Combined modality trials of the Cancer and Leukemia Group B in stage III non-small-cell lung cancer: analysis of factors influencing survival and toxicity.

BACKGROUND: Combined modality therapy (CMT) is the standard of care for patients with unresectable stage III non-small-cell lung cancer (NSCLC); however, insufficient data are available regarding prognostic factors in this disease setting. PATIENTS AND METHODS: Six hundred and ninety-four patients included in five trials conducted by the Cancer and Leukemia Group B evaluating CMT in stage III NSCLC were included in this analysis. The primary objective was to identify factors that were predictors of survival and selected radiation-related toxicities using Cox regression models and logistic regression analysis. RESULTS: The Cox model shows that performance status (PS) 1 [hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.06-1.45; P=0.009] and thoracic radiation therapy (TRT) only (HR 1.58; 95% CI 1.22-2.05; P=0.001) predicted for poorer survival, while baseline hemoglobin >/=12 g/dl predicted for improved survival (HR 0.67; 95% CI 0.55-0.81; P 5% weight loss (OR 2.9; 95% CI 1.3-6.6; P=0.008) and patients receiving concurrent chemoradiation (OR 7.3; 95% CI 3.4-15.6; P=0.0001). CONCLUSIONS: Baseline hemoglobin and PS, as well as the use of CMT, have the greatest effect on survival in unresectable stage III NSCLC. The use of concurrent chemoradiation increases the risk of esophagitis, which remains the primary radiation-related toxicity.

Survival of docetaxel-resistant prostate cancer cells in vitro depends on phenotype alterations and continuity of drug exposure.

We evaluated in vitro the effect of paclitaxel and docetaxel on PC-3 and DU-145 prostate cancer cell lines to understand better the downstream events in drug-induced tumor cell death. Taxane treatments of DU-145 cells induced rapid cell death by apoptosis, but in PC-3 cells, treatments achieved growth arrest, followed by extensive karyokinesis resulting in multinucleation, giant-cell formation and delayed cell death. To determine if the giant multinucleated cells were able to produce proliferating and drug-resistant survivors, we first delineated the kinetics of drug activity and cytotoxic dose range. Analysis of both lines by colorimetric and cell viability assays demonstrated improved cytotoxicity of taxanes applied continuously. Selected doses and schedules of docetaxel were used to induce giant multinucleated cells that gave rise to docetaxel-resistant survivors, which remained sensitive to paclitaxel and other chemotherapeutics. Growth and morphology of the recovered clones was similar to parental cells. The resistant phenotype of these clones determined by immunofluorescence and immunoblot was associated with transient expression of the beta-tubulin i.v. isoform and was independent of P-glycoprotein, bcl-2 and bcl-xL. Resistant clones will be useful to model progression of resistance to taxanes and to identify unknown and clinically important molecular mechanisms of cell death and resistance.

Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B.

PURPOSE: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m(2), oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. RESULTS: Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease. CONCLUSION: This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone.

Recent developments in weekly paclitaxel therapy in lung cancer.

Paclitaxel has undergone a remarkable evolution of schedule and dosage based on observed schedule-dependent toxicity and consequent improvement of therapeutic index. A weekly schedule of administration was originally developed to exploit opportunities for radiation synergy and was subsequently explored without radiation to evaluate the potential for reduced toxicity. Three weekly schedules have emerged: paclitaxel 50 mg/m(2)/wk with concurrent radiation, paclitaxel 80 to 90 mg/m(2)/wk as a dose-dense schedule without radiation, and paclitaxel 150 to 175 mg/m(2)/wk as a dose-intensive schedule. The efficacy of these schedules, their integration as combination treatment with chemotherapy and nonchemotherapeutic agents, and their role are the subjects of substantial investigation.

Treatment of the jaundiced patient with breast carcinoma: case report and alternate therapeutic strategies.

BACKGROUND: Breast carcinoma in the setting of liver metastases and jaundice raises a complex therapeutic dilemma. Not only is the prognosis poor but toxicity related to treatment can be unpredictable due to altered drug clearance. Guidelines built around dose reduction have been suggested but often do not address the varied presentations in clinical medicine. Bilirubin exceeding 5.0 mg% often is considered an absolute contraindication to the administration of chemotherapeutic agents dependent on hepatic metabolism. METHODS: A 55-year-old woman with metastatic breast carcinoma to the liver and hyperbilirubinemia was treated with sequential, empiric chemotherapy agents with the goal of preventing severe toxicity through dose reduction, avoidance of combination therapy, divided doses (weekly therapy), and selection of drugs less dependent on hepatic clearance. Several attempts did not yield a regimen with a successful response, but toxicity was minimal. Eventually, a successful schedule and dose of an agent cleared by liver metabolism was individualized for the patient. RESULTS: After eight cycles of low dose weekly doxorubicin chemotherapy, the patient's symptoms resolved, bilirubin level normalized, and performance status returned to baseline. The patient remained on treatment and was alive 12 months later. CONCLUSIONS: The authors propose that altering a drug schedule by dividing doses may minimize toxicity, maintain dose intensity, and represent an alternative strategy for the treatment of patients with hepatic impairment.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

p53 mutations do not predict response to paclitaxel in metastatic nonsmall cell lung carcinoma.

BACKGROUND: In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function. The authors previously demonstrated that response to paclitaxel and concurrent radiation was not affected by p53 mutations in nonsmall cell lung carcinoma (NSCLC). We sought to determine whether p53 mutations affect response to paclitaxel alone in patients with metastatic NSCLC. METHODS: Twenty-five patients with metastatic NSCLC who participated in Brown University Oncology Group protocols utilizing single-agent weekly paclitaxel had tumor tissue that was adequate for p53 analysis. Tumor tissue was evaluated for p53 gene mutations in exons 5 through 8 by single-strand conformation polymorphism analysis. Mutations were confirmed by direct sequencing of altered mobility polymerase chain reaction products. RESULTS: Mutations in p53 were found in 8 of 25 patients (32%). The response rates of 75% for patients with tumors with p53 mutations and 47% for patients with wild-type p53 do not differ significantly (P = 0.12). The 1-year survival rates for patients with and without p53 mutation after treatment with weekly paclitaxel were 63% (95% confidence interval [CI], 31-100%) and 53% (95% CI, 33-86%), respectively. CONCLUSIONS: p53 mutations do not adversely affect response to paclitaxel as a single agent in metastatic NSCLC. These results provide clinical support for in vitro observations that paclitaxel can bypass mutant p53 and lead to tumor cell death by alternate pathway(s). Paclitaxel should be considered as a component of treatment for patients with metastatic NSCLC with tumors that have p53 mutations.

Paclitaxel in advanced non-small cell lung cancer : an alternative high-dose weekly schedule.

STUDY OBJECTIVES: Sequential phase I and phase II trials of paclitaxel using an extended weekly schedule were performed to explore its effect on tolerance, limits of dose intensity, and activity at maximum dose intensity in disseminated non-small cell lung cancer (NSCLC). DESIGN: Patients with stage IIIB/IV NSCLC were eligible if they had a performance status of 0 to 2, no previous chemotherapy, and normal organ function. Paclitaxel was administered as a 3-h infusion weekly for 6 weeks of an 8-week cycle. Doses were modified for toxicity observed on the day of treatment. MEASUREMENTS AND RESULTS: Paclitaxel, 100 to 200 mg/m(2)/wk, was administered in the phase I trial. Dose escalation was limited primarily by neutropenia, and a relationship between dose and response was noted. A phase II trial of paclitaxel, 175 mg/m(2)/wk, the maximum tolerated dose, was initiated; data are available for the first 25 patients. Eighty-three, 75, 58, and 50% of intended doses were delivered during cycles one to four, respectively. Grade 2 or 3 neuropathy occurred in nine patients, but improved in all following dose reduction. Platelet counts rose by 17,000/microL/wk. Partial responses occurred in 14 of 25 patients (56%; confidence interval, 46 to 66%). The duration of response was 6 months, and 1-and 2-year survival rates were 53% and 18%, respectively. CONCLUSION: Paclitaxel administered on a weekly schedule allows enhanced dose intensity, has a protective or stimulatory effect on platelets, and is active in NSCLC.

Concurrent chemotherapy and radiotherapy in patients with brain tumors.

Because treatment for most brain tumors remains inadequate, there has been a sustained interest in using concurrent chemotherapy and radiotherapy to improve local control, prolong overall survival, and reduce treatment-related toxicity. Unfortunately, many currently available radiosensitizers are either ineffective against brain tumors or have a reduced ability to cross the blood-brain barrier when administered systemically. Many agents also have overlapping toxicities with cranial irradiation or enhance the toxicity of radiation in a way that potentially compromises care. Finally, the addition of chemotherapy to cranial irradiation complicates the assessment of tumor response. Despite these barriers, trials with a number of promising agents are currently under way. These trials have already provided crucial insights into the pharmacokinetics, clinical pharmacology, and practical management of brain tumor patients with concurrent chemotherapy and radiotherapy. These findings should rapidly lead to the safer and more effective use of combined-modality therapy in patients with central nervous system cancer.

Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study.

The beneficial effects of chemotherapy in patients with advanced head and neck cancer remain controversial in terms of survival, but have shown some promise in improving locoregional control and quality of life. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel and carboplatin with concurrent conventional fractionated external-beam radiotherapy. Paclitaxel and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, cell blockage in G2/M phase and inhibition of DNA repair, respectively. Patients were stratified as either operable or inoperable. This report pertains to the inoperable patient group, who received eight cycles of weekly paclitaxel (60 mg/m2), carboplatin (area under the concentration-time curve of 1) with conventional radiotherapy (72 Gy). Chemoradiotherapy was followed by neck dissection for those patients who presented with clinically palpable lymph nodes. Thirty-three patients were enrolled in this group (23 men and 10 women with a median age of 56 years). Eleven patients (33%) had stage III disease; 22 (67%), stage IV disease. The median follow-up period was 14 months. Clinical complete response occurred in 20 patients (60%) and partial response occurred in 10 (30%), for an overall response rate of 90%. Following completion of therapy, 18 patients have undergone biopsy at the primary tumor site and 17 were negative. Eight of the 16 patients with clinically palpable neck nodes at presentation underwent neck dissection; five (63%) had negative nodes. Mucositis was the most common toxicity. Grade 3 or 4 mucositis occurred in 30 of the 33 (90%) patients. Other grade 3 or 4 toxicities included skin (22%), candidiasis (19%), neutropenia (9%), and dehydration (6%). One patient with laryngeal carcinoma who had pathologic complete response developed cartilage necrosis and is undergoing hyperbaric oxygen therapy. Survival data are early but encouraging. Concurrent paclitaxel, carboplatin, and external-beam radiotherapy yielded excellent clinical and pathologic responses. Mucositis remains the most common and significant morbidity. The study will continue for necessary accrual.

Preoperative paclitaxel, carboplatin, and radiation therapy in advanced head and neck cancer (stage III and IV).

Preoperative chemotherapy and chemoradiation protocols are generally associated with high clinical response rates but limited pathologic responses for large primary tumors. We have initiated a prospective phase II study of weekly paclitaxel and carboplatin plus concurrent, fractionated external-beam radiation, followed by organ-preserving or function-restorative surgery (when applicable to maximize locoregional tumor control). Operable patients staged by triple endoscopy received a percutaneous gastrostomy and vigorous dental and nutritional support during therapy. Paclitaxel 60 mg/m2 and carboplatin at an area under the concentration-time curve of 1 were administered weekly with radiation therapy 45 Gy, with repeat biopsy of the primary site at 5 weeks. Patients with a positive biopsy had definitive surgery within 4 to 5 weeks. Patients with a negative biopsy received 3 additional weeks of radiation therapy, to a total dose of 72 Gy plus paclitaxel and carboplatin. Forty-three patients were enrolled, including 33 men and 10 women ranging in age from 37 to 81 years. Fourteen patients had stage III disease, 19 patients had stage IVA disease, and 10 patients had stage IVB disease. Sites of disease included the floor of the mouth (n = 8), tongue (n = 8), oropharynx (n = 5), hypopharynx (n = 4), larynx (n = 12), palate-tonsil (n = 2), unknown primary (n = 3), and nasal cavity (n = 1). Of 38 patients evaluable for primary response (two patients had unknown primary tumor, two patients failed to complete the chemoradiation protocol, and one patient was evaluable for toxicity only), 18 patients had a complete clinical response and 20 patients had a partial response; the overall clinical response rate was 100%. A pathologic clinical response at the primary site occurred in 25 of these 38 patients (66%), who subsequently received completion radiation (67 to 72 Gy). After induction chemoradiation, 36 patients with N1-N3 nodes had neck dissection; seven had positive nodes (19%). Fourteen patients had residual cancer at the primary site at the time of the repeat biopsy. Sites of the lesions were the floor of the mouth/mandible (n = 4), nasal cavity/maxilla (n = 2), base of tongue (n = 2), and larynx (n = 6). All were resected with function-preserving reconstruction (two patients required total laryngectomy and one patient refused surgery). At a median follow-up of more than 16 months, progression-free and overall survival rates were 64% and 68%, respectively. Preoperative paclitaxel, carboplatin, and radiation was associated with a high clinical response rate at the primary site and a high level of organ preservation or functional restoration, if ablation was performed.

Single-agent paclitaxel and radiation for non-small cell lung cancer.

Lung cancer must be viewed as a systemic disease, and control of latent metastases at both regional and systemic sites is the goal of therapy. Combined modalities have emerged as the dominant strategy with which to manage latent metastases, and paclitaxel has several properties, including a modest toxicity profile, significant activity, and radiosensitization potential, which contribute to its effectiveness in this setting. In phase I clinical trials, paclitaxel was administered weekly in combination with radiation therapy (60 Gy) in the outpatient setting to patients with stage III non-small cell lung cancer (NSCLC). The dose-limiting toxicity, which occurred at a paclitaxel dose of 70 mg/m2/wk, was esophagitis; thus, a paclitaxel dose of 60 mg/m2/wk was recommended for phase II evaluation. In the phase II trial in patients with inoperable stage IIIA or stage IIIB NSCLC, paclitaxel 60 mg/m2/wk (for 6 weeks) plus radiation therapy (60 Gy) resulted in an overall response rate of 86%. The overall median survival was 20 months, and projected 1-, 2-, and 3-year survival rates were 60%, 54%, and 39%, respectively. These results demonstrate the feasibility and potential efficacy of this combination in the treatment of regionally advanced malignancies. When paclitaxel is administered using this schedule, it appears to exhibit an altered pattern of toxicity, with much lower incidences of hematologic and neurologic toxicities, which may improve the overall therapeutic index of this combination. Until curative systemic therapy is developed, combined modality approaches offer the greatest potential for long-term control of advanced NSCLC. Based on the observed activity and toxicity profile, concurrent radiation therapy plus paclitaxel offers significant clinical utility for control of both local and distant metastatic disease.

Concurrent paclitaxel, carboplatin, and radiation therapy for locally advanced non-small cell lung cancer.

Combination chemotherapy plus radiation therapy for non-small cell lung cancer has several theoretical advantages: the potential of chemotherapy to radiosensitize tumors, the possibility of improved local control due to combined treatment, and the opportunity for spatial cooperation, attacking disease both locally and systemically and thus potentially increasing response and, ultimately, survival. The combination of radiotherapy plus standard chemotherapy (etoposide plus cisplatin) has yielded limited success; therefore, new and novel chemotherapies have been sought. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the prototype of a novel class of drugs, the taxanes, has proven feasible both alone and with other agents in combined-modality regimens with radiation. Concurrent paclitaxel/carboplatin/radiotherapy appears to offer a relatively safe and more active regimen to control local and metastatic non-small cell lung cancer than the current standard. This report reviews the range of experience with paclitaxel-based combined-modality therapy.

Histologic evidence of a radiosensitizing effect of Taxol in patients with astrocytomas.

The new anticancer agent Taxol appears to potentiate the effects of radiation on brain tumor cell lines in vitro and was recently evaluated by our group as a radiosensitizer in a phase I study for primary brain tumors. In that study, we administered Taxol as a three-hour IV infusion repeated every week for six weeks and gave daily cranial irradiation concurrently for a total of 6000 rads. We reviewed the charts of the 60 patients who participated in the study, and identified twelve patients who underwent a second surgery after treatment because of progressive symptoms and an enlarging intracranial mass on MRI. Pathologically, each patient showed prominent radionecrosis, and other evidence of accelerated radiation changes (confluent areas of coagulative necrosis, bizarre nuclei, marked thickening and fibrinoid changes in multiple blood vessels). These changes were noted many weeks earlier than would be expected after radiation therapy alone and were independent of age, and tumor histology. We postulate that the accelerated radiation changes may be due to the radiation sensitizing effects of Taxol. We also noted a change of the pattern of tumor recurrence, compared to historic reports, and a dose-necrosis relationship where the resected tumor is formed completely of necrotic tissue in patients who received 150 mg/m2 or higher dose of Taxol. These observations may be of significance for future study design.

Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer.

PURPOSE: Combined modality therapy for non-small-cell lung cancer (NSCLC) has produced promising results. A multiinstitutional phase II clinical trial was conducted to evaluate the activity and toxicity of paclitaxel, carboplatin, and concurrent radiation therapy on patients with locally advanced NSCLC. PATIENTS AND METHODS: Forty previously untreated patients with inoperable locally advanced NSCLC entered onto a phase II study from March 1995 to December 1996. On an outpatient basis for 7 weeks, patients received paclitaxel 50 mg/m2 weekly over 1 hour; carboplatin at (area under the curve) AUC 2 weekly; and radiation therapy of 66 Gy in 33 fractions. After chemoradiation therapy, patients received an additional two cycles of paclitaxel 200 mg/m2 over 3 hours and carboplatin at AUC 6 every 3 weeks. RESULTS: Thirty-nine patients were eligible for the study. The survival rates at 12 months were 56.3%, and at 24 months, 38.3%, with a median overall survival of 20.5 months. The progression-free survival rates at 12 months were 43.6%, and at 24 months, 34.7%, with a median progression-free survival of 9.0 months. Two patients did not receive more than 2 weeks of concurrent chemoradiotherapy and were not assessable for toxicity and response. The overall response rate (partial plus complete response) of 37 assessable patients was 75.7%. The major toxicity was esophagitis. Seventeen patients (46%) developed grade 3 or 4 esophagitis. However, only two patients developed late esophageal toxicity with stricture at 3 and 6 months posttreatment. CONCLUSION: Combined modality therapy with paclitaxel, carboplatin, and radiation is a promising treatment for locally advanced NSCLC that has a high response rate and acceptable toxicity and survival rates. A randomized trial will be necessary to fully evaluate the usefulness of these findings.

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

We conducted a prospective Phase II study to determine the response rate, toxicity, and 2-year survival rate of concurrent weekly paclitaxel and radiation therapy (RT) for locally advanced unresectable non-small cell lung cancer. The weekly paclitaxel regimen was designed to optimize the radiosensitizing properties of paclitaxel. Thirty-three patients with unresectable stage IIIA and IIIB non-small cell lung cancer from six institutions were entered into the study between March 1994 and February 1995. Weekly i.v. paclitaxel (60 mg/m2; 3-h infusion) plus concurrent chest RT (60 Gy over 6 weeks) was delivered for 6 weeks. Twenty-nine patients were evaluable for response. Three patients achieved a complete response (10%), and 22 patients (76%) achieved a partial response, for an overall response rate of 86% (95% confidence interval, 68-96%). One patient progressed during the therapy, and three patients had stable disease. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (37%). One patient died of pneumonia after completion of therapy. Additional grade > or =3 toxicities included pneumonitis (12%) and neutropenia (6%). One patient had a grade 3 hypersensitivity reaction. The median overall survival duration for all 33 patients who entered the study was 20 months, and 1-, 2-, and 3-year overall survival rates were 60.6%, 33.3%, and 18.2%, respectively. The median progression-free survival duration for all 33 patients was 10.7 months, and 1-, 2-, and 3-year progression-free survival rates were 39.4%, 12.1%, and 6.1%, respectively. Weekly paclitaxel plus concurrent RT is a well-tolerated outpatient regimen. The survival outcome from this regimen is encouraging and seems to be at least equivalent to that of other chemotherapy/radiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/RT in Phase II trials in the neoadjuvant setting and in combination with other cytotoxic agents.

Unexpected in vitro chemosensitivity of malignant gliomas to 4-hydroxyperoxycyclophosphamide (4-HC).

To individually tailor chemotherapy for patients with malignant gliomas according to tumor chemosensitivity, a rapid assay system which can be performed with a high success rate is needed. The fluorescent cytoprint assay (FCA) can assess multiple chemotherapeutic agents using small (approximately 500 cells) tumor aggregates very quickly (approximately 1 wk). Tissue samples from 51 patients with malignant gliomas obtained either at time of initial diagnosis (n = 34) or at recurrence were assayed using this method. The assay success rate approached 90% in those culture samples which were histologically verified as tumor. A meaningful number of agents could be tested both on samples obtained by stereotactic biopsy (median, 5) and on specimens from more extensive resections (median, 6). One hundred ninety-three FCAs were performed on a samples obtained from 36 patients. In only twenty six assays (14%) was an agent deemed sensitive (> 90% cell kill) to a chemotherapeutic agent. Sixty-two percent of sensitive FCAs were observed in tumors tested against the activated analog of cyclophosphamide, 4-hydroxyperoxycyclophosphamide (4-HC), where a sensitivity rate (# samples sensitive/total tested against agent) of 64% (95 % CI, 36.6-77.9%) was noted. This rate was significantly higher than with any other agent tested (p = 0.012, two sided McNemar's test) and was not affected by age, histology or disease status. We conclude that: (1) the FCA represents a feasible method for quickly assaying tumors for sensitivity to multiple chemotherapeutic agents; and (ii) malignant gliomas may be particularly sensitive to 4-HC.

High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?

PURPOSE: Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis. PATIENTS AND METHODS: Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval. RESULTS: Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003). CONCLUSION: HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.