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T S Lawrence

Publications and source records attributed to T S Lawrence.

At least 91 records · Page 5Linked to original sources
PubMed1994

Use of fluorescence in situ hybridization (FISH) to study chromosomal damage induced by radiation and bromodeoxyuridine in human colon cancer cells.

PURPOSE: Although the thymidine analog radiation sensitizer bromodeoxyuridine (BrdUrd) increases radiation-induced chromosomal aberrations, it is not known whether these aberrations are uniformly distributed among chromosomes. Using fluorescence in situ hybridization, we carried out a study to test the hypothesis that BrdUrd-induced radiosensitization may be mediated by nonuniform chromosomal damage. METHODS AND MATERIALS: Log phase HT29 human colon cancer cells were exposed to 10 microM BrdUrd (or media alone) for one cell cycle, and the G1 cells were separated by centrifugal elutriation. Half of the control and BrdUrd samples were irradiated with 8 Gy. Cells were then incubated for 24-28 h, and metaphase spreads were prepared. Fluorescence in situ hybridization was performed using paint probes for chromosomes 1 and 4. RESULTS: We found that radiation induced 0.20 aberrations per chromosome in chromosome 4. Based on the ratio of the relative lengths of chromosome 1-4 (1.34), it was predicted that chromosome 1 would have approximately 0.26 aberrations per chromosome. However, we observed 0.39 aberrations per chromosome 1, which was significantly greater than the predicted (p < 0.001 by chi-square). Incubation with BrdUrd prior to irradiation significantly increased the aberrations found in chromosome 1 (by a factor of 1.4) and chromosome 4 (by a factor of 1.9) compared to radiation alone (p < 0.001) for both chromosome 1 and 4). CONCLUSION: This study demonstrates that individual chromosomes in human colon cancer cells show significantly different rates of aberration after irradiation. Furthermore, the BrdUrd-mediated increase in radiation-induced chromosomal aberrations may not be uniform among chromosomes.

Bromodeoxyuridine↗
PubMed1994

Bromodeoxyuridine-mediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation.

PURPOSE: To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of a human malignant glioma line (D-54) in vitro and in vivo. MATERIALS AND METHODS IN VITRO STUDIES: an established human malignant glioma line (D-54) was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 microM BrdUrd) and intraarterial (4 microM BrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3, and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrdUrd into the DNA of tumor, gut, and marrow were determined. RESULTS: In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 +/- 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 +/- 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells. CONCLUSION: These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. The potential benefit of FdUrd modulation demonstrated in vitro may be difficult to realize using continuous systemic infusions.

Animals↗
PubMed1994

Dependence of 5-fluorouracil-mediated radiosensitization on DNA-directed effects.

PURPOSE: Although 5-fluorouracil (FUra) has been demonstrated to be a radiation sensitizer both in the laboratory and the clinic, it is not known whether radiosensitization results primarily from FUra's DNA or RNA-directed effects. METHODS AND MATERIALS: We studied the radiosensitizing effects of FUra +/- thymidine (dThd)) on HT29 human colon cancer cells, which are relatively sensitive to the DNA-directed action of FUra, in comparison to SW620 and HuTu80 human colon cancer cells, which are relatively resistant to FUra's DNA-directed effects. We hypothesized that if FUra were acting chiefly through DNA dependent mechanisms, HT29 cells would (a) show greater radiosensitization than SW620 and HuTu80 cells under the same conditions of exposure; and (b) demonstrate selective reversal of radiation sensitivity (compared to cytotoxicity) in the presence of FUra + dThd, compared to FUra alone. RESULTS: We found that the enhancement ratio produced by a 24 h exposure to 10 microM FUra was significantly greater in HT29 cells compared to SW620 and HuTu80 cells (enhancement ratios of 2.1 +/- 0.1; 1.1 +/- 0.1, and 1.3 +/- 0.1, respectively). Furthermore, in HT29 cells, dThd blocked FUra-mediated radiosensitization to a greater extent than FUra-mediated cytotoxicity. Thus, our hypotheses were confirmed. CONCLUSION: These findings support the concept that the manipulation of FUra's DNA-dependent actions, for example, through modulators of thymidylate synthase (TS) activity, may increase radiosensitization in clinical trials in the treatment of gastrointestinal cancers. However, since resistance to the DNA-directed effects of fluoropyrimidines can result from mechanisms unrelated to TS inhibition, additional strategies will be required to potentiate fluoropyrimidine-mediated radiosensitization.

Cell Cycle↗
PubMed1994

Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells.

Difluorodeoxycytidine (dFdCyd) is a new antimetabolite with clinical activity in patients with solid tumors but not leukemias. We have studied the metabolism, cytotoxicity, and radiosensitizing properties of dFdCyd in HT-29 human colon carcinoma cells. The results demonstrated that dFdCyd rapidly accumulated as the 5'-triphosphate dFdCTP in HT-29 cells, which was eliminated slowly in the absence of dFdCyd with a half-life of > 12 h. Accumulation of dFdCTP was associated with rapid depletion of cellular dATP pools. Exposure to the concentration that reduces cell survival by 50% of 30 nM dFdCyd decreased dATP levels by > 80% within 4 h. dGTP pools were depleted at higher concentrations of dFdCyd, whereas smaller decreases were effected in dTTP and dCTP pools. These results contrast with previous reports in leukemic cells which demonstrated that dFdCyd exposure depleted the endogenous dCTP pool to a greater extent than the dTTP, dATP, or dGTP pools. Based on these data, we suggest that the profound depletion by dFdCyd of dATP and dGTP pools in HT-29 compared to leukemic cells accounts for the superiority of this agent in solid tumors versus leukemias. Additional studies demonstrated that dFdCyd was a potent radiosensitizer in HT-29 cells. Maximal radiosensitization was observed when cells were irradiated immediately following dFdCyd exposure instead of prior to or in the middle of drug treatment. Radiation sensitization was dose and time dependent, with a noncytotoxic exposure to 10 nM dFdCyd for 24 h or 30 nM dFdCyd for 16 h producing a radiation enhancement ratio of approximately 2. Under these conditions, only the cellular dATP pool was depleted. When cells were exposed to higher concentrations of dFdCyd for 4 h, equivalent radiosensitization with a radiation enhancement ratio of 1.4 was obtained using 0.1, 1.0, or 10 microM dFdCyd. Despite a 15-fold increase in dFdCTP and depletion of dGTP and dCTP pools to < 25% of the control value with 10 microM compared to 0.1 microM dFdCyd, no increase in radiosensitization was observed. These results suggest that dATP depletion is an important factor in the radiosensitizing property of this promising new antitumor compound.

Antimetabolites, Antineoplastic↗
PubMed1994

Kinetics of bromodeoxyuridine elimination from human colon cancer cells in vitro and in vivo.

We have previously shown that the thymidine analogue radiation sensitizer bromodeoxyuridine (BrdUrd) is incorporated into human tumors to a greater extent than into the livers of athymic mice bearing these tumors as xenografts. However, incorporation into the intestine and bone marrow exceeds that of the tumor (T. S. Lawrence, M. A. Davis, J. Maybaum, S. K. Mukhopadhyay, P. L. Stetson, D. P. Normolle, P. E. McKeever, and W. D. Ensminger, Cancer Res., 52: 3698-3704, 1992). We hypothesized that the ratio of tumor incorporation to intestinal or bone marrow incorporation might increase during a period of drug elimination following the termination of an infusion. To test this hypothesis, we infused athymic mice bearing HT29 human colon cancer xenografts with BrdUrd and measured incorporation in the tumor and normal tissues up to 7 days after the infusion was discontinued. In addition, we assessed the effect of exposure to BrdUrd on subsequent incorporation in vitro and in vivo through the use of a stable isotope of BrdUrd ("isotopic BrdUrd"), which could be differentiated from normotopic BrdUrd using the gas chromatographic-mass spectrometric assay. We found a significant increase in the ratio of BrdUrd in the tumor compared to bone marrow and intestine during the drug elimination period. We also found that BrdUrd incorporation slowed the kinetics of subsequent BrdUrd incorporation and elimination. These findings suggest that when the radiation dose-limiting organ is rapidly proliferative, such as the intestine or bone marrow, delivering radiation during a drug elimination period may improve the therapeutic index.

Animals↗
PubMed1994

Induction of resistance to fluorodeoxyuridine cytotoxicity and DNA damage in human tumor cells by expression of Escherichia coli deoxyuridinetriphosphatase.

Recent studies from our laboratory suggested that, in some human colorectal tumor cell lines, sensitivity to fluorodeoxyuridine may depend upon the extent of dUTP accumulation that occurs following drug treatment and that elevation of dUTPase activity might be the basis for some instances of resistance to fluoropyrimidines. To test this model, we expressed Escherichia coli dUTPase in an established human tumor cell line (HT29) and measured the effect of this manipulation on response to fluorodeoxyuridine. As predicted, HT29 derivatives containing dUTPase activity 4-5-fold higher than controls were protected from fluorodeoxyuridine-induced loss of clonogenicity and from formation of DNA double strand breaks. These data provide the first direct evidence that alteration in a component of the uracil misincorporation/misrepair pathway can confer resistance to fluoropyrimidines in human tumor cells.

Base Sequence↗
PubMed1994

Clinical pharmacology of hepatic arterial infusions of 5-bromo-2'-deoxyuridine.

This investigation was undertaken to determine the pharmacokinetic parameters relevant to hepatic arterial (HA) infusion of 5-bromo-2'-deoxyuridine (BrdUrd) and to ascertain the maximum tolerated dose and related toxicities of BrdUrd administered as a 14-day HA infusion. In the pharmacokinetic study, 6 patients received a 2-h i.v. infusion (to steady-state) of BrdUrd at each of 5 escalating dose rates (10 to 160 mg/kg/day) with simultaneous blood sampling for BrdUrd levels from HA and hepatic venous catheters. Dose dependent HA and hepatic venous drug levels, total body clearance, hepatic extraction, and estimated regional exposure advantage were determined. The total body clearance of BrdUrd was high and dose rate dependent, falling from 3340 ml/min with a 10-mg/kg/day infusion to 2180 ml/min at a 160-mg/kg/day dose rate. Hepatic extraction was high and dose rate dependent as well, declining from 80% extraction at 10 mg/kg/day to 68% at 160 mg/kg/day. The calculated estimate for the exposure advantage achievable with HA as compared with i.v. infusion reflects the dose rate dependence of total body clearance and hepatic extraction and decreases from a 70-fold advantage at 10 mg/kg/day to a 30-fold advantage at 160 mg/kg/day. In the Phase I study aimed at determining the maximum tolerated dose, successive groups of 3 patients were administered continuous HA infusions for 14 days at escalated BrdUrd dose rates (5, 10, 15, 25, and 35 mg/kg/day) in order to ascertain dose-limiting toxicity. The maximum tolerated dose of BrdUrd for a 14-day continuous HA infusion was found to be 35 mg/kg/day with reversible thrombocytopenia as the sole dose-limiting toxicity. Skin and other toxicities were infrequent, minor, reversible, and non-dose dependent. No hepatic toxicity was detected despite direct drug infusion into the liver. The high total body clearance and hepatic extraction of BrdUrd substantiate its administration via the hepatic artery as a means to achieve higher exposure with intrahepatic tumors than can be obtained by systemic administration. Despite higher hepatic exposures, no hepatic toxicity was noted, and readily reversible systemic toxicity (thrombocytopenia) was dose limiting for the 14-day continuous HA infusion. Thus, HA infusion of the potent radiosensitizer BrdUrd is both pharmacokinetically rational and well tolerated.

Adult↗
PubMed1994

Sensitization of radiolabeled monoclonal antibody therapy using bromodeoxyuridine.

BACKGROUND: Although treatment with radiolabeled monoclonal antibodies (MoAb) against tumor-associated antigens offers the potential for targeted therapy, the efficacy of this approach is limited by the low dose-rate delivered. This could be overcome by increasing tumor sensitivity through the use of radiation sensitizers. METHODS AND RESULTS: In vitro studies using LS174T human colon cancer cells showed that exposure to 1 microM bromodeoxyuridine (BrdUrd), a thymidine-analog radiation sensitizer, at a plasma concentration easily achievable through systemic administration in both animals and patients, increased the cytotoxicity of continuous low dose-rate irradiation delivered by a cesium-137 irradiator (at 12 cGy/h which resembles the dose-rate delivered by radiolabeled MoAb therapy). It was found that 1 microM BrdUrd produced marked radiosensitization (enhancement ratio of 1.42 +/- 0.03) but did not affect cell cycle distribution. Systemic administration of BrdUrd in athymic nude mice bearing LS174T xenografts was performed using osmotic pumps. Animals tolerated infusions of 200 mg/kg/day BrdUrd for 4 days, which resulted in 8.4 +/- 0.8% of thymidine replacement by BrdUrd in tumors. However, bone marrow incorporation was 15.8 +/- 1.1% under these conditions. To improve the ratio of incorporation in the tumor compared to that in the bone marrow, animals were given an infusion of BrdUrd and the pumps were removed. Incorporation of BrdUrd in the bone marrow and intestine decreased rapidly after the infusion was completed. In contrast, there was relatively little change in the incorporation into the tumor after an initial decrease. Based on these data, experiments were performed comparing the effects of 500 microCi iodine-131-labeled 17-1A MoAb alone to the same dose of iodine-131-labeled 17-1A administered 1 day after discontinuation of the infusion of BrdUrd (200 mg/kg/day for 4 days). BrdUrd tended to increase the delay in tumor growth produced by iodine-131-labeled 17-1A administration. CONCLUSIONS: Radiosensitization by BrdUrd in vitro appears to be caused not by cell cycle effects but by increased radiation sensitivity. The in vivo data suggests that BrdUrd improved the efficacy (tumor growth inhibition) of radiolabeled MoAb.

Animals↗
PubMed1994

Influence of cell cycle phase on radiation-induced cytotoxicity and DNA damage in human colon cancer (HT29) and Chinese hamster ovary cells.

We have previously shown that fluorodeoxyuridine (FdUrd) radiosensitizes HT29 human colon carcinoma cells. Since treatment with FdUrd arrests cells at the G1/S-phase interface, a condition associated with increased radiation sensitivity in some cells, it seemed possible that redistribution of cells in the phases of the cell cycle might account for FdUrd-mediated radiosensitization. To begin to test this, HT29 cells were separated by centrifugal elutriation according to cell cycle phase and assessed for radiosensitivity, using a clonogenic assay, and radiation-induced DNA damage, using pulsed-field gel electrophoresis. We found that all of the elutriated fractions (which contained cells enriched in G1, G1/early S, mid to late S or G2/M phase) had the same radiation sensitivity and expressed a similar extent of radiation-induced DNA damage. To determine if the techniques used in this study could detect differences between the radiation sensitivity of cells in different phases of the cell cycle, analogous experiments were carried out using Chinese hamster ovary (CHO) cells. In contrast with the results of experiments with HT29 cells, but in agreement with previous studies, CHO cells separated under the same conditions as were used for HT29 cells showed a marked dependence on cell age of both clonogenic survival and radiation-induced DNA damage. Thus, within the limitations of the purity of separation obtained using elutriation, the radiation sensitivity of HT29 cells does not vary substantially as a function of cell cycle phase. Therefore, it seems unlikely that cell cycle redistribution alone explains the radiation sensitivity produced by exposure to FdUrd.

Animals↗
PubMed1993

Resistance to fluorodeoxyuridine-induced DNA damage and cytotoxicity correlates with an elevation of deoxyuridine triphosphatase activity and failure to accumulate deoxyuridine triphosphate.

Deoxyuridine triphosphate (dUTP) misincorporation and uracil misrepair have long been implicated in fluoropyrimidine-induced DNA damage; however, the enzymatic activities responsible for these lesions have not been previously identified as critical determinants of overall sensitivity to the antitumor effects of these agents. The purpose of this study was to determine whether differences in uracil misincorporation/misrepair could account for the difference in sensitivity to fluorodeoxyuridine (FdUrd)-induced cytotoxicity and DNA damage in 2 human colorectal tumor cell lines having identical sensitivities to FdUrd-induced thymidylate synthase inhibition. Compared to HT29 cells, SW620 cells were resistant to both cytotoxicity and induction of DNA double-strand breaks, as assessed by pulse field gel electrophoresis. Alkaline elution experiments demonstrated that this resistance coincided with delayed induction of DNA single-strand breaks on parental DNA and, to a lesser extent, on nascent DNA. Following treatment with FdUrd for 24 h, HT29 cells accumulated 904 +/- 273 pmol deoxyuridine triphosphate (dUTP)/10(7) cells, whereas SW620 cells accumulated 20 +/- 7 pmol dUTP. Consistent with this difference in extent of dUTP accumulation was the observation that deoxyuridine triphosphatase levels in SW620 cellular extracts were 4.4-fold higher than in HT29 extracts. The ability to accumulate dUTP, intracellular deoxyuridine triphosphatase activity, and extent of DNA damage appear to be important determinants for predicting the response to FdUrd treatment in these cell lines.

Cell Survival↗
PubMed1993

The use of biphasic linear ramped pulsed field gel electrophoresis to quantify DNA damage based on fragment size distribution.

PURPOSE: The development of biphasic linear pulse ramping gel electrophoresis has permitted resolution of DNA fragments from 200 Kbp to 6 Mbp in a single gel. We used this technique to measure radiation-induced DNA damage based on fragment size. METHODS AND MATERIALS: Human colon cancer cells (HT29 and LS174T) and Chinese hamster ovary cells were embedded in agarose, deproteinized, irradiated with 5-80 Gy, and assessed for DNA double strand breakage using pulsed field gel electrophoresis. The frequency of DNA double strand breakage determined using a previously published method was compared to the breakage frequency calculated using the fragment size distribution. RESULTS: Both methods produced similar estimates for breakage frequency of approximately 5 x 10(-9) breaks Gy-1 bp-1. CONCLUSIONS: These findings suggest that biphasic linear pulse ramping gel electrophoresis can yield a quantitative estimate of DNA fragment distribution resulting from irradiation. The ability to quantify the distribution of DNA fragment sizes produced by irradiation should yield important information concerning the mechanisms of both DNA double strand break induction and repair.

Animals↗
PubMed1993

Use of Veff and iso-NTCP in the implementation of dose escalation protocols.

PURPOSE: This report investigates the use of a normal tissue complication probability (NTCP) model, 3-D dose distributions, and a dose volume histogram reduction scheme in the design and implementation of dose escalation protocols for irradiation of sites that are primarily limited by the dose to a normal tissue which exhibits a strong volume effect (e.g., lung, liver). METHODS AND MATERIALS: Plots containing iso-NTCP contours are generated as a function of dose and partial volume using a parameterization of a NTCP description. Single step dose volume histograms are generated from 3-D dose distributions using the effective-volume (Veff) reduction scheme. In this scheme, the value of Veff for each dose volume histogram is independent of dose units (Gy, %). Thus, relative dose distributions (%) may be used to segregate patients by Veff into bins containing different ranges of Veff values before the assignment of prescription doses (Gy). The doses for each bin of Veff values can then be independently escalated between estimated complication levels (iso-NTCP contours). RESULTS AND CONCLUSION: Given that for the site under study, an investigator believes that the NTCP parameterization and the Veff methodology at least describe the general trend of clinical expectations, the concepts discussed allow the use of patient specific 3-D dose/volume information in the design and implementation of dose escalation studies. The result is a scheme with which useful prospective tolerance data may be systematically obtained for testing the different NTCP parameterizations and models.

Humans↗
PubMed1993

Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma.

PURPOSE: To determine the potential advantage of combining halogenated pyrimidine radiosensitization and continuous low dose rate irradiation in human malignant glioma. METHODS AND MATERIALS: An established glioma line (U-251) was incubated with 5-bromo-2-doxyuridine (BrdUrd) at clinically achievable concentrations at three dose rates of interest--100 cGy/min (typical of external beam therapy), 43 cGy/hr (typical of temporary afterloaded implants), and 12 cGy/hr (typical of permanent implants). RESULTS: After exposure to 1 microM BrdUrd, the greatest enhancement ratio was seen at the 12 cGy/hr dose rate, implying a BrdUrd induced inverse dose rate effect independent of a G2M block. Under these conditions, the mean inactivation dose after 1 microM BrdUrd exposure was equivalent for 100 cGy/min and 12 cGy/hr. CONCLUSION: These results support the use of halopyrimidines as sensitizers of temporary afterloaded and permanent implants.

Bromodeoxyuridine↗
PubMed1993

Comparison of 131I- and 90Y-labeled monoclonal antibody 17-1A for treatment of human colon cancer xenografts.

The choice of radionuclide remains an important question in clinical radioimmunotherapy. Therefore, a study was initiated, using an in vivo model system, to assess the relative merits of 131I- and 90Y-labeled 17-1A monoclonal antibody as therapeutic agents in the treatment of colon cancer. 131Iodine- and 90Y-labeled 17-1A were assessed in animal therapy trials using athymic nude mice bearing LS174T human colon cancer xenografts. 131Iodine-labeled 17-1A decreased tumor growth in a dose-dependent fashion without lethality. In contrast, the doses of 90Y-labeled 17-1A which were required to produce a significant increase in tumor doubling time also caused marked toxicity. Although similar tumor growth inhibition was produced by 250 microCi 90Y- and 150 microCi 131I-labeled 17-1A, Medical Internal Radiation Dose calculations based on biodistribution data estimated that the dose delivered by 90Y was greater than that delivered by 131I. To investigate this discrepancy, 3-dimensional dose distributions within LS174T tumors were assessed using autoradiography and 3-dimensional calculational techniques. It was found that a greater fraction of the dose was deposited in the tumor after treatment with 131I- compared to 90Y-labeled 17-1A. When the Medical Internal Radiation Dose calculations were adjusted using the 3-dimensional dose distributions, 250 microCi of 90Y- and 150 microCi of 131I-labeled 17-1A were found to deliver similar tumor doses. These studies suggest that 131I-labeled 17-1A is superior to 90Y-labeled 17-1A, since 131I-labeled antibody produced less hematological and animal toxicity and was more effective at inhibiting LS174T tumor growth than 90Y-labeled antibody across the range of radionuclide doses tested. Furthermore, they suggest that it will be necessary to perform 3-dimensional dose calculations in addition to Medical Internal Radiation Dose calculations in order to interpret tumor dosimetry.

Adenocarcinoma↗
PubMed1993

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.

Actuarial Analysis↗