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Radionuclide therapy beyond radioiodine Wiener Medizinische Wochenschrift

ISSN 0043-5341
Wien Med Wochenschr
DOI 10.1007/s10354-012-0128-6
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Wien Med WochenschrDOI 10.1007/s10354-012-0128-6 Radionuclide therapy beyond radioiodine
Michael Gabriel

Received: 4 May 2012 / Accepted: 21 June 2012 Springer-Verlag Wien 2012 Radionuklidtherapien jenseits von Jod-131 Schlüsselwörter:  Radionuklide, Nuklearmedizin, Onko-
logie, Systemischer Therapieansatz
Zusammenfassung  Seit Jahrzehnten wird Iod-131 in
der Behandlung von Patienten mit Schilddrüsenkrebs
Summary  For decades, Iodine-131 has been used for
verwendet. In den letzten Jahren finden zunehmend the treatment of patients with thyroid cancer. In recent auch andere Radiopharmaka im klinischen Betrieb bei years, increasingly, other radiopharmaceuticals are in der Behandlung von verschiedenen malignen Erkran- clinical use in the treatment of various malignant dis- kungen Anwendung. Obgleich bei diesen Therapien eases. Although in principle these therapies—as in all grundsätzlich – wie bei sämtlichen Therapien mit of- applications of radionuclides—special radiation protec- fenen Radionukliden – spezielle Strahlenschutzvorkeh- tion measures are required, a separate nuclear medicine rungen erforderlich sind, ist eine eigene nuklearmedi- therapy department is not necessary in many cases due zinische Therapiestation in vielen Fällen aufgrund der to the lower or lack of gamma radiation. In the follow- geringeren bzw. fehlenden Gammastrahlung im Unter- ing article, four different radionuclide therapies are schied zur Radiojodtherapie nicht notwendig. Im Fol- more closely presented which are emerging in the last genden werden vier verschiedene Radionuklidtherapien years. One of them is the "Peptide Receptor Radionu- näher beleuchtet, die in den letzten Jahren zunehmend clide Therapy," the so-called PRRT in which radiola- an Bedeutung gewonnen haben. Bei der sog. Radionuk- beled somatostatin (SST)-receptor(R) ligands are used lidpeptidtherapie bekommen die Patienten einen radio- in patients with neuroendocrine tumors. On the basis of aktiv markierten Rezeptorliganden appliziert, welcher radiolabeled antibodies against CD20-positive cells, the an Somatostatin-Rezeptor-exprimierendes Gewebe in so-called radioimmunotherapy is used in the treatment neuroendokrinen Tumoren bindet. Auf der Basis eines of certain forms of malignant lymphoma. In primary or Antikörpers gegen CD20-positive Zellen wird die sog. secondary liver tumors, the 90Y-labeled particles can be Radioimmuntherapie in der Behandlung von bestimm- administered. Last but not the least, the palliative ap- ten Formen eines malignen Lymphoms eingesetzt. Bei proach of bone-seeking radiopharmaceuticals is noted primären oder sekundären Lebertumoren können 90Y- in patients with painful bone metastases.
markierte Partikel verwendet werden, welche direkt in das Zielgewebe appliziert werden. Desweiteren ist auch Keywords:  Radionuclides, Nuclear medicine, Oncol-
der palliative Ansatz von knochenaffinen Radiopharma- ogy, Systemic therapy ka zur Behandlung von Tumorschmerzen aufgrund von Knochenmetastasen zu erwähnen.
M. Gabriel, MD ()Department of Nuclear Medicine and Endocrinology, General Iodine-131 was one of the first radionuclides used for Hospital of Linz, Krankenhausstrasse 9, 4021 Linz, Austria therapy in clinical oncology especially for treatment of thyroid cancer patients Due to promising clinical results of this isotope, other radionuclides were also con- University Clinic of Nuclear Medicine, Medical University of sidered to treat several malignant diseases. At present, Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria various alpha- and beta-radiation emitting isotopes are Radionuclide therapy beyond radioiodine 1 Author's personal copy main topic
used, most of them labeled with peptides and antibodies using radiolabeled peptide ligands, in particular with for specific tumor targeting. Unlike chemotherapeutic long-acting somatostatin (SST)-analogs, is nowadays agents, radiopharmaceuticals are used only as vehicles established in the clinical practice.
to deliver ionizing radiation to the tumor tissue.
Several mechanisms may contribute to the therapeu- Radionuclide therapies can be applied in a very indi- tic effect of somatostatin receptor (SSTR) therapy. Among vidualized way which is based on pretherapeutic func- these, there is the internalization of the receptor ligand tional imaging in many cases. Decision on radionuclide complex This binds the radiopharmaceutical to the therapy can be made by visual scoring of scintigrams targeted cells and will be indispensable when using Auger before therapy, e.g. the degree of somatostatin receptor- emitters such as Indium (In)-111 as radionuclide, which expression in neuroendocrine tumors (NETs) [and by was the first radionuclide used for this purpose. On the (semi-)quantitative evaluation with concomitant the- other hand, ß-particles turned out to be more effective to rapy dosimetry of tracer uptake in tumor lesions and in damage and kill not only the cell the radiopharmaceuti- organs ]. This also allows better prediction of the most cal is bound to, but also a number of cells in the vicinity. tolerable dose to avoid severe side effects. The aim of this This phenomenon is the so-called "cross-fire" effect. approach is to offer the patients a personalized and tailo- Lower tissue penetration of Lutetium(Lu)-177 favors red therapy concept taking also into account the primary the use in small-sized tumors, whereas in larger tumors focus of the treatment in each patient, either to improve Yttrium(Y)-90 might be a better choice [In addition, overall prognosis, or to improve quality of life or both of dosimetric data can be obtained when using Lu-177. A them. Several attempts are under investigation, for exam- small fraction of gamma photons offers the possibility to ple the combination with chemotherapeutic agents ], perform intratherpeutic imaging. At present, 90Y-DOTA- to further optimize the outcome of these tumor patients.
D-Phe1-Tyr3-octreotide (90Y-DOTA-TOC) and 177Lu-DO- Since some of these approaches using radionuclides TA-0-Tyr3-octreotate (177Lu-DOTA-TATE) are the most are rather sophisticated, patients should be managed used compounds for clinical application which are focu- by an interdisciplinary team. A key feature here is cer- sed on in this ar].
tainly held to nuclear medicine, which can provide with the help of functional imaging, e.g. when using 18F-fluo-rodesoxyglucose (18F-FDG), information on biological Clinical data of PRRT using 90Y-DOTA-D-Phe1-Tyr3- characteristics of the tumor and the spread of disease. Furthermore, nuclear medicine also can assess the radia-tion risk to patients, relatives, and ward staff and propose The Basel group was the first to report the in vivo admi- the most appropriate protection measures.
nistration of 90Y-DOTA-TOC in patients with NETs ]. The present article reviews procedural aspects and In their first group of patients a dose-escalating treatment the basis for selection and performance of radionuclide scheme was applied with a cumulative dose of 6 GBq/m2 therapy in certain clinical situations. Due to the ionizing []. Later, in four treatment cycles [], or two treat- radiation, specific regulatory requirements have to be ment cycles the treatment substance was given up fulfilled. Despite strict regulations in terms of the appli- to a cumulative dose of 7.4 GBq/m2. Tumor response was cation of ionizing radiation to patients some of these the- found in 23 % [] and 33 % [respectively. Whereas rapies, e.g. using Yttrium(Y)-90 or Strontium(Sr)-89,can the first applications were done without renal protection, be administered in the ambulant setting due to the lower all later studies were performed under amino acid infu- or even missing gamma beam component of the isotopes sion to avoid severe nephrotoxic side effects.
which make them more attractive for clinical application. Recently, this group published a clinical Phase II sin- This is in contrast to Iodine-131 which regularly requires gle-center open-label trial with neuroendocrine can- a dedicated nuclear medicine therapy ward.
cer patients and documents the long-term outcome of treatment with 90Y-DOTA-TOC in a larger cohort ]. Each cycle consisted of a single intravenous injection Peptide receptor radionuclide therapy (PRRT) of 3.7  GBq/m2 body-surface 90Y-DOTA-TOC. Additional in neuroendocrine tumors (NETs) cycles were withheld in case of tumor progression and/or permanent toxicity. Overall, 1,109 patients received 2,472 cycles of 90Y-DOTA-TOC (median, 2; range, 1–10 cycles per patient). Of the 1,109 patients, 378 (34.1  %) Several radionuclides have been used for peptide therapy experienced morphologic response; 172 (15.5  %), bio- in neuroendocrine tumor (NET) patients. The expression chemical response; and 329 (29.7 %), clinical response. of peptide receptors on various tumor cells including During a median follow-up of 23 months, 491 patients NETs was shown to be significantly higher as compared (44.3 %) died. Longer survival was correlated with each: to normal tissues or cells Over the last decade such morphologic (hazard ratio (HR), 0.46; 95 % CI, 0.38–0.56; receptors have become recognized targets for molecular median survival, 44.7 versus 18.3 months; p 0.001), bio- imaging and therapy, because they are expressed on the chemical (HR, 0.75; 95 % CI, 0.59–0.96; 35.3 versus 25.7 cell surface and, upon binding of a ligand, the receptor- months; p 0.023), and clinical response (HR, 0.68; 95 % ligand complex is internalized. Receptor scintigraphy CI, 0.56–0.82; 36.8 versus 23.5 months; p 0.001). Over- 2 Radionuclide therapy beyond radioiodine Author's personal copy main topic
all, 142 patients (12.8 %) developed grade 3–4 transient Quality of life (QoL) and PRRT hematologic toxicities, and 103 patients (9.2 %) expe-rienced grade 4–5 permanent renal toxicity. Multivaria- Beside convincing results in terms of the objective ble regression revealed that tumoral uptake in the initial response as based on morphological and biochemical somatostatin receptor imaging is predictive for both, sur- criteria, various other studies also showed an impact vival after 90Y-DOTA-TOC treatment and occurrence of on the Quality of Life (QoL) in patients with NETs. For instance, the group of Rotterdam showed that QoL, Kar- The Milano group injected up to 5.2  GBq per cycle nofsky performance index, and symptoms improved which they defined as maximum tolerated dose per cycle significantly after 177Lu-DOTA-TATE therapy, and there [The group reported a response rate of 29  % in was no significant decrease in QoL in patients who had patients with 21 gastro-entero-pancreatic (GEP) tumors no symptoms before therapy In patients who had after two treatment cycles with a cumulative dose of 5.9– suboptimal scores for QoL or symptoms before therapy, a clinically significant improvement was demonstrated. The Rotterdam group together with centers in Brus- These results indicate that 177Lu-DOTA-TATE therapy has sels, Belgium, and Tampa (Florida) injected escalating not only an impact on tumor burden and can prolong doses up to 14.8 GBq in four cycles, or up to 9.3 GBq in overall survival but also improves the patients' self-as- a single administration These administrations were sesment in a considerable number of patients In done up to a cumulative radiation dose to the kidneys patients with metastatic carcinoids and at least one sign/ limited to 27 Gy and all 54 patients received amino acids symptom refractory to octreotide, 90Y-DOTA-TOC tre- concomitantly for kidney protection. In 7 %, the partial atment improved also most symptoms associated with response (PR) and in 13  %, the minor response (MR) malignant carcinoid among subjects with no treatment was measured. The median time to progression was 30 alternatives. Furthermore, treatment was also well-tole- months in 44 patients who had stable disease.
rated and had an acceptable adverse events profile ]. In this context, PRRT can be also considered as treatment choice when symptoms of an excreting tumor cannot be Clinical data of PRRT using 177Lu-DOTA-Tyr3-Oc- sufficiently controlled by other regimes, e.g. with long- acting SST analogs.
The Rotterdam group reported on overall promising results in treatment protocols with 177Lu-DOTA-TATE Future directions in PRRT [In 131 patients, cumulative doses of 22.2–29.8 GBq were applied, and (complete remission) CR was observed Several authors report on the use of PRRT in an earlier in 2 %, PR in 26 %, MR in 24 %, and stable disease (SD) in setting of disease to offer the opportunity of surgical 35 % of patients. Remission rates were higher in patients intervention to even remove all visible tumor sites in case with high pretherapeutic uptake of the radiopharmaceu- of good response on PRRT. Ezziddin et al. showed that a tical and a limited number of liver metastases, whereas NET patient of the pancreas who had obtained internal progressive disease (PD) was more frequent in patients radiation for neoadjuvant downsizing was in complete with a low performance score and extensive disease.
local remission for 22 months after surgery ]. Another The same group also reports on toxicity in 504 patients concept to further improve efficacy of PRRT includes the and efficacy in 310 patients Any hematologic toxi- use of differently labeled tracers (Y-90 or Lu-177) and city grade 3 or 4 occurred after 3.6 % of administrations. different SST-analogs for labeling depending on indivi- Serious adverse events that were likely attributable to the dual parameters, e.g. pretherapeutic imaging charac- treatment were myelodysplastic syndrome in three pati- teristics. Our own results with more than 100 patients ents, and temporary, nonfatal, liver toxicity in two pati- favor the combined use of radio-labeled SST-analogs ents. Complete and partial tumor remissions occurred in providing a customized tumor targeting ]. For custo- 2 and 28 % of 310 GEP-NET patients, respectively. Minor mizing patients' therapy assessment of the individual tumor response (decrease in size > 25  % and < 50  %) tumor and patient characteristics is required. For this, occurred in 16  %. Median time to progression was 40 the generator-derived radionuclides for PET-CT ima- months taking into consideration that a large proportion ging are playing an important role to evaluate prether- of patients were enclosed without progressive disease. apeutic parameters, e.g. SST receptor profile, as well as Median overall survival (OS) from start of treatment was for assessment of treatment response after radionuclide 46 months, median OS from diagnosis was 128 months. therapy as illustrated in Fig. To further enhance Compared with historical controls, there was a survival the efficacy of PRRT, especially in NETs refractory to the- benefit of 40–72 months from diagnosis. In general, only rapy with Y-90 or Lu-177, the additional application of few adverse effects were seen [ chemotherapy, e.g. capecitabine, as a radio-sensitizer, may improve the antitumoral effects ]. In addition, the group of Heidelberg recently showed that peptide recep-tor alpha-therapy with Bismuth(Bi)-213 can be a promi- Radionuclide therapy beyond radioiodine 3 Author's personal copy main topic
The major advantage of radioimmunotherapy against unlabeled anti-CD20 antibody therapy is derived from the potential to amplify the cytotoxic effect via a radia-tion cross-fire effect, whereby ionizing radiation has an effect on neighboring cells surrounding the deposited radionuclide. The range of the radiation in the tissue is about 250 cell diameters around the 90Y-ibritumomab tiuxetan-binding cell and the radiation can penetrate into surrounding tumor tissue up to 5 mm [ Clinical data of RIT using 90Y-ibritumomab tiuxetan Follicular lymphoma, the second most common subtype of B-cell NHL, is usually characterized by a slow progres-sion with many relapses. About 65–70  % of all patients are older than 65 years and many patients are diagno-sed in advanced stages. The clinical presentation can be Fig. 1  A 68-year-old male patient with an insulinoma of the
extremely heterogeneous; the majority of patients show pancreatic tail. 68Ga-DOTA-NOC PET-CT showed in particular an indolent course of disease. Prognostic risk assess- enhanced tracer uptake in the liver lesions (big arrow) and at ment by simple and reproducible parameters (age, stage, the site of the primary tumor (small arrow), (a). Because of this
feature, the PRRT was performed using 90Y-DOTA-TOC with
hemoglobin level, lymph node involvement, LDH) is an overall activity of 8580 MBq. Reevaluation after two cycles done according to the Follicular Lymphoma Internatio- of therapy showed impressive response (b), i.e. most of the
nal Prognostic Index (FLIPI) index in three (low, inter- lesions diminished and the patient also showed clear impro- mediate, high) stages. In a randomized Phase III trial vement of the clinical symptoms for the treatment of patients with relapsed or refractory follicular or transformed low-grade B-cell NHL, a single sing treatment option customized for patients refractory treatment dose of 90Y-ibritumomab tiuxetan resulted in to beta-emitters [].
a substantially improved outcome than those after four weekly doses of rituximab in 143 patients [In addition to statistically significant higher overall response (ORR 80 Radioimmunotherapy of malignant lymphoma versus 56 %, p 0.002), good tolerability was observed ].
An updated evaluation of the same group of patients also showed a trend to a longer average time to progres-sion (TTP; 15 versus 10.2 months, p 0.07), longer dura- Radioimmunotherapy (RIT), a combination of immu- tion of response (DR; 16.7 months versus 11.2, p 0.44) nological mechanisms with targeted local exposure of and prolonged time to next therapy (21.1 versus 13.8 radiation to neoplastic cells, represents a well-esta- months; p 0.27) comparing 90Y-ibritumomab tiuxetan blished development of the therapy of non-Hodgkin's with rituximab in patients previously treated with low- lymphoma (NHL). The radiation is delivered by an anti- grade follicular or transforme].
body targeting the CD20 epitope. CD20 is one of many Because of the overall convincing study results of epitopes expressed on the mature B cells. Because it is 90Y-ibritumomab tiuxetan, the indication of this com- so frequently overexpressed in B-cell lymphomas, it was pound was extended recently by the European Com- earlier selected as a target for monoclonal antibody the- mission on the first-line therapy. Thus, there is now also rapy This epitope serves as a relatively specific target an approved early consolidation therapy for previously for RIT to enhance the efficacy of conventional treatment treated patients, which have responded to induction using nonlabeled monoclonal antibodies The tre- atment regime actually includes sequential infusions of A prospective, nonrandomized Phase II study of Zin- both unlabeled and radiolabeled antibodies. 90Y-ibri- zani et al. ] (FLUMIZ (fludarabine, mitoxantrone, tumomab tiuxetan (Zevalin®, Schering AG, Berlin, Ger- Zevalin) study) evaluated the efficacy and tolerability of many) consists of ibritumomab, the mouse IgG1 parent the combination of fludarabine plus mitoxantrone follo- of rituximab linked by the chelator, tiuxetan, to Y-90 for wed by a consolidation with 90Y-ibritumomab tiuxetan in treatment [].
untreated patients with follicular NHL (stage III/IV). The Rituximab, the "cold" antibody to CD20 epitope estimated progression-free survival (PFS) at 3 years after expressed on cell membrane has a cytotoxic effect via a an average follow-up of 30 months was found to be 76 % variety of mechanisms including promoting apoptosis. with an overall survival of 100 % after 3 years and sho- The therapeutic benefit, however, is limited to the num- wing an overall response in 98 % of patients. Grade 3 or ber of tumor cells directly affected by the antibody [].
4 hematologic toxicity was observed in 36 of 57 patients. Altogether, this study demonstrated the efficacy and 4 Radionuclide therapy beyond radioiodine Author's personal copy main topic
tolerability of combination therapy with fludarabine plus Radioembolization of liver tumors mitoxantrone plus 90Y-ibritumomab tiuxetan in untrea-ted patients with follicular NHL [].
In retrospective analysis, it was shown that in the course of the disease early use of RIT results in a better Following lung, the liver is the most commonly affec- therapeutic outcome. An analysis of data from four clini- ted organ of distant metastasis. Since almost the whole cal trials (n = 211) from Emmanouilides et al. [], showed venous blood of the gastrointestinal tract first flows that the early application of RIT significantly improves through the liver, liver metastases of tumors of the gas- response rate. When administered in the first recurrence, trointestinal tract can be frequently found. Particularly, the rates of complete remission were significantly higher colon cancer metastasizes early into the liver. In addition, than when administered by two or more prior regimens other primary tumors, such as breast, bronchial carci- (49 versus 28  %, p < 0.01). Consecutively, a significant noma, neuroendocrine tumors, pancreatic tumors, cho- prolongation of time to progression was observed (12.6 langiocellular tumors, and melanomas also show a lot of versus 7.9 months, p < 0.05).
hepatic deposits during the course of disease. Another malignancy primarily restricted to the liver is the group Preconditions for treatment and safety profile of primary hepatic tumors, which normally occur on the bottom of liver cirrhosis. These tumors, however, are far rarer than metastases in the liver derived from extrahe- Taking into account the potential adverse effects of RIT, patic tumors.
it is required to have a sufficient bone marrow reserve (at Due to the low symptoms, early stages of the hepatic least 1,500/mm3 neutrophils and 100,000/mm3 platelets), involvement are sometimes diagnosed in advanced sta- a limited bone marrow infiltration (< 25  %) and should ges not accessible to surgery without definite chance of not previously have received extensive radiation therapy cure which requires systemic therapeutic approaches in or no signs of myelodysplasia []. The RIT with 90Y-ibri- a high percentage of cases.
tumomab tiuxetan has a favorable safety profile and a A relatively new treatment option is the "Selective delayed hematopoietic nadir The number of myelo- Internal Radiation Therapy," the so-called SIR therapy dysplastic syndrome (MDS) and acute myeloid leukemia (SIRT). This treatment option is in particular related to (AML) is also not elevated by the use of 90Y-ibritumomab patients whose liver tumors are not resectable or do not as compared to patients with follicular lymphoma after adequately respond to chemotherapy. SIRT is based on intensive chemotherapy, which represents a risk factor the administration of ("Y-90 microspheres"). The small for the development of MDS and AML [ radiolabeled particles get administered directly into the tumor tissue of the liver by means of transfemoral cathe-ter application. In the liver, the microspheres remain in Future directions in radioimmunotherapy the arterial tumor be].
of lymphoma Selective Internal Radiation Therapy requires a spe- cialized multidisciplinary team. The indication is done The value of 90Y-ibritumomab tiuxetan in autologous or in close cooperation of medical oncologists, nuclear allogenic stem cell transplantation (SCT) is on the rise. medicine physicians, and interventional radiologist. RIT can be applied in combination with high-dose che- The catheter is placed exactly after guidance of repeated motherapy or used in escalating doses as monotherapy angiograms. Several vessels, e.g. to the stomach, duo- considering also the positive safety profile. In a Phase denum, and pancreas, have to be embolized before the II study, the Groupe d'Etude of lymphoma de l'Adulte application of the radiolabeled microspheres into the (GELA) working group evaluated the impact of RIT with hepatic artery where these spheres remain stuck in the 90Y-ibritumomab tiuxetan in the conditioning of relapsed capillaries of the tumor. Since the liver tumors are mostly low-grade follicular lymphoma prior to autologous SCT. supplied by the hepatic artery, the SIR-spheres particu- The combination of 90Y-ibritumomab with the Z-BEAM larly deposit in the tumor and irradiate, consecutively, regimen (BCNU, etoposide, Ara-C, and melphalan) the tumor tissue from the inside and embolize the fee- resulted in a progression-free survival of 86  % after a ding vessels ]. Due to the very selective accumulation follow-up of 18 months The good acceptance and of the radiolabeled microspheres, hepatic lesions are the ability to perform outpatient therapy make RIT also receiving radiation exposure of more than 1,000 Gy while attractive for older patients, especially in poor tolerability the exposure to healthy liver tissue is less than 25 Gy ].
of chemotherapy-associated toxicity. The good tolerabi-lity profile of 90Y-ibritumomab tiuxetan in elderly patients with NHL was assessed in a retrospective analysis of four Clinical data of SIRT using 90Y-spheres registration trials in which no difference in efficacy and incidence of hematological grade 3/4 toxicity in older As previously mentioned, SIRT represents an effective patients (> 70 years) versus younger patients was found tool for the treatment of primary and secondary liver tumors. Several data on the adequate use of this therapy are included in this overview which requires multidisci- Radionuclide therapy beyond radioiodine 5 Author's personal copy main topic
plinary effort in order to obtain optimal results and avoid ferred in patients with widespread liver metastases and therapy-related complications ]. When considering in poorly differentiated tumors while PRRT shows hig- metastatic colorectal cancer (mCRC) lots of innovative her efficacy in grade 1 tumors. Furthermore, the status of therapeutic approaches have been introduced in the cli- the individual organ function as well as the availability nical use which has significantly improved the overall plays an important role in the decision process. Never- survival of patients with mCRC in the last decade. Beside theless, both therapies can also be applied sequentially systemic therapeutic approaches, several other—espe- in selected cases depending on the course of disease and cially antibody-based—treatment regimes, e.g. Avastin® the function of the organs.
(bevacizumab) or Erbitux® (cetuximab), have successfully Generally, liver radioembolization accounts to a well- been launched []. Contrary to these early procedures, tolerated procedure with less but potentially life-threa- SIRT is normally used in more subsequent way, e.g. in tening complications. In addition to well known mild mCRC patients refractory to chemotherapy. However, postembolization symptoms complications include not even in this situation, the SIRT showed that the median only intrahepatic but also various extrahepatic complica- survival time has increased compared to best suppor- tions which are based on nontarget radiation exposure, tive care and was tolerated with acceptable toxicities e.g. pancreatitis, gastrointestinal ulcers, cholecystitis, [Also the combination of SIRT with other standard radiation pneumonitis, radiation-induced liver disease, chemotherapeutic regimes was evaluated in various and biliary complications [ clinical situations, e.g. in advanced stages refractory to standard chemotherapy and in earlier stages as first-line regime ]. In a randomized trial, Van Hazel et al. Future directions in SIRT compared the response rate and time to progression in a regime of systemic flurouracil/leucovorin chemother- There is increasing interest in the estimation of the- apy versus the same chemotherapy along with a single rapy doses and the prediction of response to therapy. administration of SIR-spheres in patients with advanced One approach is based on the use of 90Y-PET to predict colorectal liver metastases The time to progression the outcome of lesions after SIRT using biodistribution and median survival were significantly longer in patients assessment []. The 90Y-PET images are of high quality receiving the combination treatment [].
enabling accurate dosimetry which correlates well with The inoperable hepatocellular carcinoma (HCC) treatment response assessed using 18F-FDG PET-CT. has a poor prognosis which might be largely related to Dieudonné et al. studied the clinical feasibility of 3-D the overall less effectiveness of chemotherapy in these dosimetry with 99mTc SPECT-CT scans. The analysis was tumors. Patients with irresectable, advanced HCC also accurate in determining absorbed dose to liver tumors showed improvements either as first or as second-line and absorbed dose to nontumoral liver tissue in the tre- treatment with SIRT showing a median survival of 14.2 atment of HCC with 90Y-microspheres to provide a very months after one dose of 90Y-SIRT []. A portal vein individualized therapy schemig.  thrombosis has no effect on overall survival. Patients with good performance status showed a survival of 18.1 months and patients in early inoperable stages even showed a median survival over 24 months . In com-parison to the transarterial chemotherapy (TACE), the SIRT, with a single-application regime, was found to be superior in terms of higher downstaging rate from T3 to T2 and longer progression-free survival. In HCC tumors, an increase of the overall survival can also be expected []. As previously mentioned NETs are belonging to a slowly growing heterogeneous group of tumors. NETs of the gastrointestinal tract are known to frequently deve-lop metastases in the liver. If liver metastases from the NET cannot be removed by surgery, symptomatic the-rapy is required in many cases. Recently, SIRT was also used showing high response rate of liver metastases. Kennedy et al. consecutively examined 148 patients with progressive hepatic NET lesions and at least one syste-mic pretreatment. An overall response and stabilisation of liver lesions was observed in about 85  % of patients Fig. 2  18F-FDG PET-CT was performed in this 48-year-old
[]. In many other tumors with predominant liver invol- female patient during follow-up after treatment of a follicular vement, e.g. breast cancer [] or cholangiocarcinoma lymphoma with a stage IVa disease. The PET-image before [], the SIRT also showed promising results in terms radionuclide therapy clearly indicated hypermetabolic lymph of objective response and survival rate after therapy. In node involvement (a), which completely disappeared after 90Y-
contrast to PRRT, the application of SIRT should be pre- Zevalin 4 months later (b)
6 Radionuclide therapy beyond radioiodine Author's personal copy main topic
Bone-seeking radiopharamaceuticals for therapy "super-bone-scan", limited bone marrow reserve can be of metastatic bone pain assumed which requires splitting in smaller doses and/or reduction of the overall dose. Impaired renal function is also frequently related with a higher risk of myeloto-xicity due to decelerated radiopharmaceutical excretion Bone metastases occur in many patients with different []. In about 10–15 % patients, a flare-up phenomenon types of solid malignant tumors, particularly in advanced of pain aggravation can be observed prior to measurable stages of prostate and breast cancer, and are commonly response of pain relief which can be normally observed associated with increased morbidity and mortality. The in the range between 4 and 28 days [During this ini- resulting bone pain interferes with quality of life and thus tial aggravation of pain, an intensified use of analgesics requires effective treatment. However, various nonra- and steroids should be considere diotherapeutic modalities such as analgesics, hormone According to the prospective open-label study by Pons therapy, orchidectomy, cytostatic and cytotoxic drugs, et al. ] in 76 patients (50 males with prostate carci- bisphosphonates, and surgery are not universally effec- noma and 26 female with breast cancer), duration of the tive. External-beam radiotherapy is feasible only for well- response ranged from 3 to 12 months (mean 6 months) defined localized bone metastases, and extended field using 89Sr-chloride. Baziotis et al. ] also reported on radiation is often accompanied by serious side effects. high efficacy of Sr-89 treatment in the majority of 64 Therefore, systemic radionuclide therapy must be consi- patients with painful bone metastasis from breast cancer. dered as a valuable and effective method in pain manage- This finding was basically confirmed by a recent systemic ment in patients with widespread skeletal metastases review of the available literature by Finlay et al. [, giving either using Sr-89, which is taken as a calcium analog, a mean overall response of 76 % and duration of pain relief or as a labeled radioisotopes such as Samarium(Sm)-153 up to 15 months in patients treated with Sr-89 ].
at a bisphosphonate as a carrier in the bone matrix [ Comparative studies among radiopharmaceuticals ]. Palliative pain therapy with a radionuclide is based have not found significant differences between the dif- on the intravenous injection of a beta-radiation emit- ferent radionuclides [], so the choice of the radio- ting radioactive pharmaceuticals (89Sr-chloride, 153Sm- pharmaceutical used in clinical practice is particularly EDTMP) showing enhanced and specific uptake in these dependent on site-specific factors such as availability lesions while largely sparing the surrounding tissue as [, ]. An advantage of 153Sm-EDTMP lies in the emis- also clearly depicted in the bone scan prior to therapy.
sion of gamma rays (103.2 keV) which accompanies the Accordingly, this therapy is indicated in all patients beta-decay. These can be used for imaging after therapy, with positive bone scan and multiple osteoplastic meta- as shown in Fig, and even for individual dosimetry ].
stases, with the previous pain therapy cannot be treated Since bisphosphonates also accumulate in osteo- satisfactorily. The individual radionuclides differ in the blastic metastases, it was assumed that the biological energy and in the range of the particles [ competition between biphosphonates and radiolabeled bone-seeking agents may negatively affect the efficacy of radionuclide therapy which has not been assessed by cli- Clinical data of systemic radionuclide therapy nical trials so far. Quite the contrary was found by Storto in the treatment of skeletal metastases et al. in 49 patients with painful osseous metastasis. The group of patients who were chronically treated with zole- Radionuclide therapy with 89Sr-chloride and 153Sm- dronic acid showed improvement in clinical conditions EDTMP has been approved for use in different countries after treatment with 89Sr-chloride and this regime was in Europe and the USA for the treatment of bone pain more effective in terms of pain relief than 89Sr-chloride due to osteoblastic or mixed osseous metastasis as previ- or zoledronic acid used separately Furthermore, ously mentioned and has to be documented by who- repeated treatment with radiolabeled agents is feasible le-body scintigraphy performed within at least 8 weeks and has proven to be safe and efficacious with the res- before therapy [Kraeber-Bodere et al. have clearly triction of transient bone marrow suppression which indicated that this kind of targeted systemic radionuc- frequently occurs after each application with the nadir at lide therapy should preferably be administered early in 12–16 weeks for Sr-89 and 3–5 weeks for Sm-153 []. This the metastatic phase showing higher efficacy in terms of requires a close blood count monitoring by the medical overall response, reduction of analgesic use and duration of pain relief when compared to patients with extensive osseous disease ]. In addition, it has been proven to be a safe tool for bone pain therapy especially in earlier Future directions in radionuclidtherapy with stages of bone involvement On the other hand, this therapy should be cautiously applied in patients with preexisting cytopenia as the bone-seeking radiophar- The α-emitter Radium(Ra)-223-Chloride (Alpharadin®) maceuticals can cause further myelotoxicity, aggravating is a new radiopharmaceutical under clinical evaluation. low blood cell counts []. Especially, when bone marrow Early clinical data demonstrated a significant decrease shows extensive tumor infiltration or in the presence of a in bone-alkaline phosphatase levels following therapy Radionuclide therapy beyond radioiodine 7 Author's personal copy main topic
viable complement to the established forms of therapy in clinical routine.
Conflict of interest
The authors declare that there is no actual or potential
conflict of interest in relation to this article.
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10 Radionuclide therapy beyond radioiodine

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Prac recommendations on signals adopted at the prac meeting of 8-11 september 2014

25 September 2014 EMA/PRAC/490498/2014 Pharmacovigilance Risk Assessment Committee PRAC recommendations on signals Adopted at the PRAC meeting of 8-11 September 2014 This document provides an overview of the recommendations adopted by the Pharmacovigilance Risk Assessment Committee (PRAC) on the signals discussed during the meeting of 8-11 September 2014 (including the signal European Pharmacovigilance Issues Tracking Tool [EPITT]reference numbers).

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