Long-Term Tumor Control Following Targeted Alpha Therapy (TAT) of Low-Grade Gliomas (LGGs): A New Treatment Paradigm?

The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [213Bi]Bi/[225Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [90Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG

Cardiovascular magnetic resonance findings in a case of Danon disease

Danon disease is a rare X-linked dominant lysosomal glycogen storage disease that can lead to severe ventricular hypertrophy and heart failure. We report a case of Danon disease with cardiac involvement evaluated with cardiovascular magnetic resonance, including late gadolinium enhancement and perfusion studies

Efficacy and safety of 90Y-DOTATATE therapy in neuroendocrine tumours

Wstęp: Celem pracy była ocena skuteczności oraz toksyczności celowanej terapii receptorowej (PRRT) guzów neuroendokrynnych z wykorzystaniem analogu somatostatyny Tyr3-octreotate znakowanego 90Y (90Y-DOTATATE). Materiał i metody: Do badania włączono 46 pacjentów z rozsianym lub nieoperacyjnym guzem NET. 90Y-DOTATATE podawano w 3–5 kursach w odstępach 4–9-tygodniowych. Każdorazowo wyznaczano aktywność terapeutyczną, uwzględniając taką całkowitą powierzchnię ciała, by nie przekroczyć sumarycznej wartości 7,4 GBq/m2. Przed terapią i po niej wykonano oznaczenia parametrów morfotycznych, nerkowych oraz wątrobowych, a także stężenia chromograniny A. Wyniki: Spośród 46 leczonych pacjentów jeden chory zmarł przed zakończeniem pełnego cyklu terapeutycznego, a 16 po zakończeniu terapii, w tym jeden z powodu zawału serca. W 12. miesiącu obserwacji stwierdzono 47% stabilizacji, 31% częściowych odpowiedzi oraz 9% progresji wśród 45 pacjentów, którzy ukończyli leczenie. Pięciu chorych zmarło przed 12. miesiącem obserwacji. W jednym przypadku utracono możliwość uzyskania informacji o chorym po 12 miesiącach. Okres czasu bez progresji choroby wyniósł 37,4 miesiąca. W ciągu pierwszego roku od zakończenia terapii zaobserwowano jedynie przejściowe obniżenie wartości morfotycznych krwi oraz przejściowy wzrost stężenia kreatyniny i spadek wartości przesączania kłębuszkowego (GFR). Wnioski: Celowana terapia receptorowa z użyciem 90Y-DOTATATE może być skuteczną oraz stosunkowo bezpieczną metodą leczenia prowadzącą do częściowej odpowiedzi lub stabilizacji choroby u większości pacjentów. (Endokrynol Pol 2011; 62 (5): 392–400)Background: The aim of this study was to assess the efficacy and toxicity of peptide receptor radionuclide therapy (PRRT) with the use of the high affinity somatostatin receptor subtype 2 analogue, 90Y labelled Tyr3-octreotate, (90Y-DOTATATE) in neuroendocrine tumours (NETs). Material and methods: 46 patients with disseminated or non-operable NET were enrolled in this study. The 90Y-DOTATATE therapeutic activity was calculated per total body surface area up to a total of 7.4 GBq/m2 administered in three to five cycles, repeated every four to nine weeks. Before and after the therapy, blood tests for haematology, kidney and liver function, and chromogranin A were performed. Results: Out of 46 90Y-DOTATATE treated patients, one died before completing the therapy and 16 died after completing the therapy, among them one due to myocardial infarction. After 12 month follow-up, stabilisation of disease was observed in 47%, partial remission in 31%, and progression in 9% of the 45 patients who completed the therapy. Five patients died before completion of 12 months of follow-up. One of the patients died due to myocardial infarction. In one case, the information after 12 months is incomplete. The progression free survival was 37.4 months. During 12 months follow-up, transient decrease of PLT, WBC and haemoglobin values was observed. A transient increase of creatinine level (within normal ranges) and decrease of GFR values were found. Conclusions: NETs 90Y-DOTATATE therapy results in symptomatic relief and tumour mass reduction. The mild critical organ toxicity does not limit the PRRT of NETs. (Pol J Endocrinol 2011; 62 (5): 392–400

Locoregional treatment of brain tumours

Glioblastoma multiforme (GBM), primary brain tumor is the most common and most malignant of the glia tumors. It is characterized by the worst prognosis with a median overall survival time of only 9-15 months. The infiltrating character of the tumor, its molecular heterogeneity, as well as the protective effects of the blood-brain barrier are the main causes for the insufficiency of established front line treatments (surgery, radio- and chemotherapy). The best treatment strategy for patients with recurrent GBM is unclear and controversial. Even with established state of the art treatment in almost 90% of patients the recurrence of disease is observed and median survival after recurrence is less than 6 months. An alternative method of treatment is to apply the drug locally. It has been shown that GBM overexpresses the of NK-1 receptor and substance P (SP) can be used as a ligand. Alpha emitters, with shorter range and higher energy than beta emitters, offer the new potential for selective irradiation of tumors, with minimizing damage to adjacent tissue. This chapter describes the use of radiolabeled SP for intratumoral treatment of the glia tumors.JRC.G.I.5-Advanced Nuclear Knowledg

Targeted alpha therapy of glioblastoma multiforme: First clinical experience with 213Bi-substance P

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, has a very poor prognosis with a median overall survival of 15 months despite of aggressive therapy including surgery, chemotherapy and radiation therapy. Targeted alpha therapy with the short range, high LET alpha emitter 213Bi offers the potential for selective irradiation of tumors, while minimizing damage to adjacent, functional critical areas of the brain. The peptide carrier substance P is targeting NK 1 receptors, which are consistently over-expressed on GBM cells. Here we report the first clinical experience with 213Bi-labeled DOTA-Substance P (213Bi-SP) in patients with recurrent GBM.JRC.E.5-Nuclear chemistr

Nuclear medicine training and practice in Poland.

In Poland, nuclear medicine (NM) has been an independent specialty since 1988. At the end of 2013, the syllabus for postgraduate specialization in NM has been modified to be in close accordance with the syllabus approved by the European Union of Medical Specialists and is expected to be enforced before the end of 2014. The National Consultant in Nuclear Medicine is responsible for the specialization program in NM. The Medical Center of Postgraduate Training is the administrative body which accepts the specialization programs, supervises the training, organizes the examinations, and awards the specialist title. Specialization in NM for physicians lasts for five years. It consists of 36 months of training in a native nuclear medicine department, 12 months of internship in radiology, 3 months in cardiology, 3 months in endocrinology, 3 months in oncology, and 3 months in two other departments of NM. If a NM trainee is a specialist of a clinical discipline and/or is after a long residency in NM departments, the specialization in NM can be shortened to three years. During the training, there are obligatory courses to be attended which include the elements of anatomy imaging in USG, CT, and MR. Currently, there are about 170 active NM specialists working for 38.5 million inhabitants in Poland. For other professionals working in NM departments, it is possible to get the title of a medical physics specialist after completing 3.5 years of training (for those with a master's in physics, technical physics or biomedical engineering) or the title of a radiopharmacy specialist after completing 3 years of training (for those with a master's in chemistry or biology). At present, the specialization program in NM for nurses is being developed by the Medical Centre of Postgraduate Education. Continuing education and professional development are obligatory for all physicians and governed by the Polish Medical Chamber. The Polish Society of Nuclear Medicine (PTMN) organizes regular postgraduate training for physicians working in NM. Educational programs are comprehensive, covering both diagnostics and current forms of radioisotope therapy. They are aimed not only at physicians specialized/specializing in NM, but also at other medical professionals employed in radionuclide departments as well as physicians of other specialties.5 halama

Alphaknife for glioma tumors: two years experiences with targeted alpha therapy of 213Bi-substance P

Glioblastoma multiforme (GBM) is characterized by the worst prognosis with an overall survival (OS) 9-15 months, median 13 months. The infiltrating character of the tumor, molecular heterogeneity, as well as the protective effects of blood-brain barrier are the causes of insufficient front line treatments (surgery, radio and chemotherapy); 90% of patients have a recurrence at the original tumor location. Therefore a new type of strategies must be implemented and proofed. It has been demonstrated that NK-1 receptor system is extensively expressed in glioma cells, and substance P can be used as a ligand for targeted therapy. On the other hand alpha emitter, like 213Bi offers the new potential for selective irradiation of tumors, with minimizing damage to adjacent tissue.JRC.E.5-Nuclear chemistr

Improved tumor control and absence of late neurotoxicity using alpha (213Bi) as compared to beta (90Y) labelled-DOTA-Substance P for the treatment of low grade gliomas

Low-grade gliomas (LGG) of astrocytic, oligodendrocytic or mixed phenotype represent an unmet medical need as orphan disease. Due to relatively long median survival time of 8-15 years, prospective clinical studies are rarely conducted. Recommended therapeutic regimens range from an observational strategy to extensive resection with awake craniotomy in order to diminish the risk of transformation into a higher grade glioma. We have conducted an observational study in 8 low grade gliomas using the radiopeptidic targeting vector [213Bi]/[90Y]-DOTA-substance over a period of 18 years (4-18 years, median ). Besides therapeutic efficacy, we assessed long-term effects, especially late neurotoxicity of beta- and alpha-therapy following local injection. Since biodistribution of the small peptidic vector (1.8 KD) extends over large parts of the ipsi- and possibly contralateral CNS, late toxicity is of principal concern although no NK-1 receptors are expressed in the normal supratentorial brain. The alpha particles releases their decay energy within an ultrashort range that represents the diameter of 1-2 tumor cells (virtual single cell radiotherapy) while beta-therapy targets many more cells (cross-fire effect). We are comparing long-term side effects following alpha-therapy (Bi-213, range 0.1mm) with those of beta-therapy (Y-90: range 5mm, 2.3 MeV). So far, no recurrence or late toxicity has been observed in newly alpha-treated LGG over a period of 18 (OGII), 11 (AII), 10 (AII), 7 (OGII), 4 (OGII) and 3 (AII) years. Injection of [213Bi]-DOTA-substance into an LGG infiltrating the motor cortex was well tolerated with only transient neurological deficits. In contrast, all Y-90 treated LGG cases either developed signs of late radiotoxicity or recurrence after an observation interval of 8-10 years. Two of these beta-cases were subsequently treated with one cycle of alpha-therapy. One of them showed a slight worsening of pre-existing aphasia, presumably due to previous application of high-dose beta irradiation. In conclusion, local alpha therapy appears to be superior to beta-therapy regarding long-term tumor control and late toxicity.JRC.G.I.5-Advanced Nuclear Knowledg

Recurrent glioblastoma multiforme - local alpha emitters targeted therapy with 213Bi-DOTA-substance P

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor. The median survival time is 14.6 months from time of diagnosis, in spite of aggressive surgery, radiation therapy and chemotherapy. Only 3 to 5% of patients survive more than three years. Recurrence of GBM is nearly universal, confers a dismal prognosis with a 6-months progression free survival (6M-PFS) rate of 15% to 21% and a median survival of 6.2 months. Advancements in the past decades have not significantly increased the overall survival of patients with this disease. GBM has been demonstrated NK-1 receptor system and substance P can be used as a ligand for targeted therapy. Alpha emitter, like 213Bi offers the new potential for selective irradiation of tumors, with minimizing damage to adjacent tissue. Material and methods: 21 patients with primary recurrent glia tumor IV after standard therapy were included in the study during two years. Following intracavitary or intratumoral insertion of 1-2 catheter systems, patients were treated with 1-8 doses of 2 GBq 213Bi-DOTA-Substance P (213Bi-SP) in intervals of 2 months. 68Ga-DOTA-Substance P (68Ga-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI. Study was approved by the ethical committee of the Medical University of Warsaw. Results: Treatment with activity up to 13 GBq 213Bi-SP was tolerated well with only mild transient adverse reactions: in 1 patient transient increase of focal neurological symptoms and in 3 patients episodes of epileptic seizures several days after treatment. PET/CT imaging showed high retention of the radiolabeled peptide at the tumor site. Out of 21 evaluable patients, 17 progressed within the follow-up period, 5 of them are alive at the end of follow-up. Four patients were excluded from evaluation due to lack of data. Median progression free survival was 3.7 months, with a 6 months progression free survival rate of 19% . The median overall survival from the first diagnosis was 25.2 months, and from the start of 213Bi-SP was 6.5 months. Follow up of therapeutic responses and toxicity is continued and patient recruitment is ongoing. Conclusions: Treatment of recurrent GBM with 213Bi-SP is safe and well tolerated. Targeted alpha therapy with 213Bi-SP may evolve as a promising novel option for treatment of recurrent GBM.JRC.E.5-Nuclear chemistr