Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.

PURPOSE: To develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd). PATIENTS AND METHODS: Twenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months. RESULTS: Whole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months. CONCLUSION: These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.

The use of 3-D dose volume analysis to predict radiation hepatitis.

Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence. Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated. Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients. Nine of the 79 patients treated developed clinical radiation hepatitis. None of the patient related variables assessed were associated with radiation hepatitis. All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose greater than or equal to 37 Gy. Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature. The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment. An estimation of model parameters based on the clinical results indicated a larger magnitude for the "volume effect parameter" than the literature estimate (n = 0.69 +/- 0.05 vs 0.32; p less than 0.001). Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis. These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation. The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial.

Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young healthy volunteers.

BACKGROUND: Zinc is an important nutrient and is necessary to maintain a multitude of physiologic processes. Mineral supplements that provide physiologic doses of zinc may be used when dietary zinc is inadequate. Zinc is also used in pharmacologic doses to treat zinc deficiency and diseases such as Wilson's disease and acrodermatitis enteropathica. Although there are several zinc salts available, they are not equal in solubility, which is thought to be a key factor in zinc absorption. Moreover, the solubility of the salts is affected by pH, which may vary between pH 1 and 7 under various physiologic conditions in the stomach. The objectives of this 2-way 4-phase crossover study were to evaluate the effect of high (> or = 5) and low (< or = 3) intragastric pH on the absorption of zinc from the acetate and oxide salt in young healthy volunteers. METHODS: After a 9-hour fast, 10 healthy subjects (5 males and 5 females) were given a single oral dose of 50 mg of elemental zinc as the acetate or the oxide salt and under either high or low intragastric pH conditions. In all phases, a Heidelberg capsule pH detector-transmitter was used to continuously monitor intragastric pH. During the high pH phases, single oral doses of famotidine 40 mg oral suspension were administered before the zinc to raise the intragastric pH above 5. Intragastric pH < or = 3 was maintained in the low pH phases. RESULTS: The mean plasma zinc area under the curve for zinc acetate at low pH (AL), zinc acetate at high pH (AH), zinc oxide at low pH (OL), and zinc oxide at high pH (OH) were 524, 378, 364, and 66 micrograms x h/dL, respectively. The highest zinc plasma concentrations occurred with the acetate salt at a low intragastric pH, while the lowest plasma concentrations occurred with the oxide salt at a high intragastric pH. The importance of pH to the dissolution of these salts was verified by in vitro tests. Twenty-four-hour urinary zinc excretion was the highest for the AL phase and lowest for the OH phase. CONCLUSION: This study indicates that intragastric pH and salt solubility-dissolution are important in the oral absorption of zinc. Specifically, the oxide salt is not an appropriate zinc salt to use in those patients with elevated intragastric pH.

Use of zinc tolerance test and 24-hour urinary zinc content to assess oral zinc absorption.

OBJECTIVES: The sensitivity of one plasma and two urinary methods to assess zinc absorption after oral dosing were compared over the dose range of 10 to 100 mg. METHODS: Eleven healthy subjects participated in this four-way crossover design study. After an overnight fast, the subjects received a single oral dose of zinc acetate corresponding to 10, 25, 50, or 100 mg of elemental zinc. Plasma zinc concentrations were measured at baseline (pre-zinc administration) and hourly intervals post-zinc administration for 9 hours. Urine was collected for 24 hours prior to and for 24 hours after zinc administration. During this 48-hour period, subjects consumed an isocaloric, caffeine-free diet containing 18 mg of elemental zinc per day. RESULTS: The area under the plasma zinc concentration versus time curve (PZAUC) increased linearly with doses between 10 and 50 mg, then flattened out. By contrast, urinary zinc excretion was approximately linear with doses in the 25 to 100 mg range, but no differences were observed in urinary zinc excretion after doses of 10 and 25 mg. CONCLUSIONS: Plasma zinc concentration is a useful method of evaluating oral zinc absorption from doses of 10 to 50 mg. Urinary zinc excretion is an alternative method of assessing zinc absorption, particularly when doses of 50 to 100 mg of elemental zinc are administered.