Lack of efficacy of two consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with metastasized clear cell renal cell carcinoma.

PURPOSE: A previous activity dose-escalation study using 131I-labeled chimeric monoclonal antibody cG250 in patients with progressive metastatic renal cell carcinoma (RCC) resulted in occasional therapeutic responses. The present study was designed to determine the safety and therapeutic efficacy of two sequential high-dose treatments with 131I-cG250. PATIENTS AND METHODS: Patients (n = 29) with progressive metastatic RCC received a low dose of (131)I-cG250 for assessment of preferential targeting of metastatic lesions, followed by the first radioimmunotherapy (RIT) with 2220 MBq/m2 131I-cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low-dose 131I-cG250 (n = 20) was given 3 months later. When blood clearance was not accelerated, a second RIT of 131I-cG250 was administered at an activity-dose of 1110 MBq/m2 (n = 3) or 1665 MBq/m2 (n = 16). Patients were monitored weekly for toxicity, and tumor size was evaluated by computed tomography once every 3 months intervals. RESULTS: The maximum-tolerated dose (MTD) of the second RIT was 1,665 MBq/m2 because of dose-limiting hematological toxicity. Based on an intention-to-treat analysis, after two RIT treatments, the disease stabilized in five of 29 patients, whereas it remained progressive in 14 of 29 patients. Two patients received no RIT, and eight of 29 received only one 131I-cG250 RIT because of grade 4 hematologic toxicity, formation of human antichimeric antibodies, or disease progression. CONCLUSION: In patients with progressive end-stage RCC, the MTD of the second treatment was 75% of the MTD of the first RIT. In the majority of patients, two cycles of 131I-cG250 could be safely administered without severe toxicity. No objective responses were observed, but occasionally two RIT doses resulted in stabilization of previously progressive disease.

Radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell cancer: dosimetric analysis and immunologic response.

PURPOSE: A study was designed to define the therapeutic efficacy, safety, and toxicity of two sequential high-dose treatments of radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell carcinoma. Here, we report the dosimetric analysis and the relationship between the development of a human antichimeric antibody response and altered pharmacokinetics. EXPERIMENTAL DESIGN: Patients (n = 29) with progressive metastatic renal cell carcinoma received a low dose (222 MBq) of [131I]cG250 for dosimetric analysis, followed by the first radioimmunotherapy with 2,220 MBq/m2 [131I]cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low dose of [131I]cG250 (n = 20) was given 3 months later. Provided that no accelerated blood clearance was observed, a second radioimmunotherapy of [131I]cG250 was administered at an activity-dose level of 1,110 MBq/m2 (n = 3) or 1,665 MBq/m2 (n = 16). After each administration, whole-body images were obtained and the pharmacokinetics and the development of human antichimeric antibody responses were determined. Radiation-absorbed doses were calculated for whole body, red marrow, organs, and metastases. RESULTS: No correlation was found between hematologic toxicity and radiation-absorbed dose to the whole body or bone marrow, nor administered activity (MBq and MBq/kg). The tumor-absorbed doses varied largely. An inverse relation between tumor size and radiation-absorbed dose was found. Most tumor lesions received <10 Gy, whereas only lesions <5 g absorbed >50 Gy. A relatively high number of patients developed a human antichimeric antibody response (8 of 27) with altered pharmacokinetics, hampering additional radioimmunotherapies in four of these patients. CONCLUSIONS: Dosimetric analysis did not adequately predict the degree of bone marrow toxicity. When human antichimeric antibody developed, the rapid clearance of radioactivity from the blood and body prohibited further treatment. According to the calculated absorbed dose in metastatic lesions, future radioimmunotherapy studies with radiolabeled cG250 should aim at treatment of small-volume disease or treatment in an adjuvant setting.

Targeting of metastatic renal cell carcinoma with the chimeric monoclonal antibody G250 labeled with (131)I or (111)In: an intrapatient comparison.

PURPOSE: There is increasing evidence that the chimeric monoclonal antibody G250 (cG250) can be internalized by G250 antigen-expressing renal cell carcinoma (RCC) cells. Thus, accumulation in tumors of cG250 labeled with residualizing radionuclides might be higher than that of nonresidualizing (131)I-cG250. Here, we present a study comparing intrapatiently the accumulation of (131)I-cG250 and (111)In-cG250 in RCC metastases. EXPERIMENTAL DESIGN: Five patients were i.v. injected with 222 MBq (111)In-ITC-DTPA-cG250 and 222 MBq (131)I-cG250 on days 0 and 4, respectively. Directly and 4 days after the injection of both antibody preparations, whole body gamma camera images were acquired. The scintigraphic images were analyzed visually and quantitatively. The radioactivity in tissues was calculated and expressed as percentage injected dose in organs or percentage injected dose/g in metastases. For the latter, tumor:blood ratios were also calculated. Twenty-five metastases were analyzed completely. RESULTS: At 4 days postinjection, the (111)In-ITC-DTPA-cG250 images revealed more metastatic lesions (n = 47) than (131)I-cG250 (n = 30). Quantitative analysis of the images showed higher activities of (111)In-ITC-DTPA-cG250 than (131)I-cG250 in 20 of 25 lesions. The mean overall half-life of both antibody preparations in plasma was similar. CONCLUSIONS: (111)In-ITC-DTPA-cG250 outperformed (131)I-cG250 for visualization of metastatic RCC lesions, not just because of the superior gamma camera characteristics of (111)In, but more importantly, also because higher tumor:blood ratios were obtained. The higher activities of (111)In-ITC-DTPA-cG250 in metastatic lesions might be caused by internalization and subsequent intracellular retention of the radiolabel, implying that in future radioimmunotherapy trials with cG250 in RCC patients, the use of a residualizing radionuclide should be considered.

Dosimetric analysis of radioimmunotherapy with 186Re-labeled bivatuzumab in patients with head and neck cancer.

UNLABELLED: From December 1999 until July 2001, a phase I dose escalation study was performed with (186)Re-labeled bivatuzumab, a humanized monoclonal antibody against CD44v6, on patients with inoperable recurrent or metastatic head and neck cancer. The aim of the trial was to assess the safety and tolerability of intravenously administered (186)Re-bivatuzumab and to determine the maximum tolerated dose (MTD) of (186)Re-bivatuzumab. The data were also used for dosimetric analysis of the treated patients. Dosimetry is used to estimate the absorbed doses by nontarget organs, as well as by tumors. It can also help to explain toxicity that is observed and to predict organs at risk because of the therapy given. METHODS: Whole-body scintigraphy was used to draw regions around sites or organs of interest. Residence times in these organs and sites were calculated and entered into the MIRDOSE3 program, to obtain absorbed doses in all target organs except for red marrow. The red marrow dose was calculated using a blood-derived method. Twenty-one studies on 18 patients, 5 female and 16 male, were used for dosimetry. RESULTS: The mean red marrow doses were 0.49 +/- 0.03 mGy/MBq for men and 0.64 +/- 0.03 mGy/MBq for women. The normal organ with the highest absorbed dose appeared to be the kidney (mean dose, 1.61 +/- 0.75 mGy/MBq in men and 2.15 +/- 0.95 mGy/MBq in women; maximum kidney dose in all patients, 11 Gy), but the doses absorbed are not expected to lead to renal toxicity. Other organs with doses exceeding 0.5 mGy/MBq were the lungs, the spleen, the heart, the liver, the bones, and the testes. The doses delivered to the tumor, recalculated to the MTD level of 1.85 GBq/m(2), ranged from 3.8 to 76.4 Gy, with a median of 12.4 Gy. A good correlation was found between platelet and white blood cell counts and the administered amount of activity per kilogram of body weight (r = -0.79). CONCLUSION: Dosimetric analysis of the data revealed that the range of doses to normal organs seems to be well within acceptable and safe limits. Tumor doses ranged from 4 to 76 Gy. Given the acceptable tumor doses, (186)Re-labeled bivatuzumab could be a good candidate for future adjuvant radioimmunotherapy in patients with minimal residual disease.

Population exposure to diagnostic use of ionizing radiation in The Netherlands.

The use of ionizing radiation for diagnostic medical procedures and the exposure of the Dutch population to this radiation were assessed for 1998. The annual average effective dose from diagnostic medical exposures has increased by 26% to 0.59 mSv per capita since the last inventory of medical radiation exposure in the Netherlands a decade ago. The population-averaged effective dose comprises x-ray procedures in hospitals (87%), nuclear medicine examinations (11%), mammography screening (1.5%), and extramural dentistry (0.2%). The rise has resulted mainly from an increase in frequency and patient dose for CT examinations and from vascular radiology. The increase in the number of CT examinations leveled off in the mid-1990's. Medically exposed people were found to be significantly older than the general population. Based on age distribution alone, an "age reduction factor" for the risk coefficient of 0.64 was found to apply to the medically exposed group. More information on patient dose for the complete set of procedures should, according to this study, become available.