¹²³I-BZA2 as a Melanin-Targeted Radiotracer for the Identification of Melanoma Metastases: Results and Perspectives of a Multicenter Phase III Clinical Trial

Abstract

Our group has developed a new radiopharmaceutical, 123 I-N-(2-diethylaminoethyl)-2-iodobenzamide ( 123 I-BZA2), a benzamide derivative able to bind to melanin pigment in melanoma cells. In a prospective and multicentric phase III clinical study, the value of 18 F-FDG PET/CT and 123 I-BZA2 scintigraphy was compared for melanoma staging. Methods: Patients with a past history of cutaneous or ocular melanoma were included from 8 hospitals. 18 F-FDG imaging was performed according to a standard PET protocol. Whole-body, static planar, and SPECT/CT (if available) images were acquired 4 h after injection of a 2 MBq/kg dose of 123 I-BZA2. 18 F-FDG and 123 I-BZA2 sensitivity and specificity for the diagnosis of melanoma metastasis were calculated and compared on both a lesion basis and a patient basis. True-positive and true-negative lesion status was determined after 6 mo of clinical follow-up or according to lesion biopsies (if available). Melanin content in biopsies was evaluated with the standard Fontana-Masson silver method and was correlated with 123 I-BZA2 uptake. Based on statistical analysis, the number of inclusions was estimated at 186. Results: In all, 87 patients were enrolled from 2008 to 2010. Of these, 45 (52%) had metastases. A total of 338 imaging abnormalities were analyzed; 86 lesions were considered metastases, and 20 of 25 lesion biopsies found melanoma metastases. In a patient-based analysis, the sensitivity of 18 F-FDG for diagnosis of melanoma metastases was higher than that of 123 I-BZA2, at 87% and 39%, respectively (P , 0.05). For specificity, 18 F-FDG and 123 I-BZA2 were not statistically different, at 78% and 94%, respectively. In a lesion-based analysis, the sensitivity of 18 F-FDG was statistically higher than that of 123 I-BZA2 (80% vs. 23%, P , 0.05). The specificity of 18 F-FDG was lower than that of 123 I-BZA2 (54% vs. 86%, P , 0.05). According to biopsy analysis, only 9 of 20 metastatic lesions (45%) were pigmented with high melanin content. 123 I-BZA2 imaging was positive for 6 of 8 melanin-positive lesions, fairly positive for 3 of 10 melanin-negative lesions, and negative for 7 of 10 melaninnegative lesions. The sensitivity and specificity of 123 I-BZA2 for the diagnosis of melanin-positive lesions were 75% and 70%, respectively. Because of a low 123 I-BZA2 sensitivity, this clinical trial was prematurely closed after 87 patients had been included. Conclusion: This study confirms the value of 18 F-FDG PET/CT for melanoma staging and strengthens the high accuracy of 123 I-BZA2 for diagnosis of melanin-positive metastatic melanoma. Moreover, benzamide derivatives radiolabeled with therapeutic radionuclide may offer a new strategy for the treatment of metastatic melanoma patients harboring melanin-positive metastases. Mel anoma accounts for nearly 80% of all deaths related to cutaneous cancer (1). It is the second most common cancer among patients in their second decade (2). For localized lesions with a tumor thickness of less than 1.5 mm (stage I or II), melanoma can be cured by tota...

High-dose proton beam therapy for sinonasal mucosal malignant melanoma

“…However, defining the border of tumor abutted brain or occulomotor is still challenging, because the both show higher uptake of FDG. Another type of radiotracer specific for melanin in melanoma cells, known as a benzamide derivative could be useful for defining the extension of tumor arose head and neck region [15]. …”

Imaging malignant melanoma with 18F-5-FPN

“…Several radiopharmaceuticals have been developed to bind to melanoma and localize metastatic melanoma lesions, including radiolabelled monoclonal antibodies [10,11], peptides (melanocortin type 1 receptor, MC1R) [12][13][14], iodoamphetamine [15,16], benzamide (BZA) [17][18][19], and BZA analogues [20][21][22][23][24]. Monoclonal antibodies labelled with different radioisotopes against melanoma-associated antigens (MAA), and labelled α-melanocyte-stimulating hormone (α-MSH) or α-MSH analogues binding to MC1R, have shown some potential in diagnosis and radioimmunotherapy [10,14].…”

Synthesis, radiolabeling and preliminary in vivo evaluation of multimodal radiotracers for PET imaging and targeted radionuclide therapy of pigmented melanoma

“…The same observation was made in a phase III clinical study involving the melanin-binding benzamide, N-(2-diethylaminoethyl)-2-iodobenzamide (BZA2) (Fig. 1), radiolabeled with iodine-123 (T 1/2 ¼ 13.2 h; g 159 keV) for melanoma SPECT imaging purpose [17]. Therefore, TRT with melanin-targeting radiotracers first requires a "melanin-positive" subpopulation selection.…”