Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for 90Y resin microspheres

Background

Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-(⁹⁰Y)-labeled resin microspheres.

Methods

Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fisher’s exact test and Kaplan-Meier estimates, respectively.

Results

Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade ≥3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2^nd-line, 3^rd-line, or 4^th-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. ≥1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy.

Conclusions

Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received ≥3 prior lines of chemotherapy.     

Yttrium-90 internal radiation therapy for hepatic malignancy

Surgical resection is the only potentially curative strategy in the treatment of patients with hepatic malignancy. Unfortunately, due to advanced stage, underlying liver disease, or medical comorbidities, most patients are inoperable at the time of presentation. As a result, various locoregional therapies have emerged for otherwise unresectable hepatic tumors. One such modality is Yttrium-90 (Y(90)) internal radiation therapy. Numerous studies demonstrate the safety and potential survival benefit of intra-arterial Y(90) for primary and metastatic liver tumors. However, more data is needed in order to understand the exact role of Y(90) in the algorithm of hepatic tumor management. This review presents the available literature on Y(90) with the aim of defining the current status of Y(90) in the armamentarium of therapeutic strategies for hepatic malignancy.     

Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium

PURPOSE: To standardize the indications, techniques, multimodality treatment approaches, and dosimetry to be used for yttrium-90 (Y90) microsphere hepatic brachytherapy. METHODS AND MATERIALS: Members of the Radioembolization Brachytherapy Oncology Consortium met as an independent group of experts in interventional radiology, radiation oncology, nuclear medicine, medical oncology, and surgical oncology to identify areas of consensus and controversy and to issue clinical guidelines for Y90 microsphere brachytherapy. RESULTS: A total of 14 recommendations are made with category 2A consensus. Key findings include the following. Sufficient evidence exists to support the safety and effectiveness of Y90 microsphere therapy. A meticulous angiographic technique is required to prevent complications. Resin microsphere prescribed activity is best estimated by the body surface area method. By virtue of their training, certification, and contribution to Y90 microsphere treatment programs, the disciplines of radiation oncology, nuclear medicine, and interventional radiology are all qualified to use Y90 microspheres. The panel strongly advocates the creation of a treatment registry with uniform reporting criteria. Initiation of clinical trials is essential to further define the safety and role of Y90 microspheres in the context of currently available therapies. CONCLUSIONS: Yttrium-90 microsphere therapy is a complex procedure that requires multidisciplinary management for safety and success. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.     

Radioembolization with Yttrium-90 microspheres for patients with unresectable hepatocellular carcinoma

Background

Hepatocellular carcinoma (HCC) is aggressive primary malignancy of the liver that most commonly presents late in the disease course. As a result, the majority of patients are not candidates for curative therapies. Locoregional therapies including Yttrium-90 (Y-90) radioembolization play an important role in management of the vast majority of patients with HCC.

Methods

Patients with unnresectable HCC (n=17) treated with Y-90 radioembolization from 2005 to 2014 were evaluated retrospectively. Data was abstracted from medical records including patient charts, laboratory data, and imaging. Toxicities were recorded using Common Terminology Criteria 3.0. Response was recorded according to modified RECIST (mRECIST) criteria.

Results

Seventeen patients received 33 treatments with Y-90 radioembolization. A majority (65%) received TheraSphere with a minority (35%) receiving SIR-Spheres. The median treatment activity delivered was 1.725 gBq (range, 1.4-2.5 gBq). The median treatment dose delivered was 100 Gy (range, 90-120 Gy). The median lung shunt fraction was 2.02% (range, 1.5-4.1%). The most common clinical toxicity among all patients was nausea and vomiting (59%), primarily grade 1 and 2. Other post-treatment findings included abdominal pain (29%), fatigue (53%), and weight loss (18%). One patient developed a grade 5 gastric ulcer after the treatment. A clinical benefit, defined as patients achieving complete response (CR), partial response (PR) or stable disease (SD), was seen in 48% of patients. PR was seen in 24% of cases; progressive disease (PD) was noted in 35%. Patients survived for a median of 8.4 months (range, 1.3 to 21.1 months) after the first radioembolization treatment. Median survival after Y-90 treatment was 8.4 months among patients treated TheraSphere as compared with 7.8 months in patients treated with SIR-Spheres. The mean overall survival from the time of diagnosis was 11.7 months (range, 3.4 to 43.2 months).

Conclusions

For patients with unresectable HCC, Y-90 radioembolization is a safe and well-tolerated procedure. Our experience suggests that a significant percentage of patients achieve clinical benefit including many with PR. Survival after treatment from this single-center, transplant center is in line with prior reports. Prospective, randomized data is required to compare radioembolization with other therapies including chemoembolization and systemic therapy with sorafenib.     

First report on a prospective trial with yttrium-90–labeled ibritumomab tiuxetan (Zevalin) in primary CNS lymphoma

Most patients with primary CNS lymphoma (PCNSL) relapse after primary therapy. Standard salvage treatment has not yet been established in PCNSL. Anti-CD20 immunotherapy has expanded treatment options in systemic B-cell lymphoma; however, its use is limited by reconstitution of the blood–brain barrier after tumor shrinkage. The aim of this phase II trial was to evaluate the therapeutic efficacy, toxicity, and biodistribution of yttrium-90 (⁹⁰Y) ibritumomab tiuxetan in PCNSL. Ten patients with relapsed PCNSL were included in a phase II trial and treated with the ⁹⁰Y-labeled anti-CD20 antibody ibritumomab tiuxetan. Nine patients actually received the planned radioimmunotherapy. In six patients, biodistribution of the antibody was measured by indium-111 (¹¹¹In) ibritumomab tiuxetan whole-body scans and single-photon-emission CT (SPECT) of the brain. All patients were evaluated for toxicity and response at least 4 weeks after therapy. Four patients responded: one patient had a complete response lasting 30+ months, and three patients had short-lived responses of ≤4 weeks. Five patients progressed, and one patient did not receive treatment due to an infection prior to ⁹⁰Y-antibody administration. Target accumulation of the antibody was demonstrated in four of the six patients examined by SPECT imaging with ¹¹¹In ibritumomab tiuxetan. All patients experienced grade 3/4 hematotoxicity but no acute neurotoxicity. Penetration of a therapeutic antibody into PCNSL and significant clinical activity was shown. Because of limited response duration and considerable hematotoxicity, future investigations should focus on a multimodal approach with additional chemotherapy and preferably autologous stem cell support.     

Radioembolization with (90)Y-labeled microspheres: post-therapeutic therapy validation with Bremsstrahlung-SPECT

During the last years angiographic Selective Internal Radiotherapy (SIRT) with ⁹⁰Y-labelled microspheres has become a common technique for the local-ablative treatment of cancer patients. SIRT is a palliative therapy concept for the treatment of liver malignancies. As a result of ⁹⁰Y-decay as β^--emitter without a concomitant gamma radiation, Bremsstrahlung imaging is needed to validate the distribution achieved by radioembolisation. This article demonstrates the method of imaging through phantom measurement and shows the advantages of post-therapeutic tomography by means of a patient study. Approaches for further optimization of Bremsstrahlung imaging are discussed.     

Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases

BACKGROUND: There are limited effective treatment options available and a poor 5-year survival for patients with inoperable neuroendocrine liver metastases (NETLMs). In this study, the authors prospectively assessed the safety and efficacy of treatment with yttrium 90 ((90)Y) radioactive microspheres for patients with unresectable NETLMs. METHODS: Radioactive (90)Y resin microspheres (selective internal radiation [SIR-Spheres]) were administered through a temporarily placed percutaneous hepatic artery catheter concomitantly with a 7-day systemic infusion of 5-fluorouracil to patients with progressive, unresectable NETLMs. Patients were monitored prospectively, and the response to treatment was measured by using cancer markers and tumor size on computed tomography imaging studies. RESULTS: Thirty-four patients (22 men) with a mean age 61 years (range, 32-79 years) who had unresectable NETLMs were treated between December 2003 and December 2005. The mean (+/-standard error) follow-up was 35.2 +/- 3.2 months. The site of the primary neuroendocrine tumor was the bronchus in 1 patient, the medullary thyroid in 2 patients, gastrointestinal in 15 patients, the pancreas in 8 patients, and of unknown origin in 8 patients. The tumors were classified as vipoma (1 tumor), somatostatinoma (1 tumor), glucagonoma (2 tumors), large cell (3 tumors), carcinoid (25 tumors), and of unknown origin (2 tumors). Complications after (90)Y radioembolization included abdominal pain, which was mild to severe; nausea and fever; and lethargy that lasted from 1 week to 1 month. Two patients developed biopsy-proven radiation gastritis, 1 patient developed a duodenal ulcer, and there was 1 early death from liver dysfunction and pneumonia. Subjective changes from recorded baseline hormone symptoms were reported every 3 months. Symptomatic responses were observed in 18 of 33 patients (55%) at 3 months and in 16 of 32 patients (50%) at 6 months. Radiologic liver responses were observed in 50% of patients and included 6 (18%) complete responses and 11 (32%) partial responses, and the mean overall survival was 29.4 +/- 3.4 months). In patients who had evaluable chromogranin A (CgA) marker levels, there was a fall in CgA marker levels after (90)Y radioembolization in 19 patients (26%) at 1 month, in 19 patients (41%) at 3 months, in 15 patients (43%) at 6 months, in 11 patients (42%) at 12 months, in 8 patients (38%) at 24 months, and in 3 patients (46%) at 30 months. CONCLUSIONS: In this open study of 34 patients, the results demonstrated that radioembolization with (90)Y resin microspheres can achieve relatively long-term responses in some patients with nonresectable NETLMs.     

Oncogenic KRAS promotes malignant brain tumors in zebrafish

Background

Zebrafish have been used as a vertebrate model to study human cancers such as melanoma, rhabdomyosarcoma, liver cancer, and leukemia as well as for high-throughput screening of small molecules of therapeutic value. However, they are just emerging as a model for human brain tumors, which are among the most devastating and difficult to treat. In this study, we evaluated zebrafish as a brain tumor model by overexpressing a human version of oncogenic KRAS (KRAS^G12V).

Methods

Using zebrafish cytokeratin 5 (krt5) and glial fibrillary acidic protein (gfap) gene promoters, we activated Ras signaling in the zebrafish central nervous system (CNS) through transient and stable transgenic overexpression. Immunohistochemical analyses were performed to identify activated pathways in the resulting brain tumors. The effects of the MEK inhibitor U0126 on oncogenic KRAS were evaluated.

Results

We demonstrated that transient transgenic expression of KRAS^G12V in putative neural stem and/or progenitor cells induced brain tumorigenesis. When expressed under the control of the krt5 gene promoter, KRAS^G12V induced brain tumors in ventricular zones (VZ) at low frequency. The majority of other tumors were composed mostly of spindle and epithelioid cells, reminiscent of malignant peripheral nerve sheath tumors (MPNSTs). In contrast, when expressed under the control of the gfap gene promoter, KRAS^G12V induced brain tumors in both VZs and brain parenchyma at higher frequency. Immunohistochemical analyses indicated prominent activation of the canonical RAS-RAF-ERK pathway, variable activation of the mTOR pathway, but no activation of the PI3K-AKT pathway. In a krt5-derived stable and inducible transgenic line, expression of oncogenic KRAS resulted in skin hyperplasia, and the MEK inhibitor U0126 effectively suppressed this pro-proliferative effects. In a gfap-derived stable and inducible line, expression of oncogenic KRAS led to significantly increased mitotic index in the spinal cord.

Conclusions

Our studies demonstrate that zebrafish could be explored to study cellular origins and molecular mechanisms of brain tumorigenesis and could also be used as a platform for studying human oncogene function and for discovering oncogenic RAS inhibitors.

Electronic supplementary material

The online version of this article (doi:10.1186/s12943-015-0288-2) contains supplementary material, which is available to authorized users.     

The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity

First-line therapy for patients with glioblastoma multiforme includes treatment with radiation and temozolomide (TMZ), an oral DNA alkylating chemotherapy. Sensitivity of glioma cells to TMZ is dependent on the level of cellular O(6)-methylguanine-DNA methyltransferase (MGMT) repair activity. Several common coding-region polymorphisms in the MGMT gene (L84F and the linked pair I143V/K178R) modify functional characteristics of MGMT and cancer risk. To determine whether these polymorphic changes influence the ability of MGMT to protect glioma cells from TMZ, we stably overexpressed enhanced green fluorescent protein (eGFP)-tagged MGMT constructs in U87MG glioma cells. We confirmed that the wild-type (WT) eGFP-MGMT protein is properly localized within the nucleus and found that L84F, I143V/K178R, and L84F/I143V/K178R eGFP-MGMT variants exhibited nuclear localization patterns indistinguishable from WT. Using MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] proliferation and clonogenic survival assays, we confirmed that WT cells expressing eGFP-MGMT are resistant to TMZ treatment compared with control U87MG cells, and that each of the polymorphic eGFP-MGMT variants confers similar resistance to TMZ. However, upon exposure to O(6)-benzylguanine (O(6)-BG), a synthetic MGMT inhibitor, the L84F and L84F/I143V/K178R variants were degraded more rapidly than WT or I143V/K178R in a proteasome-dependent manner. Despite the increased O(6)-BG- stimulated protein turnover caused by the L84F alteration, cells expressing L84F eGFP-MGMT did not exhibit altered sensitivity to the combination of O(6)-BG and TMZ compared with WT cells. In conclusion, we demonstrated that the L84F polymorphic variant has altered protein turnover without modifying sensitivity of U87MG cells to TMZ or combined TMZ and O(6)-BG. These findings may provide a clue to determining the clinical significance of MGMT coding-region polymorphisms.     

Transcatheter embolization therapy in liver cancer:an update of clinical evidences

Transarterial chemoembolization(TACE) is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization.Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma(HCC) patients who cannot receive potentially curative therapies such as transplantation,resection or percutaneous ablation.TACE for liver cancer has been proven to be useful in local tumor control,to prevent tumor progression,prolong patients’ life and control patient symptoms.Recent evidence showed in patients with single-nodule HCC of 3 cm or smaller without vascular invasion,the5-year overall survival(OS) with TACE was similar to that with hepatic resection and radiofrequency ablation.Although being used for decades,Lipiodol~(Lipiodol~ Ultra Fluid~,Guerbet,France) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology.There have been efforts to improve the delivery of chemotherapeutic agents to tumors.Drug-eluting bead(DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner.Three DEBs are available,i.e.,Tandem~(CeloNova Biosciences Inc.,USA),DC-Beads~(BTG,UK) and HepaSphere~(BioSphere Medical,Inc.,USA).Transarterial radioembolization(TARE) technique has been developed,and proven to be efficient and safe in advanced liver cancers and those with vascular complications.Two types of radioembolization microspheres are available i.e.,SIR-Spheres~(Sirtex Medical Limited,Australia) and TheraSphere~(BTG,UK).This review describes the basic procedure of TACE,properties and efficacy of some chemoembolization systems and radioembolization agents which are commercially available and/or currendy under clinical evaluation.The key clinical trials of transcatheter arterial therapy for liver cancer are summarized.     

Association of 82 Rubidium and 11C-methionine uptake in brain tumors measured by positron emission tomography

Summary Positron emission tomography (PET) studies have indicated that alteration of active transport contributes to increased net amino acid accumulation into human brain tumors. We compared the uptake of ¹¹C-methionine (MET) and the K⁺ analog ⁸²Rubidium (RUB) in 30 patients suffering from various brain tumors using PET. MET and RUB accumulated rapidly in tumor tissue and remained on average at a stable level thereafter from which normalized uptake values were calculated (tissue radioactivity over injected radioactivity × body weight (NU)). K1 (RUB) and K1, k2, 0 (MET) were also estimated using non-linear rate constant fitting in 17/30 patients. NU and K1 values were significantly correlated for MET (Spearman Rank p < 0.005) and RUB (p < 0.001). NU and K1 values for MET and RUB were higher in meningiomas compared to gliomas and were significantly correlated for the whole spectrum of tumors (p < 0.001). When meningiomas were excluded, the correlation was maintained. K3 values for MET (metabolic rate) in tumors were in the range of normal brain. No correlation between RUB and MET was found for normal brain. With increasing RUB uptake, the ratio of NU MET over NU RUB approached the value of 1.0. These results suggest that apart from active transport, also passive diffusion across the blood-brain barrier (BBB) may account for MET uptake from blood into tumor tissue. This probably limits the use of MET in the differential diagnosis of brain lesions where BBB disruption is present.     

Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis

Background

For the past decade ¹⁸F-fluoro-ethyl-l-tyrosine (FET) and ¹⁸F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) have been used for the assessment of patients with brain tumor. However, direct comparison studies reported only limited numbers of patients. Our purpose was to compare the diagnostic performance of FET and FDG-PET.

Methods

We examined studies published between January 1995 and January 2015 in the PubMed database. To be included the study should: (i) use FET and FDG-PET for the assessment of patients with isolated brain lesion and (ii) use histology as the gold standard. Analysis was performed on a per patient basis. Study quality was assessed with STARD and QUADAS criteria.

Results

Five studies (119 patients) were included. For the diagnosis of brain tumor, FET-PET demonstrated a pooled sensitivity of 0.94 (95% CI: 0.79–0.98) and pooled specificity of 0.88 (95% CI: 0.37–0.99), with an area under the curve of 0.96 (95% CI: 0.94–0.97), a positive likelihood ratio (LR+) of 8.1 (95% CI: 0.8–80.6), and a negative likelihood ratio (LR−) of 0.07 (95% CI: 0.02–0.30), while FDG-PET demonstrated a sensitivity of 0.38 (95% CI: 0.27–0.50) and specificity of 0.86 (95% CI: 0.31–0.99), with an area under the curve of 0.40 (95% CI: 0.36–0.44), an LR+ of 2.7 (95% CI: 0.3–27.8), and an LR– of 0.72 (95% CI: 0.47–1.11). Target-to-background ratios of either FDG or FET, however, allow distinction between low- and high-grade gliomas (P > .11).

Conclusions

For brain tumor diagnosis, FET-PET performed much better than FDG and should be preferred when assessing a new isolated brain tumor. For glioma grading, however, both tracers showed similar performances.     

Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling

One challenge in biology is signal transduction monitoring in a physiological context. Intravital imaging techniques are revolutionizing our understanding of tumor and host cell behaviors in the tumor environment. However, these deep tissue imaging techniques have not yet been adopted to investigate the second messenger calcium (Ca²⁺). In the present study, we established conditions that allow the in vivo detection of Ca²⁺ signaling in three-dimensional tumor masses in mouse models. By combining intravital imaging and a skinfold chamber technique, we determined the ability of photodynamic cancer therapy to induce an increase in intracellular Ca²⁺ concentrations and, consequently, an increase in cell death in a p53-dependent pathway.     

Clinical and imaging experience with yttrium-90 microspheres in the management of unresectable liver tumours.

INTRODUCTION: Selective internal radiation therapy (SIRT) is emerging as a new therapeutic modality in recent years for management of non-resectable hepatic malignancies. Our experience in clinical application of this treatment is reported here. MATERIAL AND METHODS: From June 2004, patients whose liver tumours were no longer amenable for any conventional treatment with either chemotherapy or surgery were considered for yttrium-90 microspheres treatment after discussion at our multidisciplinary meeting. A pre-treatment planning was carried out with visceral angiography and technetium-99m macroaggregated albumin (MAA) for assessment of both tumour volume and extrahepatic shunting in addition to a baseline PET and CT scans, respectively. Two weeks later, a second visceral angiogram was performed to deliver the calculated dosage of microspheres into the arterial system supplying the tumour. Patients were then followed up with tumour markers, repeat PET and CT scans of abdomen at 6 weeks and 3 monthly thereafter. RESULT: Twenty-one patients (F=11, M=10; age range 40-75 years, mean=58 years) received yttrium-90 microspheres consisting of liver metastases from colorectal primary (n=10) and non-colorectal primaries (n=8), and primary liver tumours (n=3). One patient received 2 treatments. The mean administered activity of microspheres delivered was 1.9 GBq (range 1.2-2.5 GBq). Injection of microspheres had no immediate effect on either clinical haematology or liver function tests. At follow-up, 86% of patients showed decreased activity on PET scan at 6 weeks (p=0.01). The mean pre-treatment SUV was 12.2+/-3.7 and the mean post-treatment SUV was 9.3+/-3.7, indicating a significant improvement measured with PET activity. Only 13% showed a reduction in the size of tumour on CT scan. For patients with colorectal liver metastases, there was no significant reduction in CEA level (127+/-115 vs 75+/-72 micro/l, p=0.39). Complications were seen in 4 patients (19%) including radiation hepatitis (n=2), cholecystitis (n=1) and duodenal ulceration (n=1). All resolved without surgical intervention. Seven patients died at follow-up from progressive extrahepatic disease (33%). CONCLUSION: SIRT should be considered for patients with advanced liver cancer. It has a significant effect on liver disease in the absence of extrahepatic disease. PET imaging has an integral role in the assessment of patients treated with yttrium-90 SIR-Spheres.     

A descriptive analysis of the characteristics,treatment response and prognosis of hepatic dominant solid tumors undergoing selective internal radiation therapy (SIRT)

BackgroundSelective internal radiotherapy is widely used for liver dominant diseases of solid tumors. However, data about sequential treatment and prognostic factors are lacking.MethodsWe consecutively included all 209 patients who received a selective internal radiotherapy intervention between January 2015 and May 2019. A retrospective analysis of their electronic patient records was performed regarding diagnosis of cancer, previous therapies and applied radioactive activity. A multicenter follow-up at least 6 weeks after intervention to assess radiological response and irregular subsequent follow-ups to asses disease progression were conducted. In addition, subgroup analyses were carried out.ResultsThe most frequently treated indications were hepatocellular carcinoma (37%), colorectal cancers (14%), neuroendocrine tumors (9%), and breast cancer (8%). In hepatocellular carcinoma, selective internal radiotherapy was most performed without prior systemic therapy (40%), and for the remaining indications, most often after surgery with systemic therapy in sequence. Local radiological response, defined as either regression or stable disease, was assessed at least 6 weeks after intervention and showed 52% across all indications. Hepatocellular carcinoma (59%) and breast cancer (67%) showed an excellent, colorectal cancers (29%) a particularly poor response rate. Neuroendocrine tumors showed the third longest median post-selective internal radiation therapy (SIRT) survival with 12.4 months and the second longest median progression-free time with 5.2 months. Hepatocellular carcinoma showed even better results with a post-SIRT survival of 15.7 months and a median progression-free time of 5.3 months. Pancreatic neuroendocrine tumors showed significantly worse outcomes than other neuroendocrine tumors, regarding median post-SIRT survival and median progression-free time. No relevant SIRT related differences among sexes were detected.ConclusionsPatients with neuroendocrine tumors, breast cancer in late therapy lines and early-stage hepatocellular carcinoma seem to show better responses to SIRT than other entities. Colorectal cancers were mainly treated with SIRT in a second or third therapy line but with considerably weaker results than other entities.     

Enhancement of ACNU cytotoxicity by pretreatment withO 6-methylguanine in ACNU-resistant brain tumors

Summary O ⁶-Methylguanine is a substrate of the DNA repair enzymeO ⁶-methylguanine-DNA methyltransferase, which is involved in the repair mechanism of DNA damage induced by chloroethylnitrosoureas such as 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). We tested the enhancement effect ofO ⁶-methylguanine pretreatment on ACNU cytotoxicity in ACNU-resistant brain tumors. Exposure toO ⁶-methylguanine at various times ranging from 2 to 48 hours increased the cytotoxic effects of ACNU on C6-1 cells, and this effect was highest at higher concentrations 500 and 1,000 M. Colorimetric cytotoxicity assay revealed at least a two-fold increase in ACNU cytotoxicity relative to controls withoutO ⁶-methylguanine. Intraarterial ACNU after treatment withO ⁶-methylguanine (two intravenous bolus injections of 80 and 40 mg/kg) significantly (P < 0.05 or P < 0.01) reduced the proliferation activity of transplanted C6-1 tumors for 96 hours after injection, whereas intravenous ACNU together withO ⁶-methylguanine significantly (P < 0.05) reduced C6-1 activity for only 48 hours. Thus, pretreatment withO ⁶-methylguanine prolonged the suppression effect of ACNU. The C6-1 tumors treated only with intravenous or intraarterial ACNU showed transient inhibition and rapid regrowth for 24 hours after treatment. These results indicate thatO ⁶-methylguanine increases ACNU cytotoxicity in anin vitro andin vivo brain tumor model.     

Factors Affecting Oncologic Outcomes of 90Y Radioembolization of Heavily Pre-Treated Patients With Colon Cancer Liver Metastases

Introduction

The purpose of this study was to identify predictors of overall (OS) and liver progression-free survival (LPFS) following Yttrium-90 radioembolization (RAE) of heavily pretreated patients with colorectal cancer liver metastases (CLM), as well as to create and validate a predictive nomogram for OS.