Madhav Prasad Yadav

Concomitant 177lu-dotatate and Capecitabine Therapy in Patients With Advanced Neuroendocrine Tumors: A Long-term-outcome, Toxicity, Survival, and Quality-of-life Study

Purpose The purpose of this study was to evaluate the outcome, toxicity, survival, and quality of life in patients with advanced neuroendocrine tumors. Methods One hundred sixty-seven patients were enrolled in the study. All patients underwent baseline 68Ga-DOTANOC PET/CT scans. 177Lu-DOTATATE therapy was administered quarterly along with oral capecitabine therapy in group 1 patients (n = 88), whereas group 2 patients (n = 79) were treated only with 177Lu-DOTATATE. Hematologic, kidney function, liver function tests and chromogranin A levels were recorded before and after therapy at 2-week, 4-week, and 3-month intervals. Biochemical and morphological responses were assessed with the trend in chromogranin A levels and Response Evaluation Criteria in Solid Tumors 1.1 criteria, respectively. Results There was no significant difference in the hemoglobin levels after 177Lu-DOTATATE therapy (P = 0.4892). In most patients, there was a decrease in the platelet levels; however, all the patients had platelet counts greater than 100,000/&mgr;L with no platelet toxicity. There was no toxicity related to leukocytes. Two patients showed renal insufficiencies. No hepatotoxicity was observed in any of the patients. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months. Ki-67 tumor proliferation index was significantly associated with increased risk of disease progression. Conclusions Addition of capecitabine therapy with 177Lu-DOTATATE therapy lengthens the OS and PFS. Patients with aggressive disease may benefit from this synergetic therapeutic approach.

Cocktail Therapy of 177Lu-PSMA-617 and 177Lu-EDTMP in Patients With mCRPC: A Proof-of-Principle Application.

Prostate cancer is the second most common primary tumor affecting men worldwide. Among them, 10-20% develop castration resistant prostate cancer (CRPC). Ga-PSMA-PET/CT is an important theranostic agent for the evaluation of CRPC to assess the feasibility of treatment with Lu-PSMA-617 which is a novel therapeutic agent. Interestingly, in certain cases, we have observed non-PSMA-avid lesions despite raised sPSA levels. In this regard, we present a case of cocktail therapy applied using Lu-PSMA-617 and Lu-EDTMP therapy in a 38-year-old male CRPC patient with both soft tissue and extensive skeletal metastases.

Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer.

Objective 177Lu-DKFZ-PSMA-617, a urea-based compound, binds to the extracellular domain of prostate-specific membrane antigen, thus providing an effective target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Before its therapeutic use, it is necessary that the radiation dosimetry of this radiopharmaceutical be studied to determine the safe activity that can be administered in patients to prevent haematological, renal and liver toxicity. The present study thus aimed to assess the pharmacokinetics and dosimetry of 177Lu-DKFZ-PSMA-617 in CRPC patients. Materials and methods After obtaining ethical clearance from the institute ethics review board, we enrolled mCRPC patients who were positive on a Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] PET/CT scan. For kidney protection, a cocktail of lysine and arginine diluted in 2 litres of normal saline was infused, starting from 30 to 60 min before 177Lu-DKFZ-PSMA-617 infusion. The mean administered activity in the overall population was 2.52±1.3 GBq. For the purpose of dosimetry, each patient underwent nine planar whole-body scans along with blood and urine sample collection at 0.5, 3.5, 24, 48, 72, 96, 120, 144 and 168 h, respectively. SPECT/CT was performed to derive the volume of salivary glands (parotid and submandibular glands) and tumour. Dosimetric evaluation was carried out using the OLINDA/EXM 1.0 software. Results A total of 26 mCRPC patients with a mean age of 66.30±9.95 years (range: 38–81 years) were recruited. Normal physiological uptake was observed in all the patients in the lacrimal glands, salivary glands (parotid glands and submandibular glands), liver, spleen, kidneys, intestines and urinary bladder. Organs with the highest absorbed doses were the salivary glands, followed by the kidneys, receiving 1.24±0.26 and 0.99±0.31 mGy/MBq, respectively. The mean absorbed doses to the liver, urinary bladder and red marrow were 0.36±0.10, 0.243±0.09 and 0.048±0.05 mGy/MBq, respectively. The mean whole-body dose was 0.016±0.003 mGy/MBq. Conclusion 177Lu-DKFZ-PSMA-617 therapy is a safe option in the treatment of mCRPC patients.

Reply to Rahbar K et al.

We appreciate the interest of Rahbar et al. in our recent article BLu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment^ [1]. Rahbar et al. expressed certain reservations and queries concerning our article to which we now respond. Rahbar et al. question the definition of biochemical remission as a serum prostate-specific antigen (PSA) level of <4 ng/ ml. The cut-off serum PSA level for complete biochemical response varies in the literature [2, 3]. We considered <4 ng/ ml as representing normalization of the serum PSA level as this is considered the cut-off level in our clinic. In our study, on the basis of this cut-off level, two of 31 patients achieved a complete biochemical response with 1.3 and 1.5 ng/ml serum PSA, respectively. A complete metabolic response was also achieved in the same patients. Schmitz et al. studied PSA normalization with intensity-modulated radiotherapy in patients with clinically localized prostate cancer. They chose a cut-off value of 2 ng/ml [2]. Similarly, Di Lorenzo et al. defined a complete biochemical response as serum PSA normalization [3]. However, they considered a decrease in serum PSA level of >50 % as a biochemical partial response, in agreement with Scher et al. [4]. The second issue raised by Rahbar et al. concerns the utility of amino acid infusion. In the initial phase of the study, we did not know if the kidneys could be protected by positive amino acid infusion as can be achieved during Lu-DOTATAE therapy. We infused the patients with positive amino acids in the hope that this would protect the kidneys. In a study using a protocol similar to ours, Baum et al. used an amino acid infusion procedure solely for patient hydration [5]. The small molecular PSMA and radioligand Lu-PSMA agents concentrate in the kidneys because PSMA receptors are expressed in the proximal convoluted tubules; thus it seems that there is no additional benefit from amino acid infusion. There is an aphorism in statistics that ‘absence of evidence is not evidence of absence’. However, we found evidence that amino acid infusion has a negligible effect in protecting the kidneys during Lu-DKFZ-PSMA-617 therapy. Interestingly, a groundbreaking preclinical study in mice by Benešová et al. showed that coinjection of 2 mg/kg of the carboxypeptidase II inhibitor 2-PMPA (4-(phosphonomethyl)piperazine-2-carboxylic acid) nearly completely blocked Lu-DKFZ-PSMA-617 uptake in the kidneys [6]. However, its utility in humans is yet to be assessed. We agree with Rahbar et al. that infusion of amino acid solutions could make this simple therapy complicated. Rahbar et al. also raised a concern regarding the infusion of Lu-DKFZ-PSMA-617 for up to 4 h as per the EANM guidelines [7]. However, we presume that the authors have misinterpreted the Lu-DKFZ-PSMA-617 infusion duration. To clarify, amino acids were infused for up to 4 h starting 30 – 60min before Lu-DKFZ-PSMA-617 infusion, and the Lu-DKFZ-PSMA-617 was infused over 10 – 30 min. This information is provided in the paper in the ‘Materials and methods’ section under the heading ‘Lu-DKFZ-PSMA617 infusion and dosing of Lu-DKFZ-PSMA-617’. At the time the study was initiated, there was no literature regarding the safety and duration of Lu-DKFZ-PSMA-617 infusion. Hence, we initially started with a slow infusion of LuDKFZ-PSMA-617 over 30 min. When no side effects were observed, we gradually reduced the infusion time to 10 min. This reply refers to the letter to the editor at http://dx.doi.org/10.1007/s00259016-3530-2.

Dosimetric analysis of 177Lu-DOTA-rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

ObjectiveRadioimmunotherapy targeting CD20 receptors in lymphoma using radiolabeled chimeric antibodies may lead to better therapeutic responses than cold anti-CD20 antibodies. This study aimed to assess the biodistribution and present reasonable estimates of normal organ doses, including red marrow using 177Lu-DOTA-rituximab. Materials and methodsPatients with relapsed/refractory CD20+ B-cell non-Hodgkin’s lymphoma were recruited into this prospective study. In-house labeling of 177Lu-DOTA-rituximab was performed and administered after quality assurance. Rituximab (375 mg/m2), followed by 50 mCi (1850 MBq) of 177Lu-DOTA-rituximab was administered as a slow intravenous infusion and emission images were acquired. Regions of interest were drawn for kidney, liver, heart, bladder, spleen, and tumor lesions on both anterior and posterior images. Internal dose estimation was performed using OLINDA v1.0 software. ResultsThe mean age of the 10 patients (eight men and two women) was 52±13 years. The uptake of radiolabeled antibody was visualized within 30 min of administration in the liver, kidneys, heart, spleen, and bladder. The coefficient of determination (R2) was greater than 0.95 for organs and the whole body in all patients. The effective half-life of radioimmunoconjugate was 100±28 h (42–126 h). The critical organ in our study was the red marrow. The average total body dose, effective dose, and effective dose equivalent calculated in all 10 patients were 0.13±0.02, 0.15±0.03, and 0.22±0.04 mGy/MBq, respectively. ConclusionThere may be considerable interindividual differences in absorbed doses of organs and generalization or extrapolation of doses in the clinical setting at present is not feasible with 177Lu-DOTA-rituximab in non-Hodgkin’s lymphoma patients. Patient-specific dosimetry is thus recommended to eliminate the variations and reduce the possibility of dose-limiting toxicity.

Incidental Detection of Parathyroid Adenoma on Somatostatin Receptor PET/CT and Incremental Role of 18 F-Fluorocholine PET/CT in MEN1 Syndrome

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by combined occurrence of tumors of endocrine glands including the parathyroid, the pancreatic islet cells, and the anterior pituitary gland. Parathyroid involvement is the most common manifestation and usually the first clinical involvement in MEN1 syndrome, followed by gastroentero-pancreatic neuroendocrine tumors (NETs). Here we present a case where the patient initially presented with metastatic gastric NET and a single parathyroid adenoma was detected incidentally on 68Ga-DOTANOC PET/CT done as part of post 177Lu-DOTATATE therapy (PRRT) follow-up. Further 18F-fluorocholine PET/CT showed four adenomas for which the patient subsequently underwent subtotal parathyroidectomy.

Comparison of Conventional Ultrasound, Doppler, Elastography and Contrast Enhanced Ultrasonography Parameters with Histopathology Findings in the Differential Diagnosis of Benign and Malignant Thyroid Nodules

Background: Though neck ultrasound is the first line of choice for the screening of thyroid nodules, very few studies have compared the diagnostic performances of both conventional and advanced ultrasound parameters. In this study, we aim to compare various conventional and advanced ultrasound imaging parameters and confirm it with histopathology findings to differentiate between benign and malignant thyroid nodules. Methods: One hundred and thirty nine patients with 173 thyroid nodules underwent conventional ultrasonography (cUSG) which included gray-scale parameters, colour Doppler (CD) and power Doppler (PD) followed by elastography and contrast enhanced ultrasonography (CEUSG). Post-USG imaging all patients underwent fine needle aspiration cytology followed by surgery if indicated and histopathological results were obtained. Stata 11.2 statistical software was used for the statistical analysis. Results: Of 173 nodules, 65 were benign and 108 were malignant. cUSG had a sensitivity, specificity, PPV, NPV and accuracy of 94.4%, 90.4%, 94.4%, 90.4%, and 91.9%, respectively with AUC:0.97. On ROC analysis, the cut-off value for differentiating malignant from benign thyroid nodules on Ueno elasticity scoring was >3; AUC: 0.86 versus >2.2 using elasticity ratio method, AUC: 0.90. CEUSG and elastography had sensitivity, specificity, PPV, NPV and accuracy of 93.8%, 95.3%, 97.2%, 89.8%, and 94.2%, respectively with AUC:0.98. On combining and ranking, both conventional and advanced cUSG parameters, the significant indicators for malignancy were heterogeneous contrast enhancement, followed by Type-IV/V PD flow patterns, absence of ring enhancement and elasticity ratio >2.2 patterns with the largest AUC:0.994. Conclusions: Conjoint analysis of specific features of thyroid nodules on cUSG, elastography and CEUSG will enhance the diagnostic value in the screening of thyroid nodules.

Estimation of whole body radiation exposure to nuclear medicine personnel during synthesis of 177lutetium-labeled radiopharmaceuticals

Purpose of the Study: With rapid development in the field of nuclear medicine therapy, radiation safety of the personnel involved in synthesis of radiopharmaceuticals has become imperative. Few studies have been done on estimating the radiation exposure of personnel involved in the radio labeling of 177Lu-compounds in western countries. However, data from the Indian subcontinent are limited. We have estimated whole body radiation exposure to the radiopharmacist involved in the labeling of: 177Lu-DOTATATE, 177Lu-PSMA-617, and 177Lu-EDTMP. Materials and Methods: Background radiation was measured by keeping a pocket dosimeter around the workbench when no radioactive work was conducted. The same pocket dosimeter was given to the radiopharmacist performing the labeling of 177Lu-compounds. All radiopharmaceuticals were synthesized by the same radiopharmacist with 3, 1 and 3 year experience, respectively, in radiolabeling the above compounds. Results: One Curie (1 Ci) of 177Lu was received fortnightly by our department. Data were collected for 12 syntheses of 177Lu-DOTATATE, 8 syntheses of 177Lu-PSMA-617, and 3 syntheses of 177Lu-EDTMP. Mean time required to complete the synthesis was 0.81, 0.65, and 0.58 h, respectively. Mean whole body radiation exposure was 0.023 ± 0.01 mSv, 0.01 ± 0.002 mSv, and 0.002 ± 0.0006 mSv, respectively. Overall mean radiation dose for all the three 177Lu-compounds was 0.014 mSv. Highest exposure was obtained during the synthesis of 177Lu-DOTATATE. Conclusion: Our data suggest that the manual radiolabeling of 177Lu compounds is safe, and the whole body radiation exposure to the involved personnel is well within prescribed limits.

Preliminary Experience with Yttrium-90-labelled Rituximab (Chimeric Anti CD-20 Antibody) in Patients with Relapsed and Refractory B Cell Non-Hodgkins Lymphoma

BACKGROUND AND OBJECTIVES The aim of the study is to evaluate the therapeutic efficacy and safety of Yttrium- 90 radiolabelled chimeric anti CD20 antibody-Rituximab in the treatment of patients with relapsed/ refractory B cell Non-Hodgkins Lymphoma (NHL). METHODS Twenty patients with relapsed/refractory CD20+ NHL in progressive state were included in the study. These patients had undergone a median of 2 (range 2-5) prior standard chemotherapy ± immunotherapy regimens. All the patients received rituximab 250 mg/m2 on days 1 and 8, and either 14 MBq/kg (0.4 mCi/kg) or 11 MBq/kg (0.3 mCi/kg) of Y-90 Rituximab on day 8 (maximum dose, 32 mCi) depending upon their platelet count. The patients were observed for systemic toxicity and response for at least 12 weeks after therapy. RESULTS No acute adverse effects were observed after the administration of 90Y-Rituximab. Overall response rate (ORR) was 45% of which complete response (CR) was observed in 2 patients, stable disease in 1 patient and partial response in 6 patients. The therapy was well tolerated with grade IV thrombocytopenia, neutropenia and anemia observed in 3, 4 and 2 patients respectively. CONCLUSION 90Y-Rituximab therapy is safe and well tolerated in high risk extensively pretreated NHL patients. Toxicity is primarily hematologic, transient and reversible.