Tumor-Absorbed Dose Predicts Progression-Free Survival Following (131)I-Tositumomab Radioimmunotherapy.

UNLABELLED: The study aimed at identifying patient-specific dosimetric and nondosimetric factors predicting outcome of non-Hodgkin lymphoma patients after (131)I-tositumomab radioimmunotherapy for potential use in treatment planning. METHODS: Tumor-absorbed dose measures were estimated for 130 tumors in 39 relapsed or refractory non-Hodgkin lymphoma patients by coupling SPECT/CT imaging with the Dose Planning Method (DPM) Monte Carlo code. Equivalent biologic effect was calculated to assess the biologic effects of nonuniform absorbed dose including the effects of the unlabeled antibody. Evaluated nondosimetric covariates included histology, presence of bulky disease, and prior treatment history. Tumor level outcome was based on volume shrinkage assessed on follow-up CT. Patient level outcome measures were overall response (OR), complete response (CR), and progression-free survival (PFS), determined from clinical assessments that included PET/CT. RESULTS: The estimated mean tumor-absorbed dose had a median value of 275 cGy (range, 94-711 cGy). A high correlation was observed between tracer-predicted and therapy-delivered mean tumor-absorbed doses (P < 0.001; r = 0.85). In univariate tumor-level analysis, tumor shrinkage correlated significantly with almost all of the evaluated dosimetric factors, including equivalent biologic effect. Regression analysis showed that OR, CR, and PFS were associated with the dosimetric factors and equivalent biologic effect. Both mean tumor-absorbed dose (P = 0.025) and equivalent biologic effect (P = 0.035) were significant predictors of PFS whereas none of the nondosimetric covariates were found to be statistically significant factors affecting PFS. The most important finding of the study was that in Kaplan-Meier curves stratified by mean dose, longer PFS was observed in patients receiving mean tumor-absorbed doses greater than 200 cGy than in those receiving 200 cGy or less (median PFS, 13.6 vs. 1.9 mo for the 2 dose groups; log-rank P < 0.0001). CONCLUSION: A higher mean tumor-absorbed dose was significantly predictive of improved PFS after (131)I-tositumomab radioimmunotherapy. Hence tumor-absorbed dose, which can be estimated before therapy, can potentially be used to design radioimmunotherapy protocols to improve efficacy.

131I-tositumomab radioimmunotherapy: initial tumor dose-response results using 3-dimensional dosimetry including radiobiologic modeling.

UNLABELLED: For optimal treatment planning in radionuclide therapy, robust tumor dose-response correlations must be established. Here, fully 3-dimensional (3D) dosimetry was performed coupling SPECT/CT at multiple time points with Monte Carlo-based voxel-by-voxel dosimetry to examine such correlations. METHODS: Twenty patients undergoing (131)I-tositumomab for the treatment of refractory B-cell lymphoma volunteered for the study. Sixty tumors were imaged. Activity quantification and dosimetry were performed using previously developed 3D algorithms for SPECT reconstruction and absorbed dose estimation. Tumors were outlined on CT at multiple time points to obtain absorbed dose distributions in the presence of tumor deformation and regression. Equivalent uniform dose (EUD) was calculated to assess the biologic effects of the nonuniform absorbed dose, including the cold antibody effect. Response for correlation analysis was determined on the basis of the percentage reduction in the product of the largest perpendicular tumor diameters on CT at 2 mo. Overall response classification (as complete response, partial response, stable disease, or progressive disease) used for prediction analysis was based on criteria that included findings on PET. RESULTS: Of the evaluated tumor-absorbed dose summary measures (mean absorbed dose, EUD, and other measures from dose-volume histogram analysis), a statistically significant correlation with response was seen only with EUD (r = 0.36 and P = 0.006 at the individual tumor level; r = 0.46 and P = 0.048 at the patient level). The median value of mean absorbed dose for stable disease, partial response, and complete response patients was 196, 346, and 342 cGy, respectively, whereas the median value of EUD for each of these categories was 170, 363, and 406 cGy, respectively. At a threshold of 200 cGy, both mean absorbed dose and EUD had a positive predictive value for responders (partial response + complete response) of 0.875 (14/16) and a negative predictive value of 1.0 (3/3). CONCLUSION: Improved dose-response correlations were demonstrated when EUD incorporating the cold antibody effect was used instead of the conventionally used mean tumor-absorbed dose. This work demonstrates the importance of 3D calculation and radiobiologic modeling when estimating absorbed dose for correlation with outcome.

Hepatic absorbed radiation dosimetry during I-131 metaiodobenzylguanidine (MIBG) therapy for refractory neuroblastoma.

PURPOSE: To compare the prediction of therapeutic hepatic radiation-absorbed dose rates from tracer imaging plus a linearity assumption to estimation based on intra-therapy imaging in (131)I metaiodobenzylguanidine (MIBG) therapy of refractory neuroblastoma. MATERIALS AND METHODS: Conjugate-view images of the liver were obtained before therapy for seven patients at seven times after a tracer infusion of (131)I MIBG and at three times after the therapy infusion. Measured liver activities were converted to dose-rate estimates. Three statistical models of the rates assuming double exponential dependences on time were examined. One of the three models allowed for a multiplicative correction to the therapeutic late-phase dose-rate amplitude. Results from that model: (1) the tracer prediction of the late-phase absorbed-dose-rate amplitude was a factor of 1.75 times the intra-therapy-estimated value, and (2) the difference between tracer prediction of the radiation-absorbed dose and intra-therapy estimation of it was statistically significant, and (3) the liver radiation-absorbed dose did not reach 30 Gy. CONCLUSIONS: A statistical modeling analysis finds that the radiation-absorbed dose after therapy appears to be lower than that which is predicted from the linear scaling with administered activity of the tracer radiation-absorbed dose. Hepatocyte toxicity is the most likely reason but it is not high enough to produce clinically observable results.

131I-tositumomab therapy as initial treatment for follicular lymphoma.

BACKGROUND: Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients. METHODS: Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body. RESULTS: Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed. CONCLUSIONS: A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.

Update on hybrid conjugate-view SPECT tumor dosimetry and response in 131I-tositumomab therapy of previously untreated lymphoma patients.

UNLABELLED: A study of the use of (131)I-labeled tositumomab, preceded by an unlabeled tositumomab predose, for therapy of 76 previously untreated non-Hodgkin's lymphoma patients has been completed at the University of Michigan. Fifty-two of the 76 treated patients were imaged once during therapy with SPECT to assist in dosimetric estimation. In this article, the patient's average tumor dose, estimated by a hybrid method using that SPECT, is compared with the same statistic estimated by pretherapy conjugate views. METHODS: The SPECT activity-quantification procedure used 3-dimensional CT-to-SPECT image registration. Daily pretherapy conjugate-view images provided the shape of the time-activity curve for the hybrid dose estimation. RESULTS: With the hybrid method, the mean of the patient's average tumor dose over 8 patients using only their axillary tumors (162 cGy) was very significantly lower (P < 0.0001) than the mean over 47 patients using only their evaluated chest, abdominal, and pelvic tumors (624 cGy) for unknown reasons. Excluding axillary tumors as a best case for prediction, there still was considerable overlap in the distribution of a patient's average tumor dose over 38 patients who went on to a complete response (CR) and that from 9 patients who went on to a partial response (PR) using either method. However, a high value of the patient's average tumor dose was correctly associated with a CR for 15 of 16 patients (94%) with hybrid SPECT and for 9 of 12 patients (75%) with conjugate views. Also, the mean of the patient's average tumor dose for the CR patients was larger than the mean for PR patients; the P value was 0.18 with hybrid SPECT and 0.25 with conjugate views. A multiple logistic regression analysis combining the dose, tumor burden, and level of lactate dehydrogenase as explanatory variables for response did not yield statistical significance with either method. CONCLUSION: Patients with evaluated tumors that receive the highest tumor radiation dose are most likely to achieve a CR. Dosimetry based on a combination of pretherapy conjugate views and intratherapy SPECT provides somewhat better correspondence between the patient's average tumor dose and his or her degree of response compared with dosimetry from pretherapy conjugate views alone. Statistical significance for the correspondence is not reached either with the dosimetric method or with either method in combination with the tumor burden and level of lactate dehydrogenase.

A practical methodology for patient release after tositumomab and (131)I-tositumomab therapy.

UNLABELLED: A methodology was developed determining patient releasability after radioimmunotherapy with tositumomab and (131)I-tositumomab for the treatment of non-Hodgkin's lymphoma. METHODS: Dosimetry data were obtained and analyzed after 157 administrations of (131)I-tositumomab to 139 patients with relapsed or refractory non-Hodgkin's lymphoma. Tositumomab and (131)I-tositumomab therapy included dosimetric (low activity) and therapeutic (high activity) administrations. For each patient, the total-body residence time was calculated after the dosimetric administration from total-body counts obtained over 6 or 7 d and was then used to determine the appropriate therapeutic activity to deliver a specific total-body radiation dose. Patient dose rates at 1 m were measured immediately after the therapeutic infusion. Patient-specific calculations based on the measured total-body residence time and dose rate for (131)I-tositumomab were derived to determine the patient's maximum releasable dose rate at 1 m, estimated radiation dose to maximally exposed individuals, and the amount of time necessary to avoid close contact with others. RESULTS: The mean administered activity (+/-SD), determined by dosimetry studies for each patient before therapy, was 3,108 +/- 1,073 MBq (84 +/- 29 mCi) (range, 1,221 +/- 5,957 MBq [33--161 mCi]). Immediately after treatment, the mean measured dose rate (+/- SD) at 1 m was 0.109 +/- 0.032 mSv/h (10.9 +/- 3.2 mrem/h; range, 0.04--0.24 mSv/h [4--24 mrem/h]). The measured dose rates were 60% (range, 37%--90%; P < 0.0001) of the theoretic dose rates from a point source in air predicted using the dose equivalent rate per unit activity of (131)I (5.95 x 10(-5) mSv/MBq h [0.22 mrem/mCi h] at 1 m). The mean estimated radiation dose to the maximally exposed individual was 3.06 mSv (306 mrem) (range, 1.95--4.96 mSv [195--496 mrem]). On the basis of current regulatory patient-release criteria, all (131)I-tositumomab--treated patients were determined to be releasable by comparing the dose rate at 1 m with a predetermined maximum releasable dose rate. Detailed instructions were provided to limit family members' exposure. CONCLUSION: A methodology has been developed for the release of patients administered radioactive materials based on the new Nuclear Regulatory Commission regulations. This approach uses a patient-specific dose calculation based on the measured total-body residence time and dose rate. This analysis shows the feasibility of outpatient radioimmunotherapy with tositumomab and (131)I-tositumomab.