Phase I trial of outpatient weekly docetaxel, carboplatin and concurrent thoracic radiation therapy for stage III unresectable non-small-cell lung cancer: a Vanderbilt cancer center affiliate network (VCCAN) trial.

PURPOSE: Docetaxel, an active agent for non-small cell lung cancer (NSCLC), has demonstrated activity as a radiosensitizer in numerous pre-clinical studies. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly Docetaxel, Carboplatin with concurrent thoracic radiation therapy (TRT) in patients with unresectable stage III NSCLC. PATIENTS AND METHODS: In this phase I clinical trial, Docetaxel was administered weekly as a 1-h intravenous infusion for 6 weeks with a starting dose of 20 mg/m(2). Docetaxel doses were escalated by 10 mg/m(2) increments in successive cohorts of three patients. DLT was defined as grade >or=3 nonhematologic and hematologic toxicity according to RTOG toxicity criteria. Once the DLT of Docetaxel alone was reached, weekly Carboplatin (AUC 2) was added at a DLT-2 dose of Docetaxel (two dose levels below that of dose limiting toxicity). Docetaxel doses were again escalated at 10 mg/m(2) increments in successive cohorts of three new patients to define further DLT and MTD of Docetaxel/Carboplatin with TRT. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Fifteen patients were entered onto this study with Docetaxel alone through three dose escalations (from 20 to 40 mg/m(2) weekly). The DLT of weekly Docetaxel/TRT was esophagitis and the MTD was 30 mg/m(2) per week for 6 weeks. Nine more patients were added with the Docetaxel/Carboplatin/TRT regimen. The DLT of weekly Docetaxel/Carboplatin with TRT was esophagitis and the MTD of Docetaxel was 20 mg/m(2) per week with weekly Carboplatin (AUC 2). There were 2 complete responses and 13 partial responses in 25 evaluable patients (RR 60%). CONCLUSIONS: This combination regimen has activity with manageable toxicity in patients with stage III NSCLC. A phase II study is planned to define activity.

A phase I trial of outpatient weekly docetaxel and concurrent radiation therapy for stage III unresectable non small-cell lung cancer: a Vanderbilt Cancer Center Affiliate Network (VCCAN) Trial.

Docetaxel has demonstrated activity as a radiosensitizer in numerous preclinical studies, probably due to its role as a cell cycle synchronizer for the G2/M radiosensitive phase of the cell cycle. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of docetaxel with concurrent thoracic radiation therapy (TRT) to patients with unresectable stage III non small-cell lung cancer (NSCLC). Fifteen patients were entered into this study. Docetaxel was administered as a 1-hour intravenous (I.V.) infusion, repeated every week for 6 weeks with starting dose of 20 mg/m2. Doses were escalated in 10 mg/m2 increments in successive cohorts of three new patients, if tolerated. Unacceptable toxicity was defined as grade = 3 nonhematologic or hematologic toxicity according to Eastern Cooperative Oncology Group (ECOG) toxicity criteria. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). At the first dose level (20 mg/m2/week), one patient developed grade 4 hyperglycemia and accrual was expanded to five patients. At the second level (30 mg/m2/week), two out of six patients developed grade 3 esophagitis. At the third level (40 mg/m2/week), two out of four patients developed grade 3 esophagitis and one patient developed grade 3 pulmonary toxicity. The weekly docetaxel MTD with concurrent radiation therapy (RT) was found to be 30 mg/m2. The DLT was esophagitis and pulmonary toxicity. Other toxicities encountered included skin reaction, nausea and vomiting, as well as diarrhea. Additionally, there were no treatment-related mortalities or late-occurring toxicities. Esophagitis was the principal DLT of concurrent weekly docetaxel and thoracic radiation in the outpatient setting. The MTD of concurrent weekly docetaxel with TRT is 30 mg/m2 weekly for 6 weeks. This study is still open to accrual with weekly docetaxel and TRT in locally advanced NSCLC patients.

Esophagitis in combined modality therapy for locally advanced non-small cell lung cancer.

Within the last 10 to 15 years, several randomized trials have validated the importance of chemotherapy in the treatment of locally advanced non-small cell lung cancer and have shown that combined modality therapy improves survival compared with radiotherapy alone. Esophagitis appears to be the primary toxicity, with an increased incidence in combined modality trials. Esophagitis is an inflammatory response of the esophageal mucosa. Treatment with chemotherapy or radiotherapy destroys rapidly dividing cells, such as those in the basal epithelial cell layer. Cell death decreases the renewal rate of the basal epithelium, causing mucosal atrophy, ulceration, and initiation of the inflammatory response. Synergy between chemotherapy and radiotherapy may increase the severity and extent of esophagitis observed with combined modality therapy. Based on Radiation Therapy Oncology Group criteria, the incidence of >/=grade 3 esophagitis following radiation therapy alone or combined modality therapy ranges from less than 5% to 53%. Four sequential, multi-institutional phase I or II studies were conducted during the last 5 years to explore the use of paclitaxel in combined modality therapy for patients with non-small cell lung cancer. In the three phase II trials, esophagitis was the main toxicity, with incidences ranging from 17% to 26% using Radiation Therapy Oncology Group criteria. A multivariate analysis identified a statistically significant correlation between esophageal toxicity and both response to therapy and performance status. Other factors, including gender, age, histology, survival, and length of esophagus within the primary and boost radiation field, were not significantly correlated with esophageal toxicity.

Preliminary analysis of a phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small cell lung cancer.

We conducted a prospective phase II study to determine the response rate, toxicity profile, and survival rate among patients with locally advanced unresectable non-small cell lung cancer receiving concurrent weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), carboplatin, and hyperfractionated radiation therapy followed by two cycles of adjuvant paclitaxel and carboplatin. The weekly paclitaxel/carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. Thirty-two patients with unresectable stage IIIA and IIIB non-small cell lung cancer from Vanderbilt Cancer Center Affiliate Network institutions entered the study from June 1996 until February 1997. Weekly intravenous paclitaxel (50 mg/m2 over 1 hour) and weekly carboplatin (area under the concentration-time curve of 2) plus concurrent hyperfractionated chest radiotherapy (1.2 Gy twice daily [69.6 Gy total]) delivered for 6 weeks were followed by two cycles of paclitaxel (200 mg/m2) and carboplatin (area under the concentration-time curve of 6). Among 22 patients evaluable for response, one (4.5%) achieved a complete response and 16 (72.7%) achieved partial response, for an overall response rate of 77%. Among 23 patients evaluable for toxicity, esophagitis was the principal finding: grade 3 or 4 esophagitis occurred in eight patients (35%). Grade 3 and 4 pulmonary toxicities each occurred in 26% of patients. Thus, weekly paclitaxel/carboplatin plus concurrent hyperfractionated radiotherapy is a well-tolerated outpatient regimen with an encouraging response rate that is at least equivalent to more toxic chemoradiation regimens. These findings indicate that further clinical evaluation of weekly paclitaxel/carboplatin/hyperfractionated radiotherapy is warranted in phase III trials.

The Canadian Human Activity Pattern Survey: report of methods and population surveyed.

The assessment of health risk due to environmental contaminants depends upon accurate estimates of the distribution of population exposures. Exposure assessment, in turn, requires information on the time people spend in micro-environments and their activities during periods of exposure. This paper describes preliminary results including study methodology and population sampled in a large Canadian survey of time-activity patterns. A 24-hour diary recall survey was performed in 2381 households (representing a 65% response rate) to describe in detail the timing, location and activity pattern of one household member (the adult or child with the next birthday). Four cities (Toronto, Vancouver, Edmonton and Saint John, NB) and their suburbs were sampled by random-digit dialling over a nine-month period in 1994/1995. Supplemental questionnaires inquiring about sociodemographic information, house and household characteristics and potential exposure to toxins in the air and water were also administered. In general, the results show that respondents spend the majority of their time indoors (88.6%) with smaller proportions of time outdoors (6.1%) and in vehicles (5.3%). Children under the age of 12 spend more time both indoors and outdoors and less time in transit than do adults. The data from this study will be used to define more accurately the exposure of Canadians to a variety of toxins in exposure assessment models and to improve upon the accuracy of risk assessment for a variety of acute and chronic health effects known or suspected to be related to environmental exposures.

The course of seizure disorders in patients with malignant gliomas.

OBJECTIVE: To describe the morbidity associated with seizures and the efficacy of anticonvulsant therapy in adult patients with malignant gliomas (MGs). STUDY DESIGN: A retrospective review of charts was performed to determine the occurrence of seizures at diagnosis, the frequency and character of subsequent seizures, and the use and toxic side effects of anticonvulsants. PATIENTS: Sixty-five consecutive adult patients with supratentorial MGs who were examined in the neurooncology clinic at a university medical center were studied. The diagnosis was glioblastoma in 47 of the patients, and it was anaplastic astrocytoma in 18 patients. The mean age of the patients was 49.5 years. The median Karnofsky status score was 80. The median survival was 18 months. RESULTS: Twenty-nine patients presented with seizures, and 21 of these had subsequent (eg, "recurrent") seizures while they were receiving anticonvulsant therapy. Ten of 36 patients who were free of seizures at diagnosis experienced seizures after diagnosis (eg, "late onset") while they were being treated with anticonvulsants, including five patients who had single seizures. Long-term seizure frequency in excess of one per month was observed in 13 patients. Ten patients had episodes of partial motor status epilepticus. Most recurrent and late-onset seizures occurred despite therapeutic anticonvulsant levels, and without evidence of tumor progression. Rash associated with anticonvulsants was observed in 26% of the patients. Other clinically important toxic side effects were observed in 14% of the patients who were receiving long-term anticonvulsant therapy. CONCLUSIONS: Seizures contributed substantially to the neurologic morbidity of MGs in at least 25% of these patients. The occurrence of seizures at diagnosis was a strong predictor of subsequent seizures, and in many patients, seizures proved to be refractory to standard anticonvulsant therapy. Long-term anticonvulsant toxic side effects are relatively common in patients with MGs. The use of long-term seizure prophylaxis for patients with MGs who are free of seizures at presentation is not clearly beneficial and should be studied in a prospective trial.

Gliomatosis cerebri presenting as intractable epilepsy during early childhood.

We review 160 cases of gliomatosis cerebri from the literature and report an additional three infants and young children who presented with intractable epilepsy, corticospinal tract deficits, and developmental delay in whom a pathologic diagnosis was made. The progressive nature of the encephalopathy in our cases was documented by serial clinical examination, electroencephalograms, magnetic resonance imaging, and positron emission tomographic scans. The natural history of gliomatosis cerebri was determined by a retrospective review of the literature of 160 cases in 85 reports. The most common neurologic symptoms and signs included corticospinal tract deficits (58%), dementia/mental retardation (44%), headache (39%), seizures (38%), cranioneuropathies (37%), increased intracranial pressure (34%), and spinocerebellar deficits (33%). The most commonly involved central nervous system structures were the centrum semiovale and cerebrum (76%), mesencephalon (52%), pons (52%), thalamus (43%), basal ganglia (34%), and the cerebellum (29%). Fifty-two percent of patients were dead within 12 months of onset. Different grades of glial neoplasm may also coexist within gliomatosis cerebri such as astrocytoma with anaplastic astrocytoma, atypical or anaplastic oligodendroglioma, and glioblastoma multiforme. Hypotheses regarding the pathogenesis of gliomatosis cerebri include blastomatous dysgenesis, diffuse infiltration, multicentric origin, in situ proliferation, and "field transformation." The biologic determinants of whether a transformed glial cell behaves as a relatively localized tumor mass or truly loses anchorage dependence to become migratory as well as proliferative are not understood.

Reliability and validity of the Disability Rating Scale and the Levels of Cognitive Functioning Scale in monitoring recovery from severe head injury.

The Disability Rating Scale (DRS) and the Levels of Cognitive Functioning Scale (LCFS) are both widely used to monitor recovery from head injury, despite the total lack of published research on the reliability and validity of the LCFS, and the fragmented and incomplete reports on these characteristics of the DRS. Forty head-injured inpatients were evaluated with the DRS and LCFS four times weekly throughout their rehabilitation hospitalization. The DRS and LCFS were compared in terms of how consistently ratings could be made by different raters, how stable those ratings were from day to day, their relative correlation with Stover Zeiger (S-Z) ratings collected concurrently at admission, and with S-Z, Glasgow Outcome Scale (GOS), and Expanded GOS (EGOS) ratings collected concurrently at discharge, and finally in the ability of admission DRS and LCFS scores to predict discharge ratings on the S-Z, GOS, and EGOS. Results suggest that both scales possess significant degrees of test-retest and interrater reliabilities, and of concurrent and predictive validities, but the DRS surpasses the LCFS in nearly every regard. These results offer psychometric justification favoring the use of the DRS for monitoring recovery from head injury.