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Aim: Transarterial radioembolization (TARE) is, by all standards, a radiation therapy. As such, according to Euratom Directive 2013/59, it should be optimized by a thorough treatment plan based on the distinct evaluation of absorbed dose to the lesions and to the non-tumoural liver (two-compartment dosimetry). Since the dosimetric prediction with 99mTc albumin macro-aggregates (MAA) of non-tumoural liver is much more accurate than the same prediction on lesions, treatment planning should focus on non-tumoural liver rather than on lesion dosimetry. The aim of this study was to determine a safety limit through the analysis of pre-treatment dosimetry with 99mTc-MAA single photon emission computed tomography (SPECT/CT), in order to deliver the maximum tolerable absorbed dose to non-tumoural liver. Methods: Data from intermediate/advanced hepato-cellular carcinoma (HCC) patients treated with 90Y glass microspheres were collected in this single-arm retrospective study. Injection was always lobar, even in case of bilobar disease, to avoid treating the whole liver in a single session. A three-level definition of liver decompensation (LD) was introduced, considering toxicity only in cases of liver decompensation requiring medical action (LD type C, LDC). We report LDC rates, receiver operating characteristic (ROC) analysis between LDC and NO LDC absorbed dose distributions, normal tissue complication probability (NTCP) curves and uni- and multivariate analysis of risk factors associated with toxicity. Results: A 6-month timeline was defined as necessary to capture all treatment-related toxicity events. Previous transarterial chemoembolization (TACE), presence or extension of portal vein tumoural thrombosis (PVTT) and tumour pattern (nodular versus infiltrative) were not associated with tolerance to TARE. On the contrary, at the multivariate analysis, the absorbed dose averaged over the whole non-tumoural liver (including the non-injected lobe) was a prognostic indicator correlated with liver decompensation (odds ratio = 4.24). Basal bilirubin > 1.1 mg/dL was a second even more significant risk factor (odds ratio = 6.35). NTCP analysis stratified with this bilirubin cut-off determined a 15% liver decompensation risk at 50 Gy/90 Gy for bilirubin >/< 1.1 mg/dL. These results are valid for a 90Y glass microsphere administration 4 days after the reference time. Conclusion: Given the low predictive accuracy of 99mTc-MAA on lesion absorbed dose reported by several authors, an optimized TARE with 90Y glass microspheres with lobar injection 4 days after reference time should aim at an absorbed dose averaged over the whole non-tumoural liver of 50 Gy/90 Gy for basal bilirubin higher/lower than 1.1 mg/dL, respectively. [ABSTRACT FROM AUTHOR]

Gamma photons allow SPECT/CT imaging and dosimetry (some days after therapy to avoid gammacamera saturation) [[1]], while paramagnetism gives the additional possibility of post-therapy MRI evaluation. Median lung absorbed dose was 0.2 Gy evaluated both pre-therapy (scout dose) and post-therapy with SP 166 sp Ho SPECT/CT, while it was overestimated to 2.5 Gy according to SP 99m sp Tc MAA SPECT/CT. A partition model-based 99mTc-MAA SPECT/CT predictive dosimetry compared with 90Y TOF PET/CT posttreatment dosimetry in radioembolization of hepatocellular carcinoma: a quantitative agreement comparison. 16 Richetta E, Pasquino M, Poli M, Cutaia C, Valero C, Tabone M, Paradisi BP, Pacilio M, Pellerito RE, Stasi M. PET-CT post therapy dosimetry in radioembolization with resin 90Y microspheres: comparison with pre-treatment SPECT-CT 99mTc-MAA results. [Extracted from the article]

Purpose: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. Methods: We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate ( n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50 % and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of Tc-MAA and Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BED) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. Results: MAA and Y biodistributions were not different (71 % of cases), different in 23 % and uncertain in 6 %. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted ( p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50 %) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14 %, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD ≈ 75 Gy. Conclusion: A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed. [ABSTRACT FROM AUTHOR]

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [Y]DOTA-TATE and [Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter (Y) and a medium-energy beta/gamma emitter (Lu) in patients with metastatic NET refractory to conventional therapy. Methods: A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [Lu]DOTA-TATE (5.55 GBq) and [Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Results: Administration of tandem [Y]DOTA-TATE and [Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment Conclusion: The results of our study indicates that combined [Y]DOTA-TATE and [Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. [ABSTRACT FROM AUTHOR]

The aim of this study was to carry out two different dose estimation approaches in patients with non-Hodgkin’s lymphoma (NHL) treated with a myeloablative amount of 90Y-labelled ibritumomab tiuxetan (Zevalin®) in an open-label dose escalation study. Twenty-seven patients with relapsed/refractory or de novo high-risk NHL receiving one myeloablative dose of 90Y-ibritumomab tiuxetan followed by tandem stem cell reinfusion were evaluated for dose estimate. The injected activity was 30 MBq/kg in 12 patients and 45 MBq/kg in 15 patients. Dose estimation was performed 1 week prior to 90Y-ibritumomab tiuxetan by injection of 111In-ibritumomab tiuxetan (median activity: 200 MBq). The absorbed dose (D) and the biologically effective dose (BED) were calculated. The absorbed doses per unit activity (Gy/GBq) were [median (range)]: heart wall 4.6 (2.5–9.7), kidneys 5.1 (2.8–10.5), liver 6.1 (3.9–10.4), lungs 2.9 (1.5–6.8), red marrow 1.0 (0.5–1.7), spleen 7.0 (1.5–14.4) and testes 4.9 (2.9–16.7). The absorbed dose (Gy) for the 15 patients treated with 45 MBq/kg were: heart wall 17.0 (8.7–25.4), kidneys 17.1 (7.9–22.4), liver 20.8 (15.4–28.3), lungs 8.1 (5.4–11.4), red marrow 3.1 (2.0–4.0), spleen 26.2 (17.0–35.6) and testes 17.3 (9.0–28.4). At the highest activities the acute haematological toxicity was mild or moderate and of very short duration, and it was independent of the red marrow absorbed dose. No secondary malignancy or treatment-related myelodysplastic syndrome was observed. No non-haematological toxicity (liver, kidney, lung) was observed during a follow-up period of 24–48 months. The use of 45 MBq/kg of 90Y-ibritumomab tiuxetan in association with stem cell autografting resulted in patients being free of toxicity in non-haematological organs. These clinical findings were in complete agreement with our dose estimations, considering both organ doses and BED values. [ABSTRACT FROM AUTHOR]

Introduction: CS is characterized by flushing, diarrhea and carcinoid heart disease (CHD) alone or in association. Aim(s): To assess the incidence, clinical features and survival of WDNETs pts with CS. Materials and methods: We retrospectively analyzed 700 NET pts, between 1979 to 2009. One-hundred and ten pts with Typical (T) or Atypical (A) CS were identified. Results: Incidence of CS was 15.7%, with a prevalence of 7.5/700 cases. Median age was 55.5 years, male/female = 59/51. All pts were WDNETs and 83% were GEP: Carcinoids/pNET= 66%/34%; Midgut/Foregut/ Hindgut= 44%/35.5%/3.3%. Liver involvement was found in 96%: synchronous (42%); metacronous (68%). Primary tumor resection was performed in 67% of midgut and in 33% of foregut. TCS was evident in 92/110 (83.3%), whilst ACS in 2/110 (2.2%). The most common symptoms were flushing/diarrhea/CHD in 72 %/64%/12 % of pts. CgA/NSE/HIAA levels were pathologic in 78%/22%/50%, respectively, mOS was 90 months (range 2-274), 5- and 10-year survival rates were 58% and 43% respectively. Significant difference in mOS was found between male/female 114/90 months; midgut/foregut 114/74 months; carcinoids/pNET 131/74 months (p<0.05). Primary tumor resection may be correlated with survival amelioration. Conclusion: The advanced stage and, in particular, the liver involvement could be the main factor related to the CS appearance. The status of functional or nonfunctional NET could be mostly correlated to tumor load involvement rather than to primary tumor site, which still remains the main prognostic factor. [ABSTRACT FROM AUTHOR]