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.

Emerging therapies in non-small-cell lung cancer.

Lung cancer remains the single most devastating cause of cancer-related death with approximately 1.5 million cases of lung cancer expected worldwide and more than 1.3 million cancer-related deaths in 2001. In the United States alone, of 164,100 news cases expected in the year 2000, about 70,000 will be metastatic disease (stage IV), and another 70,000 will be locally advanced (stages IIIA and IIIB). Therefore, the five-year survival rate for lung cancer has improved only incrementally from 5% in the late 1950s to 14% by 1994. While advances in combined modality therapy have led to significant progress against locally advanced disease, it was only a decade ago that few believed that the treatment of stage IV non-small-cell lung cancer was justifiable. However, multiple randomized trials in the 1980s and 1990s have changed the role of chemotherapy in lung cancer, such that by the middle of the next decade, it may be that only patients with stage IA non-small-cell lung cancer are not considered as candidates for chemotherapy.

Docetaxel (Taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials.

The potential benefits of docetaxel (Taxotere; Aventis, Antony, France) to patients with previously-treated non-small cell lung cancer have been evaluated in two prospective randomized phase III trials. In one study, patients with stage IIIB/IV non-small cell lung cancer who had failed previous cisplatin-based chemotherapy were randomized to receive either docetaxel (100 or 75 mg/m2, once every 3 weeks) or best supportive care. Median survival was significantly longer for patients treated with docetaxel 75 mg/m2 (7.5 months v 4.6 months) as was 1-year survival (37% v 11%). A second trial, also in platinum-pretreated patients, randomized patients to docetaxel 100 mg/m2, docetaxel 75 mg/m2, or vinorelbine/ifosfamide. Median survival was similar across the three study groups. Thirty-two percent of patients assigned to docetaxel 75 mg/m2 and 21% to docetaxel 100 mg/m2, were alive at 1 year, versus 19% on the vinorelbine/ifosfamide arm. Docetaxel offers clinically meaningful benefits in the second-line setting. The recommended dose is 75 mg/m2 once every 3 weeks. The adverse events observed were predictable, tolerable, and manageable. These phase III trials showed that docetaxel provided clinical benefits to patients with non-small cell lung cancer.

ZD1839 (Iressa) in non-small-cell lung cancer.

The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in a number of processes that are key to tumor progression, including cell proliferation, angiogenesis, metastatic spread, and inhibition of apoptosis. EGFR is expressed or overexpressed in non-small-cell lung cancer (NSCLC), and EGFR-mediated growth has been associated with advanced disease and poor prognosis in NSCLC patients. ZD1839 (Iressa) is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks EGFR signal transduction. In preclinical studies using NSCLC cell lines, ZD1839 has been shown to inhibit tumor cell growth. In addition, ZD1839, as monotherapy and in combination with commonly used cytotoxic agents, has produced growth delay in NSCLC human xenografts. Preliminary results from phase I trials in patients with advanced disease have shown that ZD1839 has excellent bioavailability, an acceptable tolerability profile, and promising clinical activity in patients with a variety of tumor types, particularly in NSCLC. ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC.

Second-line chemotherapy for non-small-cell lung cancer.

Most of the experience with second-line chemotherapy for non-small-cell lung cancer (NSCLC) comes from small phase II trials, which have shown disappointing or inconsistent results. The notable exception has been docetaxel, which has been extensively studied as a second-line therapy for NSCLC. On the basis of consistent phase II activity, two large randomized phase III trials were conducted for patients with advanced NSCLC that had progressed either on or after first-line platinum-based therapy. In one trial, docetaxel, at either 100 or 75 mg/m(2), was compared with a regimen of either vinorelbine or ifosfamide. In the second trial, docetaxel 75 to 100 mg/m(2) was compared with best supportive care. Both trials showed significant improvement in survival, time to progression, and quality of life in the patients receiving docetaxel versus the control therapy. Based on these two large trials, it appears that the use of second-line therapy with single-agent docetaxel at a dose of 75 mg/m(2) every 3 weeks is a reasonable practice in patients who maintain a good performance status.

Outcome predictors for 143 patients with superior sulcus tumors treated by multidisciplinary approach at the University of Texas M. D. Anderson Cancer Center.

PURPOSE: Superior sulcus tumors (SST) of the lung are uncommon and constitute approximately 3% of non-small cell lung cancer (NSCLC). These tumors cause specific symptoms and signs, and are associated with patterns of failure that differ from those seen for NSCLC tumors in other nonapical locations. Prognostic factors and most effective treatments are controversial. We conducted a retrospective study at The University of Texas M. D. Anderson Cancer Center to identify outcome predictors for patients with SST treated by a multidisciplinary approach. METHODS AND MATERIALS: This retrospective review of 143 patients without distant metastasis at presentation is a continuation of a previous M. D. Anderson study now updated to 1994. In this study, we examine the 5-year survival rate by pretreatment tumor and patient characteristics and by the treatments received. Strict criteria were used to define SST. Actuarial life-table analyses and Cox proportional hazard models were used to compare survival rates. RESULTS: Overall predictors of 5-year survival were weight loss (p < 0.01), supraclavicular fossa (p = 0. 03), or vertebral body (p = 0.05) involvement, stage of the disease (p < 0.01), and surgical treatment (p < 0.01). Five-year survival for patients with Stage IIB disease was 47% compared to 14% for Stage IIIA, and 16% for Stage IIIB. For patients with Stage IIB disease, surgical treatment (p < 0.01) and weight loss (p = 0.01) were significant independent predictors of 5-year survival. Among patients with Stage IIIA disease, the only predictor of survival was Karnofsky performance score (KPS) (p = 0.02). For patients with Stage IIIB disease, the only independent predictor of survival was a right superior sulcus location, which was associated with a worse 5-year survival rate than that for patients with tumors in the left superior sulcus (p = 0.02). More patients with adenocarcinoma than with squamous cell tumors experienced cerebral metastases within 5 years (p < 0.01). Patients without gross residual disease after surgical resection who received postoperative radiation therapy with total doses of 55 to 64 Gy had a 5-year survival rate of 82% as compared with the 5-year survival rate of 56% in patients who received 50 to 54 Gy. Twenty-three patients survived for longer than 3 years. Of these, 4 patients (17%) received radiation therapy alone or in combination with chemotherapy without surgical resection. The other 19 patients (83%) had resection combined with radiation therapy and/or chemotherapy. CONCLUSIONS: The findings from this study confirm the importance of the new staging system, separating T3 N0 M0 (Stage IIB) from Stage IIIA, since there was a significant difference in the 5-year survival (p < 0.01). Interestingly, there was no significant 5-year survival difference between Stage IIIA (N2) and Stage IIIB (T4 or N3). This study also suggests that surgery is an important component of the multidisciplinary approach to patients with SST if their nodes were negative. Disease that is minimally invading surrounding normal structures can be resected followed by radiation therapy in doses of 55 to 64 Gy. Further investigation of treatment strategies combining high-dose radiation therapy (>/=66 Gy) with chemotherapy is indicated for patients with unresectable and/or node-positive (N2) SST.

Phase II study of intravenous Doxil in malignant pleural mesothelioma.

Twenty-four patients with pleural mesothelioma received 50 mg/m2 of Doxil every four weeks. At follow-up, the disease had stabilized in 43% percent of patients and had progressed in 57%. No objective responses were observed. Estimated median survival of all patients was 37 weeks. Major toxicities were erythrodysesthesia of hands and feet and myelosuppression. No cardiac toxicity was observed. We concluded that Doxil at this dosage and schedule is inactive against pleural mesothelioma.

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.

Adenocarcinoma of the lung in young patients: the M. D. Anderson experience.

BACKGROUND: Surveillance, Epidemiology, and End Results (SEER) data for the years 1973-1992 documented that patients age < 50 years presented with more advanced disease. Because of the increase in the incidence rate of lung adenocarcinoma in the past few decades and the presentation of more advanced disease in young patients, this study was performed to determine whether differences in survival exist between younger and older patients with this disease. METHODS: The authors reviewed the experience of the University of Texas M. D. Anderson Cancer Center between 1985-1994, encompassing 157 patients age < 40 years of 4097 patients registered with adenocarcinoma of the lung. For comparison, 157 patients age > 50 years with lung adenocarcinoma were selected; these patients were matched for gender, stage of disease at presentation, and definitive therapy modality to assess survival differences more accurately. Data regarding exposure to second-hand smoke were not collected secondary to lack of documentation in the charts reviewed. RESULTS: There were no significant differences between the 2 groups with regard to the overall survival rate (P = 0.34) or time to progression (P = 0.43). Smoking status (current vs. former vs. never-smoker) was not found to be predictive of survival in either the younger group (P = 0.51) or the older group (P = 0.92). CONCLUSIONS: The data from the current study indicate that overall survival and disease free survival rates were not significantly different in these two groups. Thus, the younger patient population should be treated similarly to the older patient population. However, a surprisingly high percentage of younger patients were female (45%) and had never smoked (27%), suggesting that risk factors other than active smoking may be involved in lung carcinogenesis in these patients.

Lymph node micrometastases in non small-cell lung cancer: clinical applications.

A large number of patients are diagnosed every year with non small-cell lung cancer, and their prognosis and response to treatment are inversely correlated to tumor stage at initial diagnosis. Despite the surgical removal of all apparent malignancy from patients with early disease, many will relapse, presumably as a result of disease that was undetected at initial evaluation. In an effort to identify those patients who have early lymph node involvement by metastatic disease, several groups of investigators have searched for the presence of micrometastases in hematoxylin-eosin-negative lymph nodes using immunohistochemical or molecular methods. Four of six groups of investigators using immunohistochemistry have found a significant incidence of lymph node micrometastases and a direct correlation between the absence of micrometastases and disease-free survival; these are encouraging results that require confirmatory studies. Molecular methods may potentially offer increased sensitivity; however, their high cost and the requirement to process large numbers of samples limits their use to research settings at present.

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.

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.

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.

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.

A pilot trial of hyperfractionated thoracic radiation therapy with concurrent cisplatin and oral etoposide for locally advanced inoperable non-small-cell lung cancer: a 5-year follow-up report.

PURPOSE: To improve the outcome of patients with locally advanced inoperable non-small cell lung cancer (NSCLC), we conducted a pilot trial of concurrent chemoradiation therapy using a cisplatin and oral etoposide regimen given concurrently with hyperfractionated radiation therapy. METHODS AND MATERIALS: In this single-institution pilot trial, we enrolled 23 patients with inoperable Stage IIIa (4) and IIIb (19) NSCLC. Treatment consisted of two cycles of chemotherapy with oral etoposide 50 mg one day alternating with 50 mg b.i.d. (50 mg/day if BSA is < 1.70 m2) on days 1-21 and intravenous cisplatin (40 mg/m2) on days 1 and 8 of a 28-day cycle. Radiation therapy was given twice a day (1.2 Gy per fraction), 5 days a week, to a total dose of 69.6 Gy in 58 fractions over 6 weeks. RESULTS: Overall, 18 (78%) of the 23 patients completed the chemotherapy as planned and 21 (91%) received thoracic irradiation per protocol. One patient died of radiation pneumonitis. Fourteen (78%) of 18 evaluable patients achieved objective responses. The median survival duration was 9.3 months for all patients and 20.2 months for 15 patients who had no more than 5% weight loss. After a minimum follow-up of 5 years, five patients (1 IIIa, 4 IIIb) are still alive and disease-free, which gives an actual 5-year survival rate of 22%. Four of the five 5-year survivors were among those who completed the treatment as planned. CONCLUSION: This long-term survival outcome compares favorably with that of other chemoradiation therapy trials and even with those reported in multimodality trials including surgery. These results suggest that intensive concurrent chemoradiation therapy is feasible, and some patients with locally advanced inoperable NSCLC may enjoy long-term survivorship following nonsurgical therapy.

Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer.

Fifteen patients with Stage IIIB or IV non-small cell lung cancer gave informed consent to receive three or more 96-hour infusions of ATP at a dose of 50 mcg/kg/min or higher to determine whether ATP has antineoplastic activity against this tumor type and to better define the spectrum of toxicity for ATP given as a single agent. There were no objective complete or partial responses observed. The median survival of the overall group was 187 days and the median time to tumor progression was 113 days. The major toxic side effects were chest pain and dyspnea, leading to the cessation of treatment in 5 patients. We conclude that ATP at this dose and schedule of administration is an inactive agent in patients with advanced non-small cell lung cancer.

Gene therapy for non-small cell lung cancer: a preliminary report of a phase I trial of adenoviral p53 gene replacement.

The identification of genetic lesions that lead a normal cell to become malignant presents us with the opportunity of targeting those lesions as a means of therapy. Given the key role played by the tumor suppressor gene p53 in cell cycle regulation and apoptosis, and the evidence linking p53 mutations with non-small cell lung cancer, attempts at p53 replacement are a logical approach to therapy in this disease. In a phase I study, administration of an adenoviral p53 vector (Adp53) to 21 patients with advanced non-small cell lung cancer produced little toxicity. Up to six intratumoral injections at monthly intervals were well-tolerated. Expression of the p53 transgene was evident, along with potentially useful clinical responses. Time to disease progression in the indicator lesion treated with Adp53 appears to be enhanced by higher doses of vector, concomitant cisplatin therapy, and evidence of apoptosis on tumor biopsy specimens. Phase II trials should now be undertaken to determine the response rate to Adp53.

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.

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.