Eleven-year experience with the avidin-biotin pretargeting system in glioblastoma: Toxicity, efficacy and survival

Background: The 3-step avidin-biotin pretargeting approach is applied in patients with recurrent glioblastoma (GBM), using biotinylated anti-tenascin monoclonal antibody as the first step of pretargeting followed by avidin and 90Ybiotin. Methods: The present study reviews objective response and overall survival rates in 502 glioblastoma patients treated with 3-step radioimmunotherapy in our institute from December 1994 to December 2005. Patients underwent standard treatment before receiving Pretargeted Antibody-Guided Radionuclide Therapy with 90Y-biotin (PAGRIT ®). Results: Of the 502 patients, 272 (54%) were evaluable for response and 375 (75%) for overall survival. 174 patients (64%) continued to progress after PAGRIT ®, 77 (28%) obtained disease stabilization, and 21 (8%) showed objective tumor regression. Survival of the 375 evaluable patients was 98.4% at 6 months, 79.2% at 12 months, 51.7% at 18 months, and 30.7% at 24 months after the first cycle of PAGRIT ®. All 375 received 3-step PAGRIT ® at recurrence of GBM. The median survival time from diagnosis was 19 months. Conclusion: The results from this retrospective analysis suggest that 90Y-biotin PAGRIT ® interferes with the progression of glioblastoma, prolonging survival in a larger number of patients. Our analysis forms the basis for further prospective trials, where radioimmunotherapy, which is known to be more effective in minimal residual disease, could be offered immediately after surgery. © Grana et al.; Licensee Bentham Open

90Y-DOTA-nimotuzumab: synthesis of a promising β⁻ radiopharmaceutical

BACKGROUND: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a beta- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach.METHODS: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50 fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma.RESULTS: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma.CONCLUSIONS: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for beta- radio-guided surgery

Peptide receptor radiotherapy: a new option for the management of aggressive fibromatosis on behalf of the Italian Sarcoma Group

The management of aggressive fibromatosis (AF) is problematic, and few options are available to patients unsuitable for surgery and resistant to external-beam radiation therapy (EBRT). We report on two patients with fast-growing recurrences of AF resistant to EBRT who obtained protracted clinical benefits with 90Y-DOTATOC. 90Y-DOTATOC should be further investigated in this setting

(188)Re radiopharmaceuticals for radiosynovectomy: evaluation and comparison of tin colloid, hydroxyapatite and tin-ferric hydroxide macroaggregates

BACKGROUND: Radiosynovectomy is a therapy used to relieve pain and inflammation from rheumatoid arthritis and related diseases. In this study three (188)Re particulate compounds were characterized according to their physico-chemical properties and their biological behavior in rabbits. The results were compared in order to establish which was the radiopharmaceutical that better fits the requirements of this kind of radiotherapy. METHODS: Three radiopharmaceutical formulations, tin colloid, hydroxyapatite particles (HA) and ferric hydroxide macroaggregates coated with tin colloid (FHMA), were physically characterized (number, volume and surface of the particles). For this purpose laser diffraction methodology was used. To evaluate cavity leakage of activity the following studies in New Zealand rabbits were performed: scintigraphic images for 48 hr after intraarticular injection of each radiopharmaceutical, biodistribution at 48 hr and urine samples collection during the first 24 hr post-radiopharmaceutical administration. RESULTS: Labeling procedures for (188)Re-HA and (188)Re-Sn-FHMA were labour intensive while (188)Re-Sn was easily prepared. Furthermore, (188)Re-Sn colloid offered the greatest surface area in the 2–10 microm range and was obtained with a radiochemical purity over 95%, while percentage of bound activity for (188)Re-HA and (188)Re-Sn-FHMA were 55% and 92% respectively. Stability was verified for the three radiopharmaceuticals for 24 hr. Scintigraphic studies and biodistribution in rabbits after intraarticular administration of the radiopharmaceuticals showed relevant activity only in the knee, this being over 90% of the residual activity in the whole body at 48 hr in every case. Renal elimination of (188)Re-Sn colloid and (188)Re-Sn-FHMA was detected by activity measurements in urine samples, during the first 12 hr post-radiopharmaceutical injection. The percentage of activity retained in the knee was 69.1% for (188)Re-Sn colloid, 55.1% for (188)Re-Sn-FHMA and 33.6% for (188)Re-HA. CONCLUSION: The (188)Re-Sn colloid was easy to prepare, minimum facilities were required, was stable for 24 hr and showed minimal leakage from the joint after intraarticular injection into the rabbit's knee. Furthermore, (188)Re-Sn colloid has greater retention in the knee when it is compared with the other radiopharmaceuticals, so it could provide the best therapeutic effect/absorbed dose ratio for the patient

Pretargeted adjuvant radioimmunotherapy with Yttrium-90-biotin in malignant glioma patients: A pilot study

In a previous study we applied a three-step avidin–biotin pretargeting approach to target 90Y-biotin to the tumour in patients with recurrent high grade glioma. The encouraging results obtained in this phase I–II study prompted us to apply the same approach in an adjuvant setting, to evaluate (i) time to relapse and (ii) overall survival. We enrolled 37 high grade glioma patients, 17 with grade III glioma and 20 with glioblastoma, in a controlled open non-randomized study. All patients received surgery and radiotherapy and were disease-free by neuroradiological examinations. Nineteen patients (treated) received adjuvant treatment with radioimmunotherapy. In the treated glioblastoma patients, median disease-free interval was 28 months (range=9–59); median survival was 33.5 months and one patient is still without evidence of disease. All 12 control glioblastoma patients died after a median survival from diagnosis of 8 months. In the treated grade III glioma patients median disease-free interval was 56 months (range=15–60) and survival cannot be calculated as only two, within this group, died. Three-step radioimmunotherapy promises to have an important role as adjuvant treatment in high grade gliomas, particularly in glioblastoma where it impedes progression, prolonging time to relapse and overall survival. A further randomized trial is justified

Therapeutic Radionuclides: Making the Right Choice

Recently, there has been a resurgence of interest in nuclear medicine therapeutic procedures. Using unsealed sources for therapy is not a new concept; it has been around since the beginnings of nuclear medicine. Treatment of thyroid disorders with radioiodine is a classic example. The availability of radionuclides with suitable therapeutic properties for specific applications, as well as methods for their selective targeting to diseased tissue have, however, remained the main obstacles for therapy to assume a more widespread role in nuclear medicine. Nonetheless, a number of new techniques that have recently emerged, (e.g., tumor therapy with radiolabeled monoclonal antibodies, treatment of metastatic bone pain, etc.) appear to have provided a substantial impetus to research on production of new therapeutic radionuclides. Although there are a number of new therapeutic approaches requiring specific radionuclides, only selected broad areas will be used as examples in this article