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H Choy

Publications and source records attributed to H Choy.

68 records · Page 4Linked to original sources
PubMed1996

Preliminary results of a phase I study of weekly paclitaxel infusion in patients with non-small cell lung cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has a broad spectrum of activity, but the optimal schedule has not yet been determined. As a phase-specific agent, more frequent administration theoretically may be more effective. We have previously demonstrated that a weekly schedule of paclitaxel used as a radiation sensitizer is well tolerated by outpatients. We therefore conducted a phase I study of weekly paclitaxel in patients with chemotherapy-naive metastatic non-small cell lung cancer to determine the maximum tolerated dose of this alternative schedule. In all, 26 patients were entered into this study through six paclitaxel dose levels (100, 125, 135, 150, 175, and 200 mg/m2/wk) administered weekly for 6 of 8 weeks. All patients had a performance status of 0 through 2, with a median age of 65 years (age range, 37 to 80 years). Sites of disease included lung, bone, liver, soft tissue, and brain. Of the 26 entered, 24 patients completed the first 8-week cycle and are evaluable for toxicity. Dose-limiting toxicity, which consisted of neutropenia, occurred in four of six patients at 200 mg/m2/wk and in two of six at 175 mg/m2/wk. Only one evaluable patient required admission for febrile neutropenia. Other toxicities included rash, pulmonary infiltrate, myalgia, neuropathy, and alopecia. Nine (38%) of the 24 patients demonstrated objective responses. One patient with stable disease completed 48 weeks of therapy. Others remain in active treatment. We conclude that the maximum tolerated dose of paclitaxel administered for 6 consecutive weeks of an 8-week cycle is 175 mg/m2/wk and is limited principally by neutropenia. The response rate with this schedule is encouraging and merits further investigation.

Adult↗
PubMed1996

Paclitaxel plus carboplatin and concurrent radiation therapy for patients with locally advanced non-small cell lung cancer.

Previously untreated patients with stages IIIA or IIIB non-small cell lung cancer entered this phase II study to evaluate the activity and toxicity of combined paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin and concurrent radiation. Patients received paclitaxel 50 mg/m2/wk as a 1-hour infusion and carboplatin area under the concentration-time curve of 2/wk for 7 weeks with radiation to the primary tumor and regional lymph nodes (44 Gy) followed by a boost to the tumor (22 Gy). In addition, patients received two additional cycles of paclitaxel 200 mg/m2 and carboplatin (area under the concentration-time curve of 6) 3 weeks apart. From March 1995 to February 1996, 23 patients entered the study and their overall response rate (complete plus partial responses) was 82%. The major toxicity was esophagitis. Nine patients (45%) had experienced grades 3 or 4 esophagitis by the end of the 7-week concurrent phase. Seven of the nine patients recovered from the esophagitis within 2 weeks and received the additional two cycles of paclitaxel 200 mg/m2 and carboplatin (area under the concentration-time curve of 6). Only one patient (4%) had grade 4 pneumonitis; this patient also recovered within 2 weeks and received the final two doses of combined chemotherapy. Therapy with paclitaxel, carboplatin, and concurrent radiation is a promising treatment for patients with locally advanced non-small cell lung cancer; it has a high response rate and acceptable toxicity.

Adult↗
PubMed1996

Weekly paclitaxel with and without concurrent radiation therapy: toxicity, pharmacokinetics, and response.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown in vitro and clinical activity against non-small cell lung cancer and astrocytic brain tumors, tumors traditionally thought of as relatively resistant to chemotherapy and radiotherapy. Because of its ability to block dividing cells in the G2/M portion of the cell cycle (the most radiosensitive phase of the cell cycle), paclitaxel is also a potentially potent radiosensitizer. To exploit these and other properties of paclitaxel, we explored a weekly, outpatient administration schedule, with and without concurrent radiation therapy, in patients with non-small cell lung cancer and astrocytic brain tumors. Our experience has shown that weekly outpatient administration is feasible, that remarkably high dose intensities can be achieved with acceptable toxicity, and that the specific dose-limiting toxicity appears to depend on administration schedule, type of concurrent radiotherapy, and certain patient characteristics. Preliminary response data are very encouraging. At the same time, pharmacokinetic studies have suggested possible reasons for our ability to use such exorbitant dose intensities safely, and also have shown that sustained plasma paclitaxel levels above the putative radiosensitizing threshold can be achieved continuously during a 6-week course of radiotherapy. Specific results, dosing recommendations, and plans for future studies are discussed.

Adult↗
PubMed1995

Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors.

BACKGROUND: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but its ability to penetrate malignant tissue in the CNS is inadequately documented. PURPOSE: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. METHODS: Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20,000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. RESULTS: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 microM. CONCLUSIONS: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. IMPLICATIONS: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.

Adult↗
PubMed1995

Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status.

BACKGROUND: The authors assessed cerebrospinal fluid (CSF) flow in patients with carcinomatous meningitis using technetium-99m-DTPA (Tc-99) ventriculography to determine the frequency of flow abnormalities, their reversibility with treatment, and the implications for successful therapy and survival. METHODS: Technetium-99m-DTPA flow studies were performed in 31 patients after placement of Ommaya reservoirs (Baxter, McGaw Park, IL). Two millicuries of Tc-99 were injected into the reservoir. Planar images of the head and entire spine were obtained after 10 and 30 minutes and after 1, 4, 6, and 24 hours. Follow-up studies were performed for 12 patients whose initial studies were abnormal or who developed complications of therapy. RESULTS: In 19 of the 31 patients (61%), ventricular-outlet, spinal, or convexity blocks were identified. In 11 of these 19 patients, focal radiotherapy to the site of the block restored normal flow. Survival among patients with initially normal, abnormal but correctable, and abnormal but uncorrectable CSF flow differed significantly (6.9, 13.0, and 0.7 months respectively; P < 0.001). Some patients who were treated intrathecally despite abnormal CSF flow experienced drug-related toxicity. CONCLUSIONS: Cerebrospinal fluid-flow blocks are common in patients with carcinomatous meningitis and may occur at the skull base, in the spinal canal, and over the convexities. These flow abnormalities often can be corrected with appropriately directed radiotherapy. If untreated, CSF tumor progression (protected site effect), neurotoxicity (high concentration effect), and systemic toxicity (reservoir effect) can occur, resulting in shortened survival and treatment-related morbidity. Therefore, intrathecal chemotherapy should be preceded by a radionuclide flow study and should be delayed if abnormal flow is documented until appropriate radiotherapy reestablishes normal flow.

Adolescent↗
PubMed1995

Concurrent paclitaxel and thoracic radiation for advanced non-small cell lung cancer.

A phase I trial of paclitaxel therapy, administered as a weekly 3-h infusion for 6 weeks with concurrent daily thoracic radiation to patients with advanced or medically inoperable non-small cell lung cancer, was performed. Paclitaxel was escalated in increments of 10 mg/m2/week in successive cohorts of three new patients as tolerated, starting at 10 mg/m2/week. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy over 4 weeks), followed by a boost to the primary tumor (20 Gy in 2 weeks). Twenty-seven patients entered this study through seven dose levels of paclitaxel ranging from 10-70 mg/m2/week for the primary purpose of evaluating the toxicity of concurrent chemoradiation treatment. Esophagitis was the principal and dose-limiting toxicity. Radiation pneumonitis occurred in two patients. Other toxicities were mild. Although not designed as an efficacy study, 23 patients were available for response, and an overall response rate of 74% (confidence interval, 65-83%) was observed.

Adult↗
PubMed1995

Weekly, outpatient paclitaxel and concurrent cranial irradiation in adults with brain tumors: preliminary results and promising directions.

In a phase I study, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was given weekly by 3-hour infusion for 6 weeks concurrent with daily cranial irradiation as initial treatment for patients with newly diagnosed astrocytic brain tumors. The primary goal of the study was to establish the maximum tolerated dose of paclitaxel when administered by this schedule. Sixty patients were entered into the study and received at least one course of therapy. Fifty-six patients completed treatment. The treatment regimen was well tolerated, with minimal hematologic toxicity. Peripheral neuropathy was dose-limiting. Median survival was 9.2 months for patients with glioblastoma multiforme and has not been reached for patients with anaplastic astrocytoma or astrocytoma. The maximum tolerated dose of paclitaxel in this study was 250 mg/m2 administered weekly. However, because five of six patients receiving this dose of paclitaxel developed peripheral neuropathy, and because patients with brain tumors may adapt to a superimposed neuropathy less well than patients without pre-existing nervous system dysfunction, we propose 225 mg/m2 as the recommended dose for subsequent phase II trials.

Adult↗
PubMed1995

Paclitaxel as a radiation sensitizer in non-small cell lung cancer.

The new anticancer agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated in vitro radiation-sensitizing effects. In this phase I study, paclitaxel in escalating doses was administered weekly with concurrent radiation therapy to patients with regionally advanced non-small cell lung cancer (NSCLC). The goal was to determine the maximum tolerated dose of paclitaxel in this combination, to identify toxicities, and to evaluate response. Twenty-seven patients with NSCLC were enrolled into a phase I trial of concurrent paclitaxel and radiation therapy administered as a 3-hour infusion each week for 6 weeks. The paclitaxel doses ranged from 10 to 70 mg/m2/wk. Radiation therapy was delivered with weekly paclitaxel as 40 Gy in 20 fractions to the original volume with a boost of 20 Gy in 10 fractions to the primary tumor. Esophagitis was the dose-limiting toxicity at a maximum tolerated dose of 60 mg/m2/wk. The combination of concurrent radiation therapy and weekly outpatient paclitaxel can be safely delivered to patients with NSCLC at a dose of 60 mg/m2. Esophagitis appeared to be the dose-limiting toxicity. A phase II study of concurrent paclitaxel and radiation therapy is under way.

Adult↗
PubMed1995

Preliminary analysis of a phase II study of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is an attractive agent to combine with radiation for non-small cell lung cancer. We have been conducting clinical trials of weekly paclitaxel and concurrent radiation therapy. In a phase I study in non-small cell lung cancer, we determined the maximum tolerated dose of paclitaxel to be 60 mg/m2/wk with radiation. Patients received paclitaxel 60 mg/m2/wk as a 3-hour infusion for 6 weeks with radiation to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). From March 1994 to February 1995, 33 patients have been entered by the Clinical Oncology Group of Rhode Island. The overall response rate (complete plus partial responses) of 25 evaluable patients as of March 1995 was 84%, with a confidence interval of 68 to 96. The major toxicity was esophagitis. Twenty percent of patients had grade 4 esophagitis. Only 8% of patients had grade 3 neutropenia. Combined-modality therapy with paclitaxel and radiation is a promising treatment for locally advanced non-small cell lung cancer with a high response rate and acceptable toxicity.

Adult↗
PubMed1995

Combined-modality therapy for advanced non-small cell lung cancer: paclitaxel and thoracic irradiation.

Despite advances in the modalities used to treat non-small cell lung cancer (NSCLC), the frequency of locoregional and distant relapses necessitates further enhancement of the therapeutic program. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated clinical efficacy against NSCLC and in vitro studies support its role as a radiation potentiator at concentrations achievable in vivo. Thus, a phase I study of weekly paclitaxel and daily concurrent thoracic radiation was conducted in patients with advanced NSCLC to determine (1) the maximum tolerated dose of paclitaxel administered on an outpatient basis for 6 consecutive weeks with daily radiation and (2) the toxicities of the paclitaxel/radiation combination. Paclitaxel was administered as a 3-hour infusion, repeated weekly for 6 weeks with the usual premedication regimen for hypersensitivity prophylaxis. The starting dose of paclitaxel was 10 mg/m2/wk, which was increased by 10 mg/m2 in successive cohorts of three new patients, as tolerated. Radiation therapy was delivered as 40 Gy in 20 fractions to the original volume with a boost of 20 Gy in 10 fractions to the primary tumor. Doses were escalated from 10 to 70 mg/m2/wk. Of the 23 patients evaluable for response, one had stage II NSCLC, four had stage IIIA, 17 had stage IIIB, and one had stage IV. Severe esophagitis (grade 4) occurred in two of the three patients treated at 70 mg/m2 and was dose limiting. One patient discontinued therapy due to hypersensitivity, two developed grade 3 neutropenia, and one developed radiation pneumonitis. With a median follow-up of 7 months, 15 of the 23 patients remain alive. Four had a complete response and 13 had a partial response, for an overall response rate of 74% (95% confidence interval, 52% to 90%). The schedule of weekly paclitaxel and daily thoracic radiation appears active in NSCLC and can be delivered safely in the outpatient setting. The principal dose-limiting toxicity is esophagitis, and the maximum tolerated dose of paclitaxel for this schedule is 60 mg/m2/wk. A phase II trial of weekly paclitaxel 60 mg/m2 and radiation has been initiated in patients with NSCLC.

Ambulatory Care↗
PubMed1994

Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered weekly on an outpatient basis with concurrent thoracic radiation to patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase I clinical trial, paclitaxel was administered as a 3-hour intravenous (IV) infusion, repeated every week for 6 weeks. The starting dose of paclitaxel was 10 mg/m2. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients if tolerated. Unacceptable toxicity was defined as grade 3 nonhematologic toxicity, excluding nausea and vomiting, and grade 4 hematologic toxicity according to Cancer and Leukemia Group B expanded common toxicity criteria. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Twenty-seven patients were entered onto this study through seven dose escalations (from 10 mg/m2/wk to 70 mg/m2/wk for 6 weeks). Severe esophagitis occurred at 70 mg/m2 (two patients with grade 4 disease and one patient with grade 2). One of six patients at 60 mg/m2 developed grade 3 esophagitis and three of seven patients had grade 2 esophagitis. One of 27 patients developed a hypersensitivity reaction. One of 27 patients developed grade 3 neutropenia. CONCLUSION: Esophagitis is the principle dose-limiting toxicity of weekly paclitaxel and thoracic radiation in the outpatient setting. A phase II trial using concurrent radiation and paclitaxel at the MTD of 60 mg/m2/wk is underway.

Adult↗
PubMed1993

Investigation of taxol as a potential radiation sensitizer.

BACKGROUND: The authors evaluated the effects of taxol, a microtubular inhibitor, as a possible radiation sensitizer on the human leukemic cell line (HL-60). Taxol acts as a mitotic inhibitor, blocking cells in the G2M-phase of the cell cycle. The differential radiation sensitivity of cells in various phases of the cell cycle has been well recognized. This study was focused on the possible interaction between radiation and a microtubular inhibitor, taxol, in regard to its ability to synchronize cells at the G2M-phase of cell cycle and, thereby, enhance the radiation sensitivity of the cells. METHODS: HL-60 cells were exposed to 3 x 10(-8) M concentrations of taxol for 1 hour at 37 degrees C followed by reculturing for 24 hours in drug-free medium. The cells were then seeded into 60-mm diameter plastic dishes at appropriate cell concentrations to estimate their colony-forming efficiency. The radiation dose ranged from 0-400 cGy and was delivered in a single fraction. The cellular survival after treatment with the drug and/or radiation was determined using a soft agar clonogenic assay. RESULTS: When HL-60 cells were treated with taxol, up to 70% of the cells were blocked in G2M-phase, as determined by flow cytometric analysis. At the low cytotoxic dose of 3 X 10(-8) M, the sensitizing enhancement ratio was 1.48. CONCLUSIONS: It appears that taxol has a radiation-sensitizing effect on HL-60 cells and deserves further investigation with other cell lines.

Cell Survival↗