Safety and Efficacy of Selective Internal Radionuclide Therapy with 90Y Glass Microspheres in Patients with Progressive Hepatocellular Carcinoma after the Failure of Repeated Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is currently the standard of care in patients with unresectable hepatocellular carcinoma (HCC), and selective internal radionuclide therapy (SIRT) with 90Y microspheres is mainly used as an alternative modality in patients considered poor candidates for TACE. Treatment with sorafenib is the recommended option for patients with progressive disease after TACE. This study aims to evaluate the safety and efficacy of SIRT with glass microspheres in patients with progressive HCC after repeated TACE who are not eligible for treatment with sorafenib. Forty-seven patients with progressive HCC after a median of three TACE sessions (range 2-14) underwent SIRT (3.5 ± 1.5 GBq; liver target dose 110-120 Gy). Toxicity was recorded 4 and 12 weeks after treatment and reported according to the Common Terminology Criteria for Adverse Events Version 5.0. Treatment response was assessed three months after SIRT using multiphase computed tomography and modified criteria in solid tumors (mRECIST). Survival analyses were performed using Kaplan-Meier curves and a Cox proportional hazards model for uni- and multivariate analyses. Significant but reversible hepatotoxicity (≥grade 3) occurred in five patients (11%). No radioembolization-induced liver disease (REILD) was observed. The number of previous TACE sessions and cumulative administered activity did not predict the incidence of post-SIRT significant hepatotoxicity. Treatment responses consisted of partial responses in 26 (55%), stable disease in 12 (26%), and progressive disease in 9 (19%) patients. The median overall survival (OS) was 11 months (95% confidence interval (CI), 9-13), and objective responses to SIRT were associated with a longer OS (p = 0.008). Significant hepatotoxicity (≥grade 3) after SIRT was a contributor to impaired survival (median OS 6 months (95% CI, 4-8) vs. 12 months (95% CI, 10-14), p < 0.001). SIRT with glass microspheres is a safe and effective salvage treatment for patients with progressive HCC refractory to TACE who are considered poor candidates for sorafenib treatment.

In Patients Treated by Selective Internal Radiotherapy, Cellular In Vitro Immune Function Is Predictive of Survival.

In patients with liver malignancies, the cellular immune function was impaired in vitro after selective internal radiotherapy (SIRT). Because immunosuppression varied substantially, in the current study, we investigated in 25 SIRT patients followed up for ten years whether the lymphocyte function was correlated with survival. Peripheral blood mononuclear cells were stimulated with four microbial antigens (tuberculin, tetanus toxoid, Candida albicans and CMV) before therapy and at four time points thereafter, and lymphocyte proliferation was determined by H3-thymidine uptake. The median sum of the responses to these four antigens decreased from 39,464 counts per minute (CPM) increment (range 1080-204,512) before therapy to a minimum of 700 CPM increment on day 7 after therapy (0-93,187, p < 0.0001). At all five time points, the median survival in patients with weaker responses was 2- to 3.5-fold shorter (p < 0.05). On day 7, the median survival in patients with responses below and above the cutoff of a 2 CPM increment was 185 and 523 days, respectively (χ2 = 9.4, p = 0.002). In conclusion, lymphocyte function could be a new predictor of treatment outcome after SIRT.

DNA lesions correlate with lymphocyte function after selective internal radiotherapy.

In patients with non-resectable hepatic malignancies selective internal radiotherapy (SIRT) with yttrium-90 is an effective therapy. However, previous data indicate that SIRT leads to impaired immune function. The aim of the current study was to determine the extent of DNA lesions in peripheral blood mononuclear cells of SIRT patients and to correlate these lesions with cellular immune responses. In ten patients γH2AX and 53BP1 foci were determined. These foci are markers of DNA double-strand breaks (DSBs) and occur consecutively. In parallel, lymphocyte proliferation was assessed after stimulation with the T cell mitogen phytohemagglutinin. Analyses of vital cells were performed prior to and 1 h and 1 week after SIRT. 1 h and 1 week after SIRT numbers of γH2AX and of 53BP1 foci were more than threefold larger than before (p < 0.01). Already at baseline, foci were more abundant than published in healthy controls. Lymphocyte proliferation at baseline was below the normal range and further decreased after SIRT. Prior to therapy, there was an inverse correlation between lymphocyte proliferation and the quotient 53BP1/γH2AX; which could be considered as a measure of the course of DNA DSB repair (r = - 0.94, p < 0.0001). Proliferative responses were inversely correlated with 53BP1 foci prior to therapy and γH2AX and 53BP1 foci 1 h after therapy (r < - 0.65, p < 0.05). In conclusion, DNA foci in SIRT patients were correlated with impaired in vitro immune function. Unrepaired DNA DSBs or cell cycle arrest due to repair may cause this impairment.

Impaired lymphocyte function in patients with hepatic malignancies after selective internal radiotherapy.

The purpose of our study was to assess the immune function of patients with inoperable hepatic malignancies after treatment with selective internal radiotherapy (SIRT) and to identify possible correlations with clinical parameters. In 25 patients receiving SIRT lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) after stimulation with mitogens and microbial antigens were tested prior to therapy, directly after therapy (day 1) and at day 2, 7 and 28 post therapy using the lymphocyte transformation test and enzyme-linked immunospot assays. Absolute counts and percentages of leukocyte and lymphocyte subsets were determined by flow cytometry. The most prominent finding was an immediate and significant (p < 0.05) decrease of lymphocyte proliferation and interferon-γ production directly after therapy which lasted until day 28 and was stronger upon stimulation with microbial antigens than with mitogens. Moreover, lymphopenia was revealed, affecting all lymphocyte subsets (CD3+, CD4+, CD8+ T cells, CD4+ CD8+ T cells, B cells and NK cells). SIRT led to a reduction in the percentage of activated HLA-DR+ monocytes and of CD45R0+ memory T cells. Higher radiation activity, the presence of liver cirrhosis, chronic kidney disease, diabetes mellitus and metastases were unfavorable factors for immunocompetence, while a better Eastern Cooperative Oncology Group performance status was associated with stronger immunological reactions. In conclusion, SIRT leads to severe impairment of cellular in vitro immune responses. Further studies are needed to assess a potential clinical impact.

Impairment of lymphocyte function following yttrium-90 DOTATOC therapy.

The radiolabeled somatostatin analogue, yttrium-90 DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC), is currently applied to treat advanced somatostatin receptor-positive tumors, e.g., neuroendocrine tumors of the pancreas, lung or gut. However, effects of this treatment on antimicrobial immune responses are not yet defined. In 20 patients treated with DOTATOC, cellular in vitro immune function was determined. Their antimicrobial lymphocyte responses were assessed by lymphocyte transformation test and enzyme-linked immunospot-measuring lymphocyte proliferation and on a single cell level production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10)-prior to therapy, at day 1, day 7 and day 90 post-therapy. Proliferative lymphocyte responses and interferon-γ production after in vitro stimulation with microbial antigens were non-significantly suppressed at day 1 and significantly (p < 0.05) at day 7 versus pre-therapy. In vitro immune responses did not fully recover until day 90. In contrast, at day 1 interleukin-10 production was significantly (p < 0.05) increased. Taken together, we observed a decrease in pro-inflammatory immune responses after DOTATOC therapy. Patients with versus without bone metastases displayed significantly (p < 0.05) lower cellular immune responses toward several microbial antigens. Progressive disease and higher tumor burden could also be defined as factors associated with impaired immune function. Spearman correlation analysis indicated that cellular in vitro immunity was positively correlated with kidney function; better kidney function led to stronger immune responses. In conclusion, DOTATOC therapy caused a decrease in in vitro immune responses against microorganisms. The clinical impact needs to be evaluated in further studies.

Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.

PURPOSE: Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response­adapted treatment guided by early interim positron emission tomography (PET)­computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely. METHODS: An imaging working group composed of representatives from major international cooperative groups was asked to review the literature, share knowledge about research in progress, and identify key areas for research pertaining to imaging and lymphoma. RESULTS: A working paper was circulated for comment and presented at the Fourth International Workshop on PET in Lymphoma in Menton, France, and the 12th ICML in Lugano, Switzerland, to update the International Harmonisation Project guidance regarding PET. Recommendations were made to optimize the use of PET-CT in staging and response assessment of lymphoma, including qualitative and quantitative methods. CONCLUSION: This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for [18F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials.

Osteoblastic response as a healing reaction to chemotherapy mimicking progressive disease in patients with small cell lung cancer.

The osteoblastic response (OR) phenomenon as a healing reaction during effective chemotherapy-defined by the appearance of new osteoblastic bone lesions while disease response in other tumor sites was well documented-has previously been described for breast and prostate cancer. The purpose of this study was to investigate this phenomenon that could erroneously be interpreted as progressive disease in patients with small cell lung cancer (SCLC) and to establish guidelines for interpretation of follow-up computed tomography (CT) examinations in this situation. Twenty-four patients with newly diagnosed SCLC and bone metastases were retrospectively included in this study. The characteristics of bone lesions in CT examinations were correlated with bone scintigraphy and magnetic resonance imaging, if available. In target lesions the CT density quantified in Hounsfield units (HU) was evaluated at baseline and during follow-up. New osteoblastic lesions occurred during follow-up in 17 of 24 patients. OR was proven in 4 patients and considered most likely in 11 patients; mean density increase in target lesions was 153 HU. The study indicates that osteoblastic response as a healing reaction seems to occur in the majority of patients with SCLC and bone metastases and should not be misinterpreted as progressive disease.

Accuracy of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: comparison with CT and PET.

PURPOSE: To assess the accuracy of positron emission tomography/computed tomography (PET/CT) when staging different malignant diseases. PATIENTS AND METHODS: This was a retrospective, blinded, investigator-initiated study of 260 patients with various oncological diseases who underwent fluorine-18-2-fluoro-2-deoxy-d-glucose PET/CT for tumor staging. CT images alone, PET images alone, PET + CT data viewed side by side, and fused PET/CT images were evaluated separately according to the tumor-node-metastasis system. One hundred forty patients with tumors not staged according to the tumor-node-metastasis system or a lack of reference standard were excluded from data analysis; 260 patients were included. Diagnostic accuracies were determined for each of the four image sets. Histopathology and a clinical follow-up of 311 (+/- 125) days served as standards of reference. RESULTS: PET/CT proved significantly more accurate in assessing tumor-node-metastasis system stage compared with CT alone, PET alone, and side-by-side PET + CT (P < .0001). Of 260 patients, 218 (84%; 95% CI, 79% to 88%) were correctly staged with PET/CT, 197 (76%; 95% CI, 70% to 81%) with side-by-side PET + CT, 163 (63%; 95% CI, 57% to 69%) with CT alone, and 166 (64%; 95% CI, 58% to 70%) with PET alone. Combined PET/CT had an impact on the treatment plan in 16, 39, and 43 patients when compared with PET + CT, CT alone, and PET alone, respectively. CONCLUSION: Tumor staging with PET/CT is significantly more accurate than CT alone, PET alone, and side-by-side PET + CT. This diagnostic advantage translates into treatment plan changes in a substantial number of patients.

Intraoperative radiation therapy in liver tissue in a pig model: monitoring with dual-modality PET/CT.

PURPOSE: To assess, in a pig model, the value of dual-modality positron emission tomography (PET)/computed tomography (CT) for monitoring radiation therapy. MATERIALS AND METHODS: Central bile duct resection followed by creation of a biliodigestive anastomosis was performed in nine pigs. Six of these pigs were also treated with intraoperative radiation therapy (IORT) (20 Gy) in the area of the anastomosis. Two, 4, and 8 weeks postoperatively, contrast material-enhanced fluorine 18 fluorodeoxyglucose (FDG) PET/CT of the liver was performed in all of the animals. The radioactive tracer concentration in the region of the anastomosis was quantified, and the values were compared intraindividually with the values at the liver periphery. Histologic evaluation of the liver was performed 8 weeks postoperatively. The PET/CT images were assessed for changes in liver volume and bile duct diameter over time. RESULTS: In all nine pigs, the region of the anastomosis could be clearly defined on the fused PET/CT images. PET/CT revealed a decreased concentration of FDG in the irradiated field 2 and 4 weeks after IORT. At 8 weeks, however, the distribution of the tracer in the irradiated pigs did not differ from that in the nonirradiated pigs. Homogeneous tracer uptake in all liver regions was observed in the nonirradiated animals. The CT images showed an increase in liver volume in all pigs and bile duct dilatation that increased over time in the irradiated pigs. CONCLUSION: The morphologic and functional changes due to IORT in liver tissue can be accurately monitored with dual-modality PET/CT. By enabling the integration of functional and morphologic data, PET/CT may have an important role in monitoring radiation treatment.

Effect of oral contrast agents on computed tomography-based positron emission tomography attenuation correction in dual-modality positron emission tomography/computed tomography imaging.

RATIONALE AND OBJECTIVES: To evaluate the effect of iodine- and barium-based contrast agents on the computed tomography (CT)-based positron emission tomography (PET) attenuation correction in dual-modality PET/CT. METHODS: Experiments were conducted on a Society of Nuclear Medicine/National Electrical Manufacturers Association-PET phantom equipped with cylinders containing [18F]-2-fluoro-2-desoxy-D-glucose. The main compartment was filled with iodine (0.5-10%), barium (0.5-50%), or water (negative control). The error in attenuation correction was determined by comparison of measured tracer quantities in the presence of contrast agents with expected quantities. Contrast agent attenuation was demonstrated to be comparable to in vivo conditions. RESULTS: The presence of contrast agents resulted in an overestimation of the intracylindrical activity concentration on PET images and overestimation directly related to contrast concentrations (iodine 5-38%; barium 15-580%). Iodine and barium concentrations in clinical use resulted in an activity overestimation of 20 +/- 1.8% for iodine and 21 +/- 2.9% for barium. CONCLUSION: An overestimation of the tracer activity concentration is to be expected in the presence of oral contrast agents, if PET attenuation correction is attained CT-based.

Whole-body positron emission tomography-CT: optimized CT using oral and IV contrast materials.

OBJECTIVE: Our objective was to show that oral and IV contrast materials improve CT image quality in dual-modality positron emission tomography (PET) and CT, resulting in an increase in diagnostic capacity. We also present a standardized scanning protocol for whole-body PET-CT with oral and IV contrast materials. SUBJECTS AND METHODS: To evaluate the use of whole-body PET-CT in clinical practice, we examined 30 patients according to the protocol. The CT images were evaluated quantitatively by signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) analyses and qualitatively by two radiologists in consensus. PET quality was assessed quantitatively by measurements of standard uptake values that were compared with standard uptake values in 10 PET-CT examinations without contrast agents. RESULTS: . The application of oral and IV contrast materials led to a highly sufficient delineation of vascular and intestinal structures in 26 of 30 patients. Quantitative analysis revealed a mean vascular SNR of 15.8 +/- 7.71 for the 30 patients who received contrast materials compared with 4.79 +/- 1.45 for the 10 control group patients (p < 0.001). Similarly, the mean intestinal SNR of 17.06 +/- 7.96 far exceeded that seen in the control group of 3.83 +/- 1.16 (p < 0.001). Analyses led to a vessel-to-muscle CNR of 10.78 +/- 5.89 (control group, -1.21 +/- 0.89; p < 0.001) and an intestine-to-muscle CNR of 12.04 +/- 6.07 (control group, -2.17 +/- 1.22; p = 0.001) in the 30 patients. An evaluation of PET quality in patients who received contrast materials showed a mean standard uptake value of 2.09 +/- 1.16 compared with 2.04 +/- 0.83 in the control group (p = 0.702). CONCLUSION: Our whole-body PET-CT protocol provided good vascular and intestinal enhancement without compromising PET quality, leading to a potential improvement in the diagnostic capacity of the combined PET-CT examination.