Critical Reviews in Oncology/Hematology 80 (2011) Accepted 27 January 2011

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1 Critical Reviews in Oncology/Hematology 80 (2011) Yttrium-90 ( 90 Y) in the principal radionuclide therapies: An efficacy correlation between peptide receptor radionuclide therapy, radioimmunotherapy and transarterial radioembolization therapy. Ten years of experience ( ) Veronica Goffredo a,, Angelo Paradiso b, Girolamo Ranieri a, Cosmo Damiano Gadaleta a a Interventional Radiology Unit with Integrated Section of Medical Oncology, National Cancer Institute Giovanni Paolo II of Bari, Via Hahnemann 10, Bari, Italy b Clinical Experimental Oncology Laboratory, National Cancer Institute Giovanni Paolo II of Bari, Bari, Italy Accepted 27 January 2011 Contents 1. Introduction Peptide receptor radionuclide therapy with 90 Y-DOTA-(TOC) in neuroendocrine tumours Development of PRRT with somatostatin radio-analogues Requisites for PRRT PRRT toxicity and dosimetry PRRT treatment procedure and response assessment PRRT clinical trials Other clinical outcomes with 90 Y-DOTATOC Clinical experiences of PRRT in rarer forms of GEP-NETs Radioimmunotherapy with 90 Y-Zevalin in non Hodgkin s lymphoma Development of RIT with radiolabelled antibodies Requisites for RIT RIT toxicity and dosimetry RIT treatment procedure and response assessment RIT clinical trials Other clinical outcomes with 90 Y-ibritumomab tiuxetan Transarterial radioembolization therapy with 90 Y-microspheres in hepatocellular carcinoma and liver metastases Development of TARET with radiomicrospheres Requisites for TARET TARET toxicity and dosimetry TARET treatment procedure and response assessment Studies with 90 Y-microspheres Clinical trials of TARET in HCC Clinical trials of TARET in liver mcrc Future developments Conclusions Reviewers Conflict of interest statement Corresponding author. Tel.: ; fax: address: v.goffredo@oncologico.bari.it (V. Goffredo) /$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 394 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) Acknowledgements References Biographies Abstract The clinical application of the pure beta emitter 90 Y constitutes a fundamental advancement in non-invasive medicine. Nowadays, mainly three oncological therapies exploit the intrinsic emissive characteristic of 90 Y. Radionuclide therapies include peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumour (NET) treatment, radioimmunotherapy (RIT) in non-hodgkin s lymphoma (NHL) treatment and transarterial radioembolization therapy (TARET) in unresectable hepatocellular carcinoma (HCC) and liver metastatic colorectal cancer (mcrc) treatment. The last ten years of clinical experience from E-PubMed research have been reviewed and an efficacy correlation between 90 Y-therapies has shown a better objective response rate for RIT (ORR 80 ± 15%; range ) compared to PRRT (ORR 23.5 ± 14%; range 9 50), and TARET (ORR for mcrc, 40 ± 25%; range 19 91, and ORR for HCC, 42 ± 20%; range 20 82). This review reports on the state of the art of the efficacy of 90 Y-therapies from the last decade and discusses new perspectives of therapeutic development Elsevier Ireland Ltd. All rights reserved. Keywords: Yttrium-90; Radionuclide therapy; DOTATOC; Neuroendocrine tumours; Non-Hodgkin s lymphoma; 90 Y-ibritumomab tiuxetan; Microspheres; Radioembolization 1. Introduction Even before the 1960s, metallic radionuclides were widely used for the diagnosis and therapy of many diseases [1]. In particular, beta particle emitters, which are able to provide a high radiation dose which induce ionizing phenomena in tumour cells, were introduced for therapeutic purposes in oncology. The pure beta emitter yttrium-90 ( 90 Y) is a radioisotope that has long received great attention for its therapeutic applications in non-invasive medicine, beginning with its topical use and direct intratumoural injection. Recently, 90 Y has been used to treat several types of unresectable neoplasm as a complement or a substitute to the classical conventional therapies (external beam radiation therapy, chemotherapy, immunotherapy, or a combination of these) or current loco-regional physical chemical techniques such as hyperthermia, transarterial chemoembolization (TACE), radiofrequency thermal ablation (RFA) [2 4], stop-flow perfusion with mitomycin-c [5,6], simultaneous TACE and RFA for hepatic malignancies (so-called single-step therapy) [7,8] and precision pulmonary TACE (PPTACE) plus percutaneous RFA (so-called double-track therapy) [9]. Many investigations have demonstrated the therapeutic efficacy and safety of this remarkable radionuclide [10 15]. 90 Y exists in equilibrium with its parent isotope strontium- 90 and decays to stable zirconium-90 with a physical half-life of 64.2 h (2.67 days). Furthermore, it can be produced by the bombardment of 89 Y with neutrons in a nuclear reactor. - Particles are emitted from 90 Y with a relatively high energy up to a maximum of 2.27 MeV (100%), resulting in a tissue penetration range of up to 11 mm and a linear energy transfer (LET) of approximately 0.2 kev/ m [16,17]. Thanks both to its capacity to release high energy and to its long penetration range, this metallic radionuclide is able to deliver -radiations not only to the target cell but also to immediately surrounding cells (the cross-fire effect) [18]. Indeed, more than 90% of emitted radiation is absorbed within an effective path-length of 5 mm (corresponding to a diameter of cells) [19]. The therapeutic -particles affect cell integrity both directly and indirectly; directly (10%), through the so-called primary radiation effect which induces irreparable damage to the structure of double-stranded nuclear DNA, and indirectly (90%), through the so-called secondary radiation effect which increases the amount of toxic free radicals in the cytosol by radiolysis of water [20,21]. The cytocidal properties of 90 Y, together with its ability to coordinate with many different ligands, have allowed us to consider this radionuclide as an important therapeutic tool. To date, it has mainly been applied in the treatment of inoperable patients with neuroendocrine tumours (NETs), non-hodgkin s lymphomas (NHLs), hepatocellular carcinoma (HCC) and liver metastatic colorectal cancer (mcrc) which are refractory to conventional systemic or locoregional therapies. The aim of this article is to overview available data from the literature of the last ten years on the clinical use of emitter 90 Y to treat malignancies, and evaluate its future perspectives of development in cancer treatment. 2. Peptide receptor radionuclide therapy with 90 Y-DOTA-(TOC) in neuroendocrine tumours Over-expression of somatostatin receptor subtypes (mainly sst-2) on the membrane of malignant cells of NETs [22,23] has laid the foundations for peptide receptor radionuclide therapy (PRRT). This relatively recent therapeutic approach is achieved with radiolabelled somatostatin analogues, which act at the molecular level via high-affinity G-protein coupled somatostatin receptors (sst-rs). According to the somatostatin ligand receptor system, the sst-r binding to the radioagonist is internalized into the cellular endosomes. In this way,

3 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) radioactivity is captured in the target cell where it carries out radiotoxic activity [24] Development of PRRT with somatostatin radio-analogues The analogue of choice of somatostatin is octreotide, a small octapeptide metabolically more stable and with a higher affinity for sst-2 receptors [25]. The first attempts to perform PRRT were made in the early 1990s using high activities of indium-111-labelled octreotide, which was already approved as gold standard for the diagnostic scintigraphy of NETs [26]. Clinical trial outcomes reported not only a benefit in symptom relief, but also an unremarkable remission in tumour size [27], evidently due to the short tissue penetration range ( m) of Auger-electrons. Accordingly, the [ 111 In- DTPA 0 ] octreotide was rejected for PRRT. Subsequently, an octreotide derivate, Tyr 3 -octreotide (TOC), with higher affinity profiles for sst-2 and sst-5 receptors [28,29], was synthesized. The pure -emitter and TOC were coordinated with the macrocyclic bi-functional chelator DOTA (a cyclic derivate of tetraacetic acid) to form a stable complex, 90 Y-[DOTA] 0 Tyr 3 -octreotide ( 90 Y- DOTATOC; OctreoTher ) [30,31]. Most recently, two new somatostatin analogues with a higher affinity for sst-2 receptors, octreotate and lanreotide, have been produced. Up to now, the corresponding radiolabelled peptide analogues, 90 Y- DOTATATE and 90 Y-DOTALAN [32,33], have not been particularly accredited [34]. To date, 90 Y-DOTATOC is considered suitable for PRRT both due to its physical characteristics and due to its high affinity for sst-rs. Recently, some clinical trials have also promoted the use of emitter Lutetium-177 in PRRT using it in a conjugate form with higher affinity to sst-2 receptors ( 177 Lu-DOTATATE) [35]. 177 Lu allows simultaneous imaging and therapy Requisites for PRRT The cancers that express high concentrations of somatostatin tumour receptor subtype 2 (sst-2) [36], such as gastroenteropancreatic (GEP) NETs, including mainly carcinoids and pancreatic endocrine tumours (PETs), are candidates for PRRT. Rarer forms of GEP-NETs, such as neuroblastoma, pheochromocytoma, paraganglioma, medullary thyroid carcinomas, small-cell lung cancer (SCLC), multiple endocrine neoplasia types 1 and 2 (MEN-1 and MEN-2) and merkeloma are also eligible. Furthermore, in non-gep- NETs, bronchial endocrine neoplasms, surrenalic medullary neoplasms, meningiomas, and other types of over-expressing sst-rs such as breast cancer, lung cancer and malignant lymphoma can be considered for treatment with PRRT. The selection of patients to be submitted to PRRT must be done according to the following inclusion criteria [37]: (a) age > 18 years; (b) positive 111 In-DOTATOC or 111 In-DTPA-octreotide (OctreoScan ; Mallinckrodt Medical, Petten, The Netherlands) scintigraphy; (c) histological positiveness to the subtype sst-2 of somatostatin receptors (tumour uptake liver uptake); (d) a tumour which is refractory to common standard therapies; (e) life-expectancy of at least 12 months; (f) acceptable haematologic parameters (granulocyte count > /L; platelet 100,000/dL; haemoglobin 5.0 mmol/l; serum bilirubin 2 mg/dl; serum creatinine < 2.0 g/dl); and (g) Karnofsky performance status score > 60% PRRT toxicity and dosimetry The main critical organs when using 90 Y-labelled somatostatin analogues are the kidneys, whose parenchyma is irradiated due to the proximal tubular reabsorption of the radiopeptide. According to the National Council on Radiation Protection and Measurements (NCRPM), the maximum dose tolerated by the kidneys has been estimated as Gray (Gy) [38]. Renal toxicity is effectively reduced, without reducing the treatment efficacy, by administering positively charged amino acids, e.g. l-lysine and/or l-arginine, which with a competitive mechanism reduce the tubular radiopeptide reabsorption [39,40]. Bone marrow has shown haematological toxicity in some studies [41 43] and, even though this does not represent the principal dose-limiting factor, the maximum tolerated dose per cycle of 5.18 gigabecquerel (GBq) has been defined [44]. The activity of 90 Y-DOTATOC to be administered in NET patients is calculated as a cumulative dose supporting renal irradiation, and using the body surface area parameter (GBq/m 2 ) PRRT treatment procedure and response assessment The procedure that correlated with PRRT consists of pretherapeutic scintigraphy in order to visualize, via Octreoscan imaging, the areas of pathological uptake over-expressing sst-rs [45]. If the scintiscan shows an appropriate tumour targeting, 90 Y-DOTATOC is administered in sequential cycles at 6 9 week intervals to allow for bone marrow recovery. The radiopharmaceutical is slowly injected into the patient by systemic intravenous, exploiting the principle of vessel communication. Concurrently, both the amino acid solutions (over a 4-h period) and a small dose of 111 In-DOTATOC are administered; the latter in order to check DOTATOC binding and thereby the internalization of sst-rs [43,46]. Functional imaging is performed at 24 and 48 h after the therapeutic dose using a -camera to acquire planar and SPECT images [41,47]. Objective therapeutic responses are assessed calculating tumour masses by computerized tomography (CT), magnetic resonance imaging (MRI) or both, and defined according to World Health Organization (WHO) [48] or standard Southwest Oncology Group (SWOG) [49] criteria as follows complete remission (CR): no evidence of disease; partial remission (PR): >50% reduction in tumour size; sta-

4 396 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) ble disease (SD): ±25% reduction or increase in tumour size; progressive disease (PD): >25% increase in tumour size. A modification of SWOG criteria includes minor remission (MR): 25 50% reduction in tumour size. Nevertheless, a correct response evaluation requires the comparison of all OctreoScan or 111 In-DOTATOC scintiscans with conventional imaging such as CT, ultra-sonography (US) or MRI [50,51] PRRT clinical trials In 1999, Otte et al. [42] were among the first to investigate the therapeutic potential of 90 Y-DOTATOC. They presented data from a phase I pilot study of 29 patients with advanced sst-rs-positive tumours of a different histology. All patients were treated with four or more single doses of 90 Y-DOTATOC according to a dose escalating scheme in order to evaluate the efficacy and toxicity. The cumulative dose administered was between 3971 and 8924 MBq/m 2 (6120 ± 1347 MBq/m 2 ). Half of the cohort did not receive renal protection with amino acid infusion and five of them developed renal and/or haematological toxicity when they received the cumulative doses of >7400 MBq/m 2. These results highlighted the importance of amino acid renal protection, and in addition showed the correlation between high cumulative doses and haematological toxicity. Although no patient had a therapeutic alternative, a remarkable tumour response and disease stabilization were observed with PRRT. In fact, 2 (7%) out of 29 patients reported a PR, 4 (14%) a MR and 20 (69%) showed a SD, which was confirmed by the same scintigraphic uptake. Following the initial encouraging clinical results, a subsequent phase II clinical trial [50] included 41 patients with progressive GEP-NETs and bronchial NETs. The entire cohort was treated with four escalating doses of 90 Y-DOTATOC which were administered in a total of 6000 MBq/m 2 at intervals of six weeks. As previously suggested, the 90 Y-DOTATOC treatment proved to be well tolerated in association with the amino acid renal protection and for cumulative doses <7400 MBq/m 2. Tumour response was assessed by conventional imaging technique and showed a CR in only one (2%) out of 41 patients, PR in 9 (22%) and MR in 5 (12%), according to WHO criteria. In addition, SD was found in 20 (49%) patients and PD in 6 (15%). The overall tumour response rate (ORR = PR + CR) of 24% was a satisfactory therapeutic outcome, which even increased to 36% for endocrine pancreatic tumours. The median followup was 15 months and the median duration of response (DR) was not reached at 26 months. Valkema et al. [52] of the Erasmus Medical Center, Rotterdam, reported a study of survival and response after PRRT in 58 patients suffering from advanced GEP-NETs and carcinoid tumours. This cohort was all veteran of their multicentre phase I study reported in 2003 and received escalating activities up to 14.8 GBq/m 2 in 4 cycles or up to 9.3 GBq/m 2 in a single dose. According to the therapeutic schedule the maximum dose was not reached. The 90 Y-DOTATOC cumulative dose ranged from 17.4 to 32.8 GBq/m 2. All patients received amino acids for kidney protection. Three patients had dose-limiting toxicity (liver toxicity, thrombocytopenia grade 4 and MDS). Assessment of objective response (OR) showed a PR in five (9%) out of 58 patients and a MR in seven (12%). In 61% of patients the disease resulted stable. The median time to progression (TTP) in the 44 responders was 30 months. The modest values of OR seemed to be offset by an encouraging overall survival (OS) Other clinical outcomes with 90 Y-DOTATOC Despite successive confirmed evidence of the need for renal protection [42], in an early study on PRRT, Otte et al. [53] found toxicity that did not exceed grade 2 according to the National Cancer Institute (NCI) grading criteria following treatment of ten patients without amino acid infusion. Furthermore, although they treated a small heterogeneous group with non-standardized single and multiple dose schedules, the results were convincing in terms of the efficacy of the therapy even showing an ORR of 50% (CR 20%). Several trials were performed to evaluate the tumour response of high-dose treatments of NETs with targeted irradiation of 90 Y-DOTATOC. Very encouraging results began coming from Waldherr et al. [47] who presented data on a cohort of 39 patients with progressive GEP-NETs and bronchial tumours. Administering four equal doses of a total of 7.4 GBq/m 2 with renal protection resulted in an ORR of 23% (CR 5%). In a subsequent study in Milan [54], with the accumulated activity ranging from 7.4 to 20.2 GBq, given in a median number of 4 cycles, ORR was shown in 28% out of 87 patients. Also, in a comparative study performed to evaluate the side effects of 90 Y carried by an appropriate ligand in two different therapies, the radiolabelled compound was administered in a high-dose treatment. In particular, 90 Y-DOTATATE administered in 32 patients with a cumulative dose of 7.4 GBq/m 2 in 3 5 cycles, determined a remarkable OR of 44%, but only in terms of PR. Bodei et al. [46] reported the results of a phase I study achieved with lower-dose treatment in 40 patients of whom 21 had GEP-NETs. Cumulative activities ranging from 5.9 to 11.1 GBq, administered in two treatment cycles, led to a PR of 29% Clinical experiences of PRRT in rarer forms of GEP-NETs Although in the last decade most trials with PRRT have been principally focused on carcinoids and PETs, there have also been experiences in less common forms of GEP-NETs. The first report on treatment with 90 Y-DOTATOC in patients with SCLC and overexpressing sst-rs was introduced by Pless et al. in 2004 [51]. Six patients were treated with 2.22 GBq in a total of 3 cycles but all showed PD. PRRT clinical trials have also been conducted in patients with progressive non-radioiodine-responsive thyroid cancer that showed sufficient uptake of 111 In-octreotide at the

5 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) Table 1 Tumour responses in patients with NETs treated with PRRT. Reference Patient number Tumour response Administration protocol Objective response rate a (ORR = CR + PR) Time-to-progression or duration of response (months) b No. of cycles Cumulative activity (GBq) or dose (GBq/m 2 ) Otte et al. [39] NR 1+ NR Otte et al. [35] 29 7 NR c Waldherr et al. [40] d Waldherr et al. [41] NR d Paganelli et al. [42] c Bodei et al. [43] c Valkema et al. [45] c Hubalewska-Dydejczyk et al. [21] d NR: not reported and GBq: gigabecquerel. a Reported as percentage of patients. b Reported as average or median value. c Cumulative activity (GBq). d Dose (GBq/m 2 ). diagnostic scintiscan. No objective response (OR) was seen in studies reviewed by Teunissen et al. [55] in Despite this, a group in Switzerland recently treated 24 patients with metastasized iodine refractory thyroid cancer with a cumulative total dose of 13.0 GBq (ranging from 1.7 to 30.3 GBq) showing a biochemical response in 29.2% of patients associated with a long survival [56]. In 2007, Iten et al., in the phase II-arm of same clinical trial, administered 90 Y-DOTATOC in 31 patients with advanced medullary thyroid cancer reporting an encouraging clinical response and managing to describe for the first time a potential long-term survival benefit after treatment with 90 Y-DOTATOC in PRRT [57]. Treatments with the radiolabelled somatostatin analogue 90 Y-DOTATOC have been episodically utilised also for rare cancers such as paragangliomas, pheochromocytomas and meningiomas that express a high density of somatostatin receptors. In a pilot study, Otte et al. [42] reported a SD in one patient with pheochromocytomas, in three patients with meningioma and one CR. Moreover, the Milan group [46] treated two patients with meningioma obtaining a SD in one case. The use of 90 Y-DOTATOC in gastrinomas associated with multiple endocrine neoplasia type 1 (MEN-1) to downstage the disease in order to allow a successful surgical resection has also been recently described [58]. Table 1 indicates the clinical response of tumours to PRRT in the considered studies. Even though the achievement of OR on all the aforementioned studies has been reported, a critical observation about the extreme heterogeneity of the adopted schedules for 90 Y-DOTATOC administration is necessary. Indeed, in some studies the radiopeptide was administered according to dose-escalating schemes, delivering in this way a relatively low dose to the target tissue, whereas in others fixed doses were administered. In addition, the number of cycles adopted was variable from single to multiple treatments (Table 1). As a consequence it is not possible to standardize the data and to define a linear correlation between the OR and the administered activity. 3. Radioimmunotherapy with 90 Y-Zevalin in non Hodgkin s lymphoma Most B-cell lymphomas express the specific surface antigen CD20, making it a suitable target antigen for radioactive monoclonal antibodies (MAbs) [59]. This excellent combination laid the premises for the novel therapeutic strategy known as radioimmunotherapy (RIT). The radioimmunoconjugate (RIC) acts with an inductive action mechanism which causes antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity and induction of apoptosis or programmed cell death [60]. In addition, antibodies can interfere with a vital function of the target antigens on cells [61] Development of RIT with radiolabelled antibodies The first immunotherapy investigations with hot - immunoconjugates in the treatment of malignant lymphomas began more than 20 years ago [62]. The number of clinical studies has continued to grow, showing encouraging results of efficacy and safety of RIT [63 65]. The success of this radioimmunotherapeutic approach depends in part on many characteristics of the antigen present on the B-cell surface. In fact, the target antigen is expressed only on the B-cell lymphomas and not on normal cells or haematopoietic stem cells. Moreover, it has a high density of expression, and does not internalize or shed from the surface into the circulation in response to MAb binding [66 68]. For several years, the Iodine-131-tositumomab (Bexxar ; GlaxoSmith, Kline, Philadelphia, PA, USA) was the main RIC used for RIT. 131 I is a dual - and -emitting radionuclide

6 398 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) with relatively low-energy -emissions and relatively highenergy -rays. Due probably to its physical characteristics, 131 I-Bexxar is not used to a great extent in RIT [69]. More recent RIT studies considered 90 Y-ibritumomab tiuxetan (Zevalin ; Bayer Schering Pharma AG, Berlin, Germany), a RIC consisting of an IgG1 anti-cd20 MAb, ibritumomab (the murine parent of chimeric rituximab), which is covalently linked by a chelating agent, tiuxetan, to the pure -emitting radioisotope 90 Y [68]. In 2002, the US Food and Drug Administration (FDA) approved the use [70] of both 90 Y-Zevalin and 131 I-Bexxar for patients with B-cell NHLs with an over-expression of CD20 antigens or with target molecules expressed on tumour cells. Despite the fact that recent studies comparing 90 Y-Zevalin and 131 I-Bexxar have shown similar response rates (RRs) and duration of response (DR) [12], the former would appear to be most used in clinical practice Requisites for RIT RIT using 90 Y-Zevalin is conducted mainly on patients with relapsed or refractory low-grade follicular lymphoma (FL) or transformed B-cell NHL, aggressive diffuse large B- cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), including those with rituximab-refractory NHL. According to IEO S187/104 HD-Zevalin protocol, the eligibility criteria include (a) confirmed histology for relapsed, refractory or transformed, indolent or aggressive, CD20- positive B-cell NHLs according to the WHO classification system [71] and International Working Formulation [72]; (b) WHO performance status of 0 2; (c) life expectancy of at least 3 months; (d) less than 25% bone marrow involvement; (e) an absolute neutrophil count (ANC) of at least /L, a haemoglobin level of at least 90 g/l (9 g/dl), and a platelet count of at least /L RIT toxicity and dosimetry For malignant lymphomas, bone marrow is the critical organ in RIT [67]. Haematological toxicity depends mainly on the degree of bone marrow infiltration (<25% for reversible myelosuppression), as well as on the stemcell reserve (higher toxicity in patients with poor-cell bone marrow after failures of earlier applied procedures). Before RIT, a dosimetric study with 111 In-ibritumomab tiuxetan is carried out in order to predict absorbed doses to non-target organs. Therapy should not be administered if the predicted radiation-absorbed dose to healthy non-tumour organs is greater than 20 Gy, or, specifically, greater than 3 Gy for red marrow [73]. According to therapeutic protocol, 90 Y-Zevalin is dosed at 14.8 MBq/kg for a blood platelet count 150,000/ L and decreased to 11 MBq/kg if the blood platelet count is 100, ,000/ L. The maximum dose should not exceed 1184 MBq [63] RIT treatment procedure and response assessment 90 Y-Zevalin is administered as a slow intravenous push over a period of 10 min [74,75]. An intravenous injection of an imaging dose of 111 In-ibritumomab tiuxetan is achieved in order to evaluate the biodistribution of the RIC. Therefore, a series of scintigraphic total-body images are acquired by a -camera with a timing of 1, 16, 24, and 48 h and on days 4 and 6 after the therapeutic injection. In most trials, all lymph nodes of the neck, chest, abdomen and pelvis are evaluated on CT scans [64,65,76]. Subsequently, the response to 90 Y-Zevalin treatment is defined in accordance with the International Workshop Response Criteria (IWRC) for NHL, used as a standard system of classification [77]. Combined use of FDG-PET and CT can help to better assess the presence of residual viable disease after RIT treatment of NHL [78] RIT clinical trials In an initial multicentre phase I/II dose escalation study with 90 Y-ibritumomab tiuxetan (initially known as IDEC- Y2B8), Witzig et al. [63] presented data on 51 patients suffering from relapsed or refractory CD20 B-cell low-grade, intermediate-grade, or mantle-cell NHL. Patients with lowgrade disease had failed 2 prior antineoplastic regimens or 1 anthracycline-containing regimen, and the dose activity of 90 Y-Zevalin administered ranged from 7.4 to 14.8 MBq/kg. The phase I arm established the maximum tolerated dose as 14.8 MBq/kg, which was reduced to 11 MBq/kg in the case of thrombocytopenia (platelets ,000/ L). Furthermore, the dose of rituximab to be infused as an unlabelled antibody before dosimetric or therapeutic administrations was established as 250 mg/m 2. The phase II arm was trialled on 36 patients and reported an ORR of 67%, with 26% of patients entering CR. The subgroup of patients with positive histology for low-grade disease showed an ORR of 82% (CR 26%), compared to 43% (CR 29%) in the one with intermediategrade disease. No response was observed in 3 patients with MCL. A Kaplan Meier analysis reported a median TTP in responders of 12.9 months and a median DR of 11.7 months. Long-term responders (>5 years) were identified and demonstrated that RIT with 90 Y-Zevalin produced durable responses in patients with indolent and diffuse large B-cell lymphoma. In fact 24% of responders had a TTP of more than 3 years [79]. Later on, Witzig et al. [64] reported the results of a pivotal randomised phase III clinical trial that led to the approval of the first RIT agent ( 90 Y-ibritumomab tiuxetan) by the US FDA. In this study, including 143 rituximab-naive patients with relapsed or refractory low-grade, follicular or transformed NHL, the efficacy of RIT was compared with standard immunotherapy; in the former a single dose of 14.8 MBq/kg of 90 Y-ibritumomab tiuxetan was administered and in the latter 375 mg/m 2 of rituximab was used once weekly for 4

7 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) weeks. The majority of patients enrolled had FL, with 17 nonfollicular low-grade lymphomas and 13 patients with disease transformation. Patient characteristics were well balanced, and both groups of patients had received a median of two prior therapies (range 1 6), of which 45% of patients had failed to respond or progressed within 6 months of their last chemotherapy. RRs were statistically significant in favour of RIT (n = 73) with an ORR of 80% vs 56% (p <.002) and a CR of 30% vs 16% (p <.04). Patients with follicular histology had a greater benefit from RIT (ORR of 86% vs 55%; p <.001) compared to the non-follicular group (ORR of 67% vs 50%; p NS). The main toxicity seen in this study with 90 Y ibritumomab tiuxetan was reversible myelosuppression. The Kaplan Meier estimated median TTP was 11.2 months (range ) and the median DR was 14.2 months (range ) in the RIT group, compared to 10.1 months and 12.1 months, respectively, in the rituximab-treated group. Subsequent to preliminary studies on the feasibility and tolerability of RIT [80], and to data demonstrating the benefit of adding rituximab to CHOP chemotherapy [81], in 2005 a phase II multicentre trial was carried out. Shipley et al. [82] used 90 Y-Zevalin as a consolidation therapy after front-line treatment with short duration chemotherapy and rituximab. Forty-two previously untreated FL patients received rituximab infusions according to the standard schedule (375 mg/m 2 weekly for 4 weeks) followed by three cycles of conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Despite a slight myelosuppression resolved in all patients within 12 weeks, the results indicated an ORR of 100% (CR 28%) according to IWRC. After 5 weeks following the last dose of R-CHOP, 90 Y-Zevalin was administered to responders. At 12 weeks after RIT, the final restaging was performed and showed an increase in CR from 28% to 67%. After 2 years, a progression-free survival (PFS) of 77% was observed Other clinical outcomes with 90 Y-ibritumomab tiuxetan A phase II trial [65] demonstrated that 90 Y-ibritumomab tiuxetan is also effective in B-cell NHL patients with mild thrombocytopenia. Indeed, a cohort of 30 patients with a low platelet count ( platelets/l) was treated with a reduced dose of 90 Y ibritumomab tiuxetan (11 MBq/kg, not to exceed 1.2 GBq) and showed an ORR of 83% (37% CR, 6.7% CRu). In patients with low-grade NHL an ORR of 92% (56% CR/CRu) was even reached. 90 Y-Zevalin was also effective in FL rituximab nonresponders from the control arm of a randomised ibritumomab tiuxetan trial [63], showing an ORR of 74% (CR 15%) after RIT compared with 32% with prior rituximab [83]. In recent years, many encouraging data have arrived on the efficacy of RIT as a first-line consolidation therapy in different histological subtypes of B-cell NHLs [82,84 87]. The function of 90 Y-Zevalin consolidation therapy in aggressive MCL, which is normally considered incurable with conventional therapy, was presented at the 2006 ASCO annual meeting [88]. Fifty-seven previously untreated MCL patients, not eligible for autologous stem cell transplantation (SCT), received R-CHOP, followed by 90 Y ibritumomab tiuxetan infusion in 50 responders. The results indicated an ORR of 72% (CR/CRu 14%) which improved to 84% (CR 45%) after RIT. Similarly, 90 Y-Zevalin has been combined with shortcourse CHOP plus rituximab as a front-line therapy for 40 previously untreated FL patients, resulting in an ORR of 95% with a final increased CR rate of 72% [89]. Highly promising RRs (ORR 66%, CR 52%) were furthermore observed in a Polish study of 90 Y ibritumomab tiuxetan applied either as consolidation therapy or as salvage therapy in 30 patients with relapsed or resistant NHL and aggressive MCL [90]. In addition, 90 Y-Zevalin consolidation following chemotherapy for previously untreated aggressive DLBCL in elderly patients and those ineligible for SCT showed a marginally lower tumour response (ORR 53%, CR 33%) [76]. The results after RIT are shown in Table Transarterial radioembolization therapy with 90 Y-microspheres in hepatocellular carcinoma and liver metastases Since liver tumours are hypervascular and supplied mainly from the hepatic artery, unresectable primary and secondary liver malignancies are treated with transarterial radioembolization therapy ( TARET ) [90,91]. This innovative therapy exploits the synergy between the cytotoxic radiation effect and embolization-induced hypoxia, both achieved by radiomicrospheres, to strengthen the tumouricidal effect. The radiomicrospheres, after injection into the hepatic artery, stick in the capillary bed of the liver inducing embolism; in this way they not only restrict blood flow to the liver but also deliver very high radiation doses to the tumour while sparing the normal hepatic parenchyma, surrounding organs and essential vascular structures [92,93] Development of TARET with radiomicrospheres Initially, yttrium-90 was administered in liver neoplasm treatments through topical applications and direct injection into cancerous masses. In 1964 Ariel [94] introduced the technique of 90 Y microspheres injected via a hepatic transarterial catheter and studies about the feasibility and effectiveness of the technique soon followed [95 102]. Not long after, the same Ariel published the first successes of mcrc treatment with 90 Y resin microspheres and chemotherapeutic intraarterial administration [103,104]. These promising results were achieved thanks to the double radio-embolizing action of the radiomicrospheres which consist of -emitter radioisotope 90 Y incorporated in small, biocompatible spheres.

8 400 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) Table 2 Tumour responses in patients with NHLs treated with RIT. Reference Patient number Tumour response Objective response rate a (ORR = CR + PR) Time-to-progression (months) b Witzig et al. [63] Witzig et al. [64] Wiseman et al. [65] Witzig et al. [83] Shipley et al. [82] NA Smith et al. [88] NA Morschhauser et al. [76] NR Hubalewska et al. [21] Hainsworth et al. [89] NR NA: not available and NR: not reported. a Reported as percentage of patients. b Reported as median value. Two types of radiomicrospheres have been developed up to now. TheraSphere (MDS Nordion Inc., Kanata, Ontario, Canada) is made of glass (Y 2 O 3 Al 2 O 3 SiO 2 ) and has a diameter of 25 ± 10 m/sphere. As a result it is minimally embolic, has a higher specific activity (2500 Bq/sphere) [105], a lower number of spheres (1.2 million spheres/3 GBq dose) and has 90 Y as an integral constituent of the glass matrix [106]. Instead, SIR-Spheres (Sirtex Medical Ltd., Sydney, Australia) are microspheres made of resin, with a diameter of 32 ± 10 m/sphere. Consequently they are moderately embolic, have a lower specific activity (50 Bq/sphere), a greater number of spheres (around million spheres/3 GBq dose) and have 90 Y labelled to cation resin spheres through ion-exchange [ ]. TheraSphere was approved by the FDA in 2000 [110] for use in radiation treatment or neoadjuvant to surgery or liver transplantation in patients with unresectable HCC [111]. However, it has also been used in liver metastases [15,112]. SIR-Spheres gained premarket approval from the FDA in 2002 for the treatment of hepatic mcrc, with adjuvant chemotherapy of Floxuridine (FUdR) administered via the hepatic artery. Furthermore, other secondary liver malignancies have also been treated [113,114] Requisites for TARET HCC and mcrc are the unresectable liver diseases which are principally treated with TARET [115,116,14, ]. However, most studies that have been published also include hepatic metastases from breast cancer [ ], NETs [113, ] and other tumour types [14,117]. According to clinical protocol [14], the ideal candidate for 90 Y radioembolization must present (a) a non-infiltrative tumour type; (b) <70% bulk disease or tumour nodules that are not too numerous to count; (c) AST/ALT < 5 ULN (Upper Limit of Normal Range); (d) tumour volume < 50%; (e) serum albumin > 3 g/dl; (f) serum bilirubin 2 mg/dl; and (g) ECOG performance status score TARET toxicity and dosimetry Following administration of -radiation, the lungs and the gastrointestinal (GI) tract are the critical organs in TARET [111]. Therefore, a pre-treatment hepatic angiogram is performed to allow a scintiscan with radiolabelled 99m Tc-MAA. This enables patients at high risk of lung (radiation pneumonitis) or GI toxicity (gastric/duodenal ulceration) due to hepato-systemic shunting or aberrant vasculature to be excluded. The fraction of extra-hepatic shunting is determined for each patient as a percentage. Patients who have shunting of greater than 20% are excluded from the treatment (30 Gy/kg) [128], whereas shunting of between 12% and 20% results in a reduction in the dosage of spheres delivered. Several dosimetric studies have reported that the lowest liver tumour dose necessary to generate a detectable response is 40 Gy [109] and that the absence of severe liver parenchyma toxicity is shown for values of absorbed radiation doses of up to 150 Gy [106, ]. The activity of 90 Y microspheres required to deliver the desired dose to the liver target is calculated empirically on the basis that 1 GBq (27 mci) of 90 Y per kilogram of tissue provides a dose of 50 Gy [133,134], excluding the lung shunt fraction as measured by 99m Tc MAA [129,135]. The calculation can be performed using the following formula: activity required (GBq) = dose (Gy) liver mass (50/kg) TARET treatment procedure and response assessment Prior to treatment, arteriography is performed by interventional radiologists in order to plan the therapy. In this way, the optimal placement of the catheter, blood-flow dynamics and the vascular and tumour anatomy are evaluated. In addition, cross-sectional CT/MR images are analysed to assess hepatic volume, and 99m Tc-labelled macroaggregated albumin (MAA) scintigraphy is executed in Nuclear Medicine to appraise significant hepatopulmonary shunting and gastrointestinal flow [136].

9 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) Table 3 Tumour responses in patients with HCC treated with TARET. Reference Patient number Tumour response Objective response rate a (ORR = CR + PR) Time-to-progression (months) b Lau et al. [121] NR Dancey et al. [129] Carr et al. [157] NR Liu et al. [145] NR Salem et al. [146] NR Sangro et al. [153] 24 NR 3 Keppke et al. [144] NR Kulik et al. [154] NR Riaz et al. [156] NR Lewandowski et al. [159] NR: not reported. a Reported as percentage of patients. b Reported as median value. Once the presence of significant extrahepatic shunting has been excluded and the administration dose calculated, the radiolabelled microspheres (either of resin or of glass) are delivered directly into the hepatic artery via a percutaneous microcatheter inserted into the femoral artery [111,129]. Liver perfusion is examined with arteriograms to monitor an accidental reflux into the gastroduodenal or right gastric arteries when they had not been previously occluded using coils to isolate hepatic arterial circulation [106,137]. Moreover, venous imaging is performed to ensure portal vein patency [138]. Tumour response in malignant liver disease is assessed using anatomic imaging such as CT and MRI, by measuring tumour size in accordance with WHO (bidimensional perpendicular measurements) [139], Response Evaluation Criteria In Solid Tumours (RECIST) (unidimensional measurements) [140], European Association for Study of the Liver (EASL) (necrosis) [ ] and combined criteria (RECIST and EASL) [143]. Because TARET often causes tumour necrosis without a change in tumour size, EASL assessment, which is based on a percent change in the amount of enhancing tumoural tissue post-treatment, has been adopted [141,144]. In order to improve the assessment of tumour response, the evaluation of non-quantitative metabolic response by PET is performed and then compared side by side on a computer display with the CT or MRI scans Studies with 90 Y-microspheres In the last ten years, some studies on HCC and liver-dominant colorectal metastasis treatment with 90 Y microspheres, either resin or glass indifferently, have been revisited. The tumour responses of the original articles are reported in Tables 3 and Clinical trials of TARET in HCC A team from California [145] published a retrospective analysis performed on fourteen patients with unresectable HCC. A total of eleven patients were administered with a median activity of 2.73 GBq delivered by 90 Y glass microspheres providing a median dose of 116 Gy (range Gy). Treatment response was based on AFP levels and CT or MR imaging. The ORR was 82%. In patients who had previously received TACE, 9% showed CR indicated by necrosis in all lesions on CT imaging and a decrease in AFP levels, and 73% showed a PR indicated by evidence of necrosis or decreased vascularisation in the majority of lesions and in AFP levels. Particularly, of these partial responders, 9% presented no new lesions after CT/MR imaging, 18% showed new lesions in the untreated lobe, 18% metastasis and 27% had new lesions in the treated lobe. In addition, 18% showed a PD after TheraSphere treatment highlighted by the expansion of current lesions, an increase in AFP levels and the appearance of new primary and secondary lesions. Salem et al. [146] presented data from a follow-up study in 2005 on 43 patients with unresectable HCC, which supported the safety and efficacy of TheraSphere treatment. Patients received one or more segmental or lobar treatments in the liver depending on liver function, tumour distribution and vascular flow dynamics. The population had been divided into three risk groups according to 90 Y risk-stratification system [140,144, ] (group 0, segmental; group 1, lobar lowrisk; group 2, lobar high-risk) and Okuda and Child Pugh scoring systems. The median liver radiation dose received by groups 0, 1, and 2 was 359 Gy, 141 Gy, and 142 Gy, respectively. The ORR was 47% if the percent reduction in tumour size was used as a composite measure of tumour response, and 79% if tumour response was based on percent reduction and/or tumour necrosis. There was no statistical difference among the three risk groups in terms of tumour response. Recently, a group from Chicago [156] has published an interesting radiologic pathologic correlation study on HCC patients who underwent radioembolization with 90 Y glass microspheres prior to resection or transplantation. Thirtyfive patients with a total of 38 lesions were -irradiated with a TheraSphere median dose of 93.5 Gy (range ) followed by liver explantation. After treatment the imaging surrogates were assessed, and the explants were examined

10 402 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) Table 4 Tumour responses in patients with mcrc treated with TARET. Reference Patient number Tumour response Objective response rate a (ORR = CR + PR) Time-to-progression (months) b Stubbs et al. [163] NA Gray et al. [165] NR Gray et al. [166] Wong et al. [160] 8 24 NR Van Hazel et al. [167] Lewandowski et al. [164] NR Kennedy et al. [116] NR Miller et al. [161] NR Mulcahy et al. [162] NA: not available and NR: not reported. a Reported as percentage of patients. b Reported as median value. to evaluate necrosis by pathology. All cross-sectional imaging between the first radioembolization and explantation was evaluated. According to WHO criteria, TARET showed 49% PR (18/37 los), 46% SD (17/32 los) and 5% PD (2/37 los). PR, SD, and PD after radioembolization were found to have complete histological necrosis in 78%, 53%, and 0%, respectively Other clinical outcomes with 90 Y-microspheres in HCC. In the last decade further studies on the intrahepatic treatment with 90 Y-microspheres have reported encouraging results in terms of therapeutic efficacy in unresectable HCC. The Hong Kong research group [121] administered 71 patients with an activity ranging from 0.8 to 5.0 GBq and reported a PR of 27% in terms of tumour size. The ORR even reached 89% if evaluated by alpha-fetoprotein (AFP) levels. Similarly, Dancey et al. [129] described tumour response in a cohort of 20 patients who were -irradiated with a median dose of 104 Gy. The ORR was 20% (CR 5%). In the same way, in a study by Carr [157] on 65 patients a satisfying tumour response (ORR 31%) and a substantial decrease in tumour vascularity were observed when the median dose of Gy was delivered to the neoplastic tissue. Contrarily, Spanish investigators [153] reported a reduction of only less than 30% in the size of target lesions in 88% of patients out of 21 assessed according to RECIST criteria. The whole cohort was administered with a median activity of 2.2 GBq that delivered a median dose of irradiation of Gy to the tumour tissue. Unlike other researchers, Keppke et al. [144] reported tumour response data using three different methods of assessment according to size criteria (WHO and RECIST), necrosis criteria, and combined criteria (RECIST and necrosis). The ORR was 23% according to RECIST criteria, 26% according to WHO criteria, 57% according to necrosis criteria, and 59% according to combined criteria. When, in a different study, a cumulative dose close to 140 Gy was delivered to the tumour foci in HCC patients with and without portal vein thrombosis (PVT), a PR of 42.2% according to WHO criteria was observed. ORR reached 70% using EASL response criteria [154]. PVT patients can be safely treated with TARET provided there is partial retention of the arterial flow in the treatment area [158]. In a retrospective analysis [159] on 86 patients conducted in order to compare the downstaging efficacy of TACE with TARET, although the objective response was higher in TARET (n = 43; PR 61%) than TACE (PR 37%), the results were satisfactory Clinical trials of TARET in liver mcrc A small prospective study evaluating TheraSphere treatment in unresectable hepatic metastases by [ 18 F]FDG PET was reported by Wong et al. in 2002 [160]. In 8 consecutive patients, with previously resected colorectal cancer, 90 Y- glass microspheres were administered via an intra-arterial catheter under low pressure, delivering a median activity of 3.01 and 0.96 GBq to the right and left lobes, respectively. The range of the absorbed dose for the tumour was Gy. In all patients, CT or MRI, [ 18 F]FDG PET, and serum CEA determination were performed both at baseline (pre-treatment) and 3 months after the last treatment. On comparison of whole-body PET/tomographic images pre- and post-treatment, results were as follows: no metastases in two patients, stable metastases in three, progressive metastases in three, and new extrahepatic metastases in two patients. In addition, evaluation of the metabolic activity of extrahepatic metastases by CEA showed a significantly decreased level in 75% of patients, a negative serum CEA in one patient, and an increased serum CEA level due to extrahepatic metastasis in one case. The Chicago group reported in 2007 [161] a study performed on patients with unresectable liver metastases focusing on the importance of using necrosis and size criteria on CT and correlation with PET for a more accurate assessment of response to 90 Y treatment. The CT imaging response of 42 patients administered with a Gy 90 Y dose was evaluated using traditional size criteria (WHO and RECIST), necrosis criteria, and combined criteria (RECIST

11 V. Goffredo et al. / Critical Reviews in Oncology/Hematology 80 (2011) and necrosis). Of eighteen patients with metastatic cancer from colorectal cancer, only 15 were assessable for CT and PET scans, and were examined immediately before treatment, at approximately 30 days after treatment, and at day intervals subsequently. ORR was 19% by WHO criteria, 24% by RECIST, 45% by necrosis criteria, and 50% by combined criteria. Stabilization of liver disease occurred in 52% by WHO criteria and 50% by RECIST. The median time to response was 68 days by WHO criteria, 116 days by RECIST, 29 days by necrosis criteria, and 34 days by combined criteria, in responders. Mulcahy et al. [162] recently presented a trial supporting the safety and efficacy of 90 Y-microspheres for liver-dominant colorectal metastases not suitable for resection. A cohort of 72 patients received a total of 136 treatments as outpatients (with a range of 1 3 treatments per patient), a median injected activity of 2.37 GBq (range GBq), and a median liver dose of 118 Gy. Follow-up data from CT imaging were reported 1 month after initial treatment and routinely every 3 months subsequently. ORR according to WHO criteria was 40.3% (PR only) and SD was 44.5%. On PET scan follow-up the RR was 77%. The median TTP was 15.4 months and the median DR was 15 months Other clinical outcomes with 90 Y-microspheres in mcrc. An initial experience [163] investigating response to 90 Y-microsphere treatment in 30 patients with unresectable colorectal liver metastases already reported very encouraging response results showing a PR of 70% and SD of 19%. In a phase II study, 27 patients in whom standard systemic chemotherapy regimen had failed received bilobar or unilobar TheraSphere treatment providing a dose ranging from 135 to 150 Gy. Although follow-up CT imaging data showed a respectable ORR of 35% and a SD of 52%, the decrease in FDG metabolic activity measure showed a higher tumour RR of 88% [164]. In a seven-centre US study [116] a cohort of 208 patients refractory to oxaliplatin and irinotecan showed similar results in a salvage therapy with SIR-Spheres. A PR of 36% was shown from CT scans, and reached 85% with PET evaluation. A reduction of 70% in carcinoembryonic antigen levels was noted. Subsequently, several studies began to combine chemotherapy with microspheres to further improve the effectiveness of TARET. In 2000, Gray et al. [165] reported a PR of 75% in 71 patients by cross-sectional imaging studies. A phase III randomised trial [166] compared 90 Y-resin microsphere treatment in combination with intra-hepatic artery chemotherapy (HAC) with HAC alone. Thirty-six patients who received 2 3 GBq of 90 Y activity plus intrahepatic floxuridine showed an ORR of 50% (CR 6%). Similarly, a randomised phase II trial [167] compared SIR-Spheres-TARET plus 5-FU/leucovorin chemotherapy with 5-FU/leucovorin chemotherapy alone. In 11 patients who received a single dose of 2.25 GBq plus a standard chemotherapeutic regimen, a markedly better response (PR 91%) compared to chemotherapy alone was observed. Fig. 1. Proportions of objective response rates to 90 Y-treatment in the NETs, NHLs, HCC and mcrc. 5. Future developments On the basis of the currently available data for 90 Y- therapies in the treatment of NETs, B-cell NHLs, and primary and secondary liver malignancies, an evidently greater efficacy (ORR 80 ± 15%; range ) of radioimmunotherapy in the care of NHLs has been found, compared to radioreceptorial therapy in NETs (ORR 23.5 ± 14%; range 9 50), and to radioembolization therapy in mcrc (ORR 40 ± 25%; range 19 91) and HCC (ORR 42 ± 20%; range 20 82) (Fig. 1). Interestingly, the use of RIT with 90 Y-immunoconjugate allows a high complete response of disease (CR vs SD, 43% vs 0%) (Fig. 2) while PRRT Fig. 2. Proportions of response to RIT in patients with B-cell non Hodgkin s lymphoma (NHLs). CR complete response; PR partial response; PD progression of disease; SD stabilization of disease; ORR objective response rate. The response rates are calculated as a median value. The number of studies considered for the response is shown below.