Quantitative imaging analysis of high dose I-131 anti-CD20 monoclonal antibody (rituximab) therapy in patients with non-Hodgkin’s lymphoma
Kyeong Min KimJeong Wan KwonTae Hyun ChoiSang Hyun ChoByung Hyun ByunGi Jeong CheonHye Jin KangChang Woon ChoiWinnie YeoSang Moo Lim
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1785 Objectives: Radioimmunotherapy (RIT) using I-131 anti-CD20 rituximab is one of the promising therapeutic model for treatment of patient with non-Hodgkin’s Lymphoma (NHL). Although dosimetric approaches of low-dose I-131 rituximab imaging have been reported, there is no study of dosimetry with high-dose imaging in patient with NHL yet. In this study, we investigated the kinetic behavior and absorbed dose to bone marrow and whole body in RIT study with high-dose strategy using I-131 rituximab for NHL. Methods: I-131 rituximab with high-dose (5032 ~ 7400 MBq) was administrated to patients (n = 4) with NHL. Both anterior and posterior planar images of whole body were acquired simultaneously using a gamma camera (Scintron, MiE, Germany) with high-energy collimator at 5 min, 5hr, 24hr, 48hr, 72hr and 1 or 2 weeks post administration. Sampling venous blood was performed at the same points of imaging time. Prior to the administration, blank and transmission images were acquired using Co-57 sheet source, for attenuation correction, respectively. During the emission acquisition, several small vials filled with known activities of I-131 were placed beside patient, for correction of deadtime due to high-activity of I-131. The acquired anterior and posterior images were converted to geometric mean image for further analysis. Using the time-activity curves (TACs) of blood and whole body, the values of effect half-life of the blood and whole body time activity curves were calculated, and mean absorbed doses to bone marrow and whole body were estimated, respectively. Results: Deadtime on gamma images induced underestimation (~64%) of area under the TAC of whole body radioactivity. The radioactivity in blood and whole body decreased rapidly with time, and the residence time of blood and whole body were 27.5 ± 6.7 hr and 32.4 ± 7.8 hr, respectively. The values of mean absorbed dose were range from 0.26 to 0.93 Gy for bone marrow and from 0.12 to 0.39 Gy for whole body, respectively. The dominant contribution of dose was from bone marrow self dose (> 60%). Conclusions: Using the RIT protocol with high-dose I-131 rituxmab, quantitative estimation of absorbed dose to bone marrow and whole body was possible. This RIT strategy of I-131 rituxmab would be useful in monitoring treatment for NHL.Keywords:
Whole body imaging
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The radiation-absorbed dose was estimated following i.p. administration of a 186Re-labeled murine antibody, NR-LU-10, in 27 patients with advanced ovarian cancer. Data for the dosimetry estimation were obtained from quantitative gamma camera imaging and gamma counting of serum and i.p. fluid radioactivity. A peritoneal cavity model was used to estimate the dose to normal organs from radioactivity within the peritoneal cavity. Estimates of radiation-absorbed dose to normal organs in rad/mCi administered (mean + SD) were: whole body, 0.7 + 0.3; marrow, 0.4 + 0.1; liver, 1.9 + 0.9; kidneys, 0.2 + 0.2, and intestine, 0.2 + 0.2. The radiation-absorbed dose estimates to the normal peritoneal surface varied depending on the volume of fluid infused and whether the activity was measured by the gamma camera or from the peritoneal fluid samples. Using gamma camera data, the peritoneal surface dose ranged from 7 to 36 rads/mCi; when using the peritoneal fluid sample data, the dose ranged from 2 to 25 rads/mCi. Myelosuppression, observed in several patients, correlated best with marrow dose estimates based on the serum radioactivity, and significant toxicity was observed at marrow doses greater than 100 rads. The noninvasive methods of dose estimation for i.p. administration of radioimmunoconjugates provided reasonable absorbed dose estimates when compared with previously described, more invasive methods.
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Objective 153 Sm EDTMP is effective in the palliation of painful bone metastases. We developed a whole body scintigraphy method for preparative individual dosimetry and the results were compared with the 5 h urine collection technique in 20 patients with bone metastases. Methods Anterior and posterior whole body images were obtained using identical acquisition parameters 10 min and 5 h after the intravenous injection of 740 MBq 153 Sm EDTMP. Total counts in each imaging study were corrected with background activity and time of injection, and the bone uptake rate was determined. Bone uptake rate was also calculated from the whole volume of urine collected over 5 h after the administration of an identical dose of the agent, and the two results were compared. Results There was a close correlation between the value obtained from whole body scintigraphy and 5 h urine collection technique ( r =0.93). The therapeutic activity administered in this study was restricted within the permissive limit of bone marrow absorbed dose of 1.4 Gy, in these patients,the therapeutic activity injected was 1.40～2.27 GBq. According to the conventionally recommended administered activity of 37 MBq·kg -1 , the therapeutic activity administered would be 1.75～2.41 GBq, then the bone marrow absorbed dose would reach 1.37～2.27 Gy (mean 1.63 Gy), this may lead to a significant myelotoxicity. Conclusions We have developed a whole body scintigraphic technique which is simple, reliable for custom design of a safe and effective dose of 153 Sm EDTMP for individual patients to palliate cancer pain without myelotoxicity.
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Estimates of radiation absorbed dose to the red marrow (RM) would be valuable in treatment planning for radioimmunotherapy if they could show a correlation with clinical toxicity. In this study, a correlation analysis was performed to determine whether estimates of radiation absorbed dose to the bone marrow could accurately predict marrow toxicity in patients who had received 186Re-labeled monoclonal antibody.White blood cell and platelet count data from 25 patients who received 186Re-NR-LU-10 during Phase I radioimmunotherapy trials were analyzed, and the toxicity grade, the fraction of the baseline counts at the nadir (percentage baseline) and the actual nadir were used as the indicators of marrow toxicity. Toxicity was correlated with various predictors of toxicity. These predictors included the absorbed dose to RM, the absorbed dose to whole body (WB) and the total radioactivity administered.Percentage baseline and grade of white blood cells and platelets all showed a moderate correlation with absorbed dose and radioactivity administered (normalized for body size). The percentage baseline platelet count was the indicator of toxicity that achieved the highest correlation with the various predictors of toxicity (r = 0.73-0.79). The estimated RM absorbed dose was not a better predictor of toxicity than either the WB dose or the total radioactivity administered. There was substantial variation in the blood count response of the patients who were administered similar radioactivity doses and who had similar absorbed dose estimates.Although there was a moderately good correlation of toxicity with dose, the value of the dose estimates in predicting toxicity is limited by the patient-to-patient variability in response to internally administered radioactivity. In this analysis of patients receiving 186Re-labeled monoclonal antibody, a moderate correlation of toxicity with dose was observed but marrow dose was of limited use in predicting toxicity for individual patients.
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1027 Objectives During the last decade, Lu-177/Y-90 labelled somatostatin analogues, which preferentially binds to somatostatin receptors have been used extensively for the therapy of somatostatin receptor expressing tumours. The aim of the present study was to calculate radiation-absorbed doses in patients treated with Lu-177-DOTA-TATE in our department. Methods The study population was composed of 27 patients, 14m, 13f, with a mean age of 55.3±12.9. For calculation of radiation absorbed doses a series of anterior-posterior whole body images were acquired for each patient at 4, 20, 44 and 68 hours after the therapeutic radiopharmaceutical administration. Blood samples at 0, 15, 30, 60, 180 min and 24, 48 and 68 hours after injection were obtained for bone marrow and whole body radiation dose calculations. For estimation of individual tumour doses, MIRD scheme with unit density sphere model was used. Tumour volumes were determined from CT images. Results The administered Lu-177-DOTA-TATE dose was ranged from 8.0 GBq to 24.2 GBq (mean dose 15.1±4.5GBq). The number of treatment cycles were 2 in 12 patients, 3 in 12 patients, 4 in 2 patients and 5 in 1 patient. The calculated radiation absorbed dose to whole body, bone marrow and kidneys were 0.8±0.3 Gy (min 0.3 and max 1.4 Gy), 0.4±0.2 (min 0.1, max 0.9 Gy) and 13.5±4.2 Gy (min 2.0, max 22.5 Gy), respectively. The tumour doses were ranged from 5.1 to 628.3 Gy with a mean value of 110.3±115.1 Gy. Conclusions This study suggested the Lu-177 DOTA-TATE therapy is a safe treatment technique and radiation absorbed doses to critical organs are within limits. Also it seems that radiation absorbed dose calculation is mandatory for planning the number of therapy cycles for each patient.
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Ibritumomab tiuxetan
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1836 Objectives Radioimmunotherapy (RIT) using high-dose I-131-tositumomab (anti-CD20) and stem cell support has been used to treat relapsed non-Hodgkin’s lymphoma (NHL). Objective was to study testicular radiation absorbed dose and its effects on testosterone level. Methods We reviewed 67 male patients with NHL treated with myeloablative I-131 tositumomab as part of research protocols. Individualized organ dosimetry was performed using serial planar imaging after infusing I-131 tositumomab antibody (370 MBq). Radiation absorbed doses (cGy/mCi) were determined for vital normal organs using standard MIRD methods. Results Absorbed doses (cGy/mCi, mean ± s.d.) were: 3.82 ±1.06 for liver, 4.40 ± 1.83 for lungs, 5.60 ± 3.94 for spleen, and 4.35±2.20 for testes. Therapeutic dose was 21.8 ± 6.7 (range 9.3- 50.8) GBq. Estimated absorbed dose for testes was 25.4±14.6 Gy, with a median of 22.0 Gy and coefficient of variation of 0.58. Twenty-eight patients (42%) received testicular doses ≥ 25 Gy. Pretreatment and one-year posttreatment plasma testosterone levels were measured in 25/67 patients. I-131-tositumomab therapy induced non-significant (p >0.05) testosterone suppression (from 4.4±2.0 to 4.2±3.0 ng/mL, 95%) in patients receiving Conclusions In 42% of patients the testicular dose was ≥ 25 Gy. Higher dose was associated with suppression of testosterone levels, but this may provide an advantage in treating a highly aggressive NHL, in which the testes may be sanctuary sites. Research Support Supported by P01 CA44991, K23 CA 85479 and The LRF and LLS grants and GSK
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1552 Objectives: Absorbed doses to target and normal organs were calculated in Phase I clinical study in which antibodies targeted to bone marrow and labelled with beta-emitter 90-Y were used in the conditioning regimen prior to stem cell transplant. Patients with myeloma or acute myeloid leukaemia receiving either autologous or allogeneic transplants were recruited. Dosimetry was carried out to measure biodistribution and to establish the maximum tolerated therapy dose. Methods: Murine anti-CD66 monoclonal antibody (TheraPharm GmbH) was labelled with 111-In, as surrogate radionuclide for 90-Y, for dosimetry. Following infusion, whole body and SPECT images were acquired over five days, to obtain several points on time-activity curves. Gamma camera acquisitions were performed using the 174keV photopeak window and two scatter windows at 140keV and 205keV. Anterior and posterior whole body views were used to calculate whole body cumulated activity. After scatter and attenuation corrections, tomographic studies were used for quantification of uptake and clearance in bone marrow, liver and spleen - organs where the antibody concentrates. Counts were converted to activity using conversion factors derived from test objects measurements. Organ volumes were assessed from images. Absorbed doses were calculated using S-values scaled from published data according to organ mass. Image-based dosimetry was supplemented by analysis of blood and urine samples. If favourable dosimetry was demonstrated, patients were treated with therapeutic quantities of antibodies labeled with 90-Y. Results: Twenty patients (age 21-67yrs, median 57, 16 male, 4 female) were treated with activities escalating in 4 steps from 7MBq to 38MBq per 1kg of lean body weight (five patients in each group). There was a close correlation between administered activity and absorbed marrow dose. Mean doses were: bone marrow 9.8mGy/MBq, (n=20, stdev=2.1), liver 2.4mGy/MBq (n=20, stdev=0.8), spleen 9.3mGy/MBq (n=20, stdev=3.9). Conclusions: Dosimetry model was developed for 90-Y labelled anti-CD66 antibody. The antibody demonstrated excellent targeting to bone marrow and consistently low uptake in the liver, with no uptake in other dose-limiting organs. Radiation doses up to 30Gy were delivered to bone marrow with liver dose not exceeding 10Gy. This suggests a role for targeted radioimmunotherapy in stem cell transplantation where intensification of treatment can be achieved without toxicity to non-hematologic tissues.
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Raji cell
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501 Objectives The clinical Phase II study protocol PH_L19SIPI131-01/09 involves radioimmunotheraphy (RIT) with the human antibody L19SIP labeled with 131I in combination with Whole Brain Radiation Therapy in patients with multiple brain metastases from solid tumors. A dosimetric study was performed using 124I-L19SIP to assess patient eligibility to RIT. Organ-at-risk absorbed doses (red marrow) and absolute quantification of target lesion activity concentration were evaluated. Methods Red marrow doses were determined by measuring activity concentration in blood samples with a HP-Ge detector and whole body activity retention with a LaBr probe from 30 minutes up to 96 hours post-injection of an average 124I-L19SIP activity of 159 MBq. A series of 124I ImmunoPET was performed and activity-time curves were determined for various organs and lesions. Hence, provisional absorbed dose to the most significant organs was calculated using the Olinda/EXM Software, as well as target lesion absorbed doses. PET scanner Recovery Coefficients for 124I were determined with the IEC Body Phantom, filling the spheres with a known activity concentration. Results The dosimetric study was performed for 4 patients eligible for RIT and treated with an average activity of 6.9 GBq of 131I-L19SIP. The average provisional red marrow dose of 0.206 Gy/GBq was always in good agreement with the post-therapy dose. The determination of activity residence times in various organs allowed the calculation of healthy organ doses. The maximum intracranial lesion dose was 4.5 Gy, while higher doses were calculated for some extracranial lesions (37.3 Gy). In some cases lesions showed good response to therapy. Conclusions The method developed for the determination of red marrow dose led to a good agreement between the dose calculated during diagnostic (124I) and therapeutic (131I) phase. The average dose received by intracranial lesions was found to be rather low while higher doses were received by some extracranial lesions
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Abstract BACKGROUND: Maximum injected activity in radioimmunotherapy (RIT) is limited by bone marrow toxicity. Many dosimetric approaches have been proposed, leading to high variability in the results and elusive absorbed dose‐effect relations. This study presents the results of red marrow (RM) absorbed dose estimates performed with 3 methods. METHODS: Five patients received 2 co‐infusions of 90 Y‐labeled (370 MBq/m2) and 111 In‐ labeled (120 MBq) epratuzumab (1.5 mg/kg) 1 week apart. RM‐absorbed dose was estimated by 3 methodologies. The first approach (M1) used L 2 ‐L 4 lumbar vertebrae imaging. M2 and M3 methods used different red marrow to blood ratios (RMBLR) to assess RM‐absorbed dose. RMBLR was set to a fixed value of 0.36 in M2 or assessed according to each patient's hematocrit in M3. RESULTS: Median RM‐absorbed doses were 4.1 (2.9‐8.4), 2.3 (2.0‐2.7), and 2.3 (1.6‐2.5) mGy/MBq for M1, M2, and M3, respectively. No trend could be found between total RM‐absorbed dose and toxicity for M2 and M3. Conversely, M1 seemed to provide the best absorbed dose‐effect relation. The 4 patients with the highest RM‐absorbed doses exhibited grade 4 toxicity. The fifth patient, with the lowest RB absorbed dose, exhibited only a mild (grade 2) toxicity. CONCLUSIONS: Image‐based methodology (M1) seems to better predict hematological toxicity as compared with blood‐based methods. Only this method provides for bone marrow involvement. Cancer 2010;116(4 suppl):1093–100. © 2010 American Cancer Society.
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