The Oncologist, Vol. 3, No. 2, 86-93,
April 1998
© 1998 AlphaMed Press
Taxotere: Clinical Trials in Non-Small Cell Lung Cancer
Deborah L. Ornstein,
James R. Rigas
Thoracic Oncology Program, Norris Cotton Cancer Center, Section of Hematology/Oncology; Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; Dartmouth Medical School, Hanover, New Hampshire, USA
Correspondence:
James R. Rigas, M.D., Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, New Hampshire, 03756-0001 USA. Telephone: 603-650-6344; Fax: 603-650-8287; e-mail: james.r.rigas{at}dartmouth.edu
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Abstract
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Cisplatin-based chemotherapy regimens of the 1980s have shown a small but significant impact on survival for patients with advanced non-small cell lung cancer (NSCLC). New agents, including docetaxel, have shown encouraging single-agent activity in this disease. This potent microtubule stabilizing agent was selected for clinical development based on its preclinical superiority to paclitaxel. Three hundred twenty-eight (328) patients with advanced or recurrent NSCLC have been enrolled in seven phase II trials of 100 mg/m2 of docetaxel administered intravenously every 21 days. Four of the trials enrolled 160 chemotherapy-naive patients, and three of the trials enrolled 168 patients who failed prior platinum-containing chemotherapy. The antitumor response rate for 160 chemotherapy-naive patients was 27% (95% confidence interval: 20%-34%) with a median survival time of 9.2 months and for 168 platinum-treated patients, 17% (95% confidence interval: 11%-23%). Alopecia, fluid retention, infusion-related reactions, leukopenia, onycholysis, and rash were adverse events observed in these trials. Dexamethasone premedication lessens the frequency and severity of fluid retention, infusion-related reactions, and rash. Docetaxel demonstrates significant antitumor activity in chemotherapy-naive and platinum-treated patients with NSCLC. Trials of docetaxel in combination with carboplatin, cisplatin, vinorelbine, gemcitabine, irinotecan, and thoracic radiation and as primary chemotherapy for stage III NSCLC are in progress.
Key Words. Non-small cell lung cancer • Docetaxel • Phase II trials
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Introduction
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Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths in the United States [1], and only recently has it been shown that treating patients having advanced disease with platinum-based regimens confers a significant survival advantage over supportive care [2, 3]. Over the past few years, however, there have been several advances in the development of cytotoxic therapy for NSCLC, leading to enthusiasm for treating patients with chemotherapy in both the initial and second-line settings. Among these advances has been the demonstration of higher antitumor response rates, symptom palliation, improved management of adverse events and trends toward improved survival. The semisynthetic taxane, docetaxel is one new agent which has shown promising activity in NSCLC
The taxane family of compounds has a common 10-deacetyl baccatin III structure. Docetaxel (Taxotere®; Rhône-Poulenc Rorer; Collegeville, PA) is a synthetic product produced by esterification of the side chain at C-13 of 10-deacetyl baccatin III, a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata) (Fig. 1
) [4]. This hemisynthetic taxane shares a similar mechanism of action with paclitaxel, which is unique among cytotoxic agents. These agents bind to the beta-subunit of tubulin and alter microtubule depolymerization [4-6].
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Figure 1. Chemical structure of docetaxel. This agent is distinguished from other taxoids by the synthetic lipophilic side chain at C-13.
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Although paclitaxel and docetaxel operate on cancer cells via a similar basic mechanism, they differ with respect to several important features, including potency, cellular pharmacokinetics, cell cycle effects, metabolism, and in vitro and in vivo antitumor activity [4-8]. In the most basic assay of tubulin polymerization, docetaxel is approximately twice as potent an inhibitor of microtubule depolymerization as paclitaxel. Paclitaxel appears to inhibit cells in the transition from G2 to M phase of the cell cycle, while maximum cytotoxicity of docetaxel occurs in the S phase. Both agents are metabolized in the liver by the cytochrome P-450 (CYP) oxidases with hydroxylation of paclitaxel by CYP 2C8 and docetaxel by CYP 3A4 [9]. The comparative cellular pharmacokinetics of the taxanes show differences in cellular uptake and efflux favoring increased intracellular exposure for docetaxel. Finally, in vitro cytotoxicity studies of docetaxel showed activity against a broad spectrum of murine and human cell lines, which was 1.3- to 12-fold higher than the antitumor activity of paclitaxel in the same panel of cell lines [10]. Similar results were obtained in studies of freshly explanted human tumor cells [11].
Initial interest in studying docetaxel in lung cancer patients grew out of preclinical studies demonstrating antitumor activity against human and murine lung cancer cells [12]. Phase I studies recommended 100 mg/m2, administered i.v. over one h every three weeks. In this paper, we review the four original phase II studies that have documented the clinical efficacy of single-agent docetaxel in previously untreated patients with advanced NSCLC. In addition, we review the results of reported phase II trials of docetaxel in patients who have failed first-line treatment with platinum agents. Finally, we summarize our approach to treating patients with advanced NSCLC with docetaxel in the outpatient setting.
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Patients and Methods
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Phase II Trials: Previously Untreated Patients
Four phase II studies of docetaxel administered as a single agent at a dose of 100 mg/m2 infused over one h every three weeks have been reported [13-16]. Collectively, these studies enrolled 160 chemotherapy-naive patients with advanced NSCLC in the United States and Europe.
Study Design
Study design was similar for the four trials, each configured as an open-label, phase II trial enrolling patients with unresectable locally advanced or metastatic NSCLC who had received no prior chemotherapy. In three of the studies, bidimensionally measurable disease was required for entry, but measurable or evaluable disease was permitted for entry into the Memorial Sloan-Kettering Cancer Center (MSKCC) trial, which enrolled 29 patients [13].
Treatment Plan
All eligible patients were to receive docetaxel, 100 mg/m2 via one-hour infusion every three weeks in the outpatient clinic until tumor progression, unacceptable toxicity, or death occurred. No antiemetics, growth factors, or corticosteroid premedications were administered initially in these trials. Later protocols were revised to include a course of corticosteroid premedication to reduce the incidence and severity of infusion-related reactions, fluid retention, and cutaneous reactions.
Response Assessment
Antitumor responses were assessed every three weeks by physical examination and chest radiograph and every six weeks by CT scan. Measurable responses were confirmed by follow-up CT scan within four to six weeks. Response to therapy was defined by the status of measurable disease before, during, and after treatment and was graded as a complete response (CR), partial response (PR), or no response. Major response was defined as a CR or PR. All major responses were reviewed by a reference radiologist and an external review panel, and only confirmed responses were included in the efficacy analysis.
Statistical Analysis
Statistical analysis was similar in all four studies. Intent-to-treat analysis was used to analyze the results, and patients with only evaluable disease were included as non-responders. Overall response rates and median and overall survival were reported.
Phase II Trials: Previously Platinum-Treated Patients
Results are available for three phase II trials of docetaxel at 100 mg/m2 every three weeks in patients with advanced NSCLC who have failed treatment with a platinum-based regimen [16-18]. The original two studies enrolled a total of 88 patients and were conducted at the MD Anderson Cancer Center (MDACC) (44 patients) and at the University of Texas Health Sciences Center at San Antonio (44 patients at three sites). The third U.S. study, reported by Gandara et al. [19, 20], was a multicenter trial which enrolled 80 previously platinum-treated patients.
Study Design
Study design was similar for all three trials. Each study enrolled patients with unresectable locally advanced or metastatic NSCLC who had been previously treated with not more than two platinum-based chemotherapy regimens. Patients were deemed platinum-resistant if their tumors responded initially to a platinum regimen but subsequently progressed. Platinum-refractory patients were defined as those whose tumors showed no response to an initial platinum-based regimen. Measurable disease and a Zubrod performance status of 0-2 were required in each study.
Treatment Plan
As in the studies with chemotherapy-naive patients, all eligible patients were to receive docetaxel, 100 mg/m2 via one-hour infusion every three weeks in the outpatient clinic until tumor progression, unacceptable toxicity, or death occurred. Antiemetics and growth factors were not used, but corticosteroids and/or diphenhydramine were administered.
Response Assessment
Antitumor responses were assessed by physical examination and radiographic studies. Response to therapy was graded as a CR, PR, or no response.
Statistical Analysis
Intent-to-treat analyses were reported for the MDACC and San Antonio studies. The recent study by Gandara et al. reported response rates for evaluable patients. As in previous studies, overall response rates and median and overall survival were reported.
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Results
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Phase II Trials: Previously Untreated Patients
Patient Characteristics
The characteristics of all 160 patients enrolled in the four trials are summarized in Table 1. The majority of patients had a good pretreatment performance status (83% Zubrod 0-1) despite the preponderance of metastatic disease (81% stage IV). Approximately one-third of patients were women. The predominant histologic subtype was adenocarcinoma, found in 54% of patients.
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Table 1. Characteristics of 160 previously untreated patients with advanced NSCLC treated with docetaxel, 100 mg/M2 every three weeks
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Antitumor Response
The median number of cycles of docetaxel administered was four (range, 1-33), and the median relative dose intensity was 96%. Efficacy data are summarized in Table 2. Patients were considered evaluable for response if they received at least one cycle of docetaxel. The overall response rate (CR + PR) among the 136 evaluable patients was 31% (95% confidence interval: 24%-39%). The overall response rate for the four studies in 160 patients using intent-to-treat analysis was 27%, with a median response duration of six months (range: 2-13+ months).
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Table 2. Response to treatment with docetaxel, 100 mg/M2 every three weeks in 160 previously untreated patients with advanced NSCLC*
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Survival
The median overall survival for all 160 patients was 9.2 months, and the one-year and two-year survival rates were 39% and 20%, respectively (Fig. 2). The results of the four individual trials are summarized in Table 3 and include an overall analysis of responses in evaluable patients compared with patients in the intent-to-treat group.
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Figure 2. Survival of 160 previously untreated patients with advanced non-small-cell lung cancer who received 100 mg/m2 of docetaxel, infused over one h, once every three weeks. Median survival time of 9.2 months. One-year survival 39%.
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Table 3. Response to treatment with docetaxel, 100 mg/M2 every three weeks in 141 previously untreated patients with advanced, evaluable NSCLC
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Adverse Events
Overall, docetaxel was well tolerated, although the majority of patients developed grade 3 or 4 neutropenia with at least one cycle of therapy. The overall incidence of febrile neutropenia was 19%. Alopecia and fluid retention were the most common nonhematologic toxicities. Fluid retention as a cause for discontinuation in these studies occurred in 6% of patients. In patients who received corticosteroid premedication, the incidence of discontinuation of therapy due to fluid retention was 0.9%. Other toxicities resulting in discontinuation included asthenia (4%), acute hypersensitivity reaction (4%), and peripheral sensory neuropathy (3%). Other side effects, which were generally mild, included nausea, vomiting, mucositis, diarrhea, and dermatitis.
Phase II Trials: Previously Platinum-Treated Patients
Patient Characteristics
The characteristics of patients enrolled in the U.S. trials are summarized in Table 4. As in the trials with previously untreated patients, the majority of patients with platinum-refractory or -resistant disease had metastatic disease and a good pretreatment performance status. Median age was similar in the three U.S. trials. All patients had received prior chemotherapy, and the majority had received prior surgery or radiation therapy. Adenocarcinoma was the predominant histology in the MDACC and San Antonio studies (65%). The MDACC and San Antonio trials included slightly more patients with platinum-resistant (58%) than with platinum-refractory (42%) disease, while the multicenter study enrolled more platinum-refractory (36%) than -resistant (59%) patients.
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Table 4. Characteristics of 168 previously treated patients with NSCLC treated with docetaxel, 100 mg/M2 every three weeks
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Antitumor Response
Efficacy for the three U.S. studies is summarized in Table 5. Overall response rates ranged from 16%-22% in evaluable patients. The overall response rate for the 168 platinum-treated patients was 17% (95% confidence interval: 11%-23%).
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Table 5. Response to treatment with docetaxel, 100 mg/M2 every three weeks in 168 previously treated patients with advanced NSCLCa
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Survival
Median survival ranged from 6 to 11 months. The estimated one-year survival rate for the MDACC and San Antonio trials combined was 40%, whereas the estimated one-year survival in the multicenter trial was 25%.
Adverse Events
Docetaxel was well tolerated by patients who had received prior chemotherapy, and the toxicity profile was similar to that for previously untreated patients. The dose-limiting toxicity was myelosuppression, with febrile neutropenia occurring in 14%-16% of patients overall. Nonhematologic toxicity was likewise similar to that seen in previously untreated patients, with the exception of peripheral neuropathy, which occurred somewhat more frequently in patients who had received prior platinum chemotherapy. The population pharmacokinetic analysis conducted as part of these phase II studies revealed an association between the clearance of docetaxel and the adverse events, particularly febrile neutropenia reports, in these patients [21]. Docetaxel clearance was decreased in patients with hepatic dysfunction as manifested by serum transaminases 
1.5x and alkaline phosphatase 2.5x the institutional upper limits of normal. The presence of liver metastases in the absence of elevated transaminases and alkaline phosphatase did not result in increased toxicity.
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Conclusions
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In phase II trials in previously untreated patients, docetaxel at a dose of 100 mg/m2 infused over one hour every three weeks achieves an overall response rate of 27%, with a median survival of 9.2 months and an estimated one-year survival rate of 39%. The results with docetaxel as a single agent are encouraging, as they compare very favorably with platinum-containing combination regimens [22] (Table 6) and are superior to best supportive care in this patient population [2, 3]. The three phase II studies in platinum-resistant and -refractory patients have demonstrated that docetaxel has significant activity as second-line therapy, with overall response rates ranging from 14% to 22% in intent-to-treat analysis. A retrospective comparison with historical controls conducted at MDACC [23-25] suggests that response rates for docetaxel in the second-line setting may translate into a clinically meaningful survival advantage for patients with a good pretreatment performance status.
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Table 6. Docetaxel versus combination chemotherapy versus supportive care as first-line treatment of advanced NSCLC
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Future Studies in NSCLC
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Docetaxel continues to be studied in order to define its optimum role in NSCLC. Two randomized phase III trials of docetaxel in platinum-resistant/refractory patients with good performance status are presently under way. One study compares docetaxel at doses of 75 and 100 mg/m2 administered over one h every three weeks with best supportive care. A second study compares docetaxel with a control arm consisting of single-agent vinorelbine or ifosfamide. In addition, a randomized phase III trial comparing docetaxel with supportive care as initial therapy for NSCLC patients with good performance status is presently under way. Each study has overall survival as the primary endpoint, with response rate and quality of life as secondary endpoints.
In previously untreated patients, docetaxel is currently being studied in phase II trials in combination with other chemotherapy agents, including cisplatin [26-30], carboplatin, gemcitabine [31], and vinorelbine [32, 33]. Preliminary results are currently available for cisplatin and vinorelbine combinations. Response rates are very encouraging, ranging from 30% to 51% for the docetaxel/cisplatin combination and 23% to 55% for the docetaxel/vinorelbine combination. Results of a phase I study of docetaxel and concomitant thoracic radiation have been reported in patients with advanced NSCLC requiring radiation as part of their treatment regimen [34]. Esophagitis and neutropenia were the dose-limiting adverse events, and the recommendation for a phase II dose and administration schedule is 20 mg/m2/week. Finally, studies using docetaxel as primary chemotherapy in the neoadjuvant setting for patients with early-stage NSCLC prior to surgical resection or thoracic radiation therapy are ongoing [35].
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Practical Use of Docetaxel in NSCLC
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Our approach to treating patients with stage IIIB (T4 pleural effusion) or IV NSCLC who have a good performance status is to use a platinum-containing regimen (e.g., vinorelbine and cisplatin) as the first-line therapy, consistent with the recently published American Society of Clinical Oncology guidelines [36]. In light of the results of recently published randomized trials [22, 37], single-agent vinorelbine for patients with advanced disease is an excellent choice for initial therapy. Single-agent vinorelbine in this setting resulted in median and one-year survival rates similar to the older platinum-containing regimen (vindesine and cisplatin). In general, we encourage patients in a position to receive second-line treatment to participate in a clinical trial whenever possible. However, in cases where patients with good performance status are otherwise not candidates to participate in a study, we regard docetaxel as an excellent second-line treatment option.
Our protocol (Fig. 3) administers docetaxel at a dose of 75 to 100 mg/m2 via one-hour i.v. infusion every three weeks in the outpatient clinic. We administer dexamethasone, 8 mg orally twice a day for five doses, beginning the day before chemotherapy administration. This oral premedication reduces the incidence and severity of infusion-related reactions, rash, and peripheral edema. We do not use growth factors, and most patients do not require antiemetics. We continue therapy in patients with stable or responding disease until disease progression, unacceptable toxicity, or patient request to stop therapy occurs. Our experience with adverse reactions parallels that of the major trials. For those patients with a normal bilirubin and hepatic dysfunction defined as transaminases 1.5x and alkaline phosphatase 2.5x upper limit of normal, the clearance of docetaxel will be delayed, and these patients are at greater risk for febrile neutropenia. We do not administer docetaxel to patients in whom there is evidence of hyperbilirubinemia. Studies are under way to define the safe dose and schedule of docetaxel for patients with hepatic dysfunction. We routinely administer docetaxel safely to patients with liver metastases whose liver enzymes are within these parameters. In patients who develop febrile neutropenia, we institute a 25% dose reduction with subsequent cycles. Other adverse events for which we dose reduce are peripheral neuropathy and severe fatigue. Infusion-related reactions and peripheral edema develop in a very small proportion of patients who receive appropriate dexamethasone treatment and are readily managed with standard supportive measures in the outpatient clinic. Specifically, infusion-related reactions are often related to the infusion rate and may be minimized by slower initial infusion. A short course of diuretics, dose reduction, and/or longer treatment intervals (every four to five weeks) are useful for managing peripheral edema, should it develop. Overall, we have found that docetaxel is an effective second-line treatment for patients with NSCLC having a good performance status after platinum-based primary therapy. Docetaxel is easily delivered in the outpatient setting, and the majority of patients find the toxicity profile acceptable.
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Summary
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The outlook for patients with advanced NSCLC has improved over the past few years with the development of more effective chemotherapy agents. Previously, treating NSCLC patients with second-line chemotherapy after first-line platinum therapy had failed was considered hopeless. Currently, however, a significant proportion of patients can look forward to improved survival with second-line treatment. The phase II data for docetaxel in advanced NSCLC are very encouraging for both chemotherapy-naive and pretreated patients. The response rates for single-agent docetaxel at 100 mg/m2 every three weeks in previously untreated patients are comparable to response rates for platinum-based combinations and are superior to those reported for best supportive care (Table 6
). In platinum failures, docetaxel shows significant antitumor activity, which appears to translate into clinically meaningful survival. Combinations of docetaxel and newer agents show significant promise in initial studies. Although the optimum role for docetaxel in NSCLC remains to be elucidated, given the encouraging phase II results in platinum failures, we regard docetaxel as a reasonable chemotherapeutic option as initial and second-line therapy for patients with a good performance status. It has demonstrated efficacy with an acceptable toxicity profile and is conveniently administered in the outpatient setting.
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Acknowledgments
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The authors do not have any financial interests and have not received any financial support for the preparation of this manuscript. The authors have received grant support for clinical research from the Hitchcock Foundation, American Cancer Society, Janssen Pharmaceutica, Ligand Pharmaceutical, Bristol-Myers Squibb, Rhône-Poulenc Rorer, and Ortho Biotech.
Presented in part at the Network for Oncology Communication and Research meeting in Boca Raton, Florida, February 21, 1997.
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accepted for publication March 3, 1998.
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Abstract
Introduction
