Systemic Radionuclide Therapy Research Articles

Rapid predictive dosimetry for Second Strike prescription based on whole body radioiodine kinetics in differentiated thyroid cancer.

In systemic radionuclide therapy such as radioiodine (I-131) for differentiated thyroid cancer, post-therapy dosimetry is essential to verify pre-therapy predictions, which in turn informs the next treatment. However, post-therapy multi-time point dosimetry is resource intensive and unfeasible in many institutions. We devised a schema of rapid predictive dosimetry by circumventing post-First Strike multi-time point dosimetry with carefully assigned gestalt values of predicted kinetics to personalise the Second Strike prescription. Verification is performed after the First Strike. Patient-specific time-activity curve is plotted from serial measurements of whole body exposure rates to obtain its decay constant; its inverse is the whole body Time Integrated Activity Coefficient (TIAC). The percentage of whole body TIAC attributed to blood is carefully assigned by gestalt based on population kinetics tabulated in Part 1, adjusted by any metastasis on I-131 whole body scintigraphy. Marrow absorbed dose is calculated by EANM formularism. Lung safety threshold at 48h post-therapy is linearly scaled by height, where the patient's risk of lung radiotoxicity is revealed from the whole body time-activity curve value at 48h. Predictive prescription for the second I-131 fraction (Second Strike) is by careful gestalt assessment based on predicted kinetics, remaining marrow and lung tolerance, marrow dose rate constraint per fraction (0.265 Gy/h), local regulatory and facility requirements in relation to radiation protection. Tumour dosimetry is obviated under the assumption of severe tumour absorbed dose heterogeneity. The final prescription for the Second Strike is usually the lowest I-131 activity amongst all clinical, dosimetric and regulatory constraints. This schema is incorporated into a Predictive Calculator spreadsheet for rapid predictive dosimetry, and is freely available. Calculations may be completed within minutes to generate personalised predictive prescriptions, making it feasible for routine clinical implementation. Our innovative schema of rapid verification and predictive dosimetry bridges the technological gap between empiric vs theranostic prescription to help institutions modernise. Its expeditious design makes this schema feasible to be integrated into the routine clinical workflow. Its predictive estimates provide invaluable dosimetric insight to inform the next I-131 fraction, allowing every prescription to be scientifically rationalised and personalised according to individual circumstances.

A simplified general schema for rapid single time-point marrow predictive dosimetry.

The red marrow is often the dose-limiting organ in systemic radionuclide therapy. However, multi-time-point personalised predictive dosimetry is resource intensive and impractical for routine clinical implementation. Single-time-point methods are a reasonable alternative for streamlining dosimetric workflows. However, there is a lack of single time-point methodology specific for the marrow. A simplified schema for rapid marrow predictive dosimetry is proposed based on direct image quantification of marrow radioconcentration, which may be generalised to most forms of systemic radionuclide therapy.

A dosimetric comparison of systemic peptide receptor radionuclide therapy and intra-arterial peptide receptor radionuclide therapy in patients with liver dominant gastroenteropancreatic neuroendocrine tumours.

Intra-arterial radionuclide therapy (IART) treatment allows direct delivery of 177 Lu-DOTATATE to the overexpressed somatostatin-positive neuroendocrine liver metastases, which led to higher tumour concentration compared with systemic radionuclide therapy (SRT). The aim was to evaluate and compare the absorbed doses of both IART and SRT to organs and hepatic metastatic sites. A total of 48 patients received SRT and IART. In SRT, activity was administered intravenously, whereas in IART, activity was administered directly into hepatic arteries. The sequential whole-body images were acquired at 2, 4, 24, 72 and 160 h. The reconstructed whole-body planar and single-photon emission computed tomography-computed tomography images were processed using the Dosimetry Toolkit for the estimation of normalized cumulated activity in the organs and tumour lesions. The absorbed dose was computed using OLINDA EXM 2.0 software. The median absorbed dose (mGy/MBq) of kidneys and spleen in IART was compared with SRT and found to be decreased by 30.7% ( P = 0.03) and 37.5% ( P = 0.08), whereas it was found to be increased by 40% ( P = 0.26) and 8.1% ( P = 0.28) in the liver and lungs. The median dose (mGy/MBq) of tumours determined in IART was found to be increased by 62.2% ( P = 0.04). IART with 177 Lu-DOTATATE significantly increases tumour dose while reducing overall systemic toxicity in comparison to SRT treatment. After considering the maximum tolerance limit of kidneys in peptide receptor radionuclide therapy, the number of treatment cycles and injected activity can be optimized further with IART for better response and survival.

Metastatic Extra-Adrenal Pheochromocytoma with Single Kidney and Renal Compromise: A Case Report of Excellent Response, Tolerability, and Outcome to a Modified Regimen of 131I-mIBG, and Decision-Making between 131I-mIBG Therapy and PRRT

AbstractDetermining the choice and the goal is key element for decision-making of a systemic radionuclide therapy. They should be clearly defined in deciding and individualizing the dose and regimen. For iodine-131 metaiodobenzylguanidine (131I-mIBG) therapy, the important considerations during dose fractionation include disease burden, tumor biology, functional symptoms, and associated comorbidities, all of which are important determinants for the intent and course of treatment. Herein, we present the case of a 67-year-old elderly female with highly functional metastatic recurrent extra-adrenal pheochromocytoma (presenting 42 years after the primary surgery and 32 years following excision of pararenal recurrence) with multiple comorbidities including single kidney and borderline renal compromise, treated successfully with a relatively lower dose of 131I-mIBG (cumulative dose of 22.2 GBq in four cycles with a mean dose of 5.7 GBq per therapy cycle). The excellent tumor burden reduction, hormonal tumor marker response, and most importantly asymptomatic status could be achieved with the administered dose. On follow-up, none of the pretherapeutic parameters (including renal function) showed any further derangement compared with the baseline during next 24 months following the treatment. All cycles were well tolerated with only reversible hematological toxicity that normalized without any active intervention. The report is intended to provide some guidance for future therapeutic regimens.

Phase I study of autolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium.

4115 Background: Metastatic neuroendocrine neoplasms (mNEN) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, systemic somatostatin analogues (SSA), and systemic peptide receptor radionuclide therapy (PRRT). Additional options are needed; we have explored intralesional (IL) rose bengal disodium (PV-10), an investigational autolytic immunotherapy that can yield immunogenic cell death and disease-specific functional adaptive immunity. Methods: This phase 1 study evaluated safety, tolerability and impact on symptoms and biochemical markers resulting from IL PV-10 administered percutaneously to hepatic lesions in patients (pts) with progressive mNEN not amenable to resection or other potentially curative therapy. Eligible lesion(s) were 1.0 - 3.9 cm in longest diameter with amount of PV-10 administered proportional to size. Cohort 1 (n = 6 pts) received PV-10 to a single lesion per treatment cycle; Cohort 2 (n = 6) could receive injection to multiple lesions per treatment cycle. Pts could receive further PV-10 ≥6 weeks after prior injection. The primary endpoint was safety. Secondary endpoints included objective response rate (ORR) assessed by contrast enhanced CT (RECIST 1.1) and 68Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21 QOL instruments). Results: Twelve pts were enrolled, 50% male, median age 66 yrs (range 47-79). Primary sites: 7 small bowel, 2 pancreas, 1 caecal, 2 unknown; grade: Gd1 = 5, Gd2 = 7. All pts had received SSA and PRRT as part of previous therapy and all had symptomatic, progressive disease. Median CgA was 1585 (range 35-10370). One lesion was injected per cycle for all 12 pts; none were suitable for multiple injections. One pt received 4 sequential PV-10 treatment cycles, 3 received 2 cycles, and 8 received 1 cycle. Toxicity was consistent with experience in other hepatic malignancies: post-procedure pain was reported by most pts; grade 3 photosensitivity reaction occurred in 1 pt; and grade 1 elevation of hepatic enzymes attributed to PV-10 occurred in 2 pts, resolving by day 7. Additionally, carcinoid flare occurred in 1 pt. ORR of injected lesions was 42%; patient-level disease control was 84%. Estimated PFS was 9.2 months; median OS was 22.5 months. CgA remained stable in 10 pts and upregulation of NK and activated CD4+ T lymphocytes was observed post-injection. QOL data at months 1 and 3 showed stable or improved carcinoid symptoms and global health status in 9 pts. Conclusions: PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease and symptom control in a heavily pre-treated population. Multiple cycles were delivered safely in suitable patients. Adaptive immune upregulation is consistent with other solid tumors and supports potential systemic benefit. Clinical trial information: NCT02693067.

Cohort 1 results of a phase I study of autolytic immunotherapy of metastatic neuroendocrine neoplasms using intralesional rose bengal disodium.

e16694 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed, especially when available options have been exhausted. Intralesional (IL) rose bengal disodium (PV-10), an autolytic immunotherapy under development for solid tumors, is being investigated as a potential option for treatment-refractory patients (pts) with hepatic metastases. Methods: This phase 1 study is evaluating the safety, tolerability and objective response resulting from percutaneous administration of PV-10 in 12 pts with progressive mNEN refractory to SSA and PPRT; pts must have at least one injectable hepatic lesion (1.0-3.9 cm in longest diameter) not amenable to resection or other potentially curative therapy. In Cohort 1 (n = 6) pts received PV-10 to a single hepatic lesion per treatment cycle, and could receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. The primary endpoint is safety. Secondary endpoints include objective response rate assessed by independent review of contrast enhanced CT and by 68Ga-DOTATATE PET. Results: Cohort 1 has fully enrolled, with 4 of 6 pts male, median age 65 yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1. NET grade: Gd1 = 5, Gd2 = 1. All pts had progressed on prior SSA and PRRT. Median baseline CgA was 645 (range 30-2819). One pt received 4 PV-10 treatment cycles, 1 received 2 cycles, and 4 received a single cycle. Toxicity was acceptable, including transient pain post procedure, carcinoid flare and nausea. A partial response of injected lesions was observed in 50% of pts (injected lesion progression in 1 pt), with an overall response of stable disease achieved in 84% of pts by RECIST 1.1 (progressive disease in 1 pt). Progression free survival (PFS) was not reached by CT (range 2.4-25.3+ months), and was 6.1 months by PET. Median overall survival (OS) was ≥22.5 months, with three subjects alive at the data cut-off of Jan 2020 (range 18.1-33.8 months). Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local response of injected tumors and prolonged systemic disease control in some pts. Enrolment to Cohort 2 is nearing completion where an additional 6 pts may receive injection of multiple lesions per treatment cycle. Clinical trial information: NCT00986661 .

Повышение доступности радионуклидной терапии рака предстательной железы в рамках системы обязательного медицинского страхования на региональном уровне: опыт Кемеровской области

The article discusses issues of antineoplastic radiation, particularly radionuclide, therapy payment through compulsory health insurance system. Healthcare organization faces several problems in this field when introducing new treatment methods. Regulatory and infrastructural aspects of the radionuclide therapy provision are brought up. The article discusses the problem raised by the average payment for the diagnostic-related groups (DRG) at the federal level, which makes it difficult to use selected medical services with the cost above the average DRG tariff. As an example, the article describes the experience of Kemerovo region on tariff correction using subgroup split-off method for DRG that includes systemic radionuclide therapy with radium-223. Splitting the federal DRG for sub-groups gave the possibility of providing therapy to patients with prostate cancer in the region. Besides, the authors discuss the relevance and practical aspects of interregional payments in the compulsory healthcare insurance system with respect to the radionuclide therapy in order to improve the quality of medical care for patients with cancer, regardless of infrastructural restrictions and the patients’ residence.

Phase 2 trial of Lu-177-DOTATATE in inoperable pheochromocytoma/paraganglioma.

TPS4159 Background: Pheochromocytoma/paraganglioma (PHEO/PGL) is a rare malignancy that arises from chromaffin cells of typically the adrenal medulla but can also be of extra-adrenal origin. These tumors produce excessive catecholamines such as epinephrine and norepinephrine which causes labile hypertension, tachycardia, and flushing. Lu-177-DOTATATE (Lu-177-dodecanetetraacetic acid‐tyrosine-3-octreotate) is a radiolabeled somatostatin analog that is FDA approved for somatostatin receptor-positive neuroendocrine tumors. It is being being investigated in PHEO/PGL, which overexpress somatostatin receptors. Amino acid solutions containing lysine/arginine (L/A) are routinely co-administered with Lu-177-DOTATATE for renal radioprotection, although solutions containing other amino acids are also used. Methods: This is a prospective, single center, open label Phase 2 study evaluating the efficacy of Lu-177-DOTATATE in PHEO/PGL. Ninety patients will be enrolled, divided into two cohorts of 45 patients each ( SDHx mutation vs. apparent sporadic). Lu-177-DOTATATE is given at a fixed dose of 200 mCi with a co-administration of L/A amino acid solution q8 weeks for 4 cycles. The primary endpoint is the progression-free-survival (PFS) rate at 6 months. Secondary endpoints include response rate, overall survival, time to progression, quality of life measures, and examination of potential biomarkers such as biochemical profiles, Ga-68-DOTATATE PET, and F-18-FDG PET scans. Eligibility criteria include inoperable disease (including non-metastatic), histological confirmation of PHEO/PGL, evidence of disease progression by RECIST 1.1, ECOG performance status of 1 or better, and a positive Ga-68-DOTATATE PET scan. Exclusion criteria include prior treatment with systemic radionuclide therapy such as I-131-MIBG, brain parenchymal metastases, and standard organ dysfunction limitations. Interim analysis using a Simon two-stage optimal design will be performed separately for each cohort after enrollment of 18 patients. First patient accrual to this ongoing study was in the Fall of 2017, and as of February 2019, fourteen patients have been accrued. Preliminary results will be reported at the completion of stage 1 for each cohort. Clinical trial information: NCT03206060.

A phase I study of oncolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium: Cohort 1 results.

4102 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed and one such option is hepatic intralesional (IL) rose bengal disodium (PV-10), an oncolytic immunotherapy under development for solid tumours. Methods: This phase 1 study is evaluating the safety, tolerability and reduction of biochemical markers and symptoms resulting from percutaneous administration of PV-10 in 12 subjects with progressive mNEN with hepatic lesions not amenable to resection or other potentially curative therapy. Target lesion(s) must be 1.0 - 3.9 cm in longest diameter. In Cohort 1 (n = 6) subjects receive PV-10 to a single hepatic lesion per treatment cycle, and can receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. Cohort 2 (n = 6) subjects may receive injection of multiple lesions per treatment cycle. The primary endpoint is safety. Secondary endpoints include objective response rate (ORR) assessed by contrast enhanced CT and 68Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21). Results: Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior SSA and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway. Clinical trial information: NCT02693067.

Review of Gallium-68 PSMA PET/CT Imaging in the Management of Prostate Cancer.

Over 90% of prostate cancers over-express prostate specific membrane antigen (PSMA) and these tumor cells may be accurately targeted for diagnosis by 68Ga-PSMA-positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) imaging. This novel molecular imaging modality appears clinically to have superseded CT, and appears superior to MR imaging, for the detection of metastatic disease. 68Ga-PSMA PET/CT has the ability to reliably stage prostate cancer at presentation and can help inform an optimal treatment approach. Novel diagnostic applications of 68Ga-PSMA PET/CT include guiding biopsy to improve sampling accuracy, and guiding surgery and radiotherapy. In addition to facilitating the management of metastatic castrate resistant prostate cancer (mCRPC), 68Ga-PSMA can select patients who may benefit from targeted systemic radionuclide therapy. 68Ga-PSMA is the diagnostic positron-emitting theranostic pair with the beta emitter Lutetium-177 PSMA (177Lu-PSMA) and alpha-emitter Actinium-225 PSMA (225Ac-PSMA) which can both be used to treat PSMA-avid metastases of prostate cancer in the molecular tumor-targeted approach of theranostic nuclear oncology.

Novel 188Re multi-functional bone-seeking compounds: Synthesis, biological and radiotoxic effects in metastatic breast cancer cells

IntroductionRadiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β− emitting radionuclides for bone pain palliation. As a β− emitter, 188Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[188Re(CO)3(k3-L)], (L=BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line. MethodsAfter synthesis and characterization of the novel organometallic compounds of the type fac-[188Re(CO)3(k3-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively. ResultsAmong all complexes, 188Re3 was obtained with high radiochemical purity (>95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of 188Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1±3.3% IA/g organ, 1h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by 188Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [188ReO4]−. Additionally, 188Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed. ConclusionAltogether, our results demonstrate that 188Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce radiation damage.

Unusual Bone Superscan, MIBG Superscan, and 68Ga DOTATATE PET/CT in Metastatic Pheochromocytoma.

A 17-year-old adolescent boy with biochemically raised 2-hour urinary metanephrine and normetanephrine as well as CT findings of retroperitoneal soft tissue mass and bony metastases was referred for further assessment. Apart from Ga DOTATATE PET/CT evaluation, pretargeted systemic radionuclide therapy assessment with I-MIBG scintigraphy showed unusual phenomenon of MIBG superscan. Postsurgically, restaging Tc-MDP bone scintigraphy showed typical bone superscan features. The MIBG superscan was better delineated on post-I-MIBG therapy images.

Evolution in the treatment of gastroenteropancreatic-neuroendocrine neoplasms, focus on systemic therapeutic options: a systematic review.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors. The present review discusses current therapeutic strategies for the treatment of gastro-entero-pancreatic NEN. Several systemic options are currently available, including medical systemic chemotherapy, biological drugs, somatostatin analogs and peptide receptor radionuclide therapy. The carcinoid syndrome can be adequately controlled with somatostatin analogs; chemotherapy has shown positive outcomes in poor prognosis patients, and peptide receptor radionuclide therapy is a promising treatment based on the use of radioisotopes for advanced disease expressing somatostatin receptors. Targeted therapies, such as multikinase inhibitors and monoclonal antibodies are also recommended or under evaluation for the treatment of advanced NENs, but some critical issues in clinical practice remain unresolved. Depending upon the development of the disease, a multimodal approach is recommended. The treatment strategy for metastatic patients should be planned by a multidisciplinary team in order to define the optimal sequence of treatments.

ВОЗМОЖНОСТИ СИСТЕМНОЙ РАДИОНУКЛИДНОЙ ТЕРАПИИ В ПАЛЛИАТИВНОМ ЛЕЧЕНИИ БОЛЬНЫХ С МЕТАСТАТИЧЕСКИМ ПОРАЖЕНИЕМ КОСТЕЙ

The pain syndrome accompanying metastatic damage of bones, significantly reduces quality of patients life. In recent decades, medical practice implemented methods systemic radionuclide therapy of bone metastases using different radionuclides, which allows to stop both the pain and the progression of the disease. Results of their application give the grounds to consider the perspective development in nuclear medicine of the direction on treatment bone metastatic defeats by means of systemic radionuclide therapy.

POSSIBILITIES OF SYSTEMIC RADIONUCLIDE THERAPY IN PALLIATIVE TREATMENT OF P ATIENTS WITH METASTATIC BONES DISEASE

The pain syndrome accompanying metastatic damage of bones, significantly reduces quality of patients life. In recent decades, medical practice implemented methods systemic radionuclide therapy of bone metastases using different radionuclides, which allows to stop both the pain and the progression of the disease. Results of their application give the grounds to consider the perspective development in nuclear medicine of the direction on treatment bone metastatic defeats by means of systemic radionuclide therapy.

Radiopharmaceutical Therapy of Patients with Metastasized Melanoma with the Melanin-Binding Benzamide 131I-BA52

The performance of cytotoxic drugs is defined by their selectivity of uptake and action in tumor tissue. Recent clinical responses achieved by treating metastatic malignant melanoma with therapeutic modalities based on gene expression profiling showed that malignant melanoma is amenable to systemic treatment. However, these responses are not persistent, and complementary targeted treatment strategies are required for malignant melanoma. Here we provide our experience with different labeling procedures for the radioiodination of benzamides and report on initial dosimetry data and the first therapeutic application of (131)I-BA52, a novel melanin-binding benzamide in patients with metastatic malignant melanoma. Twenty-six adults with histologically documented metastasized malignant melanoma received a single dose of 235 ± 62 MBq of (123)I-BA52 for planar and SPECT/CT imaging. Nine patients were selected for radionuclide therapy and received a median of 4 GBq (minimum, 0.51 GBq; maximum, 6.60 GBq) of the β-emitting radiopharmaceutical (131)I-BA52. A trimethyltin precursor-based synthesis demonstrated high radiochemical yields in the large-scale production of radioiodinated benzamides required for clinical application. (123)I-BA52 showed specific uptake and long-term retention in tumor tissue with low transient uptake in the excretory organs. In tumor tissue, a maximum dose of 12.2 Gy per GBq of (131)I-BA52 was calculated. The highest estimated dose to a normal organ was found for the lung (mean, 3.1 Gy/GBq). No relevant acute or mid-term toxicity was observed with the doses administered until now. Even though dosimetric calculations reveal that the doses applied in this early phase of clinical application can be significantly increased, we observed antitumor effects with follow-up imaging, and single patients of the benzamide-positive cohort of patients (3/5 of the patients receiving a dose > 4.3 GBq) demonstrated a surprisingly long survival of more than 2 y. These data indicate that systemic radionuclide therapy using (131)I-BA52 as a novel approach for the therapy of malignant melanoma is of considerable potential. Future trials should be done to enhance the precision of dosimetry, validate the maximum tolerable dose, and evaluate the effectiveness of the treatment in a prospective manner.

Radiometabolic Treatment of Bone-Metastasizing Cancer: From 186Rhenium to 223Radium

Skeletal metastases occur in many patients with different kinds of malignant tumors, especially in advance stage of breast cancer (in 47%-85% of patients), prostate cancer (33-85%), and lung cancer (32%-60%). The management of painful skeletal metastases is complicated and should be carried out by a multidisciplinary approach including conventional analgesics, antitumor therapy (chemo- and hormone therapy), osteoclast-inhibitory agents (bisphosphonates), corticosteroids, external-beam radiotherapy, surgery, and nuclear medicine therapy. The nuclear medicine therapy for palliation of pain from bone metastases is a systemic radionuclide therapy based on the use of radiopharmaceuticals. In several studies the efficacy of bone-seeking radiopharmaceuticals have been demonstrated in terms of pain reduction from diffuse skeletal metastases. In this review, we will summarize the current literature on bone-seeking radiopharmaceuticals for the treatment of painful bone metastases (Phosphorus-32, Strontium-89, Rhenium-186, Rhenium-188, Samarium-153, and Radium-223) and the combination therapy with biphosphonates and chemotherapy.

External Beam Radiation Therapy With or Without 131I-MIBG Systemic Radiation Therapy in the Therapy of Patients With Malignant Pheochromocytoma and Paraganglioma

Patients with malignant pheochromocytoma (PCC) and paraganglioma (PGL) of the thorax, abdomen and pelvis are often not considered for external beam radiation therapy (EBRT) due to concerns that these tumors are not radiosensitive. Therefore, we have reviewed our institutional experience with EBRT with particular attention to a subset of patients treated with combined 131I-MIBG systemic radionuclide therapy and EBRT to areas of bulky disease. Forty-nine consecutive patients with a diagnosis of PCC or PGL treated with EBRT at the University of Pennsylvania from 1984 to 2012 were reviewed in an IRB-approved retrospective study. Response rate was evaluated by RECIST v1.1 criteria as stable disease and partial responses. Of the 24 patients with tumors in the thorax, abdomen or pelvis, the median dose/fractionation was 50 Gy/25 fractions. 20 patients received megavoltage photons and 4 patients received protons. The in-field objective response rate in evaluable patients was 85% with 75% of patients maintaining local control at 12 months. Treatment toxicity was related to irradiation of tumor-adjacent normal tissues without clinically significant hematologic toxicity in the 16 patients receiving only EBRT. Because of non-overlapping toxicity of EBRT and 131I-MIBG and the potential for radiosensitization from combined low dose rate-high dose rate therapy, 8 patients with widespread systemic metastases were treated with external beam radiation therapy to 12 sites of bulky, symptomatic tumor in conjunction with systemic 131I-MIBG (2 mCi/kg per treatment, median 2 cycles 3 months apart and radiation typically given immediately after second cycle). In these patients, all areas irradiated with EBRT showed durable objective tumor response despite all patients eventually experiencing out-of-field systemic progression at a median time of 11.9 months. The median survival in the combined modality cohort is 29 months. Four of these patients remain alive with excellent performance status 27, 29, 35 and 36 months after EBRT. EBRT can be highly effective in local management of PCC and PGL. EBRT can be used safely in conjunction with 131I-MIBG due to non-overlapping toxicities with excellent control of locally bulky tumors. Based on these results, a clinical protocol with combined 131I-MIBG and EBRT is currently being designed.

Radiation Induces Up-Regulation of Somatostatin Receptors 1, 2, and 5 in Small Cell Lung Cancer In Vitro Also at Low Absorbed Doses

Radiation can be used to up-regulate the expression of the somatostatin receptor (sstr) subtype 2 in small cell lung cancer (SCLC) cells at absorbed doses of 2-8 Gy. Increased sstr expression results in increased binding of radiolabeled somatostatin analogs to the tumor cell, which enhances the efficacy of systemic radionuclide therapy. The aim of this study was to determine if lower absorbed doses could up-regulate sstr2 expression, and possibly influence other sstr subtypes. Human H69 SCLC cells were irradiated with an absorbed dose of 0.12-6.0 Gy and the sstr mRNA expression 3 days after irradiation was measured by quantitative real-time polymerase chain reaction for sstr1-5. At the same time point was the binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate to the cells measured after irradiation to an absorbed dose of 0.12-2.0 Gy and compared to the binding to nonirradiated cells. mRNA expression of sstr1, sstr2, and sstr5 was increased by a factor of 1.5-2 in cells irradiated with absorbed doses≥4 Gy and the binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate was, accordingly, 2-3 times higher to irradiated cells for all absorbed doses, except 0.25 Gy. The binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate was increased after radiation exposure. This increase was observed at low absorbed doses in parallel with up-regulation of sstr1, sstr2, and sstr5 mRNA.

Role of Radionuclide Therapy as Adjuvant to Palliative External Beam Radiotherapy for Painful Multiple Skeletal Metastasis

BackgroundThe aim of this study was to evaluate the palliative efficacy of localized external radiotherapy (RT) combined with systemic radionuclide (RN) therapy in patients who had multiple painful osseous metastases of different primary origins.MethodsThirty-three patients initially local external radiotherapy was delivered to the most symptomatic region in all patients. Then they received either Re 186 HEDP or Sm 153 EDTMP. The performance status was assessed according to ECOG scale. Before treatment, at the end of the radiotherapy and after the four weeks of systemic radionuclide therapy, analgesic intake and pain status were recorded by the RTOG scoring system, and EORTC QLQ C30 (Version 3.0 Turkish) questionnaire was performed to evaluate the quality of life.ResultsImproved performances of 33.3% for post radiation therapy and 50% for post radionuclide therapy in the ECOG scale were observed. Statistically significant correlations were found between the primary origins and decreased pain and analgesic intake (p < 0.05), but no differences were observed on the self assessment quality of life questionnaire.ConclusionsBoth Re 186 HEDP, Sm 153 EDTMP are effective and safe in bone pain palliation as an adjuvant to local field radiation therapy of breast and prostate cancer patients, who also continued to receive chemotherapy and/or hormontherapy.