A pilot clinical laboratory trial of paclitaxel and endobronchial brachytherapy in patients with non-small cell lung cancer.
Paclitaxel enhances microtubule assembly and causes a cell cycle arrest in mitosis, the most radiosensitive phase. We conducted this study to improve our understanding of paclitaxel effects in vivo and to determine the maximum tolerated dose of paclitaxel preceding endobronchial radiation therapy (brachytherapy). The treatment consisted of two cycles of paclitaxel infused over 24 hours followed by 192Ir brachytherapy; cycles were repeated every 3 weeks. Tumor samples were obtained at baseline, after each paclitaxel infusion, and 3 weeks after completion of therapy. Twenty-two non-small cell lung cancer patients with a documented endobronchial lesion were enrolled in the study and 20 patients received the therapy with different doses of paclitaxel, initially without and then later with granulocyte colony-stimulating factor (G-CSF) support (5 microg/kg subcutaneously on days 3 to 10). With the starting paclitaxel dose of 135 mg/m2, five of seven patients developed neutropenia and fever, which mandated a dose reduction to 120 mg/m2. At this dose level, three of three patients had neutropenic fever; thus, 120 mg/m2 of paclitaxel was considered above the maximum tolerated dose without G-CSF support. However, with G-CSF support the therapy was well-tolerated without dose-limiting toxicity and accrual is continuing at the paclitaxel 175-mg/m2 dose level. While no patient had achieved systemic tumor response, 11 patients achieved partial response of the endobronchial lesion, which represents 68.8% of 16 patients who received two courses of therapy and 91.8% of 12 patients who had full evaluation by bronchoscopy after completion of therapy. The in vivo paclitaxel effects were studied using the pre- and post-paclitaxel therapy tumor samples in eight patients. Four (50%) patients had a significant increase in mitotic cells after paclitaxel, as assessed by MPM-2 immunostaining that recognizes a large family of mitotic phosphoproteins. A substantial increase in the number of micronucleated apoptotic cells, another paclitaxel effect, was also found in six patients. These results clearly indicate that patients with endobronchial lesions from recurrent NSCLC could not tolerate this combined modality regimen without G-CSF support. However, this group of patients provided a unique opportunity to study in vivo paclitaxel effects in a clinical trial setting.
Lee
J S
JS
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Komaki
R
R
Morice
R C
RC
Ro
J Y
JY
Kalapurakal
S K
SK
Schea
R
R
Murphy
W K
WK
Shin
D M
DM
Fox
N T
NT
Walsh
G L
GL
Hittelman
W N
WN
Hong
W K
WK
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects; D001918:Brachytherapy / Q000379:methods*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D011838:Radiation-Sensitizing Agents; D016179:Granulocyte Colony-Stimulating Factor; D017239:Paclitaxel