Rodolfo Lanocita

Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.

Yttrium‐90 radioembolization (Y90RE) is a novel approach to radiation therapy for hepatocellular carcinoma (HCC), never tested in phase 2 studies. Fifty‐two patients with intermediate (n.17) to advanced (n.35) HCC were prospectively recruited to assess, as the primary endpoint, efficacy of Y90RE on time‐to‐progression (TTP). Secondary endpoints were tumor response, safety, and overall survival (OS). All patients were Eastern Cooperative Oncology Group (ECOG) score 0‐1, Child‐Pugh class A‐B7. Y90RE treatments aimed at a lobar delivery of 120 Gy. Retrospective dosimetric correlations were conducted and related to response. Fifty‐eight treatments were performed on 52 patients. The median follow‐up was 36 months. The median TTP was 11 months with no significant difference between portal vein thrombosis (PVT) versus no PVT (7 versus 13 months). The median OS was 15 months (95% confidence interval [CI], 12‐18 months) with a nonsignificant trend in favor of non‐PVT versus PVT patients (18 versus 13 months). Five complete responses occurred (9.6%), and the 2 year‐progression rate was 62%. Objective response was 40.4%, whereas the disease control rate (78.8%) significantly affected survival (responders versus nonresponders: 18.4% versus 9.1%; P = 0.009). Tumor response significantly correlated with absorbed dose in target lesions (r = 0.60, 95% CI, 0.41‐0.74, P < 0.001) and a threshold of 500 Gy predicted response (area under the curve, 0.78). Mortality at 30‐90 days was 0%‐3.8%. Various grades of reduction in liver function occurred within 6 months in 36.5% of patients, with no differences among stages. On multivariate analysis, tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child‐Pugh class). Conclusion: Y90RE is an effective treatment in intermediate to advanced HCC, particularly in the case of PVT. Further prospective evaluations comparing Y90RE with conventional treatments are warranted. (HEPATOLOGY 2013)

Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial

BACKGROUND The development of new drugs for patients with refractory urothelial cancer is still an unmet medical need. Preclinical evidence lends support to a rationale for targeting of the VEGF or platelet-derived growth-factor axis. We therefore investigated the activity and safety of pazopanib, a multitarget drug with antiangiogenic activity, in patients with urothelial cancer. METHODS In an open-label, single-group, phase 2 study, patients (aged ≥18 years) with relapsed or refractory urothelial cancer were given pazopanib 800 mg per day, orally. They were treated until disease progression or prohibitive toxicity occurred. The primary endpoint was the proportion of patients who achieved a confirmed objective response, defined as complete or partial response, after independent review, and was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01031875. FINDINGS The trial has been completed. 21 (51%) of 41 patients enrolled were given pazopanib as third-line or further-line treatment. 26 (63%) patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Seven patients had a confirmed objective response (17·1%, 95% CI 7·2-32·1), all of which were partial responses. The most frequent treatment-related grade 3 adverse events were hypertension (three [7%]), fatigue (two [5%]), and gastrointestinal and vaginal fistulisations (two each [5%]). One patient died as a result of duodenal fistulisation that was related to tissue response of bulky tumour masses. INTERPRETATION Pazopanib has single-agent activity in patients with heavily pretreated metastatic urothelial cancer, and warrants further study in this setting. Particular attention should be paid to patients with bulky tumour masses adjacent to viscera because fistulisation is probably related to the response to pazopanib and is the most frequent serious adverse event. FUNDING Fondazione IRCCS Istituto Nazionale dei Tumori provided the grant. GlaxoSmithKline provided the study drug and provided funding for the independent radiological review.

Phase II study of sorafenib in patients with relapsed or refractory lymphoma.

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18–74) received a median of 4 months of therapy. Grade 3–4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal‐regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.

Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: The role of circulating interleukin-8 to enhance the prognostic accuracy

Background:Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients.Methods:EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model.Results:Increasing IL8T1 level associated with lower response probability at covariance analysis (P=0.010). Both IL8T0 (P=0.019) and IL8T1 (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8T1 best-predicted OS after backward selection. The NRI for this model was 39%.When analysed as a time-varying covariate, IL8T1 level<80 pg ml−1 portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level⩾80.Conclusion:IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.

Use of a Retrievable Vena Cava Filter with Low-intensity Anticoagulation for Prevention of Pulmonary Embolism in Patients with Cancer: An Observational Study in 106 Cases

PURPOSE To evaluate a retrievable inferior vena cava (IVC) filter in combination with low-intensity oral anticoagulation for prevention of pulmonary embolism (PE) in patients with malignancy complicated by thromboembolic disease. MATERIALS AND METHODS From October 2005 to December 2009, 107 Bard G2 filters were placed in 106 patients. Forty-eight patients had deep vein thrombosis (DVT) alone, 53 had PE with DVT, and five had PE with no evidence of DVT. After an initial period of anticoagulation with heparin, low-intensity oral anticoagulant therapy to achieve a target International Normalized Ratio of 1.5-2.0 was instituted. Follow-up computed tomography to evaluate the pulmonary circulation, IVC, and lower limbs was performed at 3 and 6 months. RESULTS PE recurred in three of 58 patients (5.2%). None of the 48 patients with DVT alone developed PE, nor was there any recurrence of DVT. The filter was removed in 14 patients (13.2%). No complications occurred during the retrieval procedure. A total of 16 complications occurred in seven patients: one migration (0.9%); four cases of vena cava thrombosis (3.7%), three of which were associated with recurrent PE (2.8%); one filter fracture (0.9%); and one IVC penetration (0.9%). Filter tilting greater than 15° occurred in six patients (5.7%) and was associated with other complications in five (4.7%). CONCLUSIONS In patients with malignancies complicated by venous thromboembolic disease, an IVC filter together with low-intensity anticoagulation may be a possible treatment strategy for PE prophylaxis. Controlled studies are warranted.

Large Renal Artery Aneurysm Treated with Guglielmi Detachable Coils: Procedural and 4-Year Follow-up Results

A large aneurysm of the left renal artery was found incidentally during abdominal ultrasound in a 39-year-old woman with no medical or family history of cardiovascular disease. Vascular pathology with a dysplastic appearance was confirmed by magnetic resonance angiography and the patient was offered transcatheter embolization. Since the position and size of the neck of the aneurysm could not be determined at angiography, detachable platinum coils were used for occlusion. The procedure was performed without complications. During a 4-year follow-up no alterations of renal function, recanalization of the aneurysm, or perfusion defects in the rest of the left renal circulation were noted.

CT-guided percutaneous cryoablation of renal masses in selected patients

PurposeWe analysed our experience with computed tomography (CT)-guided percutaneous cryoablation (PCA) in patients who were not surgical candidates or refused surgery for small to medium-sized renal masses.Materials and methodsTwo freezing cycles were applied and separated by a passive warming cycle using 1.7- and 2.4-mm cryoprobes under either general anaesthesia or sedation based on patient positioning and respiratory status. Postoperative monitoring included haematological and biochemistry evaluation and CT scan 24 h after PCA. Follow-up consisted of a multislice CT scan at 1 month and every 3 months in the first year then every 6 months thereafter.ResultsThirty-seven patients (38 lesions) underwent 40 PCA procedures; 5/37 (13.5%) had a solitary kidney. Median mass size was 35 (range 12–70) mm. No complications occurred during the procedure. Clavien grade ≥2 anaemia occurred in two patients (5.4 %): one patient required 1 U of packed red blood cells; the other required an arterial embolisation. Serum creatinine did not increase in any case. Two patients showed persisting or recurrent disease at 1 and 9 months, respectively, and both could be re-treated with PCA. All other patients showed a hypodense mass 3 months after PCA, with no contrast enhancement. Subsequent examinations showed that lesion sizes decreased and CT densitometry remained stable or increased minimally, also with no contrast enhancement.ConclusionsPCA proved relatively easy and safe and could be considered an effective alternative for patients who are not surgical candidates or refuse surgery, as well as in patients with medium-sized lesions.RiassuntoObiettivoScopo del nostro lavoro è stato valutare la nostra esperienza nella crioablazione percutanea tomografia computerizzata (TC)-guidata (PCA) in pazienti con neoplasie renali di piccola-media dimensione che hanno rifiutato la chirurgia o non candidabili ad essa.Materiali e metodiDue cicli di congelamento, separati da un ciclo di riscaldamento passivo, con sonde da 1,7 e 2,4 mm, in anestesia generale o sedazione in base alla posizione e allo stato respiratorio del paziente. Il monitoraggio postoperatorio include esami ematologici e una TC dopo 24 ore. Il follow-up prevede controlli TC con contrasto a 1 mese, quindi ogni 3 mesi nel primo anno e successivamente ogni 6 mesi.RisultatiTrentasette pazienti (38 lesioni) sono stati sottoposti a 40 PCA; 5/37 (13,5%) presentavano rene unico. Il diametro mediano delle masse era 35 mm (12–70 mm). Non si è presentata nessuna complicazione durante la procedura. Abbiamo riscontrato anemia di grado ≥2 secondo Clavien in 2 casi (5,4%): un caso è stato trattato con trasfusione di emazie concentrate, l’altro con una embolizzazione arteriosa parziale del rene. La creatinina serica non è aumentata in nessun caso. Due pazienti hanno mostrato malattia persistente o recidivante a 1 e 9 mesi: entrambi sono stati ritrattati con PCA con successo. Tutti gli altri pazienti avevano alla TC una massa ipodensa dopo 3 mesi, senza captazione contrastografica. I controlli successivi hanno mostrato una progressiva riduzione dimensionale delle lesioni, con densitometria stabile o in minimo incremento, senza captazione di contrasto.ConclusioniLa PCA è procedura relativamente facile e sicura e può essere considerata una valida alternativa nei pazienti che non sono candidabili o che rifiutano la chirurgia, anche in tumori di media grandezza.

Transarterial chemoembolization using 40 µm drug eluting beads for hepatocellular carcinoma

AIM To assess the safety and efficacy of transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) using a new generation of 40 μm drug eluting beads in patients not eligible for curative treatment. METHODS Drug eluting bead TACE (DEB-TACE) using a new generation of microspheres (embozene tandem, 40 μm) preloaded with 100 mg of doxorubicin was performed on 48 early or intermediate HCC patients with compensated cirrhosis. Response to therapy was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) guidelines applied to computed tomography or magnetic resonance imaging. Eleven out of the 48 treated patients treated progressed on to receive liver orthotopic transplantation (OLT). This allowed for histological analysis on the treated explanted nodules. RESULTS DEB-TACE with 40 μm showed a good safety profile without major complications or 30-d mortality. The objective response rate of treated tumors was 72.6% and 26.7% according to mRECIST and RECIST respectively. Histological examination in 11 patients assigned to OLT showed a necrosis degree > 90% in 78.6% of cases. The overall time to progression was 13 mo (11-21). CONCLUSION DEB-TACE with 40 μm particles is an effective treatment for the treatment of HCC in early-intermediate patients (Barcelona Clinic Liver Cancer stage A/B) with a good safety profile and good results in term of objective response rate and necrosis.

Intrahepatic Flow Redistribution in Patients Treated with Radioembolization

IntroductionIn planning Yttrium-90 (90Y)-radioembolizations, strategy problems arise in tumours with multiple arterial supplies. We aim to demonstrate that tumours can be treated via one main feeding artery achieving flow redistribution by embolizing accessory vessels.MethodsOne hundred 90Y-radioembolizations were performed on 90 patients using glass microspheres. In 19 lesions/17 patients, accessory branches were found feeding a minor tumour portion and embolized. In all 17 patients, the assessment of the complete perfusion was obtained by angiography and single photon emission computerized tomography–computerized tomography (SPECT–CT). Dosimetry, toxicity, and tumor response rate of the patients treated after flow redistribution were compared with the 83 standard-treated patients. Seventeen lesions in 15 patients with flow redistribution were chosen as target lesions and evaluated according to mRECIST criteria.ResultsIn all patients, the complete tumor perfusion was assessed immediately before radioembolization by angiography in all patients and after the 90Y-infusion by SPECT–CT in 15 of 17 patients. In the 15 assessable patients, the response rate in their 17 lesions was 3 CR, 8 PR, and 6 SD. Dosimetric and toxicity data, as well tumour response rate, were comparable with the 83 patients with regular vasculature.ConclusionsAll embolization procedures were performed successfully with no complications, and the flow redistribution was obtained in all cases. Results in term of toxicity, median dose administered, and radiological response were comparable with standard radioembolizations. Our findings confirmed the intratumoral flow redistribution after embolizing the accessory arteries, which makes it possible to treat the tumour through its single main feeding artery.

Long-term infusion in cancer chemotherapy with the Groshong catheter via the inferior vena cava

Aims and background Vascular access through a vein draining into the superior vena cava is commonly used for long-term infusion of drugs inr cancer chemotherapy; prolonged cannulation of the inferior vena cava is generally considered as having an excessively high complication rate. Methods Prolonged cisplatin infusion via the inferior vena cava by means of a Groshong catheter was evaluated in 20 consecutive patients with thoracic malignancies showing evidence of superior vena cava infiltration or obstruction. Results We achieved 1,291 catheter days for our survey with a mean duration of vascular access of 64.5 days per patient and a mean duration of infusion time of 40 days. There were 2 complications, a catheter obstruction after a 7-day rest period and an ileo-femoral thrombosis 6 days after catheter placement. Conclusions Our experience compared favourably with the results obtained by long-term central venous access via the supraumbilical route, and demonstrated the reliability and safety of this approach in cases where the superior vena cava cannulation is technically difficult or impossible.