Induction of Contralateral Hepatic Hypertrophy by Unilobar Yttrium-90 Transarterial Radioembolization versus Portal Vein Embolization: An Animal Study.

PURPOSE: To compare hepatic hypertrophy in the contralateral lobe achieved by unilobar transarterial radioembolization (TARE) versus portal vein embolization (PVE) in a swine model. METHODS: After an escalation study to determine the optimum dose to achieve hypertrophy after unilobar TARE in 4 animals, 16 pigs were treated by TARE (yttrium-90 resin microspheres) or PVE (lipiodol/n-butyl cyanoacrylate). Liver volume was calculated based on CT before treatment and during 6 months of follow-up. Independent t-test (P < .05) was used to compare hypertrophy. The relationship between hypertrophy after TARE and absorbed dose was calculated using the Pearson correlation. RESULTS: At 2 and 4 weeks after treatment, a significantly higher degree of future liver remnant hypertrophy was observed in the PVE group versus the TARE group, with a median volume gain of 31% (interquartile range [IQR]: 16%-66%) for PVE versus 23% (IQR: 6%-36%) for TARE after 2 weeks and 51% (IQR: 47%-69%) for PVE versus 29% (IQR: 20%-50%) for TARE after 4 weeks. After 3 and 6 months, hypertrophy converged without a statistically significant difference, with a volume gain of 103% (IQR: 86%-119%) for PVE versus 82% (IQR: 70%-96%) for TARE after 3 months and 115% (IQR: 70%-46%) for PVE versus 86% (IQR: 58%-111%) for TARE after 6 months. A strong correlation was observed between radiation dose (median 162 Gy, IQR: 139-175) and hypertrophy. CONCLUSIONS: PVE resulted in rapid hypertrophy within 1 month of the procedure, followed by a plateau, whereas TARE resulted in comparable hypertrophy by 3-6 months. TARE-induced hypertrophy correlated with radiation absorbed dose.

Inconclusive benefit of adjuvant 90Yttrium hydroxyapatite to radiosynovectomy for diffuse-type tenosynovial giant-cell tumour of the knee.

Aims: Intra-articular 90Yttrium (90Y) is an adjunct to surgical treatment by synovectomy for patients with diffuse-type tenosynovial giant-cell tumour (dtTGCT) of the knee, with variable success rates. Clinical information is, however, sparse and its value remains unclear. We investigated the long-term outcome of patients who underwent synovectomy with and without adjuvant treatment with 90Yttrium. Patients and Methods: All patients with dtTGCT of the knee who underwent synovectomy between 1991 and 2014 were included in the study. Group A patients underwent synovectomy and an intra-articular injection of 90Yttrium between six and eight weeks after surgery. Group B patients underwent surgery alone. Results: There were 34 patients in group A and 22 in group B. Recurrence of dtTGCT was identified by MRI, which was undertaken in patients with further symptoms. At a mean follow-up of 7.3 years (2.5 to 25.4), there was residual disease in 15 patients in group A and 11 in group B (p < 0.363). The mean Musculoskeletal Tumor Society (MSTS) score at final follow-up was 85% and 83%, respectively (p < 0.91). Conclusion: There were no significant differences in outcome between patients treated surgically for dtTGCT of the knee with or without an adjuvant intra-articular injection of 90Yttrium. We were unable to provide conclusive evidence of any benefits derived from the adjuvant treatment. Cite this article: Bone Joint J 2018;100-B:984-8.

Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib.

AIM: The aim was to evaluate cost-effectiveness of yttrium-90 transarterial radioembolization (TARE) in comparison to sorafenib treatment. PATIENTS & METHODS: A single-center, retrospective, observational study was performed, 166 patients with intermediate-/advanced-stage hepatocellular carcinoma were treated with sorafenib and 19 with TARE. The patients out of the sorafenib group matching the inclusion criteria for TARE, were reassigned to a subgroup SOR3. RESULTS: Mean costs for SOR3 patients amounted to €27,992 per patient, instead for TARE treatment, mean expense per patient was €17,761 (p = 0.028). Overall survival was similar between the two groups, while midterm survival rates (p = 0.012) were significantly higher with TARE treatment. CONCLUSION: TARE causes significantly lower treatment costs than sorafenib with better outcome in midterm survival.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Current Standard and Future Perspectives in Non-Surgical Therapy for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a poor 5-year survival rate. Many HCCs are not amenable to surgical resection, because of tumor size, location, or because of the patient's poor liver function, a common obstacle to HCC therapy, because HCCs almost always develop in chronically inflamed livers. SUMMARY: In recent years, many efforts have been made to improve patient survival by conducting clinical trials investigating local and systemic treatment options for patients with unresectable tumors. These treatment options include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), selective internal radiotherapy with yttrium-90 (SIRT), stereotactic body radiation therapy (SBRT), proton beam therapy, molecular targeted therapy, and checkpoint inhibition. In this "to-the-point" article, we review the current standard and summarize the most recent findings in unresectable HCC treatment. KEY POINTS: (1) RFA is currently the preferred treatment for patients with tumor burden restricted to the liver and not eligible for surgical resection; (2) TACE is utilized in patients who are not eligible for RFA because of tumor location and/or number of tumor lesions; (3) SIRT might improve treatment responses achieved by TACE and is feasible in patients with portal vein thrombosis; (4) new radiation therapy treatment modalities such as SBRT and proton beam therapy show promising results for local tumor control; and (5) sorafenib remains the first-line systemic treatment option after several large clinical trials have failed to show superiority of other molecular targeted therapies in HCC patients.

Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

Radioembolization Is a Safe and Effective Treatment for Hepatocellular Carcinoma with Portal Vein Thrombosis: A Propensity Score Analysis.

BACKGROUND/AIMS: Limited treatment options are available for patients with hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). Transarterial radioembolization using Yttrium-90 microspheres is a new treatment modality for HCC with PVT. For this analysis, we compared responses to treatment with radioembolization and with sorafenib. METHODS: We evaluated 32 patients who were part of a multicenter retrospective cohort. All patients had PVT without extrahepatic metastasis and were treated with radioembolization in one of six tertiary referral hospitals in Korea. We retrospectively enrolled another 31 consecutive PVT patients without extrahepatic metastasis from a single center who received sorafenib treatment to serve as the control group. We used inverse probability weighting (IPW) using propensity scores to adjust for the between-group differences in baseline characteristics. RESULTS: At 3 months, the response rate and disease control rate were 32.1% (9/32) and 57.1% (16/32), respectively, in the radioembolization group and 3.2% (1/31) and 41.9% (13/31) in the sorafenib group. Median overall survival (OS) and time to progression (TTP) were not significantly different between the radioembolization group and the sorafenib group (13.8 months and 10.0 months, P = 0.22; and 6.0 months and 6.0 months, P = 0.08; respectively). No differences in OS (P = 0.97) or TTP (P = 0.34) were observed after IPW was applied to balance the population characteristics. The sorafenib group showed significantly more grade 3/4 adverse effects than the radioembolization group (P < 0.01). CONCLUSION: HCC patients with PVT who underwent radioembolization achieved comparable survival to patients who received sorafenib, even after application of IPW. The radioembolization group also experienced fewer severe adverse effects. Radioembolization can be considered a new treatment option for patients with HCC with PVT.

Independent Analysis of Albumin-Bilirubin Grade in a 765-Patient Cohort Treated with Transarterial Locoregional Therapy for Hepatocellular Carcinoma.

PURPOSE: To assess validity of albumin-bilirubin (ALBI) grade as a predictor of survival in patients undergoing transarterial embolization for hepatocellular carcinoma. MATERIALS AND METHODS: Baseline albumin and bilirubin values of 765 consecutive patients treated with conventional transarterial chemoembolization or yttrium-90 ((90)Y) radioembolization at a single institution were used to determine liver function according to ALBI grade. Survival outcomes were stratified by ALBI grade using Kaplan-Meier and stratified by Child-Pugh (C-P) class and Barcelona Clinic Liver Cancer (BCLC) stage. Discriminatory ability was assessed by C-index. RESULTS: For 428 patients receiving (90)Y radioembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade revealed different survival outcomes for C-P B (P = .001), BCLC A (P < .001), BCLC B (P = .001), and BCLC C (P < .001). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.792, 0.763, respectively). For 337 patients receiving transarterial chemoembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade provided distinct survival curves for C-P B (P = .02), BCLC B (P = .001), and BCLC C (P = .02). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.739, 0.735, respectively). CONCLUSIONS: ALBI grade outperforms C-P class at discriminating survival in patients receiving transarterial chemoembolization or (90)Y radioembolization. ALBI grade is also valuable in patients with moderate liver dysfunction and BCLC B disease.

Radioembolisation with yttrium‒90 microspheres versus sorafenib for treatment of advanced hepatocellular carcinoma (SARAH): study protocol for a randomised controlled trial.

BACKGROUND: Untreated advanced hepatocellular carcinoma (HCC) is linked to poor prognosis. While sorafenib is the current recommended treatment for advanced HCC, radioembolisation (RE; also called selective internal radiation therapy or SIRT) with yttrium-90 microspheres has shown efficacy in cohort studies. However, there are no head-to-head trials comparing radiation therapy with yttrium-90 microspheres and sorafenib in advanced HCC. The SARAH trial has been designed to compare the efficacy and safety of sorafenib therapy and RE using yttrium-90 resin microspheres (SIR-Spheres™; Sirtex Medical Limited, North Sydney, Australia) in patients with advanced HCC. Quality of life (QoL) and cost-effectiveness will also be compared between therapies. METHODS/DESIGN: SARAH is a prospective, randomised, controlled, open-label, multicentre trial comparing the efficacy of RE with sorafenib in the treatment of patients with advanced HCC. The trial aims to recruit adults with a life expectancy of >3 months, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, and: advanced HCC according to the Barcelona criteria (stage C) or recurrent HCC after surgical or thermoablative treatment who are not eligible for surgical resection, liver transplantation or thermal ablation; or two rounds of failed chemoembolisation. Patients will be randomised 1:1 to receive either RE or sorafenib 400 mg twice daily. All patients will be monitored for between 12 and 48 months following start of treatment. The primary endpoint of the SARAH trial is overall survival (OS). Secondary endpoints include: adverse events, progression-free survival at 6 months; tumour response rate; general or liver disease-specific QoL scores; and cost of each treatment strategy. Assuming an increase in median OS of 4 months with RE versus sorafenib therapy, randomising at least 400 patients (200 in each treatment arm) will be sufficient for 80% power and a bilateral alpha risk of 5%; therefore, 440 patients will be enrolled to allow for 10% loss of patients due to ineligibility. DISCUSSION: The SARAH trial is the first randomised head-to-head study to compare RE with sorafenib in advanced HCC, and will establish the potential role of RE in HCC treatment guidelines. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01482442, first received 28 November 2011.

Yttrium 90-ibritumomab tiuxetan plus rituximab maintenance as initial therapy for patients with high-tumor-burden follicular lymphoma: a Wisconsin Oncology Network study.

INTRODUCTION: Yttrium 90-ibritumomab tiuxetan (90Y-IT) radioimmunotherapy has proved to be effective in relapsed follicular lymphoma (FL). We conducted a clinical trial in which 90Y-IT followed by maintenance rituximab (MR) was evaluated as initial therapy for high-tumor-burden FL. METHODS: Eligible patients had histologically confirmed FL and met the GELF (Groupe d'Etude des Lymphomes Folliculaires) criteria for high tumor burden. All patients received a single dose of 90Y-IT. Patients with platelet counts of 150,000/mm³ or higher received 0.4 mCi/kg, and patients with platelet counts between 100,000/mm³ and 149,000/mm³ received 0.3 mCi/kg. At 6 months, patients without progressive disease (PD) received rituximab weekly for 4 weeks at a dose of 375 mg/m² (consolidation therapy), followed by MR consisting of the same dose every 3 months for a planned 5 years. RESULTS: From January 2005 through November 2007, a total of 16 patients were enrolled. The median age was 52 years (range, 37-75). The major toxicity from 90Y-IT was myelosuppression, with 88% and 31% of the patients experiencing grade 3 and grade 4 hematologic toxicity, respectively. The responses to 90Y-IT induction therapy were as follows: 7 patients with complete response/unconfirmed complete response (CR/Cru), 4 with partial response (PR), 3 with stable disease (SD), and 2 with progressive disease (PD). We identified 6 patients with early PD (range, 4-16 months) and 10 patients with prolonged remission (range, 37-101+ months). Compared with the patients who had prolonged remission, the patients who had early PD tended to have larger baseline nodal masses. The median progression-free survival (PFS) has not been reached after a median follow-up period of 48 months. The 3-year PFS and overall survival (OS) rates were 56% (95% CI, 37%-87%) and 93% (95% CI, 80%-100%), respectively. CONCLUSION: The overall response rate (ORR) to 90Y-IT was 69% in patients who had previously untreated, high-tumor-burden FL, which is lower than what is observed with contemporary rituximab/chemotherapy combinations. MR after 90Y-IT did convert all PRs to CRs. Alternative therapies should be considered for patients who have FL with large nodal masses (>9 cm), whereas very durable responses are possible in patients who have intermediate-size masses (>9 cm).

Treatment of intermediate-stage hepatocellular carcinoma.

Hepatocellular carcinoma (HCC)-closely associated with liver cirrhosis and, in fact, the main cause of death in patients with such disease-is now recognized as one of the most-prevalent and lethal neoplasms worldwide. Prognosis and allocation of the multiple available treatment options for patients with HCC are influenced not only by tumour stage, but also by the degree of liver-function impairment. Therefore, accurate assessment and classification of disease is important for patient management. According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, intermediate-stage HCC is defined as extensive multifocal disease without vascular invasion in patients with preserved liver function and absence of cancer-related symptoms; in this context, transarterial chemoembolization (TACE) is considered the standard treatment. The use of drug-eluting beads has enabled standardization of this procedure, resulting in higher reproducibility and tolerability of the treatment. Nevertheless, not all patients with intermediate-stage HCC are good candidates for TACE and, for such patients in whom TACE is not appropriate or has failed, other treatments can be considered, including sorafenib. Radioembolization is a promising alternative that deserves further prospective studies. Herein, we review the current approaches used to accurately stratify patients with intermediate-stage HCC and subsequently allocate the most-appropriate treatments. The key developments in therapeutic strategies are also discussed.

Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using an IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex.

Bispecific antibodies (BsAb) have proven to be useful targeting vectors for pretargeted radioimmunotherapy (PRIT). We sought to overcome key PRIT limitations such as high renal radiation exposure and immunogenicity (e.g., of streptavidin-antibody fusions), to advance clinical translation of this PRIT strategy for diasialoganglioside GD2-positive [GD2(+)] tumors. For this purpose, an IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 and C825, a murine scFv antibody with high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with ß-particle-emitting radiometals such as (177)Lu and (90)Y. A three-step regimen, including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with (177)Lu (as (177)Lu-DOTA-Bn; t1/2 = 6.71 days), was optimized in immunocompromised mice carrying subcutaneous human GD2(+) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were approximately 85 cGy/MBq and ≤3.7 cGy/MBq, respectively, with therapeutic indices (TI) of 142 for blood and 23 for kidney. A therapy study (n = 5/group; tumor volume, 240 ± 160 mm(3)) with three successive PRIT cycles (total (177)Lu: ∼33 MBq; tumor dose ∼3,400 cGy), revealed complete tumor response in 5 of 5 animals, with no recurrence up to 28 days after treatment. Tumor ablation was confirmed histologically in 4 of 5 mice, and normal organs showed minimal overall toxicities. All nontreated mice required sacrifice within 12 days (>1.0-cm(3) tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate subcutaneous GD2(+)-NB in mice while sparing kidney and bone marrow.

Individualized dosimetry-based activity reduction of 9°Y-DOTATOC prevents severe and rapid kidney function deterioration from peptide receptor radionuclide therapy.

PURPOSE: Assessment of kidney function evolution after (90)Y-DOTATOC peptide receptor radionuclide therapy (PRRT) with capped activity administration based on a 37-Gy threshold of biological effective dose (BED) to the kidney. METHODS: In a prospective phase II study, patients with metastasized neuroendocrine tumours were evaluated for therapy using 185 MBq (111)In-pentetreotide with amino acid coinfusion. Planar whole-body images were acquired at four time-points after injection and kidney volumes were measured using CT/MRI. BED to the kidneys was estimated using an extended BED formula and biexponential renal clearance. Based on published BED dose-toxicity relationships, we allowed a maximal kidney BED of 37 Gy; if the calculated BED exceeded 37 Gy, treatment activity was reduced accordingly. Kidney function was assessed at baseline and at 18 months, predominantly using (51)Cr-EDTA. The rate of renal function decline was expressed as annual glomerular filtration rate loss (aGFRL). RESULTS: Only 22 of 50 patients reached the 18-months time-point, with most missing patients having died due to disease progression. In the 22 patients who reached 18 months, no rapid kidney function deterioration was observed over the 18 months, aGFRL >33% was not seen, and only three patients showed an increase of one toxicity grade and one patient an increase of two grades. No significant correlations between kidney volume (p = 0.35), baseline GFR (p = 0.18), risk factors for renal function loss (p = 0.74) and aGFRL were observed. Among the 28 patients who did not reach 18 months, one developed grade 4 kidney toxicity at 15 months after PRRT. CONCLUSION: Prospective dosimetry using a 37 Gy BED as the threshold for kidney toxicity is a good guide for (90)Y-DOTATOC PRRT and is associated with a low risk of rapid renal function deterioration and evolution to severe nephrotoxicity.

Yttrium-90 radioembolization for hepatocellular carcinoma: what we know and what we need to know.

In spite of substantial progress in the management of hepatocellular carcinoma (HCC), suboptimal treatment results are frequently seen in the intermediate and advanced stages of HCC. The current staging system indicates that multinodular HCC without vascular invasion needs to be treated by transarterial chemoembolization (TACE) and HCC with vascular nvasion or distant metastasis is linked to sorafenib, an an-tiangiogenic therapy. Radioembolization with yttrium-90 ((90)Y) is a recently introduced liver-directed therapy employing a catheter-based approach. Growing data suggest that (90)Y radioembolization has a potent anticancer effect with negligible adverse events if appropriate pretreatment evaluations including dosimetry, calculation of lung shunt fraction and assessment of vascular anatomy are performed. Retrospective and small prospective studies have shown response rates and survival after (90)Y therapy which are comparable to TACE and sorafenib in the intermediate and advanced stages, respectively. Although a large sample size is necessary to compare the outcome between TACE and radioembolization in intermediate-stage HCC, selected populations, for whom TACE would not be effective, are candidates for testing the role of (90)Y radioembolization. A multidisciplinary, combined approach in advanced HCC using loco-regional therapy such as radioembolization and systemic therapy including sorafenib also has to be investigated.

Hepatic embolotherapy in interventional oncology: technology, techniques, and applications.

Embolotherapy continues to play a growing role in the management of primary and secondary hepatic malignancies. In this review article, we examine the basis of therapy with a focus on neovascularization, which makes treatments via the hepatic artery possible. An overview of the three generations of embolic and therapeutic agents follows. The techniques, technologies, and complications of bland embolization, transarterial chemoembolization, drug-eluting beads, and selective internal radiotherapy are covered to give the reader an overview of this exciting field in interventional radiology.

Interventional therapies for hepatocellular carcinoma.

Hepatocellular carcinoma is the third most common cause of cancer-related death. In the past few years, staging systems have been developed that enable patients to be stratified into treatment algorithms in a multidisciplinary setting. Several of these treatments involve minimally invasive image-guided therapy that can be performed by radiologists.

Preclinical animal research on therapy dosimetry with dual isotopes.

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray-emitting radionuclides for a chemically comparable beta-particle-emitting paired isotope for therapy evaluation would be feasible.

Radioembolization in combination with systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer.

PURPOSE: To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS: Clinical outcomes were evaluated retrospectively among 19 patients with unresectable liver metastases from CRC who had a good performance status and a low burden of extrahepatic disease (EHD) and were eligible for RE. Most (74%) had disease confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started 3-4 days before single treatment with RE. RESULTS: Overall response rate according to the Response Evaluation Criteria in Solid Tumors was 84% (two complete responses and 14 partial responses). Median progression-free survival (PFS) time was 10.4 months and median overall survival (OS) time was 29.4 months. For patients with disease confined to the liver, PFS improved (10.7 mo vs 3.6 mo; P = .09), with significant prolongation of OS (median, 37.8 mo vs 13.4 mo; P = .03) compared with those who had EHD. Nine patients, including three long-term (> 3 y) survivors, remained alive after a median follow-up of 18.6 months. Serious treatment-related toxicities included febrile neutropenia with concurrent FOLFOX treatment, a perforated duodenal ulcer, and one death from hepatic toxicity. CONCLUSIONS: The present findings confirm the effectiveness of RE plus systemic chemotherapy for metastatic CRC. Patients with liver-confined disease derived the greatest benefit, with median survival times beyond 36 months. Larger datasets from ongoing phase III trials are needed to further define the safety and efficacy of RE in the first-line setting.

Assessment of the treatment response of HCC.

Surgical hepatectomy or liver transplantation are considered as curative treatment modalities for hepatocellular carcinoma (HCC). However, many patients are not surgical candidates at the time of diagnosis. Great improvements in locoregional therapies including local ablative therapy [radiofrequency (RF) ablation or ethanol ablation] and transarterial techniques (transarterial embolization or transarterial radioembolization) have made possible local control of HCC. For unresectable HCC, a targeted therapy with sorafenib may improve survival. Unlike treatment of other oncologic tumor, the locoregional therapies are mainstay in the treatment of HCC. Therefore, the application of classical criteria such as the World Health Organization (WHO) guideline may not be suitable for accurate treatment response assessment of locoregional therapies or targeted therapy of HCC. An understanding of the imaging features of post-treatment imaging after various treatment modalities for HCC is crucial for treatment response assessment and for determining further therapy. In this article, we review the role of various imaging modalities in assessing treatment response of locoregional therapies and the targeted molecular therapy.