Radium-223 dichloride: a new paradigm in the treatment of prostate cancer

Review[Abstract] Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while β-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients' profile that make them suitable to therapy and chances for further studies

Peter Josef Ell : discurs llegit a la cerimònia d'investidura celebrada a l'aula magna de Casa Convalescència el dia 5 d'abril de l'any 2005

Peter Josef Ell , nascut el 7 de maig de 1944, és professor de Medicina Nuclear a la Universitat de Londres des de 1987, director del Institute of Nuclear Medicine, UCL, des de 1986, Honorary Consultant Physician del Middlesex Hospital des de 1976, i Clinical Director del UCLH NHS Trust des de 2001. El professor Ell és una de les figures més rellevants del món en l'àrea de la medicina nuclear i del diagnòstic per la imatge. La seva formació, variada i europeista, inclou una llicenciatura en Medicina per la Universitat de Lisboa, un màster en Ciències per la Universitat de Londres i un doctorat per la Universitat de Berna. No solament parla diverses llengües, sinó que ha integrat les cultures portuguesa, alemanya i anglesa. És director del Institute of Nuclear Medicine del UCL, un dels serveis més grans d'Anglaterra en l'especialitat, i catedràtic de Medicina Nuclear en aquest mateix centre. És autor de més de cinc-centes publicacions científiques, moltes d'elles en les revistes de més factor d'impacte (Lancet, JCO, JACC, etc.), i és editor/autor de dotze llibres de text, i de múltiples comunicacions i presentacions a congressos. Ha estat convidat a pronunciar nombroses conferències arreu del món. La seva multiculturalitat li ha permès de tenir un paper central en la creació i formació de la Societat Europea de Medicina Nuclear (EANM), de la qual va ser autor de molts dels documents fundacionals, i de la qual ha estat president entre 1994 i 1996. Ha estat quinze anys redactor en cap del European Journal of Nuclear Medicine and Molecular Imaging, revista que, sota la seva direcció, s'ha consolidat com una de les més importants del món en aquesta àrea científica.Nomenament 10/11/2004. A proposta de Facultat de Medicina. Investidura 05/05/2005. Padrí: Ignasi Carri

Multimodality Imaging in Prostate Cancer

ABSTRACT Prostate cancer is the most common cancer in men in Finland. Its aggressiveness varies widely, from indolent to fatal disease. Accurate characterization of prostate cancer is extremely essential to prevent overtreatment while sustaining good survivorship and high quality of life. This is feasible using novel technology in imaging and automatic tools in treatment planning. In the first part of this thesis work, the aim was to evaluate anti-1-amino-3-18Ffluorocyclobutane-1-carboxylic acid (18F-FACBC) PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer. The uptake of 18F-FACBC was significantly stronger in tumors with higher Gleason score and it may therefore assist in targeted biopsies when combined with MRI. 18F-FACBC PET/MRI outperformed PET/CT but did not demonstrate higher diagnostic performance than mpMRI performed separately. Furthermore, PET/MRI and mpMRI failed to detect pelvic lymph node metastasis measuring less than 8mm. 18F-FACBC PET/MRI is promising in characterization of primary prostate cancer, especially if ablative treatments are planned. It is not likely to replace mpMRI in clinical practice. The second study assessed multimodality imaging in detecting bone metastasis in high-risk prostate cancer and breast cancer patients. All patients underwent 99mTc-HDP bone scintigraphy (BS), 99mTc-HDP SPECT, 99mTc-HDP SPECT/CT, 18F-NaF PET/CT, and whole body (wb) MRI+DWI. 99mTc-HDP SPECT/CT, 18F-NaF PET/CT, and wbMRI+DWI had superior sensitivity compared to conventional nuclear imaging. In particular non-BS techniques showed less equivocal findings. wbMRI+DWI was as accurate as 18F-NaF PET/CT for detecting bone metastasis and may be considered a potential “single-step” imaging modality for detection of bone metastasis in high-risk patients with prostate and breast cancer. The purpose of the third study was to evaluate and validate the performance of a fully automated segmentation tool (AST) in MRI-based radiotherapy planning of prostate cancer. It showed high agreement for delineating prostate, bladder, and rectum, compared to manual contouring, and suggested adoption of AST in clinical practice. Finally, the fourth study investigated the long-term toxicity after biologically guided radiotherapy in men with localized prostate cancer. Carbon-11 acetate (11C-ACE) PET-CT was used to guide dose escalation into metabolically active intraprostatic lesions. 11C-ACE PET-guided radiotherapy was feasible and well tolerated. Although erectile dysfunction was relatively common, severe gastro-intestinal symptoms were very rare, and no grade 3 genitourinary symptoms were present at five years after radiotherapy. The findings of this thesis have potential to improve diagnostic imaging and radiotherapy planning in primary and metastatic prostate cancer. Eventually, they are likely to improve patients’ quality of life and survival. KEYWORDS: prostate cancer, magnetic resonance imaging, positron emission tomography, radiotherapy planning, toxicity, bone metastasisTIIVISTELMÄ Eturauhassyöpä on miesten yleisin syöpä Suomessa. Sen taudinkuva vaihtelee laajasti rauhallisesta aggressiiviseen ja tappavaan. On oleellista, että taudin luonne arvioidaan tarkasti, jotta vältytään sen liialliselta hoidolta, tinkimättä erinomaisista hoitotuloksista selviytymisessä ja elämän laadussa. Uudet kuvantamisteknologiat ja automaattityökalut mahdollistavat tämän. Tämän väitöskirjan ensimmäisessä osatyössä oli tavoitteena arvioida anti-1-amino-3-18Ffluorosyklobutaani-1-karboksyylihappo (18F-FACBC) PET-tietokonetomografiaa (TT), PET-magneettiresonanssikuvantamista (MRI) ja multiparametrista MRI-kuvantamista (mpMRI) eturauhassyövän diagnoosivaiheessa. 18F-FACBC-kertymät olivat tilastollisesti merkitsevästi voimakkaampia korkean Gleason-luokituksen kasvaimissa, joten yhdistettyä PET-MRI-kuvantamista voidaan käyttää hyväksi esimerkiksi kohdennetussa koepalojen otossa. 18F-FACBC PET-MRI oli parempi kuin PET-TT ja samanveroinen kuin mpMRI eturauhassyövän diagnostiikassa. PET-MRI ja mpMRI eivät havainneet alle 8 mm:n läpimittaisia imusolmukemetastaaseja. 18F-FACBC PET-MRI on lupaava kuvantamismuoto eturauhassyövän diagnostiikassa, erityisesti kajoavia hoitoja suunniteltaessa, mutta ei korvanne mpMRI:a kliinisessä käytössä. Toinen osatyö käsitteli luustoetäpesäkkeiden toteamista eri kuvantamismenetelmillä korkean uusiutumisriskin eturauhas- ja rintasyöpäpotilailla. Kaikille potilaille tehtiin 99mTc-HDP luustokarttakuvaus, 99mTc-HDP SPECT, 99mTc-HDP SPECT-TT, 18F-NaF PET-TT ja koko kehon MRI diffuusiopainotettuna (wbMRI+DWI). 99mTc-HDP SPECT-TT, 18F-NaF PET-TT ja wbMRI+DWI olivat perinteistä luustokarttaa herkempiä luustometastaasien toteamisessa, koska epäspesifeiksi määriteltyjä muutoksia oli vähemmän. wbMRI+DWI osoitti yhtäläistä tarkkuutta luustometastaasien diagnosoinnissa 18F-NaF PET-TT:n verrattuna, joten sitä voitaisiin hyödyntää, käytettäessä vain yhtä kuvantamistapaa näiden potilaiden luustometastaasien toteamiseen. Kolmas osatyö arvioi ja validoi täysin automaattisen piirtotyökalun käyttöä MRI-pohjaisen sädehoidon suunnittelussa eturauhassyöpäpotilailla. Työkalu suoriutui hyvin eturauhasen, virtsarakon ja peräsuolen rajauksesta asiantuntijan käsin tekemiin rajauksiin verrattuna, puoltaen työkalun käyttöä luotettavasti myös kliinisessä työssä. Viimeisenä, neljännessä osatyössä arvioitiin biologisesti ohjatun eturauhassyövän sädehoidon aiheuttamia pitkäaikaishaittoja. Hiili-11 asetaatti (11C-ACE) PET-TT-kuvantamisen avulla suunniteltiin sädehoito, jossa metabolisesti aktiivisiin eturauhasen sisäisiin muutoksiin kohdistettiin korkeammat sädeannokset. 11C-ACE-PET-TT-ohjattu sädehoito oli toteuttamiskelpoinen ja hyvin siedetty. Vaikka erektiohäiriöt olivat suhteellisen yleisiä, vakavat suoliston haittavaikutukset olivat hyvin harvinaisia, eikä kolmannen asteen virtsateiden haittavaikutuksia esiintynyt lainkaan viiden vuoden kuluttua sädehoidosta. Tämän väitöskirjan löydökset voivat parantaa eturauhassyövän primaaridiagnostiikan kuvantamista ja sädehoidon suunnittelua, sekä luustoetäpesäkkeiden diagnostiikkaa. Näin voidaan kohentaa potilaiden elämänlaatua ja selviytymistä. AVAINSANAT: Eturauhassyöpä, magneettikuvaus, positroniemissiotomografia, sädehoidon suunnittelu, haittavaikutukset, luuston etäpesäkkee

Advances in targeted Alpha therapy for prostate cancer

BACKGROUND: Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. DESIGN: In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. RESULTS: A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor (AR)-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. CONCLUSIONS: The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment

Somatostatin Receptor Scintigraphy in Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is a neuroendocrine tumor originating from the calcitonin‐secreting C cells. Surgery, consisting of a total thyroidectomy and an extensive lymph node dissection, is the only effective treatment in MTC; however, metastases are frequently found in the regional cervical lymph. The biochemical marker for MTC is calcitonin, and this is frequently used for the detection of persistent/residual/metastatic tumor. The value of 111In‐labeled somatostatin receptor scintigraphy (SRS) in patients with MTC is limited, with sensitivity ranging between 0 and 75%. Other scintigraphic imaging techniques such as 18F‐FDG PET, 18F‐DOPA PET, and PET imaging with 68Ga‐labeled DOTA peptides combined with CT imaging are upcoming. Treatment of patients with metastatic disease with the current available somatostatin analogues, octreotide and lanreotide, does not seem to have an effect on survival but may be considered to control flushing and diarrhea in some patients. Experience with peptide receptor radionuclide therapy is limited in this patient group and disappointing. New therapies in the treatment of metastatic MTC use target tyrosine kinase receptors inhibitors belonging to the same family group of proteins as RET

Other Radiopharmaceuticals for Imaging GEP‐NET

In GEP‐NETs, especially the catecholamine and serotonin biosynthetic pathways are upregulated. Therefore, increased biosynthesis of these specific amines in GEP‐NETs enables imaging with specific amine precursors. For the catecholamine pathway, 6‐18F ‐l‐3,4‐dihydroxyphenylalanine (18F‐DOPA) is available, while for the serotonin pathway, carbon‐11‐labeled 5‐hydroxy‐l‐tryptophan ([11C]‐5‐HTP) is available as tracer. 11C‐5‐HTP PET and 18F‐DOPA PET are excellent functional imaging techniques for evaluating patients with proven pancreatic islet cell tumors and carcinoids. For both tracers, the combination with CT further improves the detection rate of NET, which shows that performing PET scans with these tracers in PET/CT scanners is beneficial for patients.Since well‐differentiated GEP‐NETs generally have a low glucose metabolism, 18F‐fluorodexyglucose (18F‐FDG) PET scanning has limited value for the primary staging of patients with well‐differentiated GEP‐NETs. However, in patients with rapidly progressive disease, dedifferentiation of GEP‐NET tumors can lead to a higher glucose metabolism in tumor cells. In these patients, 18F‐FDG PET can be of benefit for tumor staging. Also, 18F‐FDG PET can be of value when other malignancies are suspected in patients with GEP‐NETs, since these patients experience a higher incidence of these malignancies compared to the general population.Nowadays, (GEP)‐NETs can also be imaged with 68Ga‐labeled analogues of somatostatin, which are also PET tracers. Advantages of 68Ga‐labeled somatostatin analogues are the relatively easy generator‐based synthesis and the possibility to evaluate whether peptide (somatostatin) receptor radionuclide therapy (PRRT) for NETs can be considered