Carlo Ludovico Maini

Survival after Yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: A European evaluation

A multicenter analysis was conducted to evaluate the main prognostic factors driving survival after radioembolization using yttrium‐90–labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole‐liver (45.2%) or right‐lobe (38.5%) infusions. Typically, patients were Child‐Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0‐1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one‐quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9‐15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6‐38.1 months]; BCLC B, 16.9 months [95% CI, 12.8‐22.8 months]; BCLC C, 10.0 months [95% CI, 7.7‐10.9 months]). Consistent with this finding , survival varied significantly by ECOG status, hepatic function (Child‐Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha‐fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All‐cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. Conclusion: This analysis provides robust evidence of the survival achieved with radioembolization, including those with advanced disease and few treatment options. (HEPATOLOGY 2011;)

Efficacy and Toxicity Related to Treatment of Hepatocellular Carcinoma with 90Y-SIR Spheres: Radiobiologic Considerations

Radioactive 90Y-selective internal radiation (SIR) sphere therapy is increasingly used for the treatment of nonresectable hepatocellular carcinoma (HCC). However, the maximum delivered dose is limited by severe injury to the nontarget tissue, including liver parenchyma. Our study aimed to implement radiobiologic models for both tumor control probability (TCP) and normal-tissue complication probability (NTCP) to describe more effectively local response and the liver toxicity rate, respectively. Methods: Patients with documented HCC, adequate bone marrow parameters, and regular hepatic and pulmonary function were eligible for the study. Patients who had pulmonary shunt greater than 20% of 99mTc-labeled macroaggregated albumin or any uncorrectable delivery to the gastrointestinal tract, reverse blood flow out of the liver, or complete portal vein thrombosis were excluded. Patients received a planned activity of the 90Y-SIR spheres, determined using the empiric body surface area method. The dose distribution was determined using posttreatment (3-dimensional) activity distribution and Monte Carlo dose voxel kernel calculations, and the mean doses to healthy liver and tumor were calculated for each patient. Response was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) and recommendations of the European Association for the Study of the Liver (EASL). Criteria were used to assess possible liver toxicities. The parameters of TCP and NTCP models were established by direct maximization of the likelihood. Results: Seventy-three patients were treated. With an average dose of 110 Gy to the tumor, complete or partial response was observed in 74% and 55% of patients according to the EASL guideline and RECIST, respectively, and the predicted TCPs were 73% and 55%, respectively. With a median liver dose of 36 Gy (range, 6–78 Gy), the ≥grade 2 (G2), ≥grade 3 (G3), and ≥grade 4 (G4) liver toxicities were observed in 32% (23/73), 21% (15/73), and 11% (8/73) of patients, respectively. The parameters describing the ≥G2 liver toxicity data using the NTCP model were a tolerance dose of the whole organ leading to a 50% complication probability of 52 Gy (95% confidence interval, 44–61 Gy) and a slope of NTCP versus dose of 0.28 (95% confidence interval, 0.18–0.60), assuming n = 1. Conclusion: The radiobiologic approach, based on patient-specific dosimetry, could improve the 90Y-microsphere therapeutic approach of HCC, maintaining an acceptable liver toxicity.

Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients.

AbstractAim. The study evaluates the therapeutic efficacy of Strontium‐89‐chloride (89Sr) and 186Re‐1,1‐hydroxy‐ethylidene diphosphonate (186Re‐HEDP) in the palliation of painful bone metastases from breast cancer. Patients and methods. Fifty patients with painful multifocal bone metastases from breast cancer entered the study and were randomized into two groups according to the radiopharmaceutical used: 148 MBq 89Sr i.v. (Group A: 25 patients) and 1406 MBq 186Re‐HEDP i.v. (Group B: 25 patients). Pain palliation was evaluated on the basis of the Wisconsin pain test improvement at two months and response was graded as complete, partial, minimal or absent. Hematological toxicity and side effects were reported according to WHO guidelines. Results. The global response rate was 84% (21/25) for 89Sr and 92% (23/25) for 186Re‐HEDP, respectively. The onset of pain palliation appeared significantly earlier in Group B (p<0.0001). The duration of pain relief ranged from two months to 14 months (mean of 125 days with a median value of 120 days) in Group A and from one month to 12 months (mean of 107 days with a median value of 60 days) in Group B (p=0.39). A moderate hematological toxicity was apparent in both groups. Platelet and white blood cell counts returned to baseline levels within 12 weeks after 89Sr administration and 6 weeks after 186Re‐HEDP administration (p<0.01). Conclusions. Both 89Sr and 186Re‐HEDP are effective and safe in bone pain palliation in breast cancer with the latter showing a significantly faster onset of pain relief.

Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89

Strontium-89 (89Sr) is currently used for the treatment of painful bone metastases. This study reports the use of low-dose carboplatin as a radiosensitizer in 89Sr radioisotope therapy. The study design comprised two groups: 15 patients treated with 89Sr (148 MBq) followed by carboplatin (100 mg m-2 at 7 and 21 days) and 15 patients treated with 89Sr alone. Their pain response was assessed 8 weeks post-injection. Follow-up was continued for up to 1 year in the survivors. Twenty-seven patients were evaluable. A pain response was observed in 20 of 27 (74%) patients. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). No clinically significant adverse effects or myelosuppression by carboplatin were observed. Low-dose carboplatin enhances the effects of 89Sr radioisotope therapy on pain from bone metastases.

Crossed cerebello-cerebral diaschisis: a SPECT study.

A scintigraphic single photon emission computed tomographic (SPECT) evaluation of frontal perfusion alteration was performed in five patients with known cerebellar lesions but with normal supratentorial computed tomographic (CT) or magnetic resonance (MR) scans. A clearly evident asymmetry was found in prefrontal areas in the four subjects with acquired cerebellar damage. The fifth subject, who had congenital left cerebellar hypoplasia, did not show any frontal flow asymmetry. The data support the growing clinical evidence that the cerebellum contributes to the cognitive processes of the frontal lobes and suggest a possible role for SPECT examination in the assessment of functional cognitive impairment in patients with acquired cerebellar lesions.

Somatostatin receptor imaging in CNS tumours using 111In-octreotide.

This study evaluates the in vivo visualization of somatostatin (SS) receptors in central nervous system (CNS) tumours using 111In-octreotide imaging and discusses the clinical implications. Ninety-five patients with histologically confirmed diagnosis of CNS tumours were imaged 2–4 and 24 h after the intravenous injection of 111–185 MBq of 111In-octreotide. An uptake index was computed using tumour/non-tumour ratios evaluated using a standard region-of-interest method. Semi-quantitative immuno-histochemical studies of SS binding sites were performed on frozen tumour sections.All meningiomas, most pituitary adenomas and many glial tumours showed a positive scan, whereas all neurinomas, craniopharingiomas and ependymomas had negative receptor scans. Radio-octreotide uptake varied among the SS receptor positive CNS tumours: very intense in meningioma, intermediate in pituitary adenoma and of a low grade in glioma. The results of immunohistochemical studies confirmed the scintigraphic findings in all cases. We believe 111In-octreotide is a suitable radiopharmaceutical for characterizing CNS tumours in vivo as SS receptor positive or negative. This new neuronuclear imaging technique may be useful for differential diagnosis in selected cases, for post-surgical follow-up and in the assessment of differentiation in glial tumours.

Clinical relevance of radionuclide angiography and antimyosin immunoscintigraphy for risk assessment in epirubicin cardiotoxicity

BackgroundCardiotoxicity is the major limiting factor in anthracycline chemotherapy of advanced neoplastic disease. Epirubicin shows a more favorable therapeutic index than does doxorubicin, but it is still cardiotoxic. Limited data regarding epirubicin cardiotoxicity are available, and suggested guidelines for doxorubicin with left ventricular ejection fraction (LVEF) measurement may not be empirically useful for epirubicin therapy. This study evaluates the diagnostic role of antimyosin immunoscintigraphy for early identification of patients at risk for late pump dysfunction from cardiotoxicity induced by high-dose administration of epirubicin up to high cumulative dosages.Methods and ResultsChemotherapy with epirubicin was administered to 36 patients with cancer at a dosing rate of 160 mg/m2 as a bolus injection every 21 days to a cumulative dosage heart-lung ratio (HLR) measurements were performed before chemotherapy, at intermediate cumulative epirubicin dosages, at the end of treatment, and during the follow-up. LVEF decreased significantly at the end of the treatment and after therapy discontinuation. HLR values were significantly increased at intermediate epirubicin dosage levels and continued to increase to the end of the treatment but thereafter remained substantially unmodified for 3 to 6 months after therapy discontinuation. A value of HLR>1.85 at intermediate epirubicin dosage level showed a sensitivity of 95% and a specificity of 57% as a predictor of late LVEF impairment.ConclusionsLVEF appears more useful at high cumulative dosages and during follow-up to monitor late pump dysfunction, whereas HLR may be effective during the early phase of the therapy in determining which patients are at risk for development of late cardiac dysfunction.

Superselective intra-arterial radiometabolic therapy with I-131 lipiodol in hepatocellular carcinoma

Superselective transcatheter arterial radioembolization with radioiodinated lipiodol and gelatin sponges was evaluated in 11 patients with nodular hepatocellular carcinoma. Thirteen tumor nodules were treated using 3-5 ml of lipiodol labeled with 259 to 2220 MBq of I-131 followed by gelatin sponge with the following results: 1) there was elevated uptake in 12 tumor nodules with high tumor-to-background ratios: 2) there was excellent clinical tolerance to the treatment (stable cirrhosis in 5 patients and cirrhosis progression in 2 cases); 3) there was good disease control with size reduction in five tumor lesions (41%) and no increase in seven lesions (59%) followed for 2 years; 4) there was a 2-year survival rate of 70%; and 5) three deaths due to hepatic failure at 2, 3, and 20 months after therapy. Superselective arterial radioembolization with I-131 lipiodol is a useful palliative approach to inoperable hepatocarcinoma, providing long-term local control without severe complications in the progression of cirrhosis.

18f-choline positron emission tomography/computed tomography-driven high-dose salvage radiation therapy in patients with biochemical progression after radical prostatectomy: Feasibility study in 60 patients

PURPOSE To retrospectively review data of a cohort of patients with biochemical progression after radical prostatectomy, treated according to a uniform institutional treatment policy, to evaluate toxicity and feasibility of high-dose salvage radiation therapy (80 Gy). METHODS AND MATERIALS Data on 60 patients with biochemical progression after radical prostatectomy between January 2009 and September 2011 were reviewed. The median value of prostate-specific antigen before radiation therapy was 0.9 ng/mL. All patients at time of diagnosis of biochemical recurrence underwent dynamic (18)F-choline positron emission tomography/computed tomography (PET/CT), which revealed in all cases a local recurrence. High-dose salvage radiation therapy was delivered up to total dose of 80 Gy to 18F-choline PET/CT-positive area. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events, version 3.0, scale. RESULTS Treatment was generally well tolerated: 54 patients (90%) completed salvage radiation therapy without any interruption. Gastrointestinal grade ≥2 acute toxicity was recorded in 6 patients (10%), whereas no patient experienced a grade ≥2 genitourinary toxicity. No grade 4 acute toxicity events were recorded. Only 1 patient (1.7%) experienced a grade 2 gastrointestinal late toxicity. With a mean follow-up of 31.2 months, 46 of 60 patients (76.6%) were free of recurrence. The 3-year biochemical progression-free survival rate was 72.5%. CONCLUSIONS At early follow-up, (18)F-choline PET/CT-driven high-dose salvage radiation therapy seems to be feasible and well tolerated, with a low rate of toxicity.

Somatostatin receptor imaging in small cell lung cancer using 111In-DTPA-octreotide: a preliminary study.

Small cell lung cancer is a common and aggressive disease. Combined multiagent chemotherapy and radiotherapy can improve short-term prognosis, but long-term prognosis remains dim. Somatostatin receptors have been identified on the cellular surface of subsets of this cancer and may be associated with less aggressive evolution. Moreover, medical therapy with somatostatin analogues holds promise for neoplastic growth control. Planar scintigraphy has been performed in 15 patients with histologically proven small cell lung cancer at 4 and 24 h after the intravenous (i.v.) injection of 185 MBq 111In-octreotide (Octreoscan, BYK-Gulden). No short-term adverse effects were recorded; tumour uptake of the radiopharmaceutical was observed in 13 patients at 4 h and in 12 patients at 24 h suggesting more extensive disease than apparent by computed tomography (CT). It is highly likely that the 24 h uptake reflects the presence of somatostatin receptors on the tumour. Previous chemotherapy does not seem to play a key role in tumour visualization. 111In-octreotide is a suitable radiopharmaceutical for in vivo evaluation of somatostatin receptor status of small cell lung cancer. Quantitative sdntigraphic methods are needed to investigate nonspecific binding and receptor kinetics.