Prospective SPECT-CT Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using the In-111 (111In)/Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Theranostic Pair in Patients with Lymphoma at Myeloablative Dose Levels.

PURPOSE: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin's lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study. METHODS: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm3, and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m2) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m2 with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 106 CD34 cells/kg) proceeded to RIT. A dosimetric administration of 111In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, 90Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed. RESULTS: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of 90Y (range: 12.1-41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes-pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post-90Y RIT for febrile neutropenia, 16/18 patients receiving 90Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent. CONCLUSIONS: Patient-specific outpatient 90Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of 111In and 90Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy.

Initial Experience with Tositumomab and I-131-Labeled Tositumomab for Treatment of Relapsed/Refractory Hodgkin Lymphoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of [131I]tositumomab in patients with refractory/recurrent Hodgkin lymphoma (HL) and to preliminarily determine if [131I]tositumomab has activity against HL and if positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]DG) performed 6 weeks post-therapy predicted 12-week response. PROCEDURES: Separate dose-finding studies were performed for patients with and without prior transplant. A single therapeutic total body radiation dose (TBD) of [131I]tositumomab was administered. TBD was escalated/de-escalated based on dose-limiting hematologic toxicity (DLT) using a modified continual reassessment method. [18F]DG-PET/CT scans were performed at baseline and 6 and 12 weeks post therapy. RESULTS: Twelve patients (nine classical HL, three lymphocyte-predominant [LP] HL) completed two dosing levels (n = 3 each) in the post-transplant (55 cGy, 79 cGy) and no transplant (75 cGy, 87 cGy) groups. Hematologic toxicities were common and transient. Twelve weeks after [131I]tositumomab, 10 patients progressed and two with LPHL achieved complete response. [18F]DG-PET/CT at 6 weeks post therapy appeared more predictive than CT at 6 weeks of a response at 12 weeks. CONCLUSIONS: Tositumomab and [131I]tositumomab was well-tolerated in patients with relapsed/refractory HL. Complete responses in LPHL support a therapeutic effect in this subtype. Early metabolic response assessments by [18F]DG-PET in HL after radioimmunotherapy appear to be more predictive than purely anatomic assessments.

Comparison of organ residence time estimation methods for radioimmunotherapy dosimetry and treatment planning--patient studies.

The estimation of organ residence time is essential for high-dose myeloablative regimens in radioimmunotherapy (RIT). Frequently, this estimation is based on a series of simple planar scans and planar processing. The authors previously performed a simulation study which demonstrated that the accuracy of this methodology is limited compared to a hybrid planar/SPECT residence time estimation method. In this work the authors applied this hybrid method to data from a clinical trial of high-dose myeloablative yttrium-90 ibritumomab tiuxetan therapy. Image data acquired from 18 patients were comprised of planar scans at five time points ranging from 1 to 144 h postinjection and abdominal and thoracic SPECT/CT scans obtained at 24 h postinjection. The simple planar processing method used in this work was based on the geometric mean method with energy window based scatter compensation. No explicit background subtraction nor object or source thickness corrections were performed. The SPECT projections were reconstructed using iterative reconstruction with compensations for attenuation, scatter, and full collimator-detector response. Large differences were observed when residence times were estimated using the simple planar method compared to the hybrid method. The differences were not constant but varied in magnitude and sign. For the dose-limiting organ (liver), the average difference was -18% and variation in the difference was 19%, similar to the differences observed in a previously reported simulation study. The authors also looked at the relationship between the weight of the patient and the liver residence time and found that there was no meaningful correlation for either method. This indicates that weight would not be an adequate proxy for an experimental estimate of residence time when choosing the activity to administer for therapy. The authors conclude that methods such as the simple planar method used here are inadequate for RIT treatment planning. More sophisticated methods, such as the hybrid SPECT/planar method investigated here, are likely to be better predictors of organ dose and, as a result, organ toxicities.

18F-FDG PET/CT for monitoring the response of lymphoma to radioimmunotherapy.

UNLABELLED: We retrospectively evaluated 18F-FDG PET/CT for monitoring the response of non-Hodgkin's lymphoma to radioimmunotherapy. METHODS: A total of 33 clinical patients received 131I-tositumomab (n=23) or 90Y-ibritumomab tiuxetan (n=10) and underwent 18F-FDG PET/CT scans before radioimmunotherapy and at 12 wk after radioimmunotherapy. A third scan was performed on 13 patients at 24 wk after radioimmunotherapy, 12 of whom did not receive interval therapy. Tumor metabolic activity was assessed before and after radioimmunotherapy visually and quantitatively by lean maximum standardized uptake value (SUVlean max). Response was assessed by the International Workshop Criteria (IWC) and Revised IWC, which includes 18F-FDG PET (IWC-PET). RESULTS: Mean SUVlean max decreased from baseline in 244 target lesions 12 wk after radioimmunotherapy (from 6.51+/-4.05 to 3.94+/-4.41; P<0.01), regardless of response at 12 wk after radioimmunotherapy (P

Comparison of 90Y-ibritumomab tiuxetan and 131I-tositumomab in clinical practice.

UNLABELLED: We retrospectively evaluated our single-center clinical experience with (90)Y-ibritumomab tiuxetan and (131)I-tositumomab for therapy of refractory non-Hodgkin's lymphoma (NHL). We evaluated the hypothesis that the patient-specific dosing regimen used with (131)I-tositumomab results in less bone marrow toxicity than does the weight-based dosing regimen used with (90)Y-ibritumomab tiuxetan. METHODS: Thirty-eight patients (25 male and 13 female; median age, 64 y) received radioimmunotherapy for NHL (20 received (90)Y-ibritumomab tiuxetan; 18 received (131)I-tositumomab). Patient and disease characteristics were evaluated to determine whether any were prognostic indicators of short- or long-term clinical response. The 12-wk response rate and clinical and hematologic toxicities attributable to each therapy were assessed. The response rate at 12 wk was correlated with long-term overall survival. RESULTS: Twenty-six patients received full-radiation-dose radioimmunotherapy and 12 received attenuated doses because of hematologic concerns. The 12-wk overall response rate for all patients was 47%, and the complete response rate was 13%. The 12-wk overall response rate did not significantly differ between the (90)Y-ibritumomab tiuxetan and (131)I-tositumomab groups. Responses at 12 wk were more frequent in patients with normal levels of serum lactate dehydrogenase, no bone marrow involvement, and International Prognostic Index scores of no more than 2 (P < or = 0.04). Grade 3 or 4 thrombocytopenia occurred in 57% and 56% of patients treated with (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, respectively. Grade 3 or 4 neutropenia was observed in 57% and 50%, respectively. The time to the absolute neutrophil count nadir was shorter for the (90)Y-ibritumomab tiuxetan group than for the (131)I-tositumomab group (36 +/- 9 vs. 46 +/- 14 d, P = 0.01). The mean percentage decline in platelet count after radioimmunotherapy was greater in the (90)Y-ibritumomab tiuxetan group than in the (131)I-tositumomab group (79% +/- 17% vs. 63% +/- 28%, P = 0.04). Overall survival was longer in responders than in nonresponders 12 wk after therapy (P < or = 0.05). CONCLUSION: Both (90)Y-ibritumomab tiuxetan and (131)I-tositumomab were well tolerated. We observed response rates at the lower range of those reported in the literature, possibly because of referral bias, dose attenuation, and reasonably liberal acceptance criteria for a patient to receive therapy. Initial response assessments 12 wk after radioimmunotherapy predict longer-term response. (131)I-tositumomab caused significantly less severe declines in platelet counts than did (90)Y-ibritumomab tiuxetan and may be a more appropriate choice for patients with limited bone marrow reserve, but large, randomized, prospective trials are needed to better compare the performance of these 2 treatments.

Lung dosimetry for radioiodine treatment planning in the case of diffuse lung metastases.

UNLABELLED: The lungs are the most frequent sites of distant metastasis in differentiated thyroid carcinoma. Radioiodine treatment planning for these patients is usually performed following the Benua-Leeper method, which constrains the administered activity to 2.96 GBq (80 mCi) whole-body retention at 48 h after administration to prevent lung toxicity in the presence of iodine-avid lung metastases. This limit was derived from clinical experience, and a dosimetric analysis of lung and tumor absorbed dose would be useful to understand the implications of this limit on toxicity and tumor control. Because of highly nonuniform lung density and composition as well as the nonuniform activity distribution when the lungs contain tumor nodules, Monte Carlo dosimetry is required to estimate tumor and normal lung absorbed dose. Reassessment of this toxicity limit is also appropriate in light of the contemporary use of recombinant thyrotropin (thyroid-stimulating hormone) (rTSH) to prepare patients for radioiodine therapy. In this work we demonstrated the use of MCNP, a Monte Carlo electron and photon transport code, in a 3-dimensional (3D) imaging-based absorbed dose calculation for tumor and normal lungs. METHODS: A pediatric thyroid cancer patient with diffuse lung metastases was administered 37 MBq of (131)I after preparation with rTSH. SPECT/CT scans were performed over the chest at 27, 74, and 147 h after tracer administration. The time-activity curve for (131)I in the lungs was derived from the whole-body planar imaging and compared with that obtained from the quantitative SPECT methods. Reconstructed and coregistered SPECT/CT images were converted into 3D density and activity probability maps suitable for MCNP4b input. Absorbed dose maps were calculated using electron and photon transport in MCNP4b. Administered activity was estimated on the basis of the maximum tolerated dose (MTD) of 27.25 Gy to the normal lungs. Computational efficiency of the MCNP4b code was studied with a simple segmentation approach. In addition, the Benua-Leeper method was used to estimate the recommended administered activity. The standard dosing plan was modified to account for the weight of this pediatric patient, where the 2.96-GBq (80 mCi) whole-body retention was scaled to 2.44 GBq (66 mCi) to give the same dose rate of 43.6 rad/h in the lungs at 48 h. RESULTS: Using the MCNP4b code, both the spatial dose distribution and a dose-volume histogram were obtained for the lungs. An administered activity of 1.72 GBq (46.4 mCi) delivered the putative MTD of 27.25 Gy to the lungs with a tumor absorbed dose of 63.7 Gy. Directly applying the Benua-Leeper method, an administered activity of 3.89 GBq (105.0 mCi) was obtained, resulting in tumor and lung absorbed doses of 144.2 and 61.6 Gy, respectively, when the MCNP-based dosimetry was applied. The voxel-by-voxel calculation time of 4,642.3 h for photon transport was reduced to 16.8 h when the activity maps were segmented into 20 regions. CONCLUSION: MCNP4b-based, patient-specific 3D dosimetry is feasible and important in the dosimetry of thyroid cancer patients with avid lung metastases that exhibit prolonged retention in the lungs.