Unresectable hepatocellular carcinoma is extremely difficult to treat. TheraSphere consists of yttrium-90 (a pure beta emitter) microspheres, which are injected into the hepatic arteries. This ...article reviews the safety and survival of patients with hepatocellular carcinoma who were treated with yttrium-90 microspheres. Eighty patients were selected from a database of 108 yttrium-90 microsphere-treated patients and were staged by using Child-Pugh, Okuda, and Cancer of the Liver Italian Program scoring systems. Patients were treated with local, regional, and whole-liver approaches. Survival from first treatment was analyzed with Kaplan-Meier and Cox regression methods. Adverse events and complications of treatment were coded by using the Southwest Oncology Group toxicity scoring system. Patients received liver doses ranging from 47 to 270 Gy. Thirty-two patients (40%) received more than 1 treatment. Survival correlated with pretreatment Cancer of the Liver Italian Program scores (
P = .002), as well as with the individual Cancer of the Liver Italian Program components, Child-Pugh class, alpha-fetoprotein levels, and percentage of tumor replacement. Patients classified as Okuda stage I (n = 54) and II (n = 26) had median survival durations and 1-year survival rates of 628 days and 63%, and 384 days and 51%, respectively (
P = .02). One patient died of liver failure judged as possibly related to treatment. Thus, in selected patients with hepatocellular carcinoma, yttrium-90 microsphere treatment is safe and well tolerated. On the basis of these results, a randomized controlled trial is warranted comparing yttrium-90 microsphere treatment with transarterial chemoembolization by using the Cancer of the Liver Italian Program system for prospective stratified randomization.
Risk stratification of patients with end-stage congestive heart failure is a critical component of the transplant candidate selection process. Accurate identification of individuals most likely to ...survive without a transplant would facilitate more efficient use of scarce donor organs.
Multivariable proportional hazards survival models were developed with the use of data on 80 clinical characteristics from 268 ambulatory patients with advanced heart failure (derivation sample). Invasive and noninvasive models (with and without catheterization-derived data) were constructed. A prognostic score was determined for each patient from each model. Stratum-specific likelihood ratios were used to develop three prognostic-score risk groups. The models were prospectively validated on 199 similar patients (validation sample) by calculation of the area under the receiver operating characteristic curve for 1-year event-free survival, the censored c-index for event-free survival, and comparison of event-free survival curves for prognostic-score risk strata. Outcome events were defined as urgent transplant or death without transplant. The noninvasive model performed well in both samples, and increased performance was not attained by the addition of catheterization-derived variables. Prognostic-score risk groups derived from the noninvasive model in the derivation sample effectively stratified the risk of an outcome event in both samples (1-year event-free survival for derivation and validation samples, respectively: low risk, 93% and 88%; medium risk, 72% and 60%; high risk, 43% and 35%).
Selection of candidates for cardiac transplantation may be improved by use of this noninvasive risk-stratification model.
Prenatal echocardiography can identify the fetus that has complex congenital heart disease and may improve early management and surgical outcome. Prenatal diagnosis may be particularly beneficial to ...patients who have hypoplastic left heart syndrome (HLHS) and who are at risk for hypoxic-ischemic insult at presentation.
We sought to determine whether prenatal diagnosis reduces neurologic morbidity and operative mortality in patients who undergo palliative surgery for the HLHS.
Data from all patients who had HLHS, except for those with lethal genetic anomalies, and who were admitted to our institution between July 1992 and September 1997 were analyzed to assess the impact of prenatal diagnosis on preoperative management, neurologic morbidity, and surgical mortality. The primary outcome measures were hospital mortality and the incidence of adverse neurologic events (seizure or coma).
There were 216 patients who had HLHS and were referred for surgical palliation, 79 (36.6%) of whom had been diagnosed prenatally. All patients who had been diagnosed prenatally were delivered in an advanced nursery and were started on prostaglandin E(1) on the first day of life. Patients whose HLHS was diagnosed postnatally were begun on prostaglandin E(1) later in life (median = day 2 range = 1-28 days). There were 4 preoperative deaths and 53 operative or postoperative deaths. Overall hospital mortality was 26.4% and did not differ between patients whose HLHS had been diagnosed prenatally and those whose HLHS had been diagnosed postnatally. With the use of multivariable analysis, prenatal diagnosis was associated with fewer adverse perioperative neurologic events in the patients whose HLHS had been diagnosed prenatally than in those whose HLHS had been diagnosed postnatally (odds ratio = 0.46).
These data suggest that prenatal diagnosis has a favorable impact on treatment of patients who have HLHS and are undergoing staged palliation and reduces early neurologic morbidity. Prenatal diagnosis was not associated with reduced hospital mortality. It is possible that prenatal diagnosis may improve long-term neurologic outcome.
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.
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.
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.
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.
The purpose of this phase II study was to determine the safety and efficacy of TheraSphere treatment (90Y microspheres) in patients with liver-dominant colorectal metastases in whom standard ...therapies had failed or were judged to be inappropriate.
Twenty-seven patients with unresectable hepatic colorectal metastases were treated at a targeted absorbed dose of 135-150 Gy. Safety and toxicity were assessed according to the National Cancer Institute's Common Toxicity Criteria, version 3.0. Response was assessed with use of computed tomography (CT) and was correlated with response on 18Ffluorodeoxyglucose (FDG) positron emission tomography (PET). Survival from first treatment was estimated with use of the Kaplan-Meier method.
Tumor response measured by FDG PET imaging exceeded that measured by CT imaging for the first (88% vs 35%) and second (73% vs 36%) treated lobes. Tumor replacement of 25% or less (vs >25%) was associated with a statistically significant increase in median survival (339 days vs 162 days; P = .002). Treatment-related toxicities included mild fatigue (n = 13; 48%), nausea (n = 4; 15%), and vague abdominal pain (n = 5; 19%). There was one case of radiation-induced gastritis from inadvertent deposition of microspheres to the gastrointestinal tract (n = 1; 4%). Three patients (11%) experienced ascites/pleural effusion after treatment with TheraSphere as a consequence of liver failure in advanced-stage metastatic disease. With the exception of these three patients whose sequelae were not considered to be related to treatment, all observed toxicities were transient and resolved without medical intervention.
TheraSphere administration appears to provide stabilization of liver disease with minimal toxicity in patients in whom standard systemic chemotherapy regimens have failed.
Hepatocellular carcinoma (HCC) constitutes a difficult health challenge because of its poor prognosis and limited treatment options. Most available therapies are used only for palliation. The use of ...yttrium-90 microspheres is a new intraarterial therapy consisting of beta-irradiating microspheres measuring 20-30 micro m in diameter that can be delivered directly to the tumors. (90)Y microspheres, which carry the radiation, are selectively taken up by the tumors, thus preserving normal liver. In several studies to date, (90)Y microspheres have proved to have a low toxicity profile and have generally been well tolerated by patients. Other than transient elevation in liver enzyme levels and mild fatigue and fever, no substantial treatment-related toxicities have been observed. Gastrointestinal toxicities occur in a limited number of cases and are preventable with proper knowledge of visceral arterial anatomy. The effect on survival is also promising, with median survival rates of 23 months (95% confidence interval = 14, 44) and 11 months (95% confidence interval = 6, 26) for patients with Okuda stage I and stage II disease, respectively. On the basis of these data, intraarterial delivery of (90)Y microspheres offers a new alternative in the treatment of unresectable HCC.
To present the findings of a risk-stratification survival analysis with use of data collected on a heterogeneous group of patients with hepatocellular carcinoma (HCC) treated with TheraSphere.
...Baseline, treatment, and follow-up data were collected and analyzed from 121 TheraSphere-treated patients. Survival analyses were performed to identify those variables most strongly associated with 3-month mortality. The presence of any of the identified risk variables resulted in the assignment of a patient to the high-risk category.
Five liver reserve and two non-liver reserve variables were identified and used to stratify patients into low- or high-risk groups. Sixteen of the 33 patients assigned to the high-risk group (49%) did not survive the first 3 months after treatment, compared with six of the 88 patients assigned to the low-risk group (7%; Fisher exact test, P < .0001). Median survival for the low- and high-risk groups were 466 days and 108 days, respectively (hazard ratio, 6.0; P < .0001). Eleven of 12 patients who experienced a treatment-related major complication ending in death were included in the high-risk group. No single variable explained the major complication relationship to treatment.
Patients with HCC who are being considered for treatment with TheraSpheres should be evaluated for the presence of the risk variables described herein. The absence of these variables is predictive of improved survival (median of 466 days) compared with patients at high risk (median of 108 days).
Postembolization syndrome (PES) occurs in the majority of patients undergoing hepatic chemoembolization, and is the major reason for hospitalization after the procedure. The ability to identify which ...groups of patients are at increased or decreased risk of PES would be useful to better counsel patients, to minimize toxicity, and to plan inpatient versus outpatient therapy.
Seventy hepatic chemoembolization procedures were performed in 29 patients using cytotoxic drugs mixed with Ethiodol and polyvinyl alcohol. The following procedural variables were retrospectively assessed and evaluated for association with PES and length of postprocedural hospitalization: gallbladder embolization, lobe embolized, percentage liver volume embolized, percentage embolized volume occupied by tumor, previous embolization of the same territory, and dose of chemoembolic emulsion. Logistic regression was used to quantify the relative effect of each procedural variable.
Gallbladder embolization and dose administered were associated with an increased risk of PES and an extended hospitalization, with odds ratios of 2.8 and 3.0, and 3.0 and 4.6, respectively. Previous embolization was associated with a decreased risk of both PES and extended hospitalization, with odds ratios of 0.5 and 0.4, respectively. There was a statistical trend toward significance for gallbladder embolization (P = .06), dose administered (P = .07), and previous embolization (P = .14).
Clinically relevant predictors of the severity of PES and length of postprocedural hospitalization may exist. Avoiding embolization of the gallbladder reduces the risk of PES. Re-embolization of previously treated vessels is associated with decreased toxicity and may assist in selecting patients for treatment on an outpatient basis, especially when a reduced dose is required.
This pharmacologic protection trial was conducted to test the hypothesis that allopurinol, a scavenger and inhibitor of oxygen free radical production, could reduce death, seizures, coma, and cardiac ...events in infants who underwent heart surgery using deep hypothermic circulatory arrest (DHCA).
This was a single center, randomized, placebo-controlled, blinded trial of allopurinol in infant heart surgery using DHCA. Enrolled infants were stratified as having hypoplastic left heart syndrome (HLHS) and all other forms of congenital heart disease (non-HLHS). Drug was administered before, during, and after surgery. Adverse events and the clinical efficacy endpoints death, seizures, coma, and cardiac events were monitored until infants were discharged from the intensive care unit or 6 weeks, whichever came first.
Between July 1992 and September 1997, 350 infants were enrolled and 348 subsequently randomized. A total of 318 infants (131 HLHS and 187 non-HLHS) underwent heart surgery using DHCA. There was a nonsignificant treatment effect for the primary efficacy endpoint analysis (death, seizures, and coma), which was consistent over the 2 strata. The addition of cardiac events to the primary endpoint resulted in a lack of consistency of treatment effect over strata, with the allopurinol treatment group experiencing fewer events (38% vs 60%) in the entire HLHS stratum, compared with the non-HLHS stratum (30% vs 27%). In HLHS surgical survivors, 40 of 47 (85%) allopurinol-treated infants did not experience any endpoint event, compared with 27 of 49 (55%) controls. There were fewer seizures-only and cardiac-only events in the allopurinol versus placebo groups. Allopurinol did not reduce efficacy endpoint events in non-HLHS infants. Treated and control infants did not differ in adverse events.
Allopurinol provided significant neurocardiac protection in higher-risk HLHS infants who underwent cardiac surgery using DHCA. No benefits were demonstrated in lower risk, non-HLHS infants, and no significant adverse events were associated with allopurinol treatment.congenital heart defects, hypoplastic left heart syndrome, induced hypothermia, ischemia-reperfusion injury, neuroprotective agents, allopurinol, xanthine oxidase, free radicals, seizures, coma.
To identify pre- and intraoperative variables associated with postoperative acute neurologic events (ANEs), including seizures and coma, in newborn survivors of congenital heart surgery undergoing ...deep hypothermic circulatory arrest (DHCA), and to risk-stratify this population on the basis of preoperative risk variables for the purpose of designing future neuroprotection trials.
Survivors of newborn heart surgery who were enrolled in a neuroprotection trial provided a comprehensive database for the evaluation of pre- and intraoperative variables that influence the postoperative occurrence of ANEs (seizures or coma). Patients with hypoplastic heart syndrome were excluded. After characterization of the study population, stepwise logistic regression, combined with clinical judgment, was used to identify variables that were most likely to be associated with an increased risk of seizures in the study sample and that were most likely to be generalized to other populations.
Data were available on 164 nonhypoplastic left heart syndrome survivors who underwent newborn heart surgery using DHCA. ANEs occurred in 31 (18.9%) including "seizures alone" (n = 28), "coma alone" (n = 2) or "seizures and coma" (n = 1). A preoperative risk model was constructed demonstrating that infants with a genetic condition and aortic arch obstruction had a 47.8% risk of ANEs compared with all other remaining infants, who had a 9.9% risk. It was also found that prolonged DHCA time (>or=60 minutes) can be a significant risk for infants who have a preexisting genetic condition; however, infants who have genetic conditions and do not undergo prolonged DHCA time or have an aortic arch obstruction are not at increased risk of ANEs.
This study provides new information about the occurrence of ANEs after newborn heart surgery. Seizures or coma, which appeared in approximately 19% of all non-hypoplastic left heart syndrome survivors, were not random events but were significantly associated with specific types of congenital heart disease, the presence of genetic conditions, and prolonged DHCA time. The 3 identified variables permitted individual cases to be assigned to low-, intermediate-, or high-risk categories. Because neonatal seizures are a good surrogate marker of long-term neurologic outcome, these models provide useful information to stratify individual patients for risk of seizures in future neuroprotection trials.
