Biomedical subjects

T S Lawrence

Publications and source records attributed to T S Lawrence.

At least 55 records · Page 3Linked to original sources

PubMed1998

Secretion and properties of the large and small lobes of the channel-forming toxin aerolysin.

Aerolysin is a dimeric protein secreted by Aeromonas spp. that binds to glycosylphosphatidylinositol-anchored receptors on target cells and becomes insertion competent by oligomerizing. The protein comprises two lobes joined by a short arm. The large lobe is thought to be responsible for channel formation, whereas the small lobe is believed to stabilize the dimer, and it may also contain the receptor binding site. We cloned and expressed the DNA for both lobes of the toxin separately and together in A. salmonicida. The large lobe produced alone was secreted, although more poorly than native protein. The small lobe with the arm produced by itself was not secreted. When the large lobe without the arm was co-produced with the small lobe with the arm, both were secreted, and they co-purified as a stoichiometric complex. Analytical ultracentrifugation showed that they form a heterotetramer corresponding to the native dimer. The purified product was nearly as active as aerolysin, but lost activity and became trypsin sensitive above 25 degreesC. The large lobe with the arm was also purified. It was shown to be monomeric, confirming that the small lobe is responsible for dimer stabilization. The large lobe had very low channel-forming activity, although it was correctly processed by trypsin, and it could form stable oligomers. Surprisingly, the large lobe was found to bind to several glycosylphosphatidylinositol-anchored proteins, indicating that it contains at least part of the receptor-binding domain.

Aeromonas↗

PubMed1998

Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model.

PURPOSE: To attempt to safely escalate the dose of radiation for patients with intrahepatic cancer, we designed a protocol in which each patient received the maximum possible dose while being subjected to a 10% risk of radiation-induced liver disease (RILD, or radiation hepatitis) based on a normal tissue complication probability (NTCP) model. We had two hypotheses: H1; with this approach, we could safely deliver higher doses of radiation than we would have prescribed based on our previous protocol, and H2; the model would predict the observed complication probability (10%). PATIENTS AND METHODS: Patients with either primary hepatobiliary cancer or colorectal cancer metastatic to the liver and normal liver function were eligible. We used an NTCP model with parameters calculated from our previous patient data to prescribe a dose that subjected each patient to a 10% complication risk within the model. Treatment was delivered with concurrent hepatic arterial fluorodeoxyuridine (HA FUdR). Patients were evaluated for RILD 2 and 4 months after the completion of treatment. RESULTS: Twenty-one patients completed treatment and were followed up for at least 3 months. The mean dose delivered by the current protocol was 56.6 +/- 2.31 Gy (range, 40.5 to 81 Gy). This dose was significantly greater than the dose that would have been prescribed by the previous protocol (46.0 +/- 1.65 Gy; range, 33 to 66 Gy; P < .01). These data are consistent with H1. One of 21 patients developed RILD. The complication rate of 4.8% (95% confidence interval, 0% to 23.8%) did not differ significantly from the predicted 8.8% NTCP (based on dose delivered) and excluded a 25% true incidence rate (P < .05). This finding supports H2. CONCLUSION: Our results suggest that an NTCP model can be used prospectively to safely deliver far greater doses of radiation for patients with intrahepatic cancer than with previous approaches. Although the observed complication probability is within the confidence intervals of our model, it is possible that this model overestimates the risk of complication and that further dose escalation will be possible. Additional follow-up and accrual will be required to determine if these higher doses produce further improvements in response and survival.

Antimetabolites, Antineoplastic↗

PubMed1997

A phase I trial of hepatic arterial bromodeoxyuridine and conformal radiation therapy for patients with primary hepatobiliary cancers or colorectal liver metastases.

PURPOSE: We have previously found that conformal radiation therapy (RT) and hepatic arterial fluorodeoxyuridine was associated with durable responses and long-term survival for patients treated for nondiffuse primary hepatobiliary tumors and colorectal liver metastases. Further improvements in hepatic control may result from the addition of selective radiosensitization using bromodeoxyuridine (BrdU) infused through the hepatic artery (HA) concurrently with RT. This is a Phase I study of escalating doses of HA BrdU combined with our standard hepatic RT. METHODS AND MATERIALS: Patients with unresectable primary hepatobiliary cancer or colorectal liver metastases were treated with concurrent HA BrdU and conformal RT (1.5 Gy per fraction, twice a day). Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of RT (24, 48, or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. HA BrdU was escalated in standard Phase I fashion with at least three patients receiving each combination of RT dose and BrdU dose. The starting dose of HA BrdU was 10 mg/kg/day, with two potential escalations to a maximum of 25 mg/kg/day (the maximum tolerable dose of HA BrdU when given alone on this same schedule). Grade > or = 3 toxicity was considered dose limiting. Patients receiving 24 Gy had one cycle of HA BrdU, while those receiving either 48 or 66 Gy had two cycles. Patients were followed for toxicity, complications, and response (when evaluable). RESULTS: A total of 41 patients (18 with colorectal liver metastases, 16 with cholangiocarcinoma and 7 with hepatoma) were treated. Five patients were removed from the protocol (three had HA catheter complications, one developed atrial fibrillation, and one was removed due to recurrent Grade 4 toxicity), although all five are included for toxicity purposes. Dose-limiting toxicity was primarily thrombocytopenia and there was no obvious relationship with the RT dose. Only 2 of 17 cycles given at 25 mg/kg/day had Grade > or = 3 toxicity. Complications developed in four patients, including one patient with radiation-induced liver disease. Response rates were not improved compared to our previous experience. CONCLUSIONS: The appropriate dose of HA BrdU for Phase II evaluation is 25 mg/kg/day. Neither the hepatic parenchyma nor the gastrointestinal mucosa appeared to be sensitized by this method of BrdU administration. It is anticipated that these, or still newer methods of therapy, can improve treatment results in the near future.

Adult↗

PubMed1997

Potential benefits of eliminating planning target volume expansions for patient breathing in the treatment of liver tumors.

PURPOSE: To investigate potential benefits derived from reduction or elimination of planning target volume (PTV) margins associated with patient breathing through examination of hepatic tumors treated with conformal therapy. METHODS AND MATERIALS: We reviewed the treatment plans of 50 patients who had previously received conformal partial organ liver irradiation for treatment of hepatic malignancies. PTVs for these plans included expansions (1-2 cm) for patient breathing. Data consisted of the three-dimensional dose distributions computed for the conformal plans generated for these volumes, and also for plans using identical beam arrangements but smaller block margins to treat planning target volumes that did not include the expansions for breathing. We calculated effective volumes (V(eff)) and normal tissue complication probabilities (NTCP) using dose-volume histograms for normal liver and analyzed changes in: V(eff), NTCP at the prescription dose, doses associated with selected NTCP levels, and tumor control probabilities (TCP) at these new dose levels. RESULTS: Elimination of the patient breathing components of the PTVs for these conformal treatments of liver tumors: (a) decreased the average V(eff) by 5%; (b) decreased the average predicted NTCP at the prescription (isocenter) dose used to treat the patients by 4.5%; (c) increased the average target volume (isocenter) dose associated with low (1-10%) predicted normal liver NTCP by 6-8 Gy, which corresponded to (d) a predicted average 6-7% increase in TCP for aggressive liver tumors. Plans with PTV expansions for breathing that occurred mostly within the liver showed greatest potential benefit. CONCLUSIONS: Elimination of the margin added to hepatic target volumes for patient ventilation could lead to clinically meaningful increases in dose without increasing the predicted frequency of complications.

Humans↗

PubMed1997

Protection of herpes simplex virus thymidine kinase-transduced cells from ganciclovir-mediated cytotoxicity by bystander cells: the Good Samaritan effect.

Although considerable attention has been directed in the field of gene therapy toward elucidating the mechanism by which a transduced cell could kill a bystander cell, little is known about how bystander cells may affect transduced cells. We hypothesized that bystander cells, particularly if they were capable of gap junctional communication, could protect cells transduced with the herpes simplex virus thymidine kinase (HSV-TK) from ganciclovir (GCV)-induced cytotoxicity. To test this hypothesis, we used a rat hepatocyte cell line (WB) that can carry out efficient gap junctional communication, a WB clone transduced with HSV-TK (WB-TK), and a communication-incompetent subclone of WB cells (aB1). We cocultured WB-TK cells with either WB or aB1 cells, treated them with GCV, and then plated the cells into selective media that permitted us to quantify independently the surviving fraction of WB-TK cells or bystander cells. We found that WB bystander cells conferred up to a 1000-fold protection on WB-TK cells treated with GCV. aB1 cells conferred detectable, but significantly less, protection. These findings demonstrate that herpes simplex virus thymidine kinase-transduced cells can be significantly protected by bystander cells, particularly those that can carry out gap junctional communication. Whether this "Good Samaritan" effect improves the overall efficacy of gene therapy, by prolonging the survival of the source of toxic metabolites, or decreases effectiveness by increasing the survival of transduced cells will need to be determined in vivo.

Animals↗

PubMed1997

A phase I trial of intravenous bromodeoxyuridine and radiation therapy for pancreatic cancer.

PURPOSE: Improved radiosensitization may lead to improved results of treatment for pancreatic cancer. This Phase I trial was designed to determine the maximum tolerable dose of intravenous bromodeoxyuridine (BrdUrd) when given in an alternating weekly fashion with radiation therapy for patients with pancreatic cancer. METHODS AND MATERIALS: Patients with resected or locally unresectable pancreatic cancer were eligible if distant metastases were not present. A continuous intravenous infusion of BrdUrd was given on weeks 1, 3, 5, and 7. Twice a day radiation therapy (1.5 Gy per fraction) was given on weeks 2, 4, 6, and 8 to the pancreas/pancreatic bed (total dose 60 Gy) and draining regional lymph nodes (total dose 45 Gy). The starting dose of BrdUrd was 800 mg/m2/day with a planned escalation to 1000 mg/m2/day if at least six out of eight patients were without Grade > or = 3 toxicity. Patients were assessed weekly for toxicity, and were followed every 3 months after treatment for complications and survival. RESULTS: Fifteen patients with resected (six) or unresectable (nine) pancreatic cancer were enrolled. One patient failed to complete therapy due to tumor progression. One of 11 patients treated with 800 mg/m2/day had a Grade 3 toxicity, while Grade 3 or 4 toxicity was found in all 3 patients receiving 1000 mg/m2/day. The dose-limiting toxicities were hematologic. The acute gastrointestinal toxicity was minimal. Two patients, including one with unresectable disease, were without evidence of disease during exploration for complications (ulcer, small bowel obstruction). CONCLUSIONS: The recommended dose of BrdUrd for Phase II study is 800 mg/m2/day. The gastrointestinal mucosa did not appear to be sensitized by this method of BrdUrd administration. The presence of a pathologic complete response is encouraging. Further improvements in radiosensitization are possible and may lead to improved local control.

Aged↗

PubMed1997

Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy for primary hepatobiliary cancers.

PURPOSE: We have previously shown that conformal radiation therapy (RT) combined with hepatic artery (HA) fluorodeoxyuridine (FdUrd) had encouraging hepatic control and survival rates for patients with nondiffuse primary hepatobiliary malignancies. With longer follow-up, we were particularly interested if long-term hepatic control and disease-free survival could be achieved, and if late hepatic complications due to radiation therapy were observed. METHODS AND MATERIALS: Patients with unresectable primary hepatobiliary cancer were treated with concurrent HA FdUrd (0.2 mg/kg/day) and conformal RT (1.5-1.65 Gy per fraction, twice a day), directed only to the liver abnormalities. Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of radiation (48 or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. Patients were followed routinely for response, patterns of failure, long-term toxicity, and survival. The median potential follow-up was 54 months. RESULTS: A total of 22 patients (11 with hepatocellular carcinoma and 11 with cholangiocarcinoma) were treated. There were 10 objective responses in the 11 evaluable patients. The overall freedom from hepatic progression at more than 2 years was about 50%. The median survival was 16 months with an actuarial 4-year survival of about 20%. Gastrointestinal bleeding was the most common long-term toxicity. Late hepatic toxicity was not observed; in fact, hypertrophy of the untreated liver was seen. CONCLUSIONS: Combined conformal RT and HA FdUrd can produce long-term freedom from hepatic progression and survival in patients with unresectable, nondiffuse primary hepatobiliary malignancies. There were no long-term liver complications observed.

Adult↗

PubMed1997

Effect of p53 overexpression on radiation sensitivity of human colon cancer cells.

Substantial controversy surrounds our understanding of the effect of p53 status on radiation sensitivity. To assess directly the role of p53 expression on radiation sensitivity, we chose a conditional expression system using a temperature-sensitive murine p53 that permitted each cell line to act as its own control. We found that the conditional expression of wild type p53 induced cell death (both apoptotic and nonapoptotic), changes in cell cycle distribution (arrest in G1 and G2, which resulted in a marked depletion of S-phase cells and an increase in the fraction of cells in G2), and an increase in the radiation resistance of G1 cells. These counterbalancing effects resulted in no significant effect on overall radiosensitivity. These findings demonstrate that wild type p53 function can produce a variety of effects that can modulate radiation sensitivity and may explain why p53 status alone has not been a strong predictor of radiosensitivity.

Apoptosis↗

PubMed1997

Prevention of fluorodeoxyuridine-induced cytotoxicity and DNA damage in HT29 colon carcinoma cells by conditional expression of wild-type p53 phenotype.

We have examined the effects of conditionally expressing wild-type p53 activity in HT29 cells on DNA damage and cytotoxicity caused by exposure to fluorodeoxyuridine (FdUrd). Expression of wild-type p53 phenotype for 24 hr before FdUrd treatment provided HT29 cells with virtually complete protection from cytotoxicity caused by this drug. In addition, wild-type p53 expression also prevented FdUrd-induced DNA double-strand breaks and, unexpectedly, single-strand breaks in parental (mature) DNA. Temporary expression of wild-type p53 activity in the absence of drug treatment caused some loss of clonogenicity, although the magnitude of this cytotoxic effect was small compared with the level of cell kill obtained by treatment with cytotoxic drugs for similar periods of time, indicating that HT29 cells are not highly sensitive to induction of programmed cell death by wild-type p53. Because these observations conflict with previously suggested models for FdUrd-induced damage to parental DNA, we propose an alternative model to explain how incorporation of uracil into nascent DNA might result in single-strand breaks in the opposite (parental) strand and how these breaks might be converted to the double-strand breaks that produce cell death.

Animals↗

PubMed1997

Gemcitabine-mediated radiosensitization.

Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes our preclinical and early clinical studies designed to elucidate the mechanism of action of gemcitabine and phase I trials conducted to determine the optimal dose and schedule. Gemcitabine was found to radiosensitize a wide variety of human tumor cells in culture, particularly cells derived from cancers of the pancreas, breast, and head and neck. Radiosensitization occurs under conditions in which cells demonstrate concurrent redistribution into S phase and deoxyadenosine triphosphate pool depletion. These conditions can be produced by either a long (24-hour) exposure to a low concentration of gemcitabine (10 nmol/L) or by a brief (2-hour) treatment with higher but clinically relevant concentrations (100 nmol/L to 3 micromol/L). Under the latter conditions, sensitization can be detected 4 hours after treatment and last for up to 2 days. These preclinical data were useful in the design of a gemcitabine dose escalation trial in combination with standard radiation for patients with unresectable head and neck cancer. Although this trial is not yet complete, the starting dose of gemcitabine, which is far below the maximum tolerated dose for the drug when used alone, significantly potentiates the toxicity of radiation treatment. We conclude that gemcitabine is a promising radiation sensitizer that needs to be developed cautiously if excessive normal tissue toxicity is to be avoided.

Carcinoma, Squamous Cell↗

PubMed1997

Delayed radiosensitization of human colon carcinoma cells after a brief exposure to 2',2'-difluoro-2'-deoxycytidine (Gemcitabine).

We have shown that 2',2'-difluoro-2'-deoxycytidine (dFdCyd; Gemcitabine), a deoxycytidine analogue, is a potent radiation sensitizer when cells are exposed to it continuously for >16 h in low concentrations (in the range of 10 nM). However, the most common method of clinical administration is by short-term infusion (30-90 min). Therefore, we wished to determine under what conditions dFdCyd could produce radiosensitization after a relatively brief exposure to drug. We hypothesized that the long half-life of the phosphorylated metabolites of dFdCyd would produce long-lasting dNTP pool perturbation, particularly dATP pools, leading to radiosensitization hours or even days after the drug was removed from the medium. We tested this hypothesis by exposing HT29 human colon cancer cells for 2 h to clinically relevant concentrations of dFdCyd, removing the drug from the medium, and assessing radiation sensitivity up to 72 h later. We found that 100 nM dFdCyd, which was noncytotoxic, radiosensitized HT29 cells up to 48 h after drug removal. During this period, there was an increase in the S phase population, whereas by 72 h after drug removal, the cell cycle distribution resembled that seen under control conditions. dATP pools remained depleted throughout the 72-h period after drug treatment. This study supports the hypothesis that radiosensitization occurs in cells that are replicating DNA in the presence of perturbed dNTP pools. Furthermore, they may be useful in the design of rational clinical trials using dFdCyd as a radiation sensitizer.

Antimetabolites, Antineoplastic↗

PubMed1996

Radiosensitizing nucleosides.

Chemotherapeutic drugs that perturb nucleotide metabolism have the potential to produce substantial sensitization of tumor cells to radiation treatment. The process is called radiosensitization, and the agents that induce it are called radiosensitizers. The clinical effectiveness of fluoropyrimidines as radiosensitizers has been proven in multiple randomized trials. Thymidine analogues and hydroxyurea also appear to produce clinically relevant increases in radiation sensitivity. Recent laboratory investigations have identified difluorodeoxycytidine (gemcitabine) and fludarabine as promising agents to use in combination with radiation. Until recently, little was known about how the biochemical changes caused by these drugs produced radiosensitization. However, advances in related fields, such as cell cycle checkpoint control, have permitted the development of a hypothesis that may explain the relative tumor selectivity of fluoropyrimidine-mediated radiosensitization. In addition, recent findings suggest that the rational manipulation of drug administration schedules and the use of combinations of radiosensitizers have the potential to improve the efficacy of the currently used agents and to establish the benefit of new ones.

Animals↗

PubMed1996

Preclinical studies of chemotherapy and radiation therapy for pancreatic carcinoma.

The use of radiation therapy combined with 5-fluorouracil (5-FU) in the treatment of pancreatic cancer has been well established. It has been hypothesized that any benefit from combined 5-FU and radiation has been due to radiosensitization. Improved therapy could result from a better understanding of the mechanism of radiosensitization and the development of compounds capable of providing better radiosensitization. This article reviews preclinical findings on the mechanism of cytotoxicity and radiosensitization for 5-FU, fluorodeoxyuridine, thymidine analogs, and gemcitabine (2',2'-difluorodeoxycytidine) and discusses the clinical implications of these findings.

Antimetabolites, Antineoplastic↗

PubMed1996

Uncertainties in CT-based radiation therapy treatment planning associated with patient breathing.

PURPOSE: To evaluate uncertainties associated with treatment-planning computed tomography (CT) data obtained with the patient breathing freely. METHODS AND MATERIALS: Patients with thoracic or abdominal tumors underwent a standard treatment-planning CT study while breathing quietly and freely, followed by CT scans while holding their breath at normal inhalation and normal exhalation. Identical treatment plans on all three CT data sets for each patient pointed out differences in: (a) radiation path lengths; (b) positions of the organs; (c) physical volumes of the lung, liver, and kidneys; (d) the interpretation of plan evaluation tools such as dose-volume histograms and normal tissue complication probability (NTCP) models; and (e) how well the planning CT data set represented the average of the inhalation and exhalation studies. RESULTS: Inhalation and exhalation data differ in terms of radiation path length (nearly one quarter of the cases had path-length differences > 1 cm), although the free breathing and average path lengths do not exhibit large differences (0-9 mm). Liver and kidney movements averaged 2 cm, whereas differences between the free breathing and average positions averaged 0.6 cm. The physical volume of the liver between the free breathing and static studies varied by as much as 12%. The NTCP calculations on exhale and inhale studies varied from 3 to 43% for doses that resulted in a 15% NTCP on the free-breathing studies. CONCLUSION: Free-breathing CT studies may improperly estimate the position and volume of critical structures, and thus may mislead evaluation of plans based on such volume dependent criteria such as dose-volume histograms and NTCP calculations.

Abdominal Neoplasms↗

PubMed1996

Fluoropyrimidine-mediated radiosensitization depends on cyclin E-dependent kinase activation.

Fluoropyrimidines radiosensitize human colon cancer cells that progress into S phase in the presence of drug (M.A. Davis, H-Y. Tang, J. Maybaum, and T.S. Lawrence. Int. J. Radiat. Biol. 67. 509-512, 1995). We hypothesized that progression occurs in cells that generate elevated levels of cyclin E-dependent kinase activity despite the presence of the fluoropyrimidine. To test this hypothesis, we treated HT29 and SW620 human colon cancer cells with fluorodeoxyuridine under conditions that produced nearly complete inhibition of thymidylate synthase but which sensitized only the HT29 cells. We found that, whereas HT29 cells progressed into S phase and demonstrated increased cyclin E-dependent kinase activity, SW620 cells arrested just past the G1-S boundary and showed no change in kinase activity. Because these cell lines have the same p53 mutation, these findings suggest that there is a p53-independent G1-S checkpoint that mediates radiosensitization produced by fluorodeoxyuridine.

Cell Cycle↗

PubMed1996

Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine.

PURPOSE: We have reported that the deoxycytidine analog 2',2'difluoro-2'-deoxycytidine (dFdCyd) is a potent radiosensitizer of HT29 human colon cancer cells probably through its effects on intracellular deoxyribonucleotide (dNTP) pools. Because dFdCyd has activity against pancreatic cancer in clinical trials, we wished to determine if dFdCyd would radiosensitize human pancreatic cancer cells. METHODS AND MATERIALS: We assessed the effect of dFdCyd on radiation sensitivity of two human pancreatic cancer cell lines, Panc-1 and BxPC-3. To begin to investigate the mechanism of sensitization, we determined the effect of dFdCyd on dNTP pools and cell cycle distribution. RESULTS: We found that dFdCyd produced radiation enhancement ratios of 1.7-1.8 under noncytotoxic conditions in both cell lines. Sensitization was not associated with intracellular levels of 2',2'-difluoro-2'-deoxycytidine triphosphate, the cytotoxic metabolite of dFdCyd, but occurred when dATP pools were depleted below the level of approximately 1 micromolar. Although both cell lines showed substantial cell cycle redistribution after drug treatment, the flow cytogram of the BxPC-3 cells would not, by itself, be anticipated to result in increased radiation sensitivity. CONCLUSIONS: These findings demonstrate that dFdCyd is a potent radiation sensitizer of human pancreatic cancer cells and support the development of a clinical protocol using combined dFdCyd and radiation therapy in the treatment of pancreatic cancer.

Adenosine Triphosphate↗

PubMed1996

Effect of irradiation on bromodeoxyuridine incorporation in human colon cancer xenografts.

PURPOSE: Although we have characterized the incorporation of the thymidine analog bromodeoxyuridine (BrdUrd) into human colon cancer xenografts under a wide variety of conditions, little is known about the effect of radiation on subsequent incorporation. Because clinical protocols include, as one component, BrdUrd administration after radiation, it was important to confirm that irradiation did not prevent subsequent BrdUrd incorporation. Therefore, we studied the effect of irradiation on BrdUrd incorporation into HT29 human colon cancer xenografts. METHODS AND MATERIALS: Two types of experiments were performed. In the first, the effect of radiation on subsequent incorporation was measured. Tumors received doses of 0, 2, 8, and 12 Gy, animals were infused with BrdUrd for 4 days, and incorporation was assessed at the end of the infusion. In the second, the effect of radiation on the elimination of BrdUrd from tumors was determined. Animals were infused with BrdUrd, tumors were irradiated with either 0 or 12 Gy, and tumor incorporation of BrdUrd was measured 1 and 3 days later. RESULTS: Radiation affected neither the incorporation into nor the elimination of BrdUrd from human tumor xenografts. CONCLUSIONS: These findings support the feasibility of clinical trials interdigitating BrdUrd infusion and radiation.

Animals↗

PubMed1996

Pelvic radiation therapy combined with hepatic artery chemotherapy for resected rectal carcinoma with liver metastases.

PURPOSE: Patients with hepatic metastases from rectal cancer treated with hepatic artery (HA) chemotherapy have a life expectancy great enough to be at risk for pelvic failure. Therefore, a treatment plan was developed for patients with resected rectal cancer and unresectable hepatic metastases, when the pathologic features of transmural invasion and perirectal lymph node metastases were present. Treatment consisted of concurrent pelvic radiation therapy (RT) and HA 5-fluorouracil (FUra), as systemic levels of FUra are achievable with HA administration, followed by HA fluorodeoxyuridine (FdUrd). METHODS AND MATERIALS: Fifteen patients were offered combined pelvic RT and HA FUra. Radiation was given to an initial dose of 45 Gy to the pelvis, followed by boost treatment for an additional 5.4-10.8 Gy. Concurrent HA chemotherapy was given using FUra or FUra/leucovorin administered in two cycles of 14 days for each cycle. If HA chemotherapy could not be done, then intravenous FUra was given during RT. Following completion of RT and HA FUra, patients were evaluated for treatment with HA FdUrd. RESULTS: Eleven patients received concurrent HA FUra or FUra/leucovorin and pelvic RT. Of these, six continued to receive HA FdUrd after completion of RT, as five patients were found to have progressive hepatic disease. Four patients could not have therapy as outlined, but did receive pelvic RT with concurrent intravenous FUra (two patients), FUra/leucovorin (one patient), or sequential HA FUra (one patient). There were four pelvic recurrences at 1, 4, 14, and 17 months after RT. One was the first site of progression, two occurred simultaneously with other failure, and one occurred after hepatic progression. The liver was the most frequent site of first progression (alone in seven patients; as a component of progression in four patients). Treatment was well tolerated with three Grade > or = 3 toxicities. The median survival was 14 months. CONCLUSIONS: These data support the hypothesis that patients with metastatic rectal cancer are also at risk for pelvic recurrence. The frequency of hepatic progression supports continued aggressive therapy directed to this site. As systemic and regional therapy of metastatic rectal cancer improves, we anticipate that more patients will be at risk for a pelvic recurrence, making it increasingly important to explore the role of pelvic radiation therapy despite the presence of metastatic disease.

Adult↗