Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer.

BACKGROUND: Taxol, a complex plant product (a diterpene) extracted from the bark of Taxus brevifolia, has demonstrated substantial anticancer activity in ovarian and breast cancers, malignant melanoma, and acute myelogenous leukemia. Due to allergic reactions in phase I and early phase II studies, use of a 24-hour infusion of taxol with prophylactic dexamethasone, diphenhydramine, and cimetidine has been recommended. PURPOSE: In this phase II study, we attempted to determine the efficacy and toxicity of taxol in patients with advanced (stage IIIB or IV) non-small-cell lung cancer who had never received chemotherapy. METHODS: Patients were not excluded because of prior surgery or because of radiotherapy administered more than 4 weeks before study entry. Taxol was administered in the hospital at a dose of 200 mg/m2 as an intravenous infusion over 24 hours and repeated every 3 weeks, provided that patients had recovered from any toxic effects. Dexamethasone, cimetidine, and diphenhydramine were given before chemotherapy to prevent hypersensitivity reactions. Therapy was continued for at least two courses unless there was rapid disease progression and for at least three courses if no change was observed and no grade 3 or 4 toxic effects occurred. Treatment was continued for six more courses after maximum response or for two more courses after complete remission but was discontinued if disease progressed. RESULTS: Of the 27 patients entered in the study, 25 were assessable for toxic effects and response. One patient had an allergic reaction that was not life threatening. The overall response rate was 24% (one complete response and five partial responses). An additional seven patients (28%) had minor response. Granulocytopenia was the dose-limiting toxic effect, and neutropenic fever occurred in eight of 118 courses. One additional patient developed neutropenic sepsis with hypotension but recovered with intensive treatment. CONCLUSIONS: Taxol appears to have activity against non-small-cell carcinoma of the lung. IMPLICATIONS: A phase II study combining taxol, etoposide, and cisplatin and using hematopoietic stimulating factors is now proposed. The optimal dose for combination chemotherapy has yet to be determined. An important consideration is potential cardiac effects of taxol with other drugs.

Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan.

PURPOSE: This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with small-cell lung cancer (SCLC) refractory to etoposide. PATIENTS AND METHODS: Refractoriness to etoposide was defined as lack of response to etoposide-containing frontline therapy, or progression during or within 3 months of the last dose of etoposide-containing frontline or second-line therapy. Other eligibility criteria were presence of measurable disease, Zubrod scale performance status (PS) < or = 2, < or = two prior chemotherapy regimens, and adequate renal and liver function. TPT was administered at a dose of 1.25 mg/m2/d for 5 days over 30 minutes every 21 days. RESULTS: Thirty-two patients were registered, of whom 28 are fully assessable. All patients had been treated with frontline etoposide and cisplatin. Three patients (11%) achieved a partial remission (PR) (durations, 7, 8, and 19 weeks) and two (7%) achieved a minor response; five patients (17%) had stable disease and 18 (65%) had progressive disease. One of the three patients who achieved a PR had failed to respond to frontline cisplatin and etoposide. The overall median survival duration was 20 weeks. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 70% and 31% of courses administered, respectively. No grade 3 to 4 non-hematological toxicities were observed. Grade 1 or 2 nonhematological toxicities (in percentage of patients) consisted of nausea (41%, 8%) and vomiting (25%, 11%), and alopecia (100%). CONCLUSION: TPT at the dose and schedule used has modest antitumor activity in SCLC patients refractory to etoposide and cisplatin, which indicates that clinical resistance to the topoisomerase II poison etoposide does not confer cross-sensitivity to the topoisomerase I poison TPT. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.

Phase I evaluation of all-trans retinoic acid with and without ketoconazole in adults with solid tumors.

PURPOSE: All-trans retinoic acid (RA) induces accelerated plasma all-trans RA clearance, presumably via cytochrome P450 enzymes. This accelerated metabolism has been shown to be inhibited in the short term by the cytochrome P450 inhibitor ketoconazole. This study was conducted to evaluate the efficacy of ketoconazole in maintaining plasma all-trans RA levels over time. PATIENTS AND METHODS: Using a randomized crossover study design, we randomly assigned six patients to receive all-trans RA (45 mg/m2 orally twice per day for 14 days of a 21-day cycle) for cycle 1 and the same dose of all-trans RA plus ketoconazole (400 mg orally for one dose, then 200 mg orally three times per day for 14 days) for cycle 2, and seven patients to receive the same treatment in the reverse order. Plasma all-trans RA levels were measured during the initial 8-hour period after all-trans RA ingestion on days 1 and 15 of cycles 1 and 2. RESULTS: There was a marked decrease in plasma all-trans RA levels after 14 days of treatment, as measured by the area under the concentration-time curve (AUC), regardless of whether ketoconazole was given (from a baseline value of 857 to 44 ng/mL/h; P = .025) or not (from 1,355 to 308 ng/mL/h; P = .123). This lack of effect on plasma all-trans RA levels was not due to inadequate plasma ketoconazole levels. Ketoconazole administration was associated with more toxicity. No objective tumor responses were observed. CONCLUSION: Ketoconazole does not appear to maintain adequate plasma all-trans RA levels over time.

Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer.

PURPOSE: We conducted a phase II study to determine the response to and toxicity of docetaxel (Taxotere; Rhône-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA) in patients with advanced non-small-cell lung cancer refractory to prior platinum-containing chemotherapy (PCC) regimens. PATIENTS AND METHODS: Forty-four patients with stage IIIb or IV platinum-refractory non-small-cell lung cancer were treated with 100 mg/m2 of docetaxel intravenously over 1 hour every 3 weeks. The responses of 42 of 44 patients were assessable. Most patients had a Zubrod performance status of 1; the predominant histologic type was adenocarcinoma (61%), and 91% of patients had stage IV disease. RESULTS: Nine of 42 assessable patients (21%) achieved a partial response to treatment. The median response duration (from response to progression) was 17 weeks, and the projected median survival duration of all patients is 42 weeks (51 weeks for adenocarcinoma and 22 weeks for nonadenocarcinoma). Grade 3/4 neutropenia occurred in 85% of patients and was associated with fever that required intravenous antibiotics in 16% of patients (3% of cycles). Other acute side effects included easily treated hypersensitivity reactions and dermatitis. Cumulative side effects included fluid retention and neuropathy. CONCLUSION: Docetaxel administered at 100 mg/m2 intravenously every 3 weeks has notable activity against platinum-refractory non-small-cell lung cancer, with a 21% major response rate. Primary side effects were neutropenia, hypersensitivity, and fluid retention.

Phase II study of docetaxel for recurrent or metastatic non-small-cell lung cancer.

PURPOSE: We conducted a phase II study to determine the response and toxicity of docetaxel (Taxotere; Rhône-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA) in chemotherapy-naive patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: We treated 41 chemotherapy-naive patients who had stage IIIb or IV non-small-cell lung cancer with 100 mg/m2 of docetaxel intravenously over 1 hour every 3 weeks. Responses were assessed after every one to two treatment courses. Responses of 39 of 41 patients were assessable. The patient's median age was 63 years; 90% of patients had a Zubrod performance status of 0 or 1. The predominant histology was adenocarcinoma (54%), and 90% of patients had stage IV disease. RESULTS: Thirteen patients (33%) achieved a partial response to treatment, and the median response duration was 14 weeks. Grade 3 or 4 neutropenia occurred in 97% of patient; this was usually of brief duration and was associated with serious infection in 17% of patients. Other acute toxic effects included easily treated hypersensitivity reactions (36% of patients) and dermatitis (74%). We also observed fluid retention (with peripheral edema or pleural effusion or both) in 54% of patients. This was a cumulative side effect that generally occurred late in treatment. CONCLUSION: Docetaxel administered at 100 mg/m2 intravenously every 3 weeks has significant activity against non-small-cell lung cancer, with a 33% major response rate. Primary toxicities were neutropenia, hypersensitivity, and fluid retention.

Concurrent chemoradiation therapy with oral etoposide and cisplatin for locally advanced inoperable non-small-cell lung cancer: radiation therapy oncology group protocol 91-06.

PURPOSE: Patients with locally advanced inoperable non-small-cell lung cancer (NSCLC) have a poor clinical outcome. We conducted a prospective study to evaluate the merit of chemotherapy administered concurrently with hyperfractionated thoracic radiation therapy. PATIENTS AND METHODS: Seventy-nine patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Treatment consisted of two cycles of oral etoposide 100 mg/d (50 mg/d if body-surface area [BSA] < 1.70 m2), intravenous cisplatin 50 mg/m2 on days 1 and 8, and hyperfractionated radiation therapy 5 days per week (1.2 Gy twice daily > 6 hours apart; total 69.6 Gy). RESULTS: Seventy-six assessable patients with a Karnofsky performance status > or = 60 and adequate organ function who had received no prior therapy were evaluated for clinical outcome and toxic effects. After a minimum follow-up duration of 21 months, the 1- and 2-year survival rates and the median survival duration were 67%, 35%, and 18.9 months overall; they were 70%, 42%, and 21.1 months for patients with weight loss of < or = 5%. Toxicity was significant; 57% developed grade 4 hematologic toxicity, 53% grade 3 or 4 esophagitis, and 25% grade 3 or 4 lung toxicity. However, only 6.6% of patients had grade 4 or lethal nonhematologic toxicity, which included three treatment-related deaths (two of pneumonitis and one of renal failure). CONCLUSION: Concurrent chemoradiation therapy with oral etoposide and cisplatin plus hyperfractionated radiation therapy is feasible. The survival outcome from this regimen compares favorably with that of other chemoradiation trials and even of multimodality trials that have included surgery.

Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.

PURPOSE: We conducted a phase I trial of the novel nucleoside analog, gemcitabine, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose and efficacy in this population. PATIENT AND METHODS: Eligibility requirements included stage III or IV NSCLC, performance status < or = 1, and no prior chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks every 4 weeks. We enrolled patients at doses that ranged from 1,000 to 2,800 mg/m2/wk (three patients per cohort). Responses were assessed after every two courses (8 weeks). RESULTS: We treated 33 chemotherapy-naive patients with stage III (n = 5) or IV (n = 28) NSCLC. Most had performance status 1, and 67% had adenocarcinoma. Eight of 32 assessable patients (25%) achieved a partial response. The projected median survival duration (all patients) is 49 weeks. The maximum-tolerated dose was 2,200 mg/m2/wk for 3 weeks every 4 weeks; dose-limiting toxicity was myelosuppression and reversible transaminase elevation. Other side effects were consistently mild. The maximum dose-intensity achieved with the first two cycles was 2,362 mg/m2/wk for 3 weeks every 4 weeks, which is a feasible phase II starting dose. CONCLUSION: This study estimates a phase II starting dose of gemcitabine in chemotherapy-naive patients to be 2,400 mg/m2/wk for 3 consecutive weeks every 4 weeks; this is much higher than that previously reported in heavily pretreated patients. Twenty-five percent of patients with advanced NSCLC achieved a partial response to gemcitabine. This significant activity in conjunction with a very favorable toxicity profile supports the further evaluation of gemcitabine in combination with other active agents.

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy.

PURPOSE: This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC with measurable disease in nonradiated fields were eligible. Other eligibility criteria were Zubrod performance status (PS) < or = 2 and adequate renal and liver function. TPT was administered at a dose of 1.5 mg/m2/d for 5 days over 30 minutes every 21 days. Of 48 registered patients, 40 were fully assessable. Nineteen patients had adenocarcinoma (AD), 14 squamous carcinoma (SCC), and seven poorly differentiated carcinoma. RESULTS: Six patients (15%) achieved a partial remission (PR) (durations: 8, 14, 18, 28, 56, and 61 weeks) and four patients a minor response; 10 patients had stable disease and 20 patients progressive disease. The PR rate was 36% (five of 14 patients) in patients with SCC versus 4% (one of 26 patients) in those with other histologies (P = .014). The overall median survival time was 38 weeks and 30% of patients were alive at 1 year. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 76% and 10% of courses administered, respectively. No grade 3 to 4 nonhematologic toxicities were observed. Grade 1 or 2 nonhematologic toxicities consisted of nausea (46% and 5%), vomiting (31% and 7%), and fatigue (53% and 16%). CONCLUSION: TPT at the dose and schedule used has moderate antitumor activity in NSCLC; its activity is mostly limited to patients with SCC. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.

Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group.

PURPOSE: To confirm the promising phase II results of docetaxel monotherapy, this phase III trial was conducted of chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC) who had previously failed platinum-containing chemotherapy. PATIENTS AND METHODS: A total of 373 patients were randomized to receive either docetaxel 100 mg/m(2) (D100) or 75 mg/m(2) (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The three treatment groups were well-balanced for key patient characteristics. RESULTS: Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response with V/I (P =.001 and P =.036, respectively). Patients who received docetaxel had a longer time to progression (P =.046, by log-rank test) and a greater progression-free survival at 26 weeks (P =.005, by chi(2) test). Although overall survival was not significantly different between the three groups, the 1-year survival was significantly greater with D75 than with the control treatment (32% v 19%; P =.025, by chi(2) test). Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel, nor did it impact survival. There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2. Toxicity was greatest with D100, but the D75 arm was well-tolerated. CONCLUSION: This first randomized trial in this setting demonstrates that D75 every 3 weeks can offer clinically meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy.

Cisplatin, etoposide, and paclitaxel in the treatment of patients with extensive small-cell lung carcinoma.

PURPOSE: The combination of cisplatin, etoposide, and paclitaxel was studied in patients with extensive small-cell lung cancer in a phase I component followed by a phase II trial to determine the maximum-tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates. PATIENTS AND METHODS: Forty-one patients were treated between October 1993 and April 1997. Doses for the initial cohort were cisplatin 75 mg/m(2) on day 1, etoposide 80 mg/m(2)/d on days 1 to 3, and paclitaxel 130 mg/m(2) on day 1 over 3 hours. Cycles were repeated every 3 weeks for up to six cycles. The MTD was reached in the first six patients. In these six patients and in the next 35 patients, who were entered onto the phase II trial, response and survival were estimated. RESULTS: At the initial dose level, one of six patients developed febrile neutropenia, and five of six achieved targeted neutropenia (nadir absolute granulocyte count, 100 to 1,000/microL) without any other dose-limiting toxicity, defining this level as the MTD. Grade 4 neutropenia was observed in 88 (47%) of 188 total courses administered at or less than the MTD. Neutropenia was associated with fever in only 17 (9%) of 188 courses, but two patients experienced neutropenic sepsis that was fatal. Nonhematologic toxicity greater than grade 2 was observed in 10 (5%) of 188 total courses, with fatigue, peripheral neuropathy, and nausea/vomiting most common. The overall objective response rate was 90% of 38 assessable patients: six complete responses (16%) and 28 partial responses(74%). Median progression-free and overall survival durations were 31 and 47 weeks, respectively. CONCLUSION: The combination of cisplatin, etoposide, and paclitaxel produced response and survival rates similar to those of other combinations and was well tolerated.

Seizures and dermatitis after exposure to caprolactam.

A 22-year-old man was initially seen with dermatitis, fever, and seizures after three days of occupational exposure to caprolactam, a nylon fiber precursor. A comprehensive neurological investigation showed no organic CNS abnormalities. Although caprolactam has been shown to induce convulsive disorders in experimental animals, to our knowledge, there are no reports of caprolactam-induced seizures in man. The coincidence of typical skin lesions with otherwise unexplained grand mal seizures in this strongly suggests that caprolactam was the cause.

Phase II trial of recombinant IFN-alpha2a with etoposide/cisplatin induction and interferon/megestrol acetate maintenance in extensive small cell lung cancer.

Previous data suggested interaction of cisplatin with interferon (IFN) in non-small cell lung cancer and a possible effect of IFN in maintaining remission in small cell lung cancer (SCLC). This study was designed to further examine the effect of IFN in the treatment of extensive disease (ED) SCLC. Forty previously untreated patients with performance status (PS) of 0-2 (Zubrod scale) were treated with etoposide (100 mg/m2 for 3 days), cisplatin (25 mg/m2 for 3 days) (EP), and recombinant IFN-alpha2a (rIFN-alpha2a) (5 x 10(6) U/m2 for 3 days) for six cycles (induction), followed by rIFN-alpha2a (5 x 10(6) U/m2) thrice weekly and megestrol acetate (40 mg q.i.d.) as maintenance therapy for 6 months or until progressive disease or intolerable toxicity was documented. Patients were 25 men (62%) and 15 women (38%), median age 58 (28-76), median Zubrod performance status 1 (0-2). Major sites of metastasis include liver (55%), bone (42%), bone marrow (25%), and adrenal gland (18%). Of 40 eligible patients accrued to this trial, 35 were evaluable for response, and 37 were evaluable for toxicity. There were 3 complete and 28 partial responses, for an overall response rate of 89%. With 39 of 40 patients followed until death, median survival (Kaplan-Meier) is estimated at 46 weeks (95% CI range 35-55). Twenty patients completed six cycles of induction, and 16 received maintenance therapy, median 2 cycles (range 1-3). Major toxicity during induction included grade 4 granulocytopenia in 24%, grade 2-3 nausea or vomiting or both in 41%, grade 2 fatigue in 24%, grade 2 anorexia in 22%, and grade 2-3 renal insufficiency in 9% of 175 total courses of chemotherapy administered. Toxicity during the maintenance phase was notable for grade 2-3 fatigue in 43%, grade 2-3 anorexia in 24%, grade 2-3 weight loss in 10%, and grade 3-4 anemia in 17% of 30 courses. There were no treatment-related deaths. The addition of rIFN-alpha2a to EP in induction chemotherapy of ED SCLC, followed by rIFN-alpha2a and megestrol acetate maintenance therapy, was reasonably well tolerated. The complete and overall response rates and duration of remission and survival appear to be similar to those generally obtained with EP alone in similar patients.

Randomized phase III study of chemoradiation with or without amifostine for patients with favorable performance status inoperable stage II-III non-small cell lung cancer: preliminary results.

A prospective randomized study was conducted to determine whether amifostine (Ethyol) reduces the rate of severe esophagitis and hematologic and pulmonary toxicity associated with chemoradiation or improves control of non-small cell lung cancer (NSCLC). Sixty patients with inoperable stage II or III NSCLC were treated with concurrent chemoradiotherapy. Both groups received thoracic radiation therapy (TRT) with 1.2 Gy/fraction, 2 fraction per day, 5 days per week for a total dose 69.6 Gy. All patients received oral etoposide (VP-16), 50 mg Bid, 30 minutes before TRT beginning day 1 for 10 days, repeated on day 29, and cisplatin 50 mg/m(2) intravenously on days 1, 8, 29, and 36. Patients in the study group received amifostine, 500 mg intravenously, twice weekly before chemoradiation (arm 1); patients in the control group received chemoradiation without amifostine (arm 2). Patient and tumor characteristics were distributed equally in both groups. Of the 60 patients enrolled, 53 were evaluable (27 in arm 1, 26 in arm 2) with a median follow-up of 6 months. Median survival times were 26 months for arm 1 and 15 months for arm 2, not statistically significantly different. Morphine intake to reduce severe esophagitis was significantly lower in arm 1 (2 of 27, 7.4%) than arm 2 (8 of 26, 31%; P =.03). Acute pneumonitis was significantly lower in arm 1 (1 of 27, 3.7%) than in arm 2 (6 of 26, 23%; P =.037). Hypotension (20 mm Hg decrease from baseline blood pressure) was significantly more frequent in arm 1 (19 of 27, 70%) than arm 2 (1 of 26, 3.8%; P =.0001). Only 1 patient discontinued treatment because of hypotension. These preliminary results showed that amifostine significantly reduced acute severe esophagitis and pneumonitis. Further observation is required to assess long-term efficacy.

Overview of docetaxel (Taxotere) in the treatment of non-small cell lung cancer.

In four initial phase II studies of docetaxel administered as a 1-hour intravenous infusion at a dose of 100 mg/m2 every 3 weeks in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC), the overall response rate was 31% in 128 evaluable patients and the median survival was 9 months. Five subsequent phase II studies of 100 mg/m2 docetaxel in the first-line setting showed similar results, with response rates in the range of 25% to 63% and favorable survival. Lower doses also have been evaluated in two trials using docetaxel 60 and 75 mg/m2, with overall response rates of 25% and 19%, respectively. In the second-line setting, after failure of first-line platinum-based chemotherapy, four studies of docetaxel 100 mg/m2 have achieved response rates of 16% to 22% and encouraging median durations of survival of 30 to 42 weeks. In both first-and second-line settings, the toxicity of docetaxel is tolerable. Docetaxel is clearly an active drug in both the first- and second-line treatment of NSCLC, and recently conducted phase III trials will further define the role of this agent in the standard treatment of NSCLC.

Docetaxel in the treatment of non-small cell lung cancer: review of single-agent trials.

Several phase II studies have evaluated docetaxel, administered as a 1-hour intravenous infusion at a dose of 100 mg/m2 every 3 weeks, for chemotherapy-naive patients with advanced non-small cell lung cancer. Results have been consistent across numerous trials, with an overall response rate in the range of 23% to 38% and a median survival of 9 months. Results of a multicenter phase III trial of docetaxel versus best supportive care for the first-line treatment of non-small cell lung cancer are pending. In the second-line setting, after failure of first-line platinum-based chemotherapy, four phase II studies of docetaxel 100 mg/m2 have achieved response rates ranging from 16% to 22%, with encouraging median survival times of 30 to 42 weeks. Preliminary results of a large, multicenter, randomized phase III trial also indicated an advantage for docetaxel over control with regard to response, time to progression, survival, and quality of life. Results of a multicenter phase III trial of docetaxel versus best supportive care as second-line treatment will be reported soon. Weekly docetaxel has been well tolerated in phase I studies, with dose-limiting toxicity being asthenia rather than myelosuppression. Phase II trials of a dosage of 36 mg/m2/wk in elderly patients with advanced non-small cell lung cancer are ongoing. Docetaxel is a potent radiosensitizer. The dose-limiting toxicity of docetaxel when administered weekly with concurrent chest radiation at 50 to 64 Gy is esophagitis. Phase II trials of weekly docetaxel plus concomitant chest radiotherapy are in progress at the recommended phase II dosage of 20 to 30 mg/m2/wk.

The use of docetaxel (Taxotere) in patients with advanced non-small cell lung cancer previously treated with platinum-containing chemotherapy regimens.

Several phase II studies have evaluated docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) at a dose of 100 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in the second-line treatment of non-small cell lung cancer (NSCLC). Two early phase II studies conducted at the University of Texas M.D. Anderson Cancer Center enrolled NSCLC patients who had failed prior platinum-containing regimen, and response rates of 22% and 17%, respectively, were observed in evaluable patients. The estimated 1-year survival rate for both studies was 40%. In the later phase II studies, patients who had received prior NSCLC treatment were enrolled and response rates ranged from 15% to 22% in evaluable patients. A phase III randomized study was conducted based on these encouraging data. In this first randomized phase III trial of second-line chemotherapy for advanced NSCLC, patients who had been previously exposed to at least one course of platinum-containing chemotherapy received docetaxel at 100 mg/m2 or 75 mg/m2 versus a control regimen of vinorelbine or ifosfamide. This is the first phase III study that has compared the benefits of different chemotherapies in the second-line treatment of NSCLC. Data from this phase III study are forthcoming. These results may provide important objective indications of the quality of life benefits that can be achieved in patients with NSCLC in the second-line setting with an active agent such as docetaxel.

Management strategies for recurrent non-small cell lung cancer.

Because the benefit of first-line chemotherapy for non-small cell lung cancer (NSCLC) may be marginal, the use of chemotherapy in the second-line setting for the patient who has failed primary platinum-containing chemotherapy (PCC) is similarly debatable. The most experience with second-line chemotherapy for NSCLC is with docetaxel. Two identical studies enrolled 88 good performance status (PS) patients with NSCLC resistant or refractory to prior PCC. The partial response rate was 17%, median survival was 39 weeks, and the 1-year survival rate was 40% (compared with historical controls who had median and 1-year survivals of 16 weeks and 16% [P = .003]). Second-line activity of paclitaxel is less clearly defined: three trials are negative, two are equivocal, and one is positive. Comparison of these studies is difficult, however, because of varying drug doses/schedules, small sample sizes, and/or incomplete data. Median and 1-year survivals (available in two studies) were 17 weeks and 16%. Other agents active against NSCLC have been disappointing in the secondline setting, including vinorelbine, irinotecan, vindesine, mitomycin, and etoposide. In conclusion, docetaxel (and perhaps paclitaxel) may offer some benefit to NSCLC patients whose disease has failed initial PCC. However, the routine use of second-line chemotherapy with a taxane should probably be limited to patients with PS of 0 or 1 only.

Summary of phase II data of docetaxel (Taxotere), an active agent in the first- and second-line treatment of advanced non-small cell lung cancer.

Six phase II studies have been conducted in the United States and Europe using docetaxel (Taxotere; Rhone-Poulenc Rorer, Antony, France) for advanced non-small cell lung cancer. One hundred eighty chemotherapy-naive patients in four studies and 88 patients who failed prior platinum-containing chemotherapy in two studies were treated with docetaxel 75 to 100 mg/m2 intravenously over 1 hour every 3 weeks. Fifty-nine percent of patients had adenocarcinoma and 82% had stage IV disease. At a dose of 100 mg/m2, 30% of evaluable chemotherapy-naive patients (27% of the intent-to-treat population) and 20% of evaluable platinum-refractory/resistant patients (17% of the intent-to-treat population) achieved a partial response; projected median survival is 9 months in both studies. Neutropenia was the primary dose-limiting acute side effect. Fluid retention, which occurred in patients who received multiple courses of treatment, was common but rarely dose-limiting, and may be ameliorated with prophylactic corticosteroids. Other toxic effects were relatively mild. Docetaxel has significant activity against advanced non-small cell lung cancer, producing a major response in both chemotherapy-naive patients and patients who had failed prior platinum-containing chemotherapy.

Paclitaxel/carboplatin chemotherapy as primary treatment of brain metastases in non-small cell lung cancer: a preliminary report.

Chemotherapy has been rarely considered an important treatment modality for brain metastases. Based on the hypothesis that the lack of efficacy of chemotherapy, rather than the blood-brain barrier itself, may be the major hindrance to the successful chemotherapeutic treatment of brain metastases, we started a trial in which a selected group of non-small cell lung cancer patients with brain metastases received primary treatment with systemic chemotherapy. The treatment consisted of three courses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 225 mg/m2 given intravenously over 3 hours and carboplatin dosed to an area under the concentration-time curve of 6, with close monitoring of the lesion by computed tomography or magnetic resonance imaging of the brain after each chemotherapy course. Any radiographic or clinical evidence of progression in the brain during treatment or no improvement in the brain after three cycles of chemotherapy mandated whole brain irradiation (30 Gy in 10 fractions). Responding patients received three additional courses of chemotherapy; whole brain irradiation was given after completion of all six chemotherapy cycles. To date, five patients have been enrolled, and one has achieved partial remission both in the brain and at the extracranial site. Other patients did not achieve major objective responses either in the brain or at the extracranial sites. These preliminary results, which are consistent with the study hypothesis, support the feasibility of our approach. We therefore continue to accrue patients for this study.