Clinical Internal Dosimetry and Biodistribution of 177 Lu-DOTA-Trastuzumab in HER2-Positive Metastatic and Locally Advanced Breast Carcinoma.

OBJECTIVE: The aim of this study was to assess the biodistribution and dosimetry of 177 Lu-DOTA-trastuzumab in patients with HER2-positive breast carcinoma using whole-body (WB) planar imaging at multiple time points. PATIENTS AND METHODS: This study was a prospective evaluation of HER2-positive metastatic/locally advanced breast carcinoma patients who underwent gamma camera imaging for dosimetry and biodistribution studies by using 177 Lu-DOTA-trastuzumab. The standard diagnostic dosimetry protocol was followed, which included cold trastuzumab injection followed by in-house produced 177 Lu-DOTA-trastuzumab. Serial WB planar images (anterior and posterior) were obtained on gamma camera after the infusion of 177 Lu-DOTA-trastuzumab at multiple time points. Whole-body and organ regions of interest were drawn, and the numbers of disintegrations were obtained. The mean absorbed doses for the liver, spleen, kidneys, heart, red marrow, and tumor were obtained from OLINDA EXM v2.1.1 and ORIGIN software. RESULTS: The study included a cohort of 21 female breast carcinoma patients. Tracer activity ( 177 Lu-DOTA-trastuzumab) was noted in the physiological organs such as the liver, spleen, kidneys, heart, as well as in the tumors. On visual analysis of 177 Lu-DOTA-trastuzumab biodistribution, the liver activity showed gradual clearance over time, and although spleen was comparatively faintly visualized than liver and similarly, kidneys were faintly visualized suggestive of the alternate route of tracer excretion. The maximum number of patients (n = 12) showed 2 components of clearance, namely, fast and slow. The average effective half-life of all the patients (including single and 2 components of clearance) was 106.25 ± 22.14 hours (84.11-128.39 hours). The mean absorbed dose for the liver, spleen, kidneys, heart, whole body, and red marrow was 1.0702 ± 0.731, 1.4114 ± 0.462, 1.4232 ± 0.364, 1.4719 ± 0.602, 0.2412 ± 0.0295, and 0.1485 ± 0.0213 mGy/MBq, respectively, by OLINDA EXM and 0.5741 ± 0.333, 0.8096 ± 0.224, 0.7943 ± 0.235, 1.8971 ± 0.713, and 0.09619 ± 0.0144 for liver, spleen, kidneys, heart and whole body respectively by ORIGIN. The absorbed radiation dose for tumor was 1.94E+2 by OLINDA EXM software and 1.78E+2 by ORIGIN software. In this study, during and after infusion of 177 Lu-DOTA-trastuzumab, no major adverse effects were noted in any patient except 1 patient who had grade 1 nausea and managed conservatively by antiemetic drug. CONCLUSIONS: The results of our study demonstrated expected and favorable biodistribution and dosimetry with 177 Lu-DOTA-trastuzumab in HER2-positive breast carcinoma patients. We noticed the mean absorbed dose to the normal organs within the limits of maximum tolerable dose, and also tumor dose was higher than the normal liver dose. Therefore, we conclude that 177 Lu-DOTA-trastuzumab radioimmunotherapy is feasible and a safe treatment option for treating HER2-positive breast carcinoma patients.

Prospective evaluation of organ-specific dose and lesional doses following therapeutic [177Lu]Lu-EDTMP administration in patients with multiple skeletal metastases and its correlation with clinical hematological toxicity.

AIM: In patients with multiple skeletal metastases, accurate estimation of absorbed doses to radiosensitive bone marrow in bone-directed systemic radionuclide therapies (RNT) is critically important from clinical dose determination standpoint. The primary aim of the present study was to estimate the radiation absorbed doses of therapeutic [177Lu]Lu-EDTMP to bone marrow by two methods viz. Medical Internal Radiation Dose (MIRD) schema and using OLINDA software and correlate with hematological toxicity. METHODS: A total of 15 patients diagnosed to have multiple painful skeletal metastases being treated with [177Lu]Lu-EDTMP for palliation of pain, were enrolled for this prospective study. For all patients, urine was collected immediately after infusion of [177Lu]Lu-EDTMP up to 24 h post-administration and cumulative activity excreted from body via urine was calculated. For dosimetry, patients underwent post-administration whole-body scintigraphy at five-time points: 0.5 (pre-void), 2, 24, 48 and 120 h (post-void). From the time-activity curves generated by drawing regions of interest (ROIs) on the images, number of disintegrations was determined. Absorbed doses for organs and bone lesions were calculated using OLINDA 2.2.0 software. For bone marrow dose estimates, in addition to OLINDA 2.2.0 software, MIRD schema was also adopted. Hematological profile was monitored in all patients during the treatment and post-treatment follow-up (estimating complete blood counts, every 15 d for 3 months after therapy). RESULTS: The mean ± standard deviation activity of [177Lu]Lu-EDTMP administered per patient per cycle was 2.08 ± 0.45 GBq. The results demonstrated higher uptake of [177Lu]Lu-EDTMP in bone metastases compared to normal bones. Within 2 and 24 h of administration of [177Lu]Lu-EDTMP, [177Lu]Lu activity excreted from the body was 24 ± 9% and 39 ± 14%, respectively. The mean absorbed organ doses (mean ± SD) in Gy/GBq were as follows: osteogenic cells 3.15 ± 1.85, bone marrow 0.57 ± 0.31, kidneys 0.08 ± 0.05, urinary bladder 0.32 ± 0.04, and bone lesions 2.91 ± 1.88. Strong correlation was found between (a) MIRD schema and OLINDA 2.2.0 software method for estimation of bone marrow doses (r = 0.96; P = <0.0001) and (b) Bone marrow absorbed dose and hematological toxicity (r = 0.81, P = 0.0027). CONCLUSION: Radiation absorbed doses to the bone marrow and skeletal metastatic lesions, following therapeutic [177Lu]Lu-EDTMP were estimated using a convenient and non-invasive quantitative imaging method. The estimated bone marrow absorbed dose, either by MIRD schema or the OLINDA 2.2.0 software method, demonstrated strong correlation. Strong correlation was also observed between bone marrow absorbed dose and hematological toxicity.

Examining Absorbed Doses of Indigenously Developed 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Patients at Baseline and During Course of Peptide Receptor Radioligand Therapy.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.