0-Tyr3-octreotide (18). This therapeutic advance combined with limiting the renal dose to <25 Gy has considerably reduced renal toxicity (18). Severe bone marrow toxicity has been also rare in adults treated with radiolabeled somatostatin analogues (19). With its low toxicity profile, the significant improvement in symptoms and quality of life and the lack of effective alternative therapies, PRRT has been suggested as possible first-line therapy in adult patients with gastroenteropancreatic neuroendocrine tumors (20). Recent data have also demonstrated a significant survival benefit with PRRT compared to historical controls in this population (21).

This study was undertaken in order to test the hypothesis that PRRT would be safe and effective in refractory solid tumors of children and young adults that express somatostatin receptors.

METHODS

Design

The 90Y-DOTA0-Tyr3-octreotide was administered in 3 cycles, 6 weeks apart, starting with 1.11 GBq/m2/cycle in cohort 1, escalating to 1.48 and then to 1.85 GBq/m2/cycle using 3 subjects per cohort. Each cohort included at least 3 subjects who received 3 complete cycles of drug with no intrapatient dose escalation (22). If 1/3 subjects in any cohort developed ≥ grade 3 toxicity, 3 additional subjects were entered in the cohort and if 2/6 subjects in the cohort developed ≥ grade 3 toxicity, no further subjects were enrolled in that dose cohort and the dose in the previous cohort was considered as the maximum tolerable dose. Because this was the first use of 90Y-DOTA0-Tyr3-octreotide in children, the starting administered activity was based on an FDA requirement that the initial dose be limited to < 50% of the dose used in the Phase II trial in adults and that the total estimated dose to the kidneys, including from both 90Y-DOTA0-Tyr3-octreotide and any prior direct or scatter doses from external beam radiotherapy, be limited to 21 Gy for children and 23 Gy for young adults (23). In a subgroup of patients in the third dose cohort, dosimetry studies were performed with 111In-DTPA-D-Phe1-octreotide to measure the renal, hepatic and bone marrow dose; however the dosimetry data were not used to adjust the dosage of 90Y-DOTA0-Tyr3-octreotide.

Eligibility Criteria

Children and young adults, age 2 – 25 years at the time of first cycle of drug treatment were eligible to participate if they had pathologically confirmed disease with at least one lesion positively imaged with 111In-DTPA-D-Phe1-octreotide (OctreoScan; Mallinckrodt Imaging, Hazelwood, MO) that was co-localized with CT or MRI. Eligible patients had progressive disease that was either not amenable to standard treatment or was recurrent after two therapies with a life expectancy of > 2 months, but < 12 months and Lansky Play Scale or Karnofsky ≥ 60%. Additionally, at least one target lesion was required that had never been irradiated or had progressed despite radiation and had not been irradiated within 4 weeks of study drug administration. No full brain or spine radiation was allowed within 3 months and no surgery or chemotherapy was allowed within 4 weeks of study drug administration. Glomerular filtration rate ≥ 80 ml/min/1.73m2 was required as measured by plasma clearance of Tc-99m DTPA. Hematopoietic status requirements included absolute neutrophil count >1000/mm3, platelets >100,000/mm3, and bone marrow cellularity of ≥ 40% or availability of ≥ 1 × 106 CD34+ hematopoietic stem cells/kg. Stem cell availability was required for any subject who had received cranial-spinal irradiation of ≥ 12 Gy. Adequate cardiac function with shortening fraction of ≥ 30% and adequate liver function with bilirubin <1.5 × and AST and ALT ≤ 2.5 × upper limit of normal were also required. All subjects were required to have signed informed consent of the protocol, which was conducted under IND #61,907 and was approved by the Institutional Review Board of the University of Iowa.

Exclusion Criteria

Concomitant therapy was not allowed except for somatostatin analogues and/or bisphosphonates; somatostatin therapy was limited to short acting subcutaneous doses between cycles with discontinuation 24 hrs prior to each dose of 90Y-DOTA-tyr3-Octreotide. Potential subjects were excluded if pregnant or breast-feeding, if more than one concurrent malignancy was present, or if they had received external beam radiation to both kidneys (scatter doses of < 0.5 Gy to a single kidney or radiation to <50% of a single kidney was acceptable).

Renal, Liver and Bone Marrow Dosimetry

Individual renal, liver and bone marrow dosimetric analyses were performed for 8 administrations of 90Y-DOTA0-Tyr3-octreotide in 5 subjects in Cohort 3, each of whom received 1.85 GBq/m2 per cycle. 111In-DTPA-D-Phe1-octreotide (222 MBq/1.73 m2) was administered concurrently with 90Y-DOTA0-Tyr3-octreotide and used as a surrogate for individual renal and liver dosimetry. 111In-DTPA-D-Phe1-octreotide SPECT-CT images of the abdomen were obtained at 4–6 hours, 20–28 hours and 44–52 hours post injection along with a 1.85 MBq 111In standard in a 30 ml plastic bottle included in the field. All imaging studies were acquired on a low power dual detector SPECT-CT system with 25 mm thick NaI(Tl) crystal (GE Hawkeye). Multiple energy windows were set to capture the 172 keV and 247 keV gamma rays of 111In as well as a window from 300 – 500 keV for the 90Y bremsstrahlung radiation with an additional scatter window for SPECT studies. Regions of interests were drawn about the kidneys and liver in the coronal views. The kidney and liver masses were determined from the co-registered SPECT-CT images. The cumulative activity in the kidneys and liver was determined from the multiple 111In-DTPA-D-Phe1-octreotide SPECT-CT scans performed over 48 hours. MIRD scheme (OLINDA software) was used to calculate the renal and liver dose from the accumulated activity (24). To compare the blood clearance of 111In-DTPA-D-Phe1-octreotide and 90Y-DOTA0-Tyr3-octreotide, blood samples were also obtained prior to administration of the radiopharmaceuticals and at 5 minutes, 4–6 hours, 20–28 hours and 44–52 hours post administration and counted for 111In and 90Y activity. The crosstalk between the counts acquired in the 111In and 90Y energy windows was measured by counting individual standards for the two radionuclides. Each standard was counted in both energy windows to determine the crosstalk ratios. For the blood samples, the 90Y bremsstrahlung window was set well above the 111In energies so that the crosstalk ration from 111In to 90Y was essentially 0. The crosstalk ratio from the 90Y bremsstrahlung into the 111In energy window was 0.695. Thus, the counts in the 111In energy window were corrected by subtracting 0.695 × the counts in the 90Y window. The calculated blood doses were used as a surrogate for the bone marrow dose.

Drug Administration

To reduce the renal radiation dose, an amino acid solution containing 0.713 mg arginine and 0.735 mg of lysine per 100 ml (Aminosyn II 7%®; Abbott Laboratories, Abbott Park, IL) was infused with each administration of 90Y-DOTA0-Tyr3-octreotide. The amino acid solution was infused over 4 hours at a dose of 8.3 ml/kg/hr, beginning 1/2 hour prior to infusion of the 90Y-DOTA0-Tyr3-octreotide. For nausea, subjects were pre-administered ondansetron and/or lorazepam 30 min prior to beginning of the amino acid infusion. 90Y-DOTA0-Tyr3-octreotide was infused over 15 minutes starting 30 minutes after the initiation of Aminosyn II infusion. 90Y-DOTA-tyr3-Octreotide was supplied by Novartis Pharmaceuticals, Inc. and Molecular Insight Pharmaceuticals, Inc. in patient-specific vials.

Response and Toxicity Assessment

CT or MRI and 111In-DTPA-D-Phe1-octreotide scans were obtained before each cycle and 6–8 weeks following the last cycle of therapy. Pediatric Oncology Group criteria were employed for response assessment (25). Complete response (CR) is defined as no measureable disease, partial response (PR) as ≥50% decrease in longest X widest perpendicular diameter of target lesions with no increase in any lesions and no new lesions; minor response (MR) as >25% and <50% decrease in target lesions with no increase in any lesion and no new lesions; stable disease (SD) as <25% increase or decrease in any target lesion and no new lesions. An increase >25% in any measureable lesion or the presence of any new lesion was considered progressive disease (PD). Response was assessed based on intent to treat for all subjects who received at least one dose of 90Y-DOTA0-Tyr3-octreotide. Toxicity was graded using NCI Common Toxicity Criteria Version 3.0. The final toxicity assessment was obtained 6–8 weeks after the last cycle of 90Y-DOTA0-Tyr3-octreotide. Clinical long-term follow-up data was obtained by contacting the referring physicians and included follow-up imaging results and relevant serum biomarkers.

RESULTS

Patient Characteristics

Characteristics of subjects are shown in Table 1. There were 17 subjects, 5 females and 12 males, age range 2–24. Neuroendocrine tumors were the most common malignancy, comprising 7 of 17 subjects who participated in the trial. Other diagnoses included neuroblastoma (2), paraganglioma (3), and one each of MEN IIB, medulloblastoma, anaplastic astrocytoma, pinealoblastoma, and choroid plexus carcinoma.

Table 1.

Characteristics and Treatment Response of subjects treated with 90Y-DOTA0-Tyr3-octreotide.

Subject Diagnosis LPS or KS* Age in yrs Cohort Total Dose, GBq Response Follow-up (Months)
Pre Post
1 Pinealoblastoma 60 0 5 1 0.74 PD DOD (0)
2 Paraganglioma 90 90 15 1 4.66 SD AWD (84)
3⊕ Anaplastic Astrocytoma 90 100 11 1 6.33 PR DOD (23)
4 Neuroblastoma 80 70 12 1 4.92 SD DOD (2)
5⊕ Gastrinoma 90 100 8 1 4.77 PR NED (68)
6⊕ Bronchial Carcinoid 90 100 17 2 10.36 SD AWD (63)
7⊕ Gastrinoma 90 100 16 2 9.81 MR NED (56)
8 Medulloblastoma 80 70 11 2 1.70 WITHDREW DOD (10)
9 Neuroblastoma 90 80 4 2 1.15 WITHDREW DOD (9)
10 Gastrinoma 100 100 24 2 9.07 SD DOD (22)
11 MENIIb 90 90 18 3 7.40 SD AWD (39)
12 Gastrinoma 100 100 15 3 8.88 MR AWD (39)
13 Paraganglioma 70 90 18 3 8.39 MR AWD (22)
14 Bronchial Carcinoid 80 90 23 3 10.77 MR AWD (22)
15 Choroid Plexus Carcinoma 80 0 2 3 0.89 PD DOD (1)
16 Pancreatic NET 80 100 16 3 8.14 MR AWD (17)
17 Paraganglioma 80 100 14 3 10.80 SD AWD (17)
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*

LPS, Lansky Play Scale; KS, Karnofsky score;

⊕

Received 4th dose with FDA and IRB permission; AWD; alive with disease, DOD: died of disease, NED: No evidence of disease; PD: progressive disease, SD: stable disease, MR: minimal response, PR: partial response, NET: Neuroendocrine Tumor.

Toxicity

Grade 1 or 2 nausea and vomiting was observed in 12/17 subjects during amino acid infusion. These symptoms resolved within 30 min of completion of the infusion. Grade 4 hyponatremia requiring IV electrolyte resuscitation was observed in one patient; six additional episodes of mild hyponatremia and 8 cases of hypokalemia self-corrected within 24 hours. Two patients developed Grade 2 neutropenia and one patient developed Grade 2 thrombocytopenia. Grade 1 decrease in GFR was observed in two patients. Carcinoid syndrome developed in two patients with metastatic neuroendocrine tumors within 96 hours of 90Y-DOTA0-Tyr3-octreotide. Both improved within 24 hours after restarting octreotide with one patient requiring hospital admission for administration of IV fluids and IV octreotide. One death occurred within 30 days of drug treatment due to tumor progression. The maximum tolerated dose was not reached in this study as no Grade 3 renal or bone marrow toxicity was observed at any dose level.

Tumor response

The overall response rate based on intent to treat was PR in 2/17 subjects (12%), MR in 5/17 subjects (29%), SD in 6/17 subjects (35%) and PD in 2/17 (12%). Two subjects withdrew. Lansky Play Scale rating or Karnofsky score increased in 8 patients (47%) and remained stable in 4 patients (23%). The treatment response and follow-up of each subject is presented in Table 1. Seven patients died of their disease 0–23 months after therapy; 8 patients are alive with disease and 2 patients have no evidence of disease after a median follow-up of 39 months (45 ± 24 months). The two subjects with no evidence of disease had partial response to therapy and both underwent surgery following 90Y-DOTA0-Tyr3-octreotide therapy, one had removal of the primary pancreatic tumor and two surgeries to remove liver metastases and the second child had a liver transplant. Hormonal response was observed in 5/6 patients with neuroendocrine tumors, who had follow-up of secretory hormones and/or peptides available (Table 2). Tumor response of three patients with astrocytoma, gastrinoma and bronchial carcinoid respectively are presented in Figures 1–3.

Table 2.

Baseline and best posttherapy secretory hormone / peptide levels for neuroendocrine tumors; data not available for Subject #6 with bronchial carcinoid. NP: Not Performed

Subject Diagnosis Gastrin pg/ml Pancreastatin pg/ml Chromogranin A ng/ml
Pretherapy Best Response Pretherapy Best Response Pretherapy Best Response
5 Gastrinoma 15440 824 243 132 NP NP
7 Gastrinoma 21500 1170 NP NP 844 744
10 Gastrinoma 1413 2500 NP NP 1769 8405
12 Gastrinoma 12260 9400 NP NP NP NP
14 Bronchial Carcinoid NP NP 41594 17793 69404 11160
16 Pancreatic NET NP NP 2737 1058 244 171
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Figure 1.

Figure 1

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Baseline and posttherapy imaging of Subject #3 with anaplastic astrocytoma. This subject had surgery and chemotherapy followed by cranial-spinal radiation as initial treatment of disease with further chemotherapy after recurrence. Baseline OctreoScan (A) shows intense uptake in the left parietal tumor seen on MRI (B). Posttherapy images show decrease in uptake (C) with partial response on MRI with reduction of tumor size and decrease in enhancement around the lesion (D). This patient was able to return to school and participate in sports for 2 years following therapy, but ultimately experienced tumor recurrence and died of the disease 23 months after the last dose of 90Y-DOTA0-Tyr3-octreotide.

Figure 3.

Figure 3

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Baseline (A1–A5) and posttherapy (B1–B5) coronal OctreoScan and CT scan images of a patient with liver metastases from poorly differentiated bronchial carcinoid (Subject #14). The primary bronchial carcinoid had not been removed due to extensive liver disease at the time of initial diagnosis. Baseline OctreoScan images show multiple hepatic metastases (A1–A2), a left lung lesion and a thoracic spine metastasis (A4; arrows) with corresponding liver and lung lesions seen on CT (A5; arrow). The standard 111In activity (S) is seen on pretherapy OctreoScan. Posttherapy images (B1–B5) show improvement in the liver lesions as well as the thoracic spine and lung lesions on OctreoScan, although this only qualified for minimal response based on the assessment of target lesions on CT. The serum chromogranin level in this patient dropped from 69404 ng/ml to 11160 ng/ml. This was followed by resection of primary lung lesion and stabilization of disease for 19 months.

Renal, Liver and Bone Marrow Dosimetry

The average blood concentration of 111In-DTPA-D-Phe1-octreotide and 90Y-DOTA0-Tyr3-octreotide normalized to the amount of administered activity for all 8 studies is depicted in Figure 4. The blood clearance for the two tracers was similar with 111In-DTPA-D-Phe1-octreotide clearing slightly faster from the blood than 90Y-DOTA0-Tyr3-octreotide. The bone marrow dose inferred from blood activity ranged between 0.07–0.19 mGy/MBq with a mean ± SD of 0.12 ± 0.03 mGy/MBq. The range of renal radiation dose was between 1.1–3.8 mGy/MBq, with a mean ± SD of 2.29 ± 0.95 mGy/MBq. The radiation dose to the liver was between 0.4–2.8 mGy/MBq, with higher doses observed in patients with diffuse liver metastases. Patients with diffuse liver metastases tended to have lower renal doses (Table 3).

Figure 4.

Figure 4

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The mean blood concentration of 111In-DTPA-D-Phe1-octreotide and 90Y-DOTA0-Tyr3-octreotide normalized to the amount of administered activity for 8 administrations in 5 patients.

Table 3.

Calculated renal, liver and bone marrow radiation doses for eight administrations of 90Y-DOTA0-Tyr3- Octreotide.

Subject # Dosimetry Performed Liver Dose (mGy/MBq) Renal Dose (mGy/MBq) Bone Marrow (mGy/MBq)**
11 Cycle 2 0.3 1.9 0.19
Cycle 3 0.4 2.7 0.13
12 Cycle 2 2.1* 1.1 0.12
Cycle 3 2.8* 2.3 0.10
13 Cycle 2 0.2 2.7 0.14
14 Cycle 1 3.0* 1.1 0.12
Cycle 3 2.8* 2.3 0.07
17 Cycle 2 0.4 3.8 0.08
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*

Patients with diffuse liver metastases

**

Inferred from blood activity

DISCUSSION

This is the first clinical trial of PRRT in children. 90Y-DOTA0-Tyr3-octreotide as utilized in this trial has a low toxicity profile with no serious adverse events attributed to the radiopharmaceutical. Kidneys are the dose limiting organs with 90Y-DOTA0-Tyr3-octreotide; however, the renal toxicity in this patient group was minimal with mild decrease in GFR observed in 2/17 patients. Chronic radiation nephropathy may however occur up to 5 years after radiation therapy and a previous report found slow deterioration of renal function with an annual median decline of 7.3% in creatinine clearance after targeted peptide radiotherapy in adult patients (26). Therefore long-term follow-up of renal toxicity is necessary after 90Y-DOTA0-Tyr3-octreotide treatment.

The most common toxicity associated with 90Y-DOTA0-Tyr3-octreotide therapy was nausea and vomiting during the 4 hr infusion of amino acids, which are used for renal radioprotection. The occurrence of nausea with aminoacid infusion appears to be related to the osmolarity and the infusion rate of amino acids (27). The commercially available Aminosyn II 7%® solution used in this study contains a multitude of amino acids in addition to arginine and lysine, the key cationic amino acids required for renal protection. Aminosyn II 7%® is therefore not the ideal amino acid solution for PRTT and is associated with a higher incidence of nausea and vomiting compared to a solution containing only arginine and lysine (27). The nausea in our patients typically subsided immediately after the infusion of Aminosyn II 7%® was completed.

Hematopoietic toxicity due to 90Y-DOTA0-Tyr3-octreotide therapy was minimal with 2 subjects who had previous chemotherapy experiencing transient Grade I or II thrombocytopenia. Although preservation of hematopoietic stem cells was required in several subjects due to previous cranial-spinal irradiation or a bone marrow cellularity of <40% at beginning of therapy, stem cell rescue was not needed in any subjects. This correlates with experience in adult patients, where severe bone marrow toxicity was seen only in 2–15% patients, who received ≥15.48 GBq of 90Y-DOTA0-Tyr3-octreotide (19). Two subjects experienced carcinoid crisis 48–96 hrs post 90Y-DOTA0-Tyr3-octreotide infusion, likely secondary to tumor cell kill and release of tumor cell contents such as serotonin, neuropeptides, or catecholamines. Both subjects who experienced a carcinoid crisis had the most severe episodes after the first cycle and both had measureable cell kill when imaged prior to the second cycle.

Quality of life during treatment is a major advantage of this therapy. Minimal toxicity of 90Y-DOTA0-Tyr3-octreotide translated into subjects being able to resume normal activity in the six-week intervals between cycles. The lack of gamma emission of 90Y permits treatment without the need for strict patient isolation allowing contact of children with parents and the care team throughout the delivery of therapy (8, 28). Although the Nuclear Regulatory Commission guidelines allow this treatment to be performed as outpatient in the United States, some patients may need to be observed for up to 24 hours depending on the severity of the initial adverse events. Convenience for subjects, families and hospital personnel is an attractive feature of 90Y-DOTA0-Tyr3-octreotide compared to external beam radiation therapy or 131I-MIBG.

The 12% partial response and 29% minor response rates to 90Y-DOTA0-Tyr3-octreotide are promising for a Phase I trial in children. The highest response rate was observed in neuroendocrine tumors. Neuroendocrine tumors are extremely rare in children and young adults (29); however most of these tumors are metastatic at diagnosis and are resistant to most chemotherapeutic agents because of their slower proliferation rate. Among seven patients with metastatic neuroendocrine tumors, five patients showed a partial or minor response to therapy based on anatomic imaging. CT or MRI based response assessment may however underestimate clinical response in neuroendocrine tumors, particularly after therapy with radiolabeled peptides, which is associated with prolonged antitumoral activity and development of residual masses of fibrotic and necrotic tissue (30, 31). A combination of anatomic imaging, functional somatostatin receptor imaging and secretory hormone/peptide levels is likely a better measure of clinical response to PRRT in this patient population. Like neuroendocrine tumors, paraganglioma is also a slow growing malignancy until it becomes metastatic. All three subjects with paraganglioma in this trial had bone metastases and all experienced symptomatic relief of bone pain after therapy with persistent stable disease on imaging studies. Symptomatic improvement was also noted in a subject with neuroblastoma metastatic to bone. This is consistent with our observations in adult neuroendocrine tumors, 66% of whom experienced improvement in clinical symptoms after treatment with 90Y-DOTA0-Tyr3-octreotide (32).

The peptide used for the pretherapy dosimetry should be ideally the same as the therapeutic radiopeptide as differences in receptor binding and kinetics may change the dosimetry estimates. 111In or 86 Y labeled DOTA0-Tyr3-octreotide would be preferable over 111In-DTPA-D-Phe1-octreotide for calculation of 90Y-DOTA0-Tyr3-octreotide dosimetry. The selection of 111In-DTPA-D-Phe1-octreotide in this study was simply due to its commercial availability in the United States. Previous dosimetry studies have reported that the renal uptake of 111In-DTPA-D-Phe1-octreotide and 111In-DOTA0-Tyr3-Octreotide were comparable although the liver uptake was higher with 111In-DTPA-D-Phe1-octreotide (33). Helisch et al noted that 111In-DTPA-D-Phe1-octreotide would be a practical second-line alternative if the gold standard imaging with 86Y-DOTA0-Tyr3-Octreotide PET is not available (34). The blood clearance rates and residence time for 90Y-DOTA0-Tyr3-octreotide and 111In-DTPA-D-Phe1-octreotide were also similar in our patients. The marrow dose estimates of 0.12 ± 0.03 mGy/MBq in our study are about a factor of two higher than reported in other studies (34, 35). One reason for this is that we took a conservative approach to the calculation and assumed that after the 48-hour measurement, clearance was the same as the 90Y physical half-life. The other possible explanation is that the subjects all had a low body mass index and that tends to increase the radiation dose because of a smaller dilution effect. The renal dosimetry data obtained in 5 patients showed significant interpatient variability with kidney radiation doses ranging between 1.1 to 3.8 mGy/MBq, which is comparable to previously reported data in adults (36). These findings indicate that the maximum tolerable dose of 90Y-DOTA0-Tyr3-octreotide therapy is highly variable among patients and individualized dose administration rather than fixed doses may be preferable to reduce toxicity and improve treatment efficacy. In fact the estimated renal dose based on dosimetry exceeded significantly the recommended upper limit of 21–23 Gy in one patient, who received 1.85 GBq/m2/cycle (Subject #17). Our findings also show potential significant intrapatient variability so that repeat dosimetry may be necessary prior to each cycle of treatment if the administered dose will be based on the maximum tolerable dose.

CONCLUSIONS

Peptide receptor radionuclide therapy with 90Y-DOTA0-Tyr3-octreotide demonstrated a favorable safety profile in this Phase 1 study in children and young adults with refractory solid tumors that express somatostatin receptors. No dose limiting toxicities were observed. Renal radiation exposure remains the dose limiting factor, and although no compromise in kidney function has been observed in any subjects, the recommended Phase II dose of 90Y-DOTA0-Tyr3-octreotide is 1.85 GBq/m2/dose co-administered with amino acids in 3 cycles, 6 weeks apart for a cumulative dose of 5.55 GBq/m2. Together, PR, MR and SD constituted a 76% overall positive response rate to 90Y-DOTA0-Tyr3-octreotide, warranting a Phase II trial.

Figure 2.

Figure 2

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Baseline (A1–A3) and posttherapy (B1–B3) coronal OctreoScan and CT scan images of Subject #5 with pancreatic gastrinoma and extensive liver metastases. The pancreatic primary tumor (A2; arrow) and an adjacent liver lesion (A3; arrow) show intense uptake of 111In-DTPA-D-Phe1-octreotide (A1; arrow). This patient was treated for gastric ulcers until liver metastases were observed on CT scan. After treatment with 90Y-DOTA0-Tyr3-octreotide, there is significant decrease in tumor burden on OctreoScan (B1) and partial response in target lesions on the CT scan (B2 and B3; arrows). The serum gastrin levels decreased from 5440 pg/ml to 824 pg/ml. The pancreatic tumor was subsequently resected along with a partial hepatectomy. A subsequent increase in gastrin level coincided with regrowth of a liver lesion at the resection margin. A second surgery was performed to extricate this lesion and achieve clear margins; this subject remains free of disease, maintained on octreotide, 68 months post 90Y-DOTA0-Tyr3-octreotide.

Acknowledgments

This study was funded by the National Cancer Institute (R21 CA91578), the Food and Drug Administration (R01FD002595), Eastern Star, University of Iowa Holden Comprehensive Cancer Center and University of Iowa Dance Marathon. The 90Y-DOTA0-Tyr3-octreotide was provided by Novartis Pharmaceuticals Inc. and Molecular Insight Pharmaceuticals Inc. We are indebted to James Ponto for the preparation of the radiopharmaceutical, John Bricker for the technical support and the nursing team at the Clinical Research Center at the University of Iowa Hospitals and Clinics.

Footnotes

This study was previously presented at the North American Neuroendocrine Tumor Society Neuroendocrine Tumor Symposium, October 2–3, 2009, Charlotte, North Carolina.

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