Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies.

PURPOSE: Radioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation. METHODS: This was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records. RESULTS: Most radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1-45.9) versus 30.9 months (19.6-46.8); p = 0.243); stage B: 18.4 months (11.2-19.4) versus 22.8 months (10.9-34.2); p = 0.815; and stage C: 8.8 months (7.1-10.8) versus 10.8 months (7.7-12.6); p = 0.976. CONCLUSIONS: Radioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.

Significant increase in detection of prostate cancer recurrence following radical prostatectomy with an early imaging acquisition protocol with ¹8F-fluorocholine positron emission tomography/computed tomography.

PURPOSE: To highlight a new imaging acquisition protocol during (18)F-fluorocholine PET/CT in patients with biochemical recurrence after RP. METHODS: A total of 146 patients with PSA levels between 0.2 and 1 ng/ml with negative conventional imaging who did not receive salvage treatment were prospectively enrolled. Imaging acquisition protocol included an early dynamic phase (1-8 min), a conventional whole body (10-20 min), and a late phase (30-40 min). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were measured. Univariable and multivariable analyses were performed to identify independent predictors of positive PET/CT. RESULTS: The median trigger PSA was 0.6 ng/ml (IQR 0.43-0.76). Median PSA doubling time (PSA DT) was 7.91 months (IQR 4.42-11.3); median PSA velocity (PSAV) was 0.02 ng/ml per month (IQR 0.02-0.04). Overall, (18)F-fluorocholine PET/CT was positive in 111 of 146 patients (76 %). Out of 111 positive examinations, 80 (72.1 %) were positive only in the early dynamic phase. Sensitivity, specificity, PPV, NPV, and accuracy were 78.9, 76.9, 97.2, 26.3, and 78.7 %, respectively. At multivariable logistic regression, trigger PSA ≥ 0.6 ng/ml [odds ratio (OR) 3.13; p = 0.001] and PSAV ≥ 0.04 ng/ml per month (OR 4.95; p = 0.004) were independent predictors of positive PET/CT. The low NPV remains the main limitation of PET/CT in this setting of patients. CONCLUSIONS: The increased sensitivity, thanks to the early imaging acquisition protocol, makes (18)F-fluorocholine PET/CT an attractive tool to detect prostate cancer recurrences in patients with a PSA level <1 ng/ml.

HF ultrasound vs PET-CT and telethermography in the diagnosis of In-transit metastases from melanoma: a prospective study and review of the literature.

BACKGROUND: Over the past several years the incidence of cutaneous melanoma has rapidly increased. This tumor develops often in-transit metastases that significantly reduce patient survival at 5 years. To improve prognosis and quality of life in patients with melanoma metastases, a mini invasive procedure like electrochemotherapy (ECT) is adopted to remove superficial tissue lesions. To detect the melanoma metastases, high frequency (HF) ultrasound (US) is used. This technique, though, can be time-consuming and it needs an expert operator and a high performing machine. Therefore, we asked whether the US could be replaced or integrated with other less time-consuming techniques such as 18-FDG positron emission tomography/computed tomography (PET-CT) and telethermography (TT). METHODS: Fifteen patients (4 males and 11 females - age range: 63-91) affected whit advanced stage melanoma were enrolled. They presented 52 in-transit metastases as detected by the three techniques used, HF-US, PET/CT and TT within 30 days before ECT. RESULTS: All the 52 lesions were detected by HF-US (100%), 24/52 were detected by PET-CT (42,6%) and 15/52 were detected by TT (27,7%). PET-CT reported 3.7% false positives, while no false positive were reported by TT. CONCLUSIONS: As US detected 100% lesions, compared to the other two techniques used, US, along with clinical examination, has still to be considered as gold standard in the diagnosis of metastatic lesions. US, associated with an exhaustive anamnesis and accurate clinical examination, cannot be replaced by either PET-CT or TT. When US performing devices and experienced operators are not available, though, it is highly recommended to integrate US with at least one of the other techniques. Under certain circumstances, as in the case of obese and non-collaborating patients or in patients with lymphatic stasis, these techniques should be integrated to obtain exact in-transit metastases evaluation.

High-risk patients with differentiated thyroid cancer T4 primary tumors achieve remnant ablation equally well using rhTSH or thyroid hormone withdrawal.

BACKGROUND: Few data exist on using thyrotropin alfa (recombinant human thyroid-stimulating hormone [rhTSH]) with radioiodine for thyroid remnant ablation of patients who have T4 primary tumors (invasion beyond the thyroid capsule). METHODS: A retrospective chart review protocol at nine centers in Europe was set up with special waiver of need for informed consent, along with a careful procedure to avoid selection bias when enrolling patients into the database. Data on 144 eligible patients with T4 tumors were collected (T4, N0-1, M0-1; mean age 49.7 years; 65% female; 88% papillary cancer). All had received (131)I remnant ablation following TSH stimulation with rhTSH or thyroid hormone withdrawal (THW) since January 2000 (rhTSH n=74, THW n=70). The primary endpoint was based on evaluation of diagnostic radioiodine scan thyroid bed uptake more than six months after the ablation procedure, while stimulated serum Tg was a secondary endpoint. Safety was evaluated within 30 days after rhTSH or (131)I. RESULTS: Successful ablation judged by scan was achieved in 65/70 (92.9%) of rhTSH and in 61/67 (91.0%) of THW patients; the success rates were comparable, since noninferiority criteria were met. Although some patients in the initial cohort had tumor in cervical nodes and metastases, considering all evaluable patients regardless of various serum anti-Tg antibody assessments, the stimulated Tg was <2 ng/mL in 48/70 (68.6%) and 39/67 (58.2%) in rhTSH and THW groups respectively; if patients with anti-Tg antibody levels >30 IU/mL were excluded, the stimulated Tg was <2 ng/mL in 42/62 (67.7%) and 37/64 (57.8%) respectively. No serious adverse events occurred within the 30-day window after ablation. CONCLUSIONS: Use of rhTSH as preparation for thyroid remnant ablation in patients with T4 primary tumors achieved a rate of ablation success that was high and noninferior to the rate seen after THW, and rhTSH was well tolerated.

Prevalence, mass, and glucose-uptake activity of ¹8F-FDG-detected brown adipose tissue in humans living in a temperate zone of Italy.

BACKGROUND: The ¹8F-fluorodeoxyglucose (¹8F-FDG)-detected brown adipose tissue (BAT), is enhanced by cold stimulus and modulated by other factors that still have to be disentangled. We investigated the prevalence, mass, and glucose-uptake activity of ¹8F-FDG-detected BAT in a population of adults living in the temperate climatic zone of the Rome area. METHODS AND FINDINGS: We retrospectively analyzed 6454 patients who underwent ¹8F-FDG positron emission tomography/computed tomography (PET/CT) examinations. We found ¹8F-FDG BAT in 217 of the 6454 patients (3.36%). Some of them underwent more than one scan and the positive scans were 278 among 8004 (3.47%). The prevalence of patients with at least one positive scan was lower in men (1.77%; 56 of 3161) compared with women (4.88%; 161 of 3293). The BAT positive patients were most frequently younger, thinner and with lower plasma glucose levels compared with BAT negative patients. The amount of BAT in the defined region of interest, the activity of BAT and the number of positive sites of active BAT were similar in both sexes. The prevalence of patients with ¹8F-FDG positive PET/CT was highest in December-February, lower in March-May and September-November, and lowest in June-August and was positively correlated with night length and negatively correlated with ambient temperature. Changes in day length and variations of temperature, associated with the prevalence of positive BAT patients. Among the patients who had multiple scans, outdoor temperature was significantly lower and day length was shorter on the occasion when BAT was detected. CONCLUSIONS: This study identifies day length, outdoor temperature, age, sex, BMI, and plasma glucose levels as major determinants of the prevalence, mass, and activity of ¹8F-FDG-detected BAT.

Laparoscopic and robotic partial nephrectomy without renal ischaemia for tumours larger than 4 cm: perioperative and functional outcomes.

PURPOSE: To evaluate the technical feasibility, safety and functional outcomes of zero ischaemia laparoscopic and robotic partial nephrectomy with controlled hypotension for renal tumours larger than 4 cm. METHODS: We evaluated 121 consecutive patients with American Society of Anaesthesiologists (ASA) scores 1-2 who underwent laparoscopic (n = 70) or robotic (n = 51) partial nephrectomy with controlled hypotension with either tumour size ≤4 cm (group 1, n = 78) or tumour size >4 cm (group 2, n = 43) performed by a single surgeon from December 2010 to December 2011. Operative data, complications, serum creatinine, estimated glomerular filtration rates and effective renal plasma flow calculated from 99mTc-mercaptoacetyltriglycine renal scintigraphy were compared. Differences between groups were evaluated by the Chi-square test and the Student's t test. RESULTS: A significant difference in mean intraoperative blood loss and postoperative complications was found between the two groups: 168 ml (range: 10-600 ml in group 1) and 205 ml (range: 90-700 ml in group 2); p = 0.005, and 6.4 % versus 18.6 %; p = 0.004, respectively. The mean percentage decrease of ERPF of the operated kidney was 1.8 % in group 1 and 4.1 % in group 2. CONCLUSIONS: Laparoscopic and robotic partial nephrectomy with controlled hypotension for tumours >4 cm in ASA 1-2 patients was feasible with significant higher intraoperative blood loss and postoperative complications compared to smaller renal masses. The benefits of avoiding hilar clamping to preserve kidney function seem excellent.

Integration of radioembolisation into multimodal treatment of liver-dominant metastatic colorectal cancer.

INTRODUCTION: Radioembolisation (selective internal radiation therapy; SIRT), as part of a continuous strategy contributed to the improvement in response rates and median survival for unresectable metastatic colorectal cancer. Therefore, the role of SIRT in the different stages of treatment plan was investigated in this review. AREAS COVERED: After a brief description of the principles of SIRT, the review focused on the clinical evidences of published trials on the current experience of radioembolisation and its role in both salvage setting and earlier lines of chemotherapy. EXPERT OPINION: Evidence from Phase I studies and small Phase II/III randomised controlled trials has provided an early signal of the safety and improved overall survival, which can be achieved with radioembolisation and chemotherapy compared with chemotherapy (alone), due to an improved liver control. In the salvage setting, interesting results were observed in term of response, toxicity and median overall survival. Until the results of these early-line randomised trials will be available, radioembolisation could be considered either alone or combined with an appropriate chemotherapy regimen following failure of first- or second-line therapy.

Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation.

UNLABELLED: 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.

FCR (Fludarabine, Cyclophosphamide, Rituximab) regimen followed by 90Yttrium ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma: a report of 9 cases.

BACKGROUND: This retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR. METHODS: The median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy. RESULTS: Nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y-RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection. CONCLUSIONS: Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS.

Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations.

UNLABELLED: Radioactive (90)Y-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 (99m)Tc-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 (90)Y-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 >or=grade 2 (G2), >or=grade 3 (G3), and >or=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 >or=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 (90)Y-microsphere therapeutic approach of HCC, maintaining an acceptable liver toxicity.

Biological optimization of heterogeneous dose distributions in systemic radiotherapy.

The standard computational method developed for internal radiation dosimetry is the MIRD (medical internal radiation dose) formalism, based on the assumption that tumor control is given by uniform dose and activity distributions. In modern systemic radiotherapy, however, the need for full 3D dose calculations that take into account the heterogeneous distribution of activity in the patient is now understood. When information on nonuniform distribution of activity becomes available from functional imaging, a more patient specific 3D dosimetry can be performed. Application of radiobiological models can be useful to correlate the calculated heterogeneous dose distributions to the current knowledge on tumor control probability of a homogeneous dose distribution. Our contribution to this field is the introduction of a parameter, the F factor, already used by our group in studying external beam radiotherapy treatments. This parameter allows one to write a simplified expression for tumor control probability (TCP) based on the standard linear quadratic (LQ) model and Poisson statistics. The LQ model was extended to include different treatment regimes involving source decay, incorporating the repair "micro" of sublethal radiation damage, the relative biological effectiveness and the effective "waste" of dose delivered when repopulation occurs. The sensitivity of the F factor against radiobiological parameters (alpha, beta, micro) and the influence of the dose volume distribution was evaluated. Some test examples for 131I and 90Y labeled pharmaceuticals are described to further explain the properties of the F factor and its potential applications. To demonstrate dosimetric feasibility and advantages of the proposed F factor formalism in systemic radiotherapy, we have performed a retrospective planning study on selected patient case. F factor formalism helps to assess the total activity to be administered to the patient taking into account the heterogeneity in activity uptake and dose distribution, giving the same TCP of a homogeneous prescribed dose distribution. Animal studies and collection of standardized clinical data are needed to ascertain the effects of nonuniform dose distributions and to better assess the radiobiological input parameters of the model based on LQ model.

Liposomal doxorubicin with and without TNFalpha in the perfusional treatment of advanced soft tissue limb sarcoma: preliminary results.

BACKGROUND: A combination of doxorubicin and tumor necrosis factor alpha (TNFalpha) has been proven to be very effective in the perfusional treatment of advanced soft tissue limb sarcoma both in terms of tumor necrosis and limb conservative surgery rate. Unfortunately, in some patients a grade IV limb reaction has been recorded. The key solution might be the use of liposomal doxorubicin (Caelyx) because the carrier seems to release the drug preferentially in the tumor rather than in the healthy tissue. PATIENTS AND METHODS: Twenty patients were treated with Caelyx: 14 with Caelyx alone and 6 in combination with a low TNFalpha dose (1 mg). In the first series of 14 patients a dose escalation study was carried out starting from a dose of 10 mg/L of limb volume. Six patients were treated with Caelyx (16 mg) and TNFalpha (1 mg). RESULTS: The maximum tolerated dose (MTD) was 16 mg/L as in two patients treated with 18 mg/L a grade IV limb reaction was observed. Tumor response was satisfactory and conservative surgery was carried out in 13 patients. In 6 patients treated with Caelyx and TNFalpha, only a grade I limb reaction was recorded, thus, confirming that TNFalpha did not increase toxicity, at least at a dose of 1 mg. The Caelyx-TNFalpha combination did increase treatment efficacy. Tumor necrosis > or = 70% was observed in 4 out of 6 patients, one with 100% necrosis (pathological complete response). All the patients underwent conservative surgery. CONCLUSION: The Caelyx-TNFalpha combination was proven to increase the efficacy of Caelyx alone, with a very low toxicity. These preliminary results have to be tested in a larger patient population.