To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of ...IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma.
Patients were required to have biopsy-proven malignant glioma. Patients received 100 (
n = 4), 200 (
n = 3), 300 (
n = 3), 400 (
n = 6), 500 (
n = 4), 625 (
n = 5), or 781 (
n = 6) mg/m
2/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost 2.0 Gy for 5 Saturdays). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used.
Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (
n = 3), thrombocytopenia (
n = 3), and elevated liver function studies (
n = 3). The maximal tolerated dose was 625 mg/m
2/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 μM).
In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m
2/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.
The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity ...of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS.
Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m(2) and either SD ifosfamide (1.5 g/m(2)/d, days 1 through 4) or HD ifosfamide (3.0 g/m(2), days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity.
The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm.
When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.
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 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.
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.
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.
Cutaneous angiosarcoma of the scalp Pawlik, Timothy M.; Paulino, Augusto F.; Mcginn, Cornelius J. ...
Cancer,
15 October 2003, Letnik:
98, Številka:
8
Journal Article
Chemotherapeutic drugs that perturb nucleotide metabolism have the potential to produce substantial sensitization of tumor cells to radiation treament. The clinical effectiveness of fluoropyrimidines ...as radiosensitizers has been proven in multiple randomized trials. The development of oral fluoropyrimidine formulations may allow protracted exposure without the need for indwelling intravenous lines and infusion pumps. These agents may also provide more selective radiosensitization and are likely to be widely incorporated into chemoradiotherapy regimens for patients with gastrointestinal malignancie. Gemcitabine has been well studied in the laboratory, with respect to mechanisms of radiosensitization and strategies that may increase the therapeutic index. Clinical trials based on these studies are now defining the role of this radiosensitizing nucleoside. Issues regarding the use oral fluoropyrimidines and gemcitabine need to be viewed in the context of both local and distant disease control, given the potential systemic activity of these agents.
Radiosensitization by gemcitabine Lawrence, T S; Eisbruch, A; McGinn, C J ...
Oncology (Williston Park, N.Y.),
10/1999, Letnik:
13, Številka:
10 Suppl 5
Journal Article
Recenzirano
Gemcitabine is a potent radiosensitizer in both laboratory studies and in the clinic. Initial laboratory studies showed that gemcitabine radiosensitizes a wide variety of rodent and human tumor cells ...in culture. Maximum radiosensitization occurs in cells that demonstrate concurrent redistribution into S phase and d-adenosine triphosphate pool depletion. Although the mechanism of sensitization is not yet clear, recent evidence from our laboratory suggests that gemcitabine lowers the threshold for radiation-induced apoptosis. Our preclinical data were used to design gemcitabine dose-escalation trials in combination with standard radiation for patients with unresectable head and neck cancer and pancreatic cancer. In head and neck cancer, we have found that gemcitabine doses far below the maximum tolerated dose for the drug when used alone significantly potentiate the toxicity of treatment. Comparatively, normal tissue sensitization has not been as marked in the treatment of pancreatic tumors. These findings have led us to conduct experiments using an animal model to improve the therapeutic index of treatment. We conclude that gemcitabine is a promising radiation sensitizer that will need to be developed cautiously if excessive normal tissue toxicity is to be avoided.
The feasibility of reducing overall treatment time by 2 weeks in the curative radiotherapeutic management of head and neck cancer patients is reported in a pilot trial of Hyperfractionated, ...Accelerated Radiotherapy with Dose Escalation (HARDE). This regimen prescribes 76 Gy in 5 weeks to definitive head and neck cancer patients, and 65 Gy in 5 weeks to high-risk postoperative patients. The linear quadratic model is used to compare predicted tumor cell kill with HARDE versus that expected with conventional fractionation (CF).
Between January 1991 and March 1992, 40 head and neck cancer patients were treated with HARDE at the University of Wisconsin Comprehensive Cancer Center. Case-matched controls treated with CF were identified from patients treated at the same institution between 1980-1990, based on tumor site, stage, and extent of prior surgery. Individual patient treatment data (total dose, fraction size, overall time) rather than idealized schedule data from each group were analyzed using the linear quadratic model.
Seventy-nine case-matched controls were identified for comparison with HARDE patients. The predicted increase in log cell kill for HARDE patients over case-matched controls was 1.5 and 1.3 logs, respectively, in the definitive and postoperative settings. This difference in log cell kill projects an improvement in locoregional tumor control for HARDE patients of between 10-25%. HARDE patients experience very brisk acute mucosal reactions and moderately prolonged mucosal healing, however, 91% have completed therapy without a treatment break.
A 2-week reduction in overall treatment time for curative head and neck cancer patients is feasible while maintaining doses > 70 Gy. Based on radiobiologic predictions, such treatment intensification may significantly improve rates of locoregional tumor control. However, intensified acute mucosal reactions accompany such accelerated therapy.
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