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Basic Science Investigations |
1 Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
2 Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands
3 Department of Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
4 Department of Otolaryngology/Head and Neck Surgery, University Medical Center Nijmegen, Nijmegen, The Netherlands
5 Boehringer Ingelheim BV, Alkmaar, The Netherlands
6 Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany
From December 1999 until July 2001, a phase I dose escalation study was performed with 186Re-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 186Re-bivatuzumab and to determine the maximum tolerated dose (MTD) of 186Re-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/m2, 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, 186Re-labeled bivatuzumab could be a good candidate for future adjuvant radioimmunotherapy in patients with minimal residual disease.
Key Words: radioimmunotherapy • dosimetry • head and neck cancer • 186Re-bivatuzumab • monoclonal antibody
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