Paola Rocca

Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours.

Somatostatin receptors are over-expressed in many tumours, mainly of neuroendocrine origin, thus enabling treatment with somatostatin analogues. Almost a decade of clinical experience of receptor radionuclide therapy with the analogue 90Y-[DOTA]0-Tyr3-octreotide [90Y-DOTATOC] has now been obtained at a few centres of excellence. This review reports on the present state of the art of receptor radionuclide therapy and discusses new perspectives.

Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas.

UNLABELLED Metastatic medullary thyroid cancer (MTC) shows a progressive course. Surgery is the only curative treatment. In advanced disease, chemo- and radiotherapy show poor results. Newly developed somatostatin analogue [DOTA0,Tyr3]octreotide (DOTATOC) labeled to 90Y is administered in patients with endocrine tumors expressing somatostatin receptors, like MTC. Preliminary studies demonstrated that 90Y-DOTATOC could be safely administered, resulting in objective responses in 27% of patients. AIMS To evaluate the efficacy of 90Y-DOTATOC therapy in metastatic MTC patients with positive OctreoScan, progressing after conventional treatments. Twenty-one patients were retrospectively evaluated after therapy, receiving 7.5-19.2 GBq in 2-8 cycles. RESULTS Two patients (10%) obtained a complete response (CR), as evaluated by CT, MRI and/or ultrasound, while a stabilization of disease (SD) was observed in 12 patients (57%); seven patients (33%) did not respond to therapy. The duration of the response ranged between 3-40 months. Using biochemical parameters (calcitonin and CEA), a complete response was observed in one patient (5%), while partial response in five patients (24%) and stabilization in three patients (14%). Twelve patients had progression (57%). Complete responses were observed in patients with lower tumor burden and calcitonin values at the time of the enrollment. CONCLUSIONS This retrospective analysis is consistent with the literature, regarding a low response rate in medullary thyroid cancers treated with 90Y-DOTATOC. Patients with smaller tumors and higher uptake of the radiopeptide tended to respond better. Studies with 90Y-DOTATOC administered in earlier phases of the disease will help to evaluate the ability of this treatment to enhance survival. New more specific peptides and new isotopes will also represent the key of a better treatment of MTC.

Radioimmunotherapy of brain tumor

Abstract Despite years of intensive research, the prognosis of high-grade gliomas (HGG) remains poor, as these tumors are highly resistant to currently available therapies. Therefore, there is a need for the development of new therapeutic strategies, such as the use of monoclonal antibodies (MoAbs) in association with radioisotopes, in order to achieve better responses and prognosis. This article describes our experience in radioimmunotherapy (RIT) with MoAbs and tumor pre-targeting with the avidin-biotin system, either in systemic or locoregional administrations. This therapy offers the exciting prospect of increasing the specificity of tumor cell irradiation with radioisotopes. We suggest that RIT, both systemic and locoregional, should be used as part of a combined modality approach: in combination with surgery, radiotherapy and chemotherapy.

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 90 Y- biotin. 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 90 Y-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 90 Y-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.

Is CD20 the only target available for radionuclide therapy in lymphoproliferative disorders

To the Editor: At the beginning of the third millennium, radioimmunotherapy represents a concrete treatment modality able to integrate the standard chemoradiotherapy approach in chronic-B lymphoproliferative disorders. The cellular research is focused on the identification of new surface targets that could be recognised by specific therapeutic agents. Among these, somatostatin receptors 2 and 3 have been identified on B-lymphocytes (1) but no data are available on their use as targets for radionuclide therapy in lymphoproliferative diseases. Y-DOTATOC, a newly developed somatostatin analogue, is currently used in therapy trials in patients affected by endocrine tumours (2, 3). We would like to draw your attention to the use of Y-DOTATOC in B-chronic lymphocytic leukaemia in a 54-year-old male patient affected by Binet A-Chronic Lymphocytic Leukaemia (CLL) and advanced neuroendocrine Merkel carcinoma admitted to our Institute to receive a radionuclidetherapy. CLL was diagnosed in September 2000 on the basis of monoclonal lymphocytosis (CD20+, CD23+, CD5+, CD19+, CD3)) and the patient received no specific treatment for this disease. On December 2000, Merkel disease was treated by left parotidectomy and omolateral neck dissection and by external radiotherapy (50 Gy) on the same area. Then the patient received four cycles of combined chemotherapy because of the presence of thoracic lymph nodal metastases. Subsequently, on September 2001 an In-OctreoScan scintigraphy assessed the expression of somatostatin receptors at the level of thoracic lesions. Therefore, the patient was proposed for a receptor radionuclide therapy with Y-DOTATOC on a compassionate basis. The patient received a cumulative activity of 5.5GBq in three cycles, 6 month apart, from January to November 2002. Despite the modest effect on the Merkel’s lesions (stability of disease), the haematological peripheral picture consistent with CLL dramatically improved after the receptor radionuclide therapy. At the time of CLL diagnosis and before YDOTATOC, the leukocyte count was 21.100 mm (Neutrophils 19%, Lymphocytes 73%), haemoglobin 13.8 g/dL, and platelets 94 000 mm; these values were unmodified even after chemoradiotherapy treatment. Fourteen days after the first Y-DOTATOC injection, the leukocytes dropped to 3700 mm (Neutrophils 60%, Lymphocyte 30%), whereas haemoglobin and platelet values remained almost stable. To date, after 20-month follow-up, the patient shows a normal haemochrome with WBC 6380 mm (Neutrophils 84%, Lymphocytes 5%, Monocytes 6%, Eosinophils 3% and Basophils 2%), Hb 13.6 g/dL and 131 000 mm platelets. Blood smear tests show normal morphology of peripheral cells. The immunophenotypic analysis on the lymphocytic-gate shows a normal subset distribution (T fi 63%, B fi 32% and NK fi 5%), albeit the majority of B cells exhibit the pathological CLL phenotype: CD 5+, CD 19+, CD23+, CD43+ without light chain (j/k) restriction. This pathologic cluster, which represents 2.5% of the overall peripheral nucleated cell population, is most seemingly consistent with a minimal residual disease (MRD). In the last decade many efforts have been made to improve the selective toxicity on tumour cells and encouraging preliminary results have been reached in lymphoproliferative disorders (4). A clinical trial with 90-Ittrium conjugated with anti CD20 antibody (Zevalin) is presently ongoing worldwide with encouraging results in relapsed lymphomas. However, its efficacy in CLL is handicapped by low expression of CD20 and the use of radiolabelled mAbs is limited by the massive Eur J Haematol 2005: 74: 450–451 All rights reserved Copyright Blackwell Munksgaard 2005