astatine and Peritoneal-Neoplasms

Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35 F(ab')2.. Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation of (211)At in thyroid and other NIS-containing tissues. Mean absorbed doses to normal tissues were calculated from clinical data, including blood and i.p. fluid samples, urine, γ-camera images, and single-photon emission computed tomography/computed tomography images. Extrapolation of preclinical biodistribution data combined with clinical blood activity data allowed us to estimate absorbed doses in additional tissues. The equivalent dose was calculated using an RBE of 5 and the effective dose using the recommended weight factor of 20. All doses were normalized to the initial activity concentration of the infused therapy solution.. The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the 3 highest estimated absorbed doses. When the tissue-weighting factors were applied, the largest contributors to the effective dose were the lungs, stomach, and urinary bladder. Using 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose.. Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective dose potentially corresponds to a risk of treatment-induced carcinogenesis, optimization may still be valuable.

Topics: Alpha Particles; Antibodies, Monoclonal; Astatine; Electrons; Female; Gastric Mucosa; Humans; Immunoconjugates; Immunoglobulin Fab Fragments; Kidney; Lung; Neoplasm Recurrence, Local; Neoplasm, Residual; Ovarian Neoplasms; Peritoneal Neoplasms; Proton Therapy; Radioimmunotherapy; Radiotherapy Dosage; Relative Biological Effectiveness; Risk Assessment; Stomach; Thyroid Gland; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Urinary Bladder

The purpose of the present study was to investigate the therapeutic efficacy of 211At-labelled specific monoclonal antibody MOv18 in nude mice with intraperitoneal growth of the human ovarian cancer cell line OVCAR3. In the first part of the study the antibody was injected intraperitoneally when the cancer growth was microscopic. The injected activity was 485-555 kBq. The median survival for treated mice was 213 days compared to 138 days for untreated mice (p < 0.014, log-rank test). No obvious toxicity was seen. Thirty-three percent of the mice were apparently free of cancer after 7 months and were probably cured. In the second part of the study mice with macroscopic cancer and signs of ascites were injected intraperitoneally with the same 211At-labelled antibody (377-389 kBq). This treatment possibly delayed the production of ascites. Hopefully radioimmunotherapy with regionally administered 211At-labelled antibody will be of value in women with ovarian cancer as well.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Ascites; Astatine; Female; Humans; Immunoconjugates; Mice; Mice, Nude; Ovarian Neoplasms; Palliative Care; Peritoneal Neoplasms; Radioisotopes; Transplantation, Heterologous; Tumor Cells, Cultured

alpha-Emitting radionuclides such as 211At have a number of physical characteristics which make them attractive for the treatment of micrometastases. 211At was bound to polymer microspheres and its efficacy was compared with the beta-emitting 32P and 90Y colloids for the treatment of intraperitoneally growing K13 hybridoma tumors in mice. Single graded doses of 0.1-2.5 MBq 211At microspheres injected intraperitoneally 24 hr after inoculation of the hybridoma cells improved survival and produced higher cure rates than 32P colloid, 90Y colloid, or no treatment. One of the most striking contrasts between 211At microspheres and 90Y or 32P colloids was the ability of relatively low doses 211At to affect cures. When comparing the groups with the highest survival rate for each radionuclide (0.1-1 MBq 211At, 2.5 MBq 90Y, and 2.5 MBq 32P), 211At treatment resulted in an improved survival over that with 32P therapy, but the difference was not significant between 211At and 90Y. Toxicity studies with 211At microspheres showed that dosages up to 17 MBq per mouse were not lethal. In conclusion, the present study suggests that the high-energy transfer and the short-range cytotoxicity of the alpha-emitter 211At might be of benefit for intracavitary radiotherapy.

Topics: Animals; Astatine; Colloids; Female; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Microspheres; Peritoneal Neoplasms; Phosphorus Radioisotopes; Yttrium Radioisotopes

Dose distributions for normal and tumor tissues from intraperitoneally administered radiolabeled antibodies have been calculated for 90-Yttrium (90Y), 131-Iodine (131I), and 211-Astatine (211At). The dose calculations use data on the activity of intraperitoneal fluid administered, the percent injected dose/gm uptake by tumor, biological half life, and a model for diffusion of antibody/radionuclide complex into peritoneal tissues. Calculations are performed for planar and hemispherical tumor shapes, ranging in size to establish the influence of geometry on dose distribution. Calculations for tumor geometry obtained from biopsies are also performed. When the activity is concentrated on or near the tumor surface, the maximum dose to a planar tumor for a 20 mci administration of 90Y is approximately 60 Gy, and falls rapidly to 50% of this value within 1 mm. However, for a hemispherical tumor, the dose is a maximum of 26 Gy, with an average of approximately 20 Gy. The surface dose from 131I (130 mci) is 240 Gy, and diminishes to 20 Gy in .05 cm in the planar case, whereas a hemispherical tumor receives a dose of 90 Gy over a large fraction of the volume, with the distal portions receiving 40 Gy. The surface dose for an administration of 70 mci of 211 At is 450 Gy and decreases to 50% of this value in 30 microns. Both surface geometry and tumor size are important determinants in the heterogeneity of tumor dose, as are the dose administered, antibody uptake, biodistribution, and residence time factors. These initial studies suggest that the size of disease which may be effectively treated is much less than the range of the particle emitted by radiolabeled antibodies. Furthermore, therapy is ultimately limited by the degree to which the antibody/radionuclide complex can diffuse and permeate the tumor.

Topics: Antibodies, Monoclonal; Astatine; Humans; Injections, Intraperitoneal; Iodine Radioisotopes; Models, Biological; Peritoneal Neoplasms; Radiotherapy Dosage; Yttrium Radioisotopes