[131I]-TYR3-octreotide: clinical dosimetry and use for internal radiotherapy of metastatic paraganglioma and carcinoid tumors

Nuclear Medicine & Biology, Vol. 27, pp. 809 – 813, 2000 Copyright © 2000 Elsevier Science Inc. All rights reserved.

ISSN 0969-8051/00/$–see front matter PII S0969-8051(00)00150-5

[131I]-TYR3-Octreotide: Clinical Dosimetry and Use for Internal Radiotherapy of Metastatic Paraganglioma and Carcinoid Tumors Jean-Louis Baulieu,1 Isabelle Resche,2 Manuel Bardies,2 Alain Faivre Chauvet,2 Joseph Lecloirec,3 Jean-Pierre Malhaire,4 Eric Thomas,5 Patrick Faurous,6 Genevie`ve Sassolas,7 Le´andre Pourcelot,1 Jean-Franc¸ois Chatal,2 Denis Guilloteau1 and Jean-Claude Besnard1 1 ˆ DEPARTMENT OF NUCLEAR MEDICINE, HOPITAL BRETONNEAU, TOURS, FRANCE; 2DEPARTMENT OF NUCLEAR MEDICINE, ` MARQUIS, RENNES, CENTRE RENE´ GAUDUCHEAU, NANTES, FRANCE; 3DEPARTMENT OF NUCLEAR MEDICINE, CENTRE EUGENE 4 5 ˆ FRANCE; DEPARTMENT OF RADIOTHERAPY, HOPITAL AUGUSTIN MORVAN, BREST, FRANCE; DEPARTMENT OF

ˆ RHEUMATOLOGY, HOPITAL LAPEYRONIE, MONTPELLIER, FRANCE; 6DEPARTMENT OF NUCLEAR MEDICINE, CENTRE VAL ˆ NEURO-CARDIOLOGIQUE, D’AURELLE, MONTPELLIER, FRANCE; AND 7DEPARTMENT OF NUCLEAR MEDICINE, HOPITAL LYON, FRANCE

ABSTRACT. Dosimetry and therapeutic application of [131I]-Tyr3-octreotide were evaluated in three patients with metastatic paraganglioma and carcinoid tumor. The in vitro stability of [131I]-Tyr3-octreotide was verified. Tumor uptake and residence time were between 0.02 and 0.1% and 0.5 to 9.8 h, respectively. The calculated tumor radiation doses were between 0.105 and 0.696 mGy 䡠 MBqⴚ1. No intolerance or adverse effects were observed after the therapeutic doses (3.3– 6.6 GBq). A partial tumor response was obtained in one patient and no response occurred in two patients. NUCL MED BIOL 27;8:809 – 813, 2000. © 2000 Elsevier Science Inc. All rights reserved. KEY WORDS. Internal radiotherapy, Somatostatin receptors, Somatostatin analogs, [131I]-Tyr3-octreotide, Malignant paraganglioma, Carcinoid tumor INTRODUCTION Somatostatin receptor scintigraphy has been developed since 1989 by using octreotide analogs radiolabeled with iodine 123 and indium 111 (8). During the past few years, a number of tumor types including carcinoid tumor and paraganglioma have been successfully imaged with [111In]-pentetreotide (10, 12, 13). The metabolism and dosimetry of [123I]-Tyr3-octreotide and 111 [ In]-pentetreotide are known (8, 9). Tumor uptake is variable according to the somatostatin receptor expression and can reach 0.2% dose per gram of tumor tissue (12). It is therefore tempting to test the possibility of treating such tumors by internal radiotherapy using radiolabeled somatostatin analogs. The requirements for such a therapeutic agent are: ␤⫺ or ␣ emission, in vitro and in vivo stability, sufficient tumor uptake and residence time, and low radiation dose to the critical organs and whole body. Among the radiolabeled derivatives, [131I]-Tyr3-octreotide was chosen because our group is familiar with iodine labeling and 131-iodine use for therapy. The aim of this work was to study the feasibility, dosimetry, tolerance, and clinical efficacy of internal radiotherapy using [131I]-Tyr3-octreotide.

Address correspondence to: Dr. Jean-Louis Baulieu, Hoˆpital Bretonneau, Service de Me´decine Nucle´aire et Ultra-sons, 2 bis, Boulevard Tonnelle´, F37044 Tours Cedex 1, France; e-mail: [email protected] Received 21 October 1999. Accepted 27 May 2000.

METHODS

[131I]-Tyr3-Octreotide Synthesis, Labeling, and Control Tyr3-octreotide was synthesized (Neosystem Laboratoire, Strasbourg, France) and radiolabeled with iodine 131 (Cis bio international, Gif sur Yvette, France) by the chloramine T method (7) under sterile conditions in phosphate-buffered saline. The specific activity was 110 MBq 䡠 mmole⫺1. The preparation was purified on a reverse phase chromatography column (Sep Pack C18; Millipore Waters Corp., Milford, MA, USA) with elution by 5 mL of ethanol. The sterile ethanolic solution was injected into a 9‰ NaCl 100-mL protected bag. The radioactivity concentration was 55 MBq 䡠 mL⫺1. The in vitro stability of the solution was measured by high pressure liquid chromatography (RP18 column, linear gradient solvant 40 to 80% methanol in NaCl 154 mM) over a 48-h period and expressed as the proportions of mono-iodinated compound, di-iodinated compound, and iodide.

Dosimetry Iodine 131 uptake into the thyroid was blocked by 5% Lugol’s solution at 30 drops per day 2 days before and 4 days after [131I]-Tyr3-octreotide injection. Blood cells were counted and biological constants (sodium, potassium, alcaline phosphatase, creatinine, and thyrotropin) were measured. An imaging dose was given first for dosimetry purpose :[131I]Tyr3-octreotide 390 ⫾ 28 MBq was injected over a 30-min period. Blood pressure was monitored for 3 h after injection. Blood samples (5 mL) were collected before and 5 min, 10 min, 15 min, 20 min, 1 h, 3 h, 5 h, 24 h, and 48 h after injection. Urine was collected

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TABLE 1. [131I]-Tyr3-Octreotide in vitro Stability Day 131

Mono-iodinated [ ]-Tyr3-octreotide (%) Di-iodinated [131]-Tyr3-octreotide (%) Iodide (%)

0

1

2

91 7 2

91 6 3

93 5 3

from 0 –5 h and from 5–24 h. Feces were collected from 0 –24 h. Planar imaging quantitation protocol has been described elsewhere (2). Briefly, whole-body transmission scan was performed at day 0 before injection, using a linear collimated source (300 – 450 MBq of 131 I). Anterior and posterior whole-body scans were performed 1, 3, 5, 24, 48, and 72 h after injection. Quantitation was performed using the geometric mean of each (ant-post) whole-body set of images. Attenuation correction was performed, but no specific scatter correction was implemented. The cumulated counting in region of interest was determined according to de Nardo et al. (4). Tumor volume was measured from computed tomography scan or magnetic resonance imaging. [131I]-Tyr3-octreotide elimination kinetics were obtained from plasma and urine curves. The absorbed dose was calculated according to the MIRD committee protocol (14). The bone marrow dose was calculated by combination of blood kinetics and whole-body counting data according to de Nardo et al. (5).

Therapy Thyroid protection and biological control were the same as for dosimetry. In addition, plasma levels of serotonin and chromogranine were measured before [131I]-Tyr-3-octreotide infusion. The patients stayed in a room designed for 131I thyroid cancer therapy for 5 days. Urines and feces were collected for decontamination. [131I]-Tyr3-octreotide 3.33 GBq was intravenously infused in a 300-mL volume at a rate of 3.3 mL 䡠 min⫺1. Enema was performed 1 and 2 days after treatment. Clinical status, heart rate, and blood pressure were monitored twice a day for 5 days. Whole-body scintiscan was performed 5 days after treatment. Somatostatin receptor scintigraphy, appropriate hormonal assays, and morphological imaging were performed after 90 days.

Patients Three patients were included between September 1995 and June 1996 after obtaining the agreement of the local Ethics Committee (April 6, 1995) and informed consent of each patient. Patient 1 was a 38-year-old man who had received surgery 5 years before for a retroperitoneal nonsecreting malignant paraganglioma and who had developed bone metastases in the sternum, the posterior part of the third right rib, the left hip, and L5. The metastases were visible on bone scan but were not visible on meta-iodobenzylguanidine (MIBG) scan, and exhibited high uptake of [111In]-pentetreotide. [111In]-pentetreotide scintigraphy was repeated 2, 24, and 48 h after injection for tumor tracer kinetics study. [123I]-Tyr3-octreotide scintigraphy was also performed to compare the indium- and iodine-labeled tracers. [123I]-Tyr3-octreotide was prepared in our laboratory; 315 MBq were injected after thyroid protection by 400 mg potassium perchlorate, and static thorax acquisitions were recorded 15 min, 150 min, 270 min, 24 h, and 48 h after injection (Sophy Camera DS7 Sopha Medical, Buc, France).

FIG. 1. [131I]-Tyr3-octreotide blood, urine, feces clearances.

The patient was treated by hip prothesis consolidated by an autologous bone graft . He received1500 ␮g octreotide per day, which was withdrawn 5 days before [131I]-Tyr3-octreotide injection for the dosimetry study and therapy. The patient received external radiotherapy (45 Gy) on the sternum and the right rib between the two [131I]-Tyr 3-octreotide treatments. Patient 2 was a 55-year-old man who had a bronchopulmonary carcinoid tumor with liver metastases 2 years before. The MIBG scan was negative and the [111In]-pentetreotide scan showed high

[131I]-TYR3-Octreotide: Dosimetry and Radiotherapy

811

TABLE 2. Dosimetric Data T1 (rib) T2 (sternum) T3 (lumbar) Thyroid Kidney Patient 1 [study 1, m (g) ˜ (MBq 䡠 h) A D (mGy/MBq) T res (h) %ID/g (J3)

A inj (MBq), 410] 249.5 142.8 188 212 0.201 0.397 28.4 24.9 0.00036 0.00070

Patient 1 [study 2, m (G) ˜ (MBq 䡠 h) A D (mGy/MBq) T res (h) %ID/g (J3)

A inj (MBq), 398] 182.8 86.9 159 219 0.239 0.693 39.0 27.3 0.00046 0.00079

Patient 2 [A inj (MBq), 341] m (g) ˜ (MBq 䡠 h) A D (mGy/MBq) T res (h) %ID/g (J3) Patient 3 [A inj (MBq), 414] m (g) ˜ (MBq 䡠 h) A D (mGy/MBq) T res (h) %ID/g (J3)

11.8 28 0.628 30.9 0.0019

20 688 9.195 277 0.018 20 278 3.819 277 0.0047

NA

120 429 0.956 22.2 0.0014

NA

NA

20 107 1.411 110.9 0.058

NA

Liver

Whole body Blood Bone marrow

1500 819 0.146 22.2 0.00028

8500 11555 0.032 29.8 0.00012

45 0.008 27.5

0.040

1500 387 0.709 18.0 0.00053

85000 14785 0.042 28.5 0.000080

32 0.006 20.8

0.048

4501 1472 0.105 21.2 0.00022

73000 7080 0.024 22.2 0.000058

350 0.075 18.9

0.099

5152 4079 0.209 29.4 0.00044

76000 1486 0.041 35.6 0.00021

96 0.017 37.7

0.058

˜ ⫽ cumulated activity, D ⫽ radiation dose, T (res) ⫽ A ˜ /Ao ⫽ residence time, %ID/g ⫽ percent of injected dose A inj ⫽ injected activity, m ⫽ mass, A per gram of tissue, NA ⫽ data not available.

tumoral uptake in the liver and in the right lung, corresponding to the primary tumor. He was treated with streptozotocin, 5-fluouracil, deticene, interferon, and octreotide. Urinary 5-hydroxy-indol-acetic acid elimination was elevated at 300 mg/24 h (normal ⫽ 5 mg/24 h), fell after medical treatment to 34 mg/24 h, then rose again to 82 mg/24 h. Platelet serotonin was initially elevated at 36 nmoles/109 platelets (normal ⫽ 2.5– 6.1 nmoles/109 platelets), fell to 17 nmoles/109 platelets, then rose again to 23.3 nmoles/109 platelets. Cold octreotide was withdrawn 3 days before dosimetry and therapeutic study. Patient 3 was a 60-year-old man who had presented a rectal carcinoid tumor with liver metastases 3 years before. He was treated by abdominoperineal resection, pelvic external radiotherapy, liver embolization, and chemotherapy by dacarbazine. [111In]-pentetreotide scan showed high heterogeneous liver uptake and multiple deposition sites in the bones (spine, pelvis, femur), mediastinum, axillary regions, and abdomen. Carcinoid syndrome was partially improved by sandostatin. This treatment was withdrawn before dosimetry and therapeutic study. RESULTS

In Vitro Stability The proportion of mono-iodinated compound was 93% after 48 h (Table 1).

Dosimetry The blood time activity curve and the urine and feces elimination of [131I]-Tyr3-octreotide injection are shown in Figure 1. Renal

clearance was 2.5 L 䡠 h⫺1, and fecal clearance was 0.35 L 䡠 h⫺1. Twenty-four hours after injection, 60% of radioactivity was eliminated in the urines and 10 –15% in the feces. The maximum elimination in urine and in feces was between 24 and 48 h after injection The percentage of dose in organs and tumors 3 days after [131I]-Tyr3-octreotide, the residence times, and the radiation doses for each patient and treatment are presented in Table 2. For patient 1, in the cases of both injections, it was possible to estimate the doses to tumor sites. For patients 2 and 3, the tumor sites were included within the liver mass. It seemed unreasonable to present the dosimetric data. In patient 1 bone tumor uptake was between 0.02 and 0.1% of the injected dose. The tumor residence time was 0.5 h in the bone tumors and 5–10 h in the liver. The biological T1/2 of the radiolabeled octreotides are shown in Table 3. [123I]Tyr3-octreotide uptake decreased more rapidly (T1/2 ⫽ 9 –11 h) than 131I-Tyr3-octreotide uptake (T1/2 ⫽ 19 –27 h) and [111In]pentetreotide uptake (T1/2 ⫽ 31–32 h). The radiation doses calculated for a 3.3 GBq [131I]-Tyr3-octreotide injection were 38 –252 cGy to the tumor sites (bone and liver) and 14 –36 cGy to the bone marrow. The tumor dose/bone marrow dose ratio was between 1.06 and 14.8.

Therapy TOLERANCE. No modifications of heart rate, blood pressure, or clinical condition were noted during or after [131I]-Tyr3-octreotide infusion. Biological and hematological constants were not modified 30, 60, and 90 days after treatment.

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TABLE 3. [111In]-Pentetreotide, [123I]-Tyr3-Octreotide, [131I]Tyr3-Octreotide Biological T1/2 in Patient 1 Bone Metastases and Organs Biological T1/2 (h) Sternum Rib Liver Kidney Colon 111

[ In]-pentetreotide [123I]-Tyr3-octreotide [131I]-Tyr3-octreotide

32 11 19

31 9 27

64 17 13

133 13 NA

9 20 NA

NA: data not available.

RESPONSE. A 65% shrinkage of the sternal tumor was observed in patient 1 on the post-therapy computed tomography scan 90 days after the second [131I]-Tyr3-octreotide perfusion and external radiotherapy. A dramatic decrease in [111In]-pentetreotide uptake in the sternum and the hip and a disappearance of L5 uptake were observed on the post-therapy somatostatin receptor scintiscan. The chromogranin plasma level, which was elevated at 1139 ng 䡠 mL⫺1 before treatment, remained elevated at 1500 ng 䡠 mL⫺1 after treatment (normal: ⬍ 150 ng 䡠 mL⫺1). There was no change of the echographic or scintigraphic appearance of the liver metastases in patient 2. The platelet serotonin concentration, which was at 23.8 nmole/109 platelets before treatment, remained elevated at 28.2 nmole/109 platelets after treatment. There was no change in the echographic and scintigraphic appearance of the liver metastases and no modification of the scintigraphic appearance of the bone metastases in patient 3. OUTCOME. Patient 1 was able to return to work, but 9 months later he developed new bone metastases in the skull, shoulder, spine, and pelvis. Uptake at these sites was visible on conventional bone scan but not on pentetreotide scan. He is still alive 2 years after treatment. There was progression of the disease in patient 2 and he died 12 months after treatment. There was also progression of the disease in patient 3, with radicular compression, ascites, and intestinal occlusion. He died 18 months after treatment. The dosimetry data and the clinical outcome are summarized in Table 4.

of 131I 370 MBq in a 217-␮L volume after 1 h (1). Working at 200 times lower volumic activity, we observed a good in vitro stability of [131I]-Tyr3-octreotide. A significant difference between the in vivo kinetics of [111In]pentetreotide and iodinated octreotide was observed, with a shorter tumor residence time and biological half-time for iodinated octreotides, due to molecular structure differences. A difference was also found between [123I]- and [131I]-Tyr3-octreotide kinetics with a shorter tumor biological half-time for the [123I]-Tyr3-octreotide. An explanation could be a radiolysis of the [123I]-Tyr3-octreotide since the specific activity of the this compound is 10 times the [131I]Tyr3-octreotide specific activity (about 1000 MBq 䡠 mmole⫺1 versus 110 MBq 䡠 mmole⫺1). However, radiolysis is a result of secondary processes and therefore is more often related to the specific concentration (MBq/mL) rather than the specific activity (MBq/ mmol). Another explanation could be a receptor up-regulation by cold octreotide treatment during the period between [123I]- and [131I]-Tyr3-octreotide treatments, as reported by Bombardieri et al. (3). The radiation doses to organs are homogeneous in the three patients. Table 2 shows tumor dosimetric data. For patient 1, the calculated doses to the tumors are lower than 2 Gy, which is insufficient to expect a tumor response. However, one can not estimate clinical efficacy on only one patient in which tumor dosimetry was performed. At the dose used, the four treatments were well tolerated since no modification of biological constants was noted. The dose of 3.3 GBq of [131I]-Tyr3-octreotide seems to be under the maximal tolerated dose (MTD). This is in agreement with the nonmyeloablative maximal tolerated dose of [131I]-Lym1 antibody of 3.7 GBq found by de Nardo et al. (6). The first report of use of radiolabeled octreotide for therapeutic purposes was by Krenning et al. in 1996 (11). He injected six patients with repeated high doses (up to 53 GBq) of [111In]pentetreotide. This analog is not appropriate because there is high kidney uptake and absence of ␤⫺ emission. Our study is the first report of the use of a beta-emitting agent in human patient. Other octreotide derivatives should be tested to improve the in vivo tumor residence time. Otte et al. recently reported the treatment of 10 patients with different receptor-positive tumors with one to seven doses of 90Y-DOTA-DPhe1-tyr3-octreotide (DOTA TOC) 1000 –3000 MBq, with no toxicity and significant reduction in tumor mass in one patient (15).

DISCUSSION We report the results of an attempt of treating three patients with advanced metastatic tumor-bearing somatostatin receptors using radiolabeled octreotide for internal radiotherapy. The data of the in vitro study indicate a good stability of [131I]-Tyr3-octreotide at 55 MBq 䡠 mL⫺1 concentration. This is in disagreement with Bakker et al., who observed a 50% radiolysis of cold pentetreotide in presence

CONCLUSION We have demonstrated for a small cohort of patients the feasibility of “near” therapeutic dose administration of [131I]-Tyr3-octreotide. This is a feasible, well-tolerated method for internal radiotherapy of somatostatin receptor-expressing tumors. However, the radiation

TABLE 4. Result of [131I]-Tyr3-Octreotide Treatments Patient

[131I]-Tyr3-octreotide (GBq)

1

3.3 (dose 1) 3.3 (dose 2) 3.3 3.3

2 3

Tumor (cGy) 67, 132, 209 (dose 1, sternum, rib, lumbar) 79, 23 (dose 2, sternum, rib) 35 70

Patients 1 and 2 tumor doses were estimated from the dose to the liver, which probably underestimates the tumor dose.

Response

Survival

partial

⬎2 years

no no

12 months 18 months

[131I]-TYR3-Octreotide: Dosimetry and Radiotherapy

dose and tumor response are limited, not by in vitro radiolysis but by rapid tumor kinetic and low uptake. We thank the “Ligue contre le Cancer” and “Electricite´ de France” for financial support, Cis bio international for collaboration, and Ste´phanie Poiron for preparation of the manuscript.

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