Internal dosimetry and biodistribution of indigenously prepared 177Lu-DOTA-rituximab in lymphoma and other hematological malignancies treated with rituximab.

OBJECTIVE: The aim of this study was to evaluate the biodistribution and dosimetry of lutetium-177-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (177Lu-DOTA)-rituximab in CD20+ non-Hodgkin's lymphoma and other hematological malignancies treated with rituximab. METHODS: The standard dosimetry protocol was used, with cold rituximab infusion, then a diagnostic activity of 177Lu-DOTA-rituximab. Planar images were acquired at multiple time points. Normal organs and tumor dosimetry were performed by using organ and tumor-specific regions of interest and whole-body counts were obtained serially after pixel matched, background, scatter, and attenuation correction. The mean radiation absorbed doses were obtained from OLINDA/EXM v2.1.1 and ORIGIN software. RESULTS: A total of 22 patients were included in this study. Prolonged blood pool clearance of 177Lu-DOTA-rituximab with long residence time in the blood pool and normal organs were observed. The whole body effective half-life was 104.5 ±â€…22 h. The mean total body radiation absorbed dose was 0.208 ±â€…0.03 mGy/MBq and the mean total body effective dose was 0.196 ±â€…0.05 mGy/MBq of 177Lu-DOTA-rituximab. The mean radiation absorbed doses of 0.613 ±â€…0.21, 1.68 ±â€…2, 1.01 ±â€…0.42, and 0.136 ±â€…0.02mGy/MBq were seen for the liver, spleen, kidneys, and bone marrow, respectively. Tumor lesion uptake was noticed in two patients with tumor radiation absorbed doses were 0.842 mGy/MBq in one and 9.9 mGy/MBq in the other patient. A strong correlation was obtained between the cumulative activities of radiation-absorbed doses derived from ORIGIN and OLINDA software methods at a significant P value less than 0.001. CONCLUSION: The results of our study demonstrated favorable biodistribution and dosimetry of indigenously produced 177Lu-DOTA-rituximab in patients with CD20+ lymphoma. These results can be used for future studies of radioimmunotherapy employing 177Lu-DOTA-rituximab.

Role of Novel Quantitative Imaging Techniques in Hematological Malignancies.

Hematological malignancies exhibit a widespread distribution, necessitating evaluation of disease activity over the entire body. In clinical practice, visual analysis and semiquantitative parameters are used to assess 18F-FDGPET/CT imaging, which solely represents measurements of disease activity from limited area and may not adequately reflect global disease assessment. An efficient method for assessing the global disease burden of hematological malignancies is to employ PET/computed tomography based novel quantitative parameters. In this article, we explored novel quantitative parameters on PET/CT imaging for assessing global disease burden and the potential role of artificial intelligence (AI) to determine these parameters in evaluation of hematological malignancies.

Evaluation of Ectopic Kidney Located at the Deep Subcutaneous Region of the Abdominal Wall: Role of Diuretic Renography with 99mTc-DTPA.

An ectopic kidney is often found inadvertently during CT, ultrasonography, MRI, or urologic physical examination. Ectopic kidneys usually occur in the pelvis. A pelvic ectopic kidney may be misinterpreted for a pelvic tumor by less experienced physicians and surgeons. We present an extremely rare case of ectopic kidney in the deep subcutaneous region of the abdominal wall and associated with the additional abnormality of spina bifida. MRI found an ectopic kidney but failed to identify ureteropelvic drainage. Diuretic renography with 99mTc-diethylenetriaminepentaacetic acid showed normal functioning and identified nonobstructive ureteropelvic drainage of the ectopic subcutaneous kidney.

Unusual Metastatic Sites and Radioiodine Uptake in Patients of Differentiated Thyroid Carcinoma with Atypical Clinical Presentations: Utilization of 131 I-Whole-Body Scintigraphy with Regional SPECT/CT.

Differentiated thyroid carcinoma (DTC) usually is slow growing and carries a good prognosis. It most commonly tends to spread locally to regional lymph nodes in 20 to 60% of patients. The presence of distant metastasis impacts overall survival and prognosis. The lungs, bones, and the brain are typically involved in distant sites with less common metastatic sites that include the liver, kidney, skeletal muscle, adrenal glands, bladder, and skin. These unusual sites are rare and pose a diagnostic challenge and impact clinical decision-making to a great extent. The radioiodine 131 I whole-body scintigraphy with single-photon emission computed tomography/computed tomography can provide a thorough investigation of unusual sites of uptake leading to diagnosis of these metastases. We present a case series of DTC showing unusual sites of metastasis and/or radioiodine uptake in urinary bladder, in the third metacarpal bone of left hand and lastly in the forearm at postoperative hypertrophic scar area.

Triple Tumors (Neuroendocrine Tumor, Schwannoma, and Papillary Thyroid Carcinoma) With Brain Lesions in a Single Patient Demonstrating Avidity on 68 Ga-DOTATATE PET/CT and Their Characterization With FDG-PET/CT and Brain MRI.

ABSTRACT: Neuroendocrine tumor (NET) typically spreads to the liver, lymph nodes, lungs, and skeleton. Brain metastasis in NET is uncommon. Therefore, each case of detected brain metastases in NET is crucial for the development of treatment guidelines for these types of tumors. We present a unique case of triple tumors (NET, papillary thyroid carcinoma, and schwannoma) in a single patient who presented with neurological symptoms and somatostatin receptor-avid T2 hyperintense multiple metastatic brain lesions from NET on 68 Ga-DOTATATE-PET/CT scan and brain MRI. Despite the rarity of brain metastases in NET, we conclude that the presence of neurological sign or symptoms and/or the detection of somatostatin receptor-avid brain lesions in patients with NET should raise suspicion of brain metastases.

Unusual Metastatic Sites of Testis and Rectum in Prostate Cancer Detected by 68 Ga-PSMA-11 PET/CT Imaging at Initial Staging.

Imaging plays a pivotal role in defining the extent of disease and deciding therapeutic strategies in recently diagnosed high-risk prostate cancer. Standard-of-care conventional imaging may often miss rare metastatic disease sites. We herein present a unique case of prostate cancer where 68 Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) detected two unusual metastatic sites (testis and rectum) in a single patient at initial staging, resulting in an accurate determination of the extent of disease, more tailored multimodal treatment planning, and exploration of the theragnostic potential.

Cutaneous, Subcutaneous, and Bilateral Adrenal Gland Metastases in Progressive Prostate Carcinoma: Theranostic Potential of 68 Ga-PSMA-11 PET/CT Imaging and 177 Lu-PSMA-617 Therapy.

ABSTRACT: Prostate carcinoma (PC) is the second most common malignant tumor in males globally. The metastatic spread of PC usually involves the pelvic and abdominal lymph nodes and the skeletal system. Cutaneous metastases are exceedingly uncommon and typically manifest themselves late in the disease course, considered as ominous sign with limited treatment options and a poor prognosis. We describe a patient wherein 68 Ga-PSMA-11 PET/CT detected multiple uncommon metastatic sites in the cutaneous region of the scrotum, penis, and thigh, as well as in the subcutaneous region of anterior abdominal wall, and in bilateral adrenal glands. These findings served as a theranostic tool for selecting 177 Lu-PSMA-617 treatment for these extremely rare metastatic sites.

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.

Evaluation of prostate-specific membrane antigen expression in locally advanced or metastatic breast carcinoma with 68 Ga-PSMA-11 positron-emission tomography/computed tomography imaging for potential theranostics.

BACKGROUND AND AIM: Prostate-specific membrane antigen (PSMA) is ubiquitously expressed in tumor-associated neovasculature and may be a potential theranostic in many solid cancers, including breast carcinoma (BC). Herein, we analyzed the presence of PSMA in BC, through qualitative and quantitative parameters on 68 Ga-PSMA-11 positron-emission tomography/computed tomography (PET/CT), across various hormonal subtypes. METHODS: This study examined 41 female patients of BC. All underwent 68 Ga-PSMA-11 PET/CT. For qualitative analysis, a visual estimation of PSMA expression was performed as per miPSMA scoring system (VISION trial) and a score ≥2 was considered eligible for lutetium-177 ( 177 Lu)-PSMA-617 radioligand therapy (Lu-PRLT). For quantitative analysis, maximum standardized uptake values (SUVmax) were determined and ratios >1 for SUVmax lesion to SUVmax liver were considered eligible for Lu-PRLT. PSMA expression was correlated with hormonal status using Chi-square test. The sensitivity, specificity and area under curve (AUC) of PSMA expression were determined using receiver-operating characteristics analysis ( P < 0.05). RESULTS: A total of 19 patients (46.3%) and 15 patients (36.7%) in stage IV were found eligible for Lu-PRLT based on qualitative and quantitative analyses, respectively. Strong PSMA expression was detected in triple-negative and hormonal receptors-negative/human epidermal growth factor receptor 2-positive status on qualitative PSMA expression analysis. A sensitivity of 65.5%, specificity of 93.3% and AUC of 0.857 for SUVmax 6.5 on 68 Ga-PSMA-11 PET/CT were detected for PSMA expression for considering Lu-PRLT. CONCLUSION: We found a modest number of BC patients suited for Lu-PRLT, indicating that PSMA PET/CT imaging may be a valuable modality for selecting theranostics in a carefully selected group of breast carcinoma.

Testicular Metastasis From Neuroendocrine Tumors: Imaging and Theranostics Through 68 Ga-DOTATATE PET/CT and 177 Lu-DOTATATE-Based Peptide Receptor Radionuclide Therapy.

ABSTRACT: Neuroendocrine tumors (NETs) are rare neoplasms arising from enterochromaffin cells, which are predominantly noted in the gastrointestinal tract and lung; metastases of NETs to the testes in NET are further uncommon. Testicular NET usually has no symptoms and/or presents with painless swelling of the scrotum. Detection of testicular lesion can be challenging and frequently missed on conventional radiological imaging. We present testicular NET missed on conventional radiological imaging, where 68 Ga-DOTATATE PET/CT imaging detected the testicular lesion, and further evident on 177 Lu-DOTATATE-based post-peptide receptor radionuclide therapy theranostic imaging.

PSMA-targeted radioligand therapy in prostate cancer: current status and future prospects.

INTRODUCTION: The prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients has generated significant interest among the oncologic community, with several publications documenting good response rates and survival benefits with low toxicity profiles. AREAS COVERED: Indications, patient preparation, dose administration, post-treatment imaging, dosimetry, and side effect profiles of 177Lu-PSMA-617 are discussed in this article. We also discuss results from prospective studies, major retrospective studies, meta-analyses, clinical trials, and mentioned major ongoing clinical trials on PRLT. We have also portrayed our own experiences and future perspectives on PRLT. EXPERT OPINION: For PRLT, PSMA-617 and PSMA-I&T molecules have revolutionized the theranostic approach in the management of advanced prostate cancer, with solid backing from several published articles showing favorable outcomes and an excellent safety profile of 177Lu-PSMA-617. Improvement in quality of life and survival was seen in the majority of mCRPC patients after 177Lu-PSMA-617 PRLT. Patients with good performance status, asymptomatic, only lymph node metastases, high PSMA expressing lesions, and no discordant FDG avid lesions have a longer survival after 177Lu-PSMA-617 PRLT than patients with poor performance status, symptomatic, hepatic, brain, and skeletal metastases, discordant PSMA, and FDG-avid lesions. Docetaxel and cabazitaxel are approved treatments for mCRPC patients. 177Lu-PSMA-617 is approved as a third-line systemic treatment for mCRPC patients with failure to respond to androgen receptor pathway inhibitors and docetaxel therapy. PRLT is a safe and effective alternative to cabazitaxel (third-line systemic treatment), but it has a higher cost. 177Lu-PSMA-617 could be a more efficient therapeutic option for mCRPC patients as first-line or combined therapy, and it may be a useful therapeutic option for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) patients. Several clinical studies and clinical trials on PRLT are currently underway. In the future, the results of these trials will be helpful in evolving treatment strategies for prostate cancer patients.

False-Positive 68Ga-DOTATATE PET/CT Findings in Hereditary Hypophosphatemia-Osteomalacia Mimicking Culprit Lesions of Tumor-Induced Osteomalacia.

68Ga-DOTATATE PET/CT is an important imaging modality for detection of culprit lesions of tumor-induced osteomalacia in clinically symptomatic patients with hypophosphatemia-osteomalacia. Somatostatin receptor expression may at times be observed in inflammatory or granulomatous conditions and in fractures or degenerative bone disease, leading to false-positive scan findings. We present a rare case of hereditary hypophosphatemia-osteomalacia that showed increased false-positive uptake (for possible tumor-induced osteomalacia lesions) in an inflammatory condition of the maxillary sinus and a fracture of the tibia on somatostatin receptor-based 68Ga-DOTATATE PET/CT.

18F-FDG PET/CT Versus 68Ga-PSMA-11 PET/CT in Evaluation of Distant Metastatic Disease in Recurrent Renal Cell Carcinoma.

Prostate-specific membrane antigen (PSMA) expression has been observed in the neovasculature of various malignancies. We present a case of metastatic renal cell carcinoma (RCC) with comparative 18F-FDG PET/CT and 68Ga-PSMA-11 imaging in which FDG PET/CT failed to detect metastatic thyroid disease and showed less 18F-FDG-concentrating lesions at other sites, whereas 68Ga-PSMA-11 PET/CT identified metastatic thyroid disease and demonstrated intensely 68Ga-PSMA-11-expressing distant metastatic lesions. 68Ga-PSMA-11 PET/CT may be considered a potentially useful imaging technique in RCC to detect metastasis and to guide the choice of specific treatments, such as PSMA-based radionuclide therapy in patients with recurrent metastatic RCC.

PET-CTBased Quantitative Parameters for Assessment of Treatment Response and Disease Activity in Cancer and Noncancerous Disorders.

The various semiquantitative and quantitative PET-CT parameters provide measurement of disease activity and assessment of treatment response in the PET-CT studies. These include standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV). Thresholding and adaptive thresholding methods are commonly used algorithms for the evaluation of global disease activity. Readily available commercial software frequently in-built with the current generation PET-CT scanners for providing easy, less time consuming, highly reproducible, and more accurate measurement of global disease activity on PET-CT imaging in evaluation of malignant as well as benign disorders.

177 Lu-DOTATATE PRRT for Multiple Unusual Metastatic Sites in Neuroendocrine Tumor.

ABSTRACT: Thyroid gland and orbit are rare sites of metastases in neuroendocrine tumors. We present an extremely rare case of rectal neuroendocrine tumor with metastases to thyroid gland and intra-orbital regions that demonstrated significant reduction in size and uptake of the lesions on somatostatin receptor based 68 Ga-DOTATATE PET/CT, following 177 Lu-DOTATATE peptide receptor radionuclide therapy. The case illustrates the efficacy of 177 Lu-DOTATATE peptide receptor radionuclide therapy for tumor cytoreduction, which can be considered as a promising treatment modality for somatostatin receptor expressing and tracer-avid metastatic lesions at multiple rare locations.

Thyroid Incidentaloma on 68Ga-PSMA-11 PET/CT Leading to Detection of Thyroid Metastasis in Metastatic Prostate Carcinoma.

ABSTRACT: 68Ga-labeled prostate-specific membrane antigen (PSMA)-11 PET/CT has evolved as the noninvasive imaging modality of choice in prostatic adenocarcinoma to detect overexpression of PSMA on prostate cancer cells. Metastasis to the thyroid gland is rarely observed in clinical practice of prostatic adenocarcinoma. Herein, we report the first and rare case of metastatic castration-resistant prostatic adenocarcinoma with thyroid metastasis. The patient demonstrated intensely PSMA-expressing primary prostatic lesion, metastatic lymph nodes, and skeletal lesions, and also mild uptake in thyroid nodule, which on further investigations was established as thyroid metastasis from prostate adenocarcinoma.

Follicular thyroid carcinoma metastasizing to rare sites and exhibiting variable inter-lesional heterogeneity on 18F-fluorodeoxyglucose positron emission tomography/computed tomography and 131I.

A patient of differentiated follicular thyroid carcinoma with unusual sites of metastases is illustrated with 131I and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging findings. The described case harbored extremely rare metastasis to the urinary bladder with multi-organ metastatic disease (including unusual sites of right bronchus and hepatic metastases). There was inter-lesional heterogeneity among the metastatic lesions with regard to the 131I and FDG uptake in the aforementioned lesions. The detection of such heterogeneity has important implications for patient management in metastatic differentiated thyroid carcinoma.

Combined 177 Lu-PSMA-617 PRLT and abiraterone acetate versus 177 Lu-PSMA-617 PRLT monotherapy in metastatic castration-resistant prostate cancer: An observational study comparing the response and durability.

OBJECTIVE: The aim of present study was to determine and compare the overall response rates, progression-free survival (PFS), overall survival (OS), and clinical toxicity of the combination of 177Lu-PSMA-617 radioligand therapy (PRLT) and abiraterone acetate (AA) versus 177Lu-PSMA-617 PRLT as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) patients. MATERIALS AND METHODS: The mCRPC patients who received at least one cycle of 177 Lu-PSMA-617 PRLT with or without AA therapy, were included and analyzed in the present study. The patients were divided into two major groups. Group 1 received only 177 Lu-PSMA PRLT and Group 2 received combined 177 Lu-PSMA PRLT + AA therapy. Therapeutic dose of 177 Lu-PSMA-617 PRLT was 4.4-5.55 GBq per patient per cycle administered at intervals of 10-12 weeks in both groups. The Group 2 patients additionally received a dose of 1000 mg of AA once daily and 5 mg of prednisone twice daily. Treatment response in two groups was evaluated under four broad categories (a) symptomatic, (b) biochemical (serum prostate-specific antigen level), (c) objective molecular imaging (68 Ga-PSMA-11 and 18 F-FDG PET/CT), and (d) objective anatomical imaging (computed tomography). For assessing treatment response, patients in two groups were categorized into responders (complete response [CR], partial response [PR], and stable disease [SD]) and nonresponders (progressive disease [PD]). The Kaplan-Meier product-limit method was used to calculate PFS and OS following first 177 Lu-PSMA PRLT in the two groups. Univariate analysis was used to compare the patients' characteristics in two groups using a χ2 or Fisher exact test. The Kaplan-Meier curves of PFS and OS between two groups were compared by using the log-rank test (p < 0.05 significant). RESULTS: A total of 58 mCRPC patients (Group 1, 38 patients and Group 2, 20 patients) were included in this study analysis. The clinical and demographic characteristics of these patients (age, Gleason score, FDG avid disease, metastatic disease burden, and average number of 177 Lu-PSMA PRLT cycles) in two groups were compared and found to be similar (p > 0.05). Post-treatment, symptomatic, biochemical, molecular, and anatomic imaging responders were found in 22 patients (58%) and 17 patients (85%), 22 patients (58%) and 16 patients (80%), 19 patients (54%) and 14 patients (78%), and 19 patients (54%) and 14 patients (78%) in Group 1 and Group 2, respectively. The median PFS of 7 months and median OS of 8 months were documented in Group 1, whereas median PFS was not reached and median OS of 16 months registered in Group 2. Transient hematological toxicity of Grades 1 and 2 was found in total seven patients (five patients in Group 1 and two patients in Group 2). On comparison of the treatment outcome between two groups, significant p value was found for symptomatic responders (58% in Group 1 vs. 85% in Group 2), median PFS (7 months in Group 1 vs. not reached in Group 2), and median OS (8 months in Group 1 vs. 16 months in Group 2), with better outcome in Group 2 patients for these variables. CONCLUSION: In the present study, the combination of 177 Lu-PSMA-617 PRLT and AA therapy showed significant improvement in mCRPC patients' symptomatic response, PFS, and OS as compared to 177 Lu-PSMA-617 PRLT monotherapy.

Initial clinical evaluation of indigenous 90Y-DOTATATE in sequential duo-PRRT approach (177Lu-DOTATATE and 90Y-DOTATATE) in neuroendocrine tumors with large bulky disease: Observation on tolerability, 90Y-DOTATATE post- PRRT imaging characteristics (bremsstrahlung and PETCT) and early adverse effects.

177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) alone has lesser potential in the clinical setting of neuroendocrine tumor (NET) with large bulky disease and nonhomogeneous somatostatin receptors (SSTR) distribution, owing to lower energy (Eßmax 0.497 MeV) and a shorter particle penetration range (maximum 2-4 mm) of 177Lu. In large bulky NETs, 90Yttrium (90Y) has the theoretical advantages because of a longer beta particle penetration range (a maximum soft tissue penetration of 11 mm). Therefore, a combination of 177Lu and 90Y is a theoretically sound concept that can result in better response in metastatic NET with large-bulky lesion and non-homogeneous SSTR distribution. The aim of the study was to determine the feasibility of combining 90Y-DOTATATE with 177Lu-DOTATATE PRRT as sequential duo-PRRT in metastatic NET with (≥5 cm) including the post 90Y-DOTATATE-PRRT imaging and also to determine early toxicity of the duo-PRRT approach. A total of 9 patients received combination of 177Lu-DOTATATE with 90Y-DOTATATE (indigenously prepared and approved) through sequential duo-PRRT approach. These 9 NET patients were included and analyzed in this study. All 9 patients had undergone post-PRRT 90Y-DOTATATE imaging, including a whole-body planar bremsstrahlung imaging followed by regional single-photon emission computed tomography (SPECT)-computed tomography (CT) imaging and also a regional positron emission tomography-computed tomography imaging. Grading of 90Y-DOTATATE and 177Lu-DOTATATE uptake was done on post-PRRT imaging by both modalities. The size of the lesions ranged from 5.5 cm to 16 cm with average size of 10 cm before sequential duo-PRRT was decided. Sequential duo-PRRT was administered because of stable, unresponsive disease following 177Lu-DOTATATE in 5 patients (55.6%), progressive disease after 177Lu-DOTATATE in 2 patients (22.2%), and with neoadjuvant intent in 2 patients (22.2%). The total cumulative dose of 177Lu-DOTATATE before duo-pRRT ranged from 11.84 GBq to 37 GBq per patient and average administered dose of 27.21 GBq per patient in this study. Out of 9 patients, 8 patients received single cycle of 90Y-DOTATATE (ranging from 2.66 GBq to 3.4 GBq per patient with average administered dose of 3.12 GBq per patient). One patient received two cycles of 90Y-DOTATATE (total dose of 6.2 GBq). Out of 9 patients, 8 patients showed excellent tracer concentration in lesions on post-PRRT 90Y-DOTATATE imaging and the remaining 1 patient showed fairly adequate 90Y-DOTATATE tracer uptake in lesion on visual analysis. There was matched 90Y-DOTATATE uptake with 68Ga-DOTATATE and also with 177LuDOTATATE in all 9 patients. The sequential duo-PRRT was well tolerated by all patients. Two patients (22.2%) developed mild nausea, one patient (11.1%) developed transient mild-grade hemoglobin toxicity, and one patient (11.1%) developed mild-grade gastrointestinal symptoms (loose motion and abdominal pain). No nephrotoxicity, hepatotoxicity, and other hematological toxicity was observed. The combination of the indigenous 90Y-DOTATATE with 177Lu-DOTATATE PRRT in NET as sequential duo-PRRT was well tolerated, feasible and safe in stable, unresponsive/progressive disease following single isotope 177Lu-DOTATATE therapy and also in neoadjuvant PRRT setting with large bulky lesion (≥≥5cm). Post-PRRT 90Y-DOTATATE imaging showed excellent 90Y-DOTATATE uptake in nearly all NET patients. Mild-grade early adverse effects were easily manageable and controllable in this sequential duo-PRRT approach.

Surgical Feasibility, Determinants, and Overall Efficacy of Neoadjuvant 177Lu-DOTATATE PRRT for Locally Advanced Unresectable Gastroenteropancreatic Neuroendocrine Tumors.

We assessed 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in the neoadjuvant setting in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We also evaluated the variables associated with resectability of the primary tumor after PRRT. Methods: This study included 57 GEP-NET patients who had a primary tumor that was unresectable (because of vascular involvement as defined using the pancreatic ductal adenocarcinoma criteria of the National Comprehensive Cancer Network) and who underwent 177Lu-DOTATATE therapy without any prior surgery. They were categorized into 2 groups: 23 patients without liver metastases (group 1) and 34 patients with potentially resectable liver metastases (group 2). 177Lu-DOTATATE was administered with mixed amino acid-based renal protection at a dose of 7.4 GBq (200 mCi) per cycle. Surgical resectability was evaluated using triphasic contrast-enhanced abdominal CT imaging at 3 different time points during the PRRT course. Four broad categories of overall PRRT response were evaluated. The Kaplan-Meier product-limit method was used to calculate progression-free survival (PFS) and overall survival (OS). Associations between variables and a resectable primary tumor after PRRT were analyzed using the χ2 test, with a P value of less than 0.05 considered statistically significant. Results: After 177Lu-DOTATATE therapy, the unresectable primary tumor became resectable in 15 of 57 (26.3%) patients (7 patients in group 1 and 8 patients in group 2). A complete or partial response to PRRT was seen in 48 patients (84%), 23 patients (40%), 18 patients (31%), and 23 patients (40%) using symptomatic, biochemical, molecular imaging, and anatomic imaging criteria, respectively. Estimated rates of PFS were 95% and 90% at 2 y in groups 1 and 2, respectively. The 2-y OS of the 2 groups combined was 92.1%. The rate at which the primary tumor was resectable after PRRT was significantly higher in patients who had duodenal neuroendocrine tumors, patients who had GEP-NETs with no regional lymph node involvement, patients for whom the primary tumor was smaller than 5 cm, patients for whom liver metastases were no larger than 1.5 cm, patients for whom there were no more than 3 liver metastases, and patients for whom 18F-FDG uptake in the primary tumor had an SUVmax of less than 5. Conclusion: In a moderate fraction of GEP-NET patients, with or without liver metastases, whose primary tumor was unresectable because of vascular involvement, the primary tumor converted from unresectable to resectable after 177Lu-DOTATATE therapy, signifying that neoadjuvant PRRT can be considered in such patients. The effective control of symptoms, favorable morphologic and functional imaging response, and durable PFS and OS that we observed after 177Lu-DOTATATE PRRT may lead to less morbidity and mortality in these patients.