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Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities.

PURPOSE: Intraarterial injection of yttrium 90 microspheres (TheraSpheres) is used in the treatment of hepatocellular carcinoma (HCC). This article presents an analysis of the incidence of liver toxicities (liver-related events) and pretreatment factors associated with liver toxicities after TheraSphere treatment. PATIENTS AND METHODS: Eighty-eight TheraSphere-treated patients with low 90-day mortality risk were selected for analysis, with liver toxicities coded with use of standard oncology criteria. Descriptive and inferential statistical methods were applied to estimate the incidence of liver toxicities and to evaluate the influence of liver radiation dose and various pretreatment factors on the risk of their occurrence. RESULTS: Sixty-eight liver toxicities occurred in 37 of the 88 patients (42%). Thirty-two patients (36%) experienced 50 liver toxicities after the first treatment and nine of 23 patients (39%) who received a second treatment experienced 18 liver toxicities. Pretreatment total bilirubin and liver radiation dose were found to be associated with the risk of at least one liver toxicity and with the time to first occurrence of a liver toxicity after first treatment. Pretreatment total bilirubin also was associated with liver toxicities after the second treatment. Most of the toxicities resolved; however, those that did not resolve were attributed to tumor progression or advancing cirrhosis. CONCLUSIONS: The risk of liver toxicities in patients with unresectable HCC treated with TheraSpheres increases with increasing pretreatment total bilirubin level and liver radiation dose to a maximum of 150 Gy for a single administration. The toxicities attributed to treatment resolved over time, and none of the patients studied had confirmed radiation-induced liver disease. Consequently, doses as high as 150 Gy on a single administration and as high as 268 Gy on repeated administrations were well tolerated.

Aged↗

Use of Yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis.

PURPOSE: Intra-arterial injection of Yttrium-90 glass microspheres ((90)Y- microS; TheraSphere, MDS Nordion, Ottawa, Canada) is indicated for treatment of unresectable hepatocellular carcinoma (HCC) in the presence of acceptable liver function. This study presents hepatic toxicity results after unilobar and bilobar intra-arterial administration of (90)Y- microS in patients with unresectable HCC who had known portal vein thrombosis (PVT) without evidence of cavernous transformation. MATERIALS AND METHODS: Fifteen patients with unresectable HCC and PVT of one or both first order and related segmental portal venous branches received a total of 29 infusions of (90)Y- microS for treatment of HCC. All patients had pretreatment evaluation including: computed tomography (CT) imaging, alpha-fetoprotein (AFP) levels, liver function tests, technetium-99m macroaggregated albumin ((99)Tc-MAA) scan for evaluation of lung and visceral shunting, and angiography with visualization into the portal venous phase. (90)Y- micro S dose was based on lobar hepatic volume with adjustment for lung shunt activity. Liver toxicity was assessed by serum total bilirubin graded for severity according to the NIH NCI Clinical Toxicity Criteria (CTC version 2.0). Other adverse events were reported according to the standards established by the Society of Interventional Radiology. RESULTS: There were no procedural complications with delivery of (90)Y- microS, and treatment was well tolerated by all patients. Increased post-treatment bilirubin levels were observed across all treatments in five patients, four of whom had CT or AFP evidence of intrahepatic disease progression. After initial treatment, two patients developed bilirubin toxicity (grades 1 and 2); one patient demonstrated an increment in bilirubin toxicity grade (grade 1 to grade 3) and one patient had an improvement in grade after initial treatment. There were no new treatment-related toxicities in nine patients after a second treatment. CONCLUSIONS: (90)Y- microS treatment was well tolerated and appears to be safe to use in patients with compromised portal venous flow in one or both first order and related segmental portal venous branches and no evidence of cavernous transformation. In patients who did not exhibit disease progression, there appeared to be no clinically significant change in bilirubin.

Adult↗

Yttrium 90 resin microspheres for the treatment of unresectable colorectal hepatic metastases after failure of multiple chemotherapy regimens: preliminary results.

PURPOSE: Responses to liver-directed therapy with yttrium 90 microspheres (SIR-Spheres) and adjuvant intraarterial chemotherapy have occurred in patients with unresectable colorectal hepatic metastases who had received less than one chemotherapy regimen. Now, SIR-Spheres are being used to treat patients with advanced disease who have received multiple chemotherapy regimens. A retrospective analysis was performed to determine the technical feasibility of SIR-Sphere treatment in this population. MATERIALS AND METHODS: The medical records of 12 patients with hepatic metastatic disease and intrahepatic progression after multiple chemotherapy regimens for unresectable colorectal hepatic metastases who were treated with one or two infusions of SIR-Spheres were retrospectively analyzed for demographics, tumor characteristics, treatment details, response, and survival. RESULTS: Twelve patients underwent 17 outpatient infusions of SIR-Spheres. Percent hepatic tumor volume was less than 25% in four patients, 25%-50% in three, and more than 50% in five. Treatment in 11 patients with bilobar disease was accomplished via single infusions in six cases and sequential unilobar infusions in five patients. A single infusion was used to treat unilobar disease in the remaining patient. Median prescribed dose was 39.6 mCi (mean, 37.2 mCi; range, 17-67.5 mCi); the prescribed dose exceeded the delivered dose in six infusions (35%) as a result of embolic arterial occlusion. Radiologic response was stable in five of nine patients. Carcinoembryonic antigen levels decreased in four of seven patients. Four patients received chemotherapy concomitantly or after completion of treatment. Gastric ulceration in one patient was managed nonoperatively. Median survival times from diagnosis and treatment were 24.6 and 4.5 months, respectively. CONCLUSIONS: Treatment with SIR-Spheres induces responses in patients with advanced unresectable colorectal hepatic metastases after multiple chemotherapy regimens. Inability to deliver the prescribed dose is related to the embolic effect of SIR-Spheres.

Adult↗

Reduction of metastatic load to liver after intraarterial hepatic yttrium-90 radioembolization as evaluated by [18F]fluorodeoxyglucose positron emission tomographic imaging.

PURPOSE: To assess the response of hepatic metastases after treatment with intraarterial yttrium 90 radioembolization (ie, use of SIR-Spheres) with use of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). MATERIALS AND METHODS: Nineteen patients with metastatic cancer to the liver from various solid tumors with progression despite polychemotherapy were included. All patients underwent baseline computed tomography, FDG PET, hepatic angiography, and intraarterial technetium 99 m macroaggregated albumin scan for assessment of lung shunting fraction. Patients were treated with 90Y resin microspheres on a lobar basis and were monitored for 3 months with use of dedicated attenuation-corrected PET. For each patient, regions of interest were drawn along the liver edge to measure total liver standard uptake value (SUV) on axial images, covering the entire liver. Visual estimates were also performed and graded as +1, 0, -1, -2, or -3 for progression, no change, and mild, moderate, and dramatic improvement by posttreatment PET. RESULTS: The median absorbed dose for the tumor was 76 Gy. There was a significant overall decrease in total liver SUV after treatment (baseline, 71,134 +/- 38,055; after SIR-Sphere treatment, 59,941 +/- 26,509; P = .028) for the entire group. Visual estimates placed 15 patients (79%) in response categories (-3 to -1) and four patients (21%) in nonresponse categories (0 to +1) for the liver. The percentage change of total liver SUV after treatment in the response group (-19%) was significantly greater and different in direction than that in the nonresponse group (+27%; P = .03). This percentage change was also correlated significantly with the respective visual estimates (r = 0.72; P < .0005) for each individual patient. Three patients had major complications related to hyperbilirubinemia (transient, n = 1; permanent, n= 2). CONCLUSIONS: The results suggest that there is significant reduction of hepatic metastatic load as evaluated objectively by PET after 90Y radioembolization for the treatment of unresectable metastatic disease to the liver. 90Y radioembolization provides encouraging results by arresting progression of metastatic cancer to the liver.

Embolization, Therapeutic↗

The effect of catheter-directed CT angiography on yttrium-90 radioembolization treatment of hepatocellular carcinoma.

PURPOSE: Yttrium 90 radioembolization is a transcatheter therapy for unresectable hepatocellular carcinoma (HCC) that delivers internal radiation to tumors. In contrast to the usual method of lobar regional delivery, catheter-directed computed tomographic (CT) angiography was investigated as a potentially useful technique to evaluate the administration of segmental 90Y tumor radiation doses superselectively without significantly altering liver function or Child-Pugh classification. MATERIALS AND METHODS: Fourteen patients underwent 90Y therapy for unresectable HCC. After standard angiographic placement of a 3-F microcatheter in a segmental hepatic artery supplying the tumor, each patient underwent CT angiography with use of segmental hepatic artery injection of iodinated contrast agent to confirm segmental perfusion and delineate segmental liver volume. 90Y was later injected into the same segmental artery. Target dose was calculated according to infused 90Y activity and targeted hepatic volume with standard lobar volume (before CT angiography) versus segmental liver volume (after CT angiography). The Wilcoxon signed-rank test (alpha = 0.05) was used to compare the estimated 90Y dose before CT angiography with the actual 90Y dose after CT angiography, as well as changes in serum bilirubin level and Child-Pugh classification as a result of treatment. RESULTS: The mean estimated tumor dose before CT angiography (SD) was 100 Gy +/- 43 (range, 35-169 Gy). The mean actual tumor dose after CT angiography was 348 Gy +/- 204 (range, 105-857 Gy), which was significantly greater (P < .001). The mean bilirubin level before treatment was 1.0 mg/dL +/- 0.97 (range, 0.2-4.0 mg/dL), whereas the mean bilirubin level after treatment was 1.3 mg/dL +/- 0.85 (range, 0.5-3.8 mg/dL). This difference, although statistically significant (P = .03), was not clinically important. Thirteen of 14 patients had no change in Child-Pugh class. CONCLUSION: CT angiography can be used to delineate the blood supply and volume to a targeted hepatic segment, allowing superselective 90Y radioembolization. This approach significantly increases effective 90Y tumor radiation dose without clinically altering liver function or Child-Pugh class.

Adult↗

Diffusion-weighted MR imaging for determination of hepatocellular carcinoma response to yttrium-90 radioembolization.

Early detection of the response of hepatocellular carcinoma (HCC) to yttrium-90 radioembolization therapy may be important to permit repeat radioembolization or alternative treatment options. Water-mobility measurements with use of diffusion-weighted (DW) magnetic resonance (MR) imaging are useful for noninvasive interrogation of microstructural tissue properties. Findings of DW MR imaging may serve as an early biomarker of HCC response. This study tested the hypothesis that DW MR imaging can detect changes in tumor tissue water diffusion in response to (90)Y therapy. In each of six patients with HCC included in the study, tumor water diffusion increased significantly after therapy. DW MR imaging is a promising technique for noninvasive assessment of tumor response to (90)Y radioembolization.

Adult↗

Radioembolization with yttrium-90 microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies: part 3: comprehensive literature review and future direction.

Treatment options for primary and secondary liver tumors that cannot be resected or ablated are based on transarterial techniques. Although the majority of these are based on bland and chemoembolization techniques, yttrium-90 microspheres represent an alternate transarterial option. Although the amount of literature on (90)Y does not rival that of bland or chemoembolization, there nevertheless are ample data that support its use for primary and metastatic liver tumors. A comprehensive review of the entire available literature dating from the early 1960s is presented, as is a discussion of the possibilities for future research with use of radioembolization as a platform.

Brachytherapy↗

Yttrium synoviorthesis of the elbow joints in persons with haemophilia.

Yttrium has been used as the material of choice for synoviorthesis in our centre since 1984. An audit was carried out to determine the long-term results of this modality for treating elbow joints. An unacceptably high percentage of patients lost range-of-movements in the articulation treated. Good results were achieved with respect to a reduction in the bleeding incidences. It is suggested that another isotope be utilized and that other centres carry out an audit and publish their data.

Elbow Joint↗

Long-term evaluation of radioisotope synovectomy with Yttrium 90 for chronic synovitis in Turkish haemophiliacs: Izmir experience.

Since 2001 we have performed 105 radioisotope synovectomy (RS) in 65 children and young adults, age ranging from 3 to 25 years with a average of 15 years in Ege University Hospital, Izmir, Turkey. One fourth of cases were below 10 years of age. All patients had severe haemophilia A and B. Ten patients (17 joints) had high responder inhibitor. We prefer to use Yttrium 90 for all joints (5 mCi for knees; 2 mCi for others). The knees were injected in 56 cases, elbows in 24 cases, ankles in 23 cases and shoulders in two cases. Steroid injections were not preferred as the principle drug of choice. Mean follow-up period after procedure was 2 years (range: 6 months to 3.5 years). All inhibitor patients had satisfactory results. The best results were obtained in elbows than knees and ankles. Excellent rates (no bleeding) were observed in grade-II synovitis 84% for knees, 93% for elbows and 50% for ankles. Because of the excellent and good response (bleeding reduction to 75%), rates were 100% for knees and elbows and 92% for ankles. In six cases, repeated injections were given at 6-month interval and all of them had good results. The grading of synovitis seems to be an important parameter than the age of the patient. Even in patients below 10 years of age, outcomes are not satisfactory in all joints with grade-III vs. grade-II synovitis (12% vs. 73%). No serious complications were observed during and after procedure except two cases. A mild and transient inflammatory reaction was observed in the ankle. There was a minimal radioisotope leakage to superficial skin in the elbow. RS seems to be a safe and effective treatment for chronic synovitis causing recurrent joint bleedings.

Adolescent↗

Imaging Yttrium-90 synovectomy studies.

The method of planar imaging utilizing Bremsstrahlung radiation in patients treated with intraarticular Yttrium-90 for joint synovitis is described, illustrated and discussed.

Brachytherapy↗

Treatment of multiple superficial transitional cell carcinoma of the bladder with intravesical yttrium-90.

Thirty-eight patients with extensive multiple superficial transitional cell carcinoma of the bladder which could not be controlled endoscopically were treated with intravesical yttrium-90. Nineteen are alive at between 1 and 9 years. Short-term control of the disease was achieved in most patients. In those followed up for at least 3 years, 48% remained alive and well and 36% avoided cystectomy or other major treatment.

Adult↗

The removal of cutaneous pigmented lesions with the Q-switched ruby laser and the Q-switched neodymium: yttrium-aluminum-garnet laser. A comparative study.

BACKGROUND: The Q-switched ruby laser (QSRL) (694 nm) has been used successfully in the removal of tattoos and a variety of cutaneous pigmented lesions. The frequency-doubled Q-switched neodymium:yttrium-aluminum-garnet laser (QSNd:YAG) (1064 and 532 nm) has also been shown to be effective in the treatment of tattoos, however, little has been published regarding the QSNd:YAG laser in the removal of cutaneous pigmented lesions. OBJECTIVE: The purpose of this study is to compare the efficacy and side effect profile of the QSRL and the frequency-doubled QSNd:YAG lasers in the removal of cutaneous pigmented lesions, including lentigines, café-au-lait macules, nevus of Ota, nevus spilus, Becker's nevus, postinflammatory hyperpigmentation, and melasma. METHODS: Twenty patients with pigmented lesions were treated with the QSRL and the frequency-doubled QSNd:YAG lasers. Clinical lightening of the lesion was assessed 1 month after a single treatment. Side effects and patient satisfaction were also evaluated. RESULTS: A minimum of 30% lightening was achieved in all patients after only one treatment with either the QSRL or the frequency-doubled QSNd:YAG laser. The QSRL seems to provide a slightly better treatment response than the QSNd:YAG laser. Neither laser caused scarring or textural change of the skin. Most patients found the QSRL to be more painful during treatment, but the QSNd:YAG laser caused more postoperative discomfort. CONCLUSION: Both the QSRL and the frequency-doubled QSND:YAG laser are safe and effective methods of treatment of epidermal and dermal pigmented lesions.

Adult↗

Neodymium:yttrium-aluminum garnet contact laser ablation of Barrett's high grade dysplasia and early adenocarcinoma.

OBJECTIVES: We describe the efficacy and safety of neodymium:yttrium-aluminum garnet (Nd:YAG) contact laser ablation of Barrett's high grade dysplasia (HGD) and/or early adenocarcinoma. METHODS: Consecutive Barrett's patients in whom HGD or adenocarcinoma was detected were eligible. Radial array echoendosonography and high frequency catheter probe ultrasonography were performed. Patients were excluded if ultrasound revealed the presence of Barrett's cancer with regional lymph nodes or celiac trunk metastases or extension of the tumor into superficial submucosa (T1sm1) or greater. Nd:YAG laser used quartz contact probes, with all Barrett's epithelium targeted at each session. Complete ablation was confirmed with Lugol's iodine chromoendoscopy followed by surveillance biopsies of the neosquamous epithelium. Adverse events were ascertained by scheduled telephone contact interviews. RESULTS: A total of 36 patients with HGD/adenocarcinoma were evaluated at our center, 17 of whom met all inclusion criteria. Of the patients, 14 have remained in the study, and all have had successful elimination of HGD and cancer. In addition, 11 patients (78.6%) achieved complete endoscopic and histological ablation of all Barrett's tissue. Two patients (14.3%) achieved 95% destruction of Barrett's with residual metaplastic columnar epithelium containing goblet cells without dysplasia. The remaining patient has obtained 75% ablation of Barrett's, with residual metaplastic columnar epithelium harboring Barrett's with low grade dysplasia. Major complications included two esophageal strictures (11.8%) and one mild upper GI bleed (5.9%). CONCLUSIONS: This preliminary experience with Nd:YAG contact laser for the treatment of Barrett's HGD and early superficial cancers seems promising. The need for additional controlled trials with larger numbers of patients with longer follow-up, as well as consideration of a head-to-head trial with Photofrin photodynamic therapy, is warranted.

Adenocarcinoma↗

Neodymium:yttrium aluminum garnet laser irradiation with low pulse energy: a potential tool for the treatment of peri-implant disease.

Bacterial contamination may seriously compromise successful implant osteointegration in the clinical practice of dental implantology. Several methods for eliminating bacteria from the infected implants have been proposed, but none of them have been shown to be an effective tool in the treatment of peri-implantitis. In the present study, we investigated the efficacy of pulsed neodymium:yttrium aluminum garnet laser irradiation (Nd:YAG) in achieving bacterial ablation while preserving the surface properties of titanium implants. For this purpose, suspensions of Escherichia coli or Actinobacillus (Haemophilus) actinomycetemcomitans were irradiated with different laser parameters, both streaked on titanium implants, and in broth medium. It was found, by light and atomic force microscopy, that Nd:YAG laser, when used with proper working parameters, was able to bring about a consistent microbial ablation of both aerobic and anaerobic species, without damaging the titanium surface.

Aggregatibacter actinomycetemcomitans↗

Childhood acromegaly successfully treated with interstitial irradiation using yttrium-90.

A child with a growth hormone producing tumour presented at the age of 4 1/2 years. The onset of the disease was at 18 months of age. Treatment was given with three doses of interstitial irradiation using yttrium-90 implants. There were no local complications from the procedures. Now, 11 years after diagnosis, she is asymptomatic, of normal appearance, and her height and the size of the pituitary fossa are normal. Growth hormone levels are almost normal, thyroid function is intact, and she is maintained on prednisone and sex hormones.

Adenoma, Acidophil↗

Quantitative imaging of bromine-76 and yttrium-86 with PET: a method for the removal of spurious activity introduced by cascade gamma rays.

Positron Emission Tomography of bromine-76 and yttrium-86 results in the detection of coincident events that are not strictly associated with annihilation photon pairs. Instead, these coincidences occur because prompt gamma rays emitted by these nuclides result in cascades of photons that are emitted within the timing window of the PET scanner. Pairs of detected photons from these cascades are not angularly correlated and therefore contain little information regarding the location of their source. Furthermore, these coincidences are not removed by correction procedures (e.g., randoms, scatter) routinely applied to PET data. If left uncorrected, the cascade coincidences will result in spurious apparent activity within the PET images. A correction, applied within projection space, that removes the cascade coincidence signal from septa-in (i.e., two-dimensional) datasets is proposed and tested on phantom data.

Algorithms↗

Quantitative bremsstrahlung imaging of yttrium-90 using a Wiener filter.

Yttrium-90 (90Y), a pure beta emitter, is an attractive radionuclide for radioimmunotherapy of cancer. Therapeutic management requires quantitative imaging to measure the pharmacokinetics of the radionuclide in the patient for radiation dosimetric calculations. The bremsstrahlung emissions can be utilized to acquire an image of beta sources using a gamma camera. Quantitation of 90Y by bremsstrahlung imaging is difficult because of poor image quality that results from septal penetration and scatter secondary to the broad bremsstrahlung energies. In this work, quantitative methods for bremsstrahlung imaging of 90Y sources that involved the use of (a) a Wiener filter to deconvolve the septal penetration and scatter while suppressing image noise, and (b) the geometric mean of the conjugate view (GM) and effective point source (EPS) methods to quantify activities were investigated. An abdominal phantom was prepared with 90Y activities in the liver, spleen, tumors, and background volumes that were similar to those observed in patient studies. A twofold improvement in resolution recovery for full width at tenth maximum of the line spread function at 11 cm depth in water was achieved using Wiener restoration. Definition of the organ and tumor edges was greatly enhanced and cross talk between adjacent sources was suppressed after Wiener restoration. These improvements in image quality led to more accurate estimation of organ and tumor activities. Using the optimum attenuation correction method for GM and EPS quantitation of filtered bremsstrahlung images, estimates of individual activities (< or = 17% error) and cumulated activities (< or = 8% error) in all of the sources were accurate except for a tumor of 2 cm diameter. The results of this study provide the basis for a method to quantify beta source distribution and demonstrate the potential use of bremsstrahlung imaging in clinical settings.

Gamma Rays↗

Radiation synovectomy with yttrium-90 for persisting arthritis has direct harmful effects on human cartilage that cannot be prevented by co-administration of glucocorticoids: an in vitro study.

BACKGROUND: It was recently shown that radiation synovectomy with yttrium-90 (90Y) and glucocorticoids is not superior to intra-articular glucocorticoids alone in the treatment of persistent gonarthritis. In that study, it seemed that in patients treated by radiation synovectomy, progression of radiographic joint damage occurred. OBJECTIVE: To test in vitro the direct effects of radiation synovectomy with 90Y on human cartilage. METHODS: Human cartilage tissue was exposed to 90Y, glucocorticoids or the combination. 1:2000 to 1:20 dilutions of the clinical dose of 5 mCi/ml 90Y and 20 mg/ml glucocorticoids were used. After a 4-day exposure and a subsequent 12-day recovery period, proteoglycan synthesis, proteoglycan release and proteoglycan content were measured. In addition, human synovial tissue was cultured for 4 days with 90Y or glucocorticoids. Culture supernatants were analysed for cartilage-destructive activity. RESULTS: 90Y, glucocorticoids and the combination inhibited proteoglycan synthesis considerably and dose dependently, an effect that sustained for at least 12 days. Proteoglycan release was transiently increased by 90Y, an effect that was not changed by addition of glucocorticoids, which had no effect on its own. Proteoglycan content was eventually adversely affected by 90Y, an effect hardly influenced by glucocorticoids. Neither 90Y nor glucocorticoids changed the cartilage-destructive properties of synovial tissue. CONCLUSIONS: 90Y, but not glucocorticoids, has direct harmful effects on cartilage in vitro. Indirect beneficial effects of 90Y via inhibition of cartilage-destructive properties of synovial tissue could not be shown. These observations may explain the possible radiographic joint damage on radiation synovectomy.

Aged↗