- © 2000 by American Society of Clinical Oncology
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
- Frank V. Fossella,
- Russell DeVore,
- Ronald N. Kerr,
- Jeffrey Crawford,
- Ronald R. Natale,
- Frank Dunphy,
- Leonard Kalman,
- Vincent Miller,
- Jin Soo Lee,
- Melvin Moore,
- David Gandara,
- Daniel Karp,
- Everett Vokes,
- Mark Kris,
- Yong Kim,
- Francis Gamza,
- Luz Hammershaimb and
- the TAX Non–Small-Cell Lung Cancer Study Group
- From the TAX 320 Non–Small-Cell Lung Cancer Study Group. See Appendix for complete list of affiliations.
- Address reprint requests to Frank V. Fossella, MD, Department of Thoracic/Head and Neck Medical Oncology University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 80 Houston, TX 77030-4009; email ffossell{at}mdanderson.org
Abstract
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/m2 (D100) or 75 mg/m2 (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 χ2 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 χ2 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.
LUNG CANCER IS THE leading cause of cancer death worldwide. In the United States alone there are more than 170,000 new cases and almost 160,000 deaths annually. It remains the leading cause of cancer-related mortality in both sexes, accounting for 32% and 24% of cancer deaths in men and women, respectively.1 Approximately 75% to 80% of lung cancers are of the non–small-cell (NSCLC) histology. The majority have locally advanced stage III (44%) or metastatic stage IV (32%) disease at diagnosis.
A meta-analysis of eight randomized studies that compared cisplatin-based combination chemotherapy with best supportive care for advanced NSCLC has shown a modest impact on survival: median survival improved from 4 to 7 months, and 1-year survival increased from 5% to 15% in patients who received chemotherapy.2,3 More recent trials have used combination therapy with newer agents, including paclitaxel, docetaxel, gemcitabine, and vinorelbine. Survival data with these newer combinations have been encouraging, with median survival times as high as 11 months and 1-year survival rates as high as 44%. Based on this data, most medical oncologists would offer a trial of systemic chemotherapy, usually with a platinum-based combination regimen as initial treatment, to patients with advanced NSCLC who have an acceptable performance status. Once a patient has progressed on or relapsed after initial platinum-based treatment, however, the role of second-line chemotherapy has been less well-defined. Until recently, most patients were treated with supportive care only or were referred to a clinical trial.
In a recent paper that reviewed the results of clinical trials of second-line chemotherapy for NSCLC, the benefit of treatment with a variety of chemotherapeutic agents was noted to be disappointing.4 Most studies showed response rates of less than 10% and median survival times of 4 months or less. The notable exception, however, has been docetaxel, which has consistently demonstrated activity in the second-line setting in phase II trials.5-8 In these four phase II studies, in which docetaxel 100 mg/m2 (D100) every 3 weeks was administered to a total of 166 patients, response rates of 22%, 17%, 15%, and 22% were observed. Median survival time ranged from 5.8 to 11 months, and the estimated 1-year survival rate ranged from 25% to 40%.
Based on this consistent activity and suggested survival benefit, a randomized phase III study was conducted that compared two doses of docetaxel versus a regimen of vinorelbine or ifosfamide. This third arm was selected as a comparator based on the consensus of investigators that both vinorelbine and ifosfamide were frequently used in this setting at the time of trial design. The primary end point of this trial was survival. Secondary end points included response rate, response duration, time to progression, toxicity, and quality of life. The data presented herein will include results regarding response rate, time to progression, survival, and toxicity. The quality-of-life data of this study will be reported separately.
PATIENTS AND METHODS
Patient Eligibility
This multicenter, open-label, randomized trial was conducted at 23 centers in the United States between June 1995 and January 1998. Eligible patients had locally advanced or metastatic NSCLC that had progressed during or after one or more platinum-based regimens. Before study entry, a minimum of 21 days must have elapsed since any prior chemotherapy. Patients may have had either measurable or assessable lesions. Eastern Cooperative Oncology Group performance status of 0 to 2 was required, as was adequate bone marrow (absolute granulocyte count of ≥ 2.0 × 109 cells/L and platelet count of ≥ 100 × 109 cells/L), hepatic (total bilirubin level within normal limits, alkaline phosphatase level ≤ five times the upper limit of normal, and serum transaminase ≤ 1.5 times the upper limit of normal), and renal (serum creatinine level ≤ 2.0 mg/dL or creatinine clearance ≥ 60 mL/min) function. No restriction was placed on the number of prior chemotherapy regimens, the amount of prior chemotherapy, or the agents used (which may have included paclitaxel). Patients who had received prior radiation therapy were eligible provided that at least 30 days had elapsed from completion of radiation to study entry. Patients with treated brain metastases were eligible provided that they were neurologically stable.
All patients provided written informed consent. The study was approved by local institutional review boards at each participating center and was conducted in compliance with institutional review board regulations.
Treatment Plan
Patients were stratified according to best response to previous platinum therapy (ie, progressive disease [defined as relapse during or within 3 months of receiving platinum] v all other response categories) and performance status (0 or 1 v 2). Patients were then randomized to one of three treatment arms: docetaxel 100 mg/m2 administered as a 1-hour infusion every 3 weeks; docetaxel 75 mg/m2 (D75) as a 1-hour infusion every 3 weeks; or a control arm of either vinorelbine 30 mg/m2 administered as an intravenous infusion on days 1, 8, and 15 of each 3-week cycle or ifosfamide 2 mg/m2/d (with standard-dose mesna) on days 1 through 3 of each 3-week cycle (V/I). For patients randomized to V/I, the choice between vinorelbine or ifosfamide was at the investigator’s discretion.
Patients who received docetaxel were given prophylactic dexamethasone 8 mg orally every 12 hours, for a total of five doses, starting 24 hours before each docetaxel infusion. Patients in the D100 group who experienced grade 4 neutropenia that lasted more than 7 days or that was associated with fever that required parenteral antibiotics were treated with prophylactic filgrastim with each subsequent cycle to avoid dose reductions in this group so that treatment at the 100-mg/m2 dose level could be maintained as long as possible. Hematopoietic growth factors were otherwise not used prophylactically but were permitted therapeutically at the discretion of the treating physician. Prophylactic antiemetics were permitted.
Toxicity evaluations were based on the National Cancer Institute’s common toxicity criteria. Adverse events not included in that toxicity scale (eg, fluid retention, hypersensitivity reaction, onychodystrophy, and asthenia) were graded as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4).
Appropriate dose modifications were made in each treatment group based on toxicity observed with the prior chemotherapy cycle and on the planned day of treatment. Grade 4 neutropenia associated with fever that required intravenous antibiotics necessitated a 25% dose reduction of subsequent cycles in the D75 and V/I groups. Such patients in the D100 group initially received prophylactic filgrastim rather than a dose reduction (as described above), but with a subsequent 25% dose reduction if neutropenic infection recurred despite prophylactic growth factors. Patients who received vinorelbine had their weekly vinorelbine dose reduced by 50% or omitted if the neutrophil count on day 8 or 15 was grade 2 or ≥ grade 3, respectively.
Grade 4 vomiting, despite prophylactic antiemetics, and other grade 3 toxicities generally required a 25% dose reduction. Side effects that mandated removal from the study included grade ≥ 3 neurotoxicity, grade 4 hypersensitivity reaction (or a hypersensitivity reaction that recurred despite treatment), and grade ≥ 3 aberration in liver function tests that lasted more than 3 weeks.
Baseline evaluation before study entry included history and physical examination, complete blood count, biochemical profile, ECG, chest x-ray, and radiographic imaging of all involved sites of disease by computed tomography scan, bone scan, and/or magnetic resonance imaging (as clinically appropriate). Complete blood count was observed weekly. Before each subsequent cycle of treatment, patients underwent history and physical examination, toxicity assessment, complete blood count, biochemical profile, and chest x-ray.
Quality of life was assessed prospectively using the Lung Cancer Symptom Scale (LCSS), a well-validated instrument that consists of both patient-rated and observer-rated items.9-11 The LCSS questionnaire was completed at baseline, immediately before each cycle of treatment, at the end of the treatment period, and at follow-up every 2 months.
Tumor responses were assessed radiographically every two cycles. Designations of complete response, partial response, no change, and progressive disease were based on the standardized response definitions established by the World Health Organization.12 Duration of response and time to progression were calculated as time from randomization to the first objective evidence of tumor progression. Survival was calculated from the date of randomization until death. Patients were treated for a minimum of two cycles (unless this was precluded by unacceptable toxicity or rapid disease progression). Patients with response or stable disease continued treatment for at least six cycles unless there was disease progression or unacceptable side effects. Patients who were responding and stable could receive more than six cycles if they were achieving continued clinical benefit as determined by the treating physician. Patients with disease progression, unacceptable toxicity, treatment delay of more than 3 weeks, or intercurrent conditions that precluded continued treatment were removed from the study. On removal from study, patients were to be observed every 2 months until death to assess adverse events, quality of life, disease status, and survival.
Statistical Analysis
The sample size of this study was based on the assumption that median survival in the group treated with either docetaxel dose would be approximately 7.5 months, compared with 5 months in the group with the V/I control treatment. Given this assumption, a sample size of 360 patients (120 per treatment arm) would allow the detection of the overall survival advantage in either docetaxel arm at an alpha level of 5% (one-sided) and 80% power. Although a one-sided test error was the basis for determination of the sample size, all statistical tests were performed based on a two-sided error of 5%.
The primary efficacy analysis was a comparison of survival in the intent-to-treat population between each dose of docetaxel to the control treatment of V/I. The survival time and time to progression were estimated for each treatment using the Kaplan-Meier (K-M) method. The overall survival curves estimated by this method were compared between treatment groups by a log-rank test. A descriptive point of the K-M curve, such as median survival or median time to progression (50th percentile in each distribution), is shown with 95% confidence intervals. Other descriptive points such as differences in progression-free survival at 26 weeks and the 1-year survival rates were compared between treatments by a χ2 test in a posthoc analysis. Because more than one third of patients continued to receive additional chemotherapy on removal from study and more than 50% of patients in the V/I control group received a taxane (cross-over), another intent-to-treat survival analysis was carried out that censored survival at the time when patients received subsequent chemotherapy on removal from study. In this analysis, the confounding effects of the poststudy chemotherapy on survival were expected to be minimized so that comparisons of docetaxel doses to the control would be robust.
The intent-to-treat population for overall survival included all randomized patients. The intent-to-treat population for time to progression included only those patients with a confirmed diagnosis of NSCLC. The intent-to-treat population for determination of response rate included patients with confirmed NSCLC who actually received at least one infusion of chemotherapy on study.
For the safety analysis, descriptive methods were used without any formal statistical testing. However, for selected adverse events, posthoc statistical testing was performed. The safety population included all patients who received at least one infusion of chemotherapy.
RESULTS
Patient Characteristics
A total of 373 patients were enrolled from 23 centers in the United States. One hundred twenty-five patients were treated in each docetaxel arm, and 123 were enrolled onto the control V/I arm (89 received vinorelbine, and 34 received ifosfamide). All randomized patients were included in the survival analyses (N = 373). Three randomized patients (one in each arm) did not have NSCLC and, so, were excluded from the time-to-progression analysis (N = 370). Twelve patients never received treatment after randomization (four patients per arm), and they have been excluded from safety analysis (N = 361). The 12 nontreated patients and the three treated patients without a diagnosis of NSCLC were excluded from the response assessment analysis (N = 358).
The three treatment groups were well-balanced for age, sex, performance status, disease stage, extent of involvement, and histology (Table 1). Most patients had performance status of 0 or 1 despite their extensive prior therapy. Approximately 90% of patients had stage IV disease. The predominant histology (41% to 56%) was adenocarcinoma. Regarding prior chemotherapy, all three groups were well-balanced for the key parameters of best response to prior platinum-containing chemotherapy (progressive disease in approximately one third of patients in each arm), two or more prior chemotherapy regimens (26% to 35%), and prior paclitaxel exposure (31% to 42% of patients).
Patient Characteristics (N = 373)
Treatment Administration
The median number of cycles of chemotherapy administered was three in each docetaxel treatment group, three in the vinorelbine treatment group, and two in the ifosfamide treatment group (Table 2). In patients who received docetaxel (either arm) and ifosfamide, the median relative dose-intensity approached 1 but was only 0.67 in patients who received vinorelbine, usually because of day 15 myelosuppression that required reduction or omission of that dose.
Dose-Intensity of Treatment (N = 361)
Patients in the D75 group remained on treatment the longest. As listed in Table 2, responding patients in the D75 group received a median of 10 cycles of chemotherapy, versus six cycles in the responders on D100. Similarly, patients with stable disease received a median of six cycles in the D75 group, versus four cycles with D100 and five with V/I.
Efficacy
Objective partial response was assessed in the 358 patients with confirmed NSCLC who received at least one chemotherapy infusion after randomization (Table 3). The partial response rates of 10.8% and 6.7% observed with D100 and D75, respectively, were each significantly greater than the response rate of 0.8% observed in the control arm (P = .001 and P = .036, respectively, by Fisher’s exact test; P = .002 for both docetaxel arms combined). Median response durations (in responding patients) were 7.5 and 9.1 months in the D100 and D75 groups, respectively.
Objective Response to Treatment (N = 358)
Time-to-progression data are shown in Fig 1 and Table 4. Overall time to progression favored treatment with docetaxel; P = .044 (by log-rank test) for D100 versus V/I, and P = .046 for both docetaxel groups combined versus the control group. Although the median time to progression was equivalent in the three treatment arms, the progression-free survival at 26 weeks was 19% with D100 and 17% with D75, compared with 8% in the V/I group. This difference was significant, with P values (by χ2 test) of .013 and .031 for D100 and D75, respectively, compared with the control group, and .005 when both docetaxel doses were combined.
Fig 1. Time to progression. Abbreviations: DOC, docetaxel; VINO/IFOS, vinorelbine or ifosfamide; PD, progression of disease.
Time to Progression (N = 370)
Survival data (N = 373 randomized patients) are shown in Fig 2 and Table 5. The survival for the initial 6 months and the median survival were similar among the three treatment groups (range, 5.5 to 5.7 months). However, 1-year survival comparisons favored patients treated with D75. The 1-year survival rate (intent-to-treat analysis of all randomized patients) of 32% estimated by the K-M method in the D75 group was significantly greater than the 19% in the control group (P = .025, by χ2 test). In this analysis, the 1-year survival estimate for patients treated with D100 was 21% (which was similar to that observed in the V/I group) (Table 5).
Fig 2. Overall survival analysis (intent to treat).
Overall Survival Analysis
These efficacy parameters were further analyzed in subgroups of patients stratified by three patient characteristics: prior paclitaxel exposure, best response to prior platinum-based therapy (progressive disease [platinum-refractory] v other [platinum-resistant]) and performance status (0 or 1 v 2). The likelihood of response to docetaxel was not impacted by prior paclitaxel exposure, because partial response rate was equivalent in patients with and without prior paclitaxel treatment. Furthermore, prior paclitaxel exposure had no bearing on the overall or 1-year survival for each treatment group.
Regarding the stratification factor of best response to prior platinum-based therapy, there was a trend toward a higher partial response rate with docetaxel for patients who were platinum-resistant (10%) versus those who were platinum-refractory (5%). Survival for the D100 and the V/I groups also favored patients whose disease was platinum-resistant, although there was no such relationship for the patients treated with D75.
There was a trend toward better survival in patients with a baseline performance status of 0 or 1 versus 2 for all three treatment groups. However, in both performance status categories the survival advantage of docetaxel over the control treatment remained evident.
In this trial, more than one third of patients continued to receive additional chemotherapy on removal from study. Moreover, of the patients in the control group who did receive subsequent chemotherapy, more than 50% received a taxane. In addition, it was found that aggregated duration of the poststudy chemotherapy (drug exposure) was imbalanced among the groups. Because of the potential impact on survival because of cross-over treatment and the apparent imbalance in exposure to subsequent chemotherapy, survival analysis was also carried out, which censored survival at the time of administration of the additional poststudy chemotherapy (Fig 3 and Table 6). In this survival analysis (which included all randomized patients on an intent-to-treat basis), overall survival was not significantly different between the three treatment arms. Of note, however, is that the overall survival for D100 was similar to that of D75, and the rates of both seemed to be better than that of V/I (P = .13 and 0.12, respectively, by log-rank test). Furthermore, this analysis showed that the 1-year survival rates were significantly greater for both docetaxel doses (32% for D100 and 32% for D75) compared with that of the control group (10%; P < .01, by χ2 test) (Table 6).
Fig 3. Overall survival analysis (intent to treat); censored for subsequent chemotherapy on removal from study (in addition to lost to contact or alive at cutoff date).
Overall Survival Analysis
Safety
Safety was assessed for the 361 patients who received at least one infusion of chemotherapy. Hematologic toxicity is summarized in Table 7. Grade 4 neutropenia occurred in 77% of patients in the D100 group and 54% of patients in the D75 group, each significantly greater than that observed in the V/I group (31%). Grade 4 febrile neutropenia also occurred with significantly greater frequency with either docetaxel dose (12% and 8% for D100 and D75, respectively) compared with the control group (1%). However, the incidence of grade 4 infection was low and did not differ between the three treatment arms. Grade 4 thrombocytopenia was also rare and did not differ between the three treatments. Filgrastim (either prophylactic or therapeutic) was used in 28% of the cycles administered in the D100 group; this was significantly higher than that in the D75 (7% of cycles) and V/I (3% of cycles) groups.
Incidence of Grade 4 Hematologic Toxicities (N = 361)
Grade 3 or 4 or severe nonhematologic side effects are summarized in Table 8. These were relatively infrequent and were no more common among patients treated with docetaxel than among controls. The incidence of treatment-related death was similar between D100 and V/I groups (2% each); there were no (0%) treatment-related deaths in the D75 group.
Incidence of Grade 3 or 4 or Severe Nonhematologic Toxicities (N = 361)
Eleven percent of patients had discontinuation of treatment because of one or more treatment-related adverse events. This occurred in 12.8% of patients in the D100 group (because of neurotoxicity, fluid retention, asthenia, infection, and/or hypersensitivity), 7.2% in the D75 group (because of asthenia, nausea/vomiting, fluid retention, and/or hypersensitivity), and 4.1% in the V/I group (because of neurotoxicity, asthenia, infection, and/or nausea/vomiting). The differences in the rate of treatment discontinuation because of drug-related side effects were not statistically significant.
Quality of Life
The quality-of-life data from this trial will be fully reported in a separate manuscript.
DISCUSSION
Modest survival benefits have been noted with the administration of platinum-based chemotherapy versus best supportive care in patients with advanced NSCLC.2,3 Virtually all patients with advanced disease, however, ultimately develop disease progression after first-line therapy, and many such patients who maintain a good performance status are offered the option of second-line treatment. Most trials of second-line chemotherapy for NSCLC have evaluated relatively small numbers of patients in the phase II setting; these are summarized in Table 9.4 Results from these studies have shown disappointing or inconsistent activity of newer agents such as paclitaxel,13-19 vinorelbine,20-22 gemcitabine,23-27 and the camptothecins28,29 in the second-line setting, with the notable exception of docetaxel. In several phase II trials, docetaxel has been the only agent to show consistently favorable response rate and survival results in the second-line treatment of advanced NSCLC5-8(Table 10). Thus, this phase III trial was initiated to compare two doses of docetaxel with a comparator regimen of vinorelbine or ifosfamide.
This is the first fully reported phase III study that has evaluated the efficacy of chemotherapy in the second-line treatment of NSCLC. Clinical benefit, as determined by objective response, progression-free survival, and 1-year survival, favored the patients who received docetaxel. Although the incidences of grade 4 neutropenia and neutropenic fever were higher in the two docetaxel arms, other treatment-related adverse events were similar across the three arms, as was the incidence of removal from study because of toxicity. The use of filgrastim was relatively high with D100 (28% of cycles). It should be noted, however, that this was more commonly used prophylactically rather than therapeutically, as mandated by the protocol to avoid dose reduction in this group to maintain the 100 mg/m2 dose-intensity. Growth factor use was otherwise infrequent: 7% in the D75 group and 3% in the V/I group.
In an intent-to-treat analysis, overall survival by K-M estimate was not significantly different between the three treatment groups. We did note, however, a significant improvement in 1-year survival for the patients randomized to D75 (32%), compared with 19% 1-year survival in the control group (P = .025). It is notable that the duration of treatment for patients in the D75 group with either responding disease (median of 10 cycles) or stable disease (median of six cycles) was longer than that of patients in the D100 group with similar response designations (medians of six and four cycles, respectively). Thus, patients who received treatment with D100 were removed from the study earlier than those in the lower-dose group; this was, at least in part, because of a lower tolerance of treatment in the D100 group. This earlier treatment discontinuation in the D100 group may account for the better survival noted in the D75 group and indicates that the 75 mg/m2 dosage is the most appropriate dose of docetaxel to use in this setting.
The survival advantage conferred by docetaxel was particularly striking when survival analysis was censored at the time of additional chemotherapy administration. This censored analysis was performed to account for the intended treatment effect on survival without the confounding effect of the poststudy chemotherapy, ie, patients in the control group crossed over to treatment with docetaxel on their disease progression. In this intent-to-treat analysis, overall survival was similar between the two doses of docetaxel and seemed to be better for both doses than for the control. The 1-year survival rate reached statistical significance for both docetaxel doses (32% 1-year survival for either docetaxel group v 10% for the control group; P < .01).
Because of the poor prognosis of patients in this study, it is not unexpected that we observed no clear survival difference in the early months or in median survival between treatments. It is relevant, nonetheless, that there was an improvement in 1-year survival with docetaxel (at 75 mg/m2 in the uncensored analysis and at both dose levels in the censored analysis), because such a plateau in the survival curve at a longer survival end point indicates that a smaller subset of patients is gaining benefit from the treatment.
Additional benefits of docetaxel were also reflected in significantly greater response rates (partial response rates of 10.8% and 6.7% with either docetaxel dose, compared with 0.8% in the V/I group), overall time to progression (which favored D100 and both docetaxel groups combined), and 26-week progression-free survival (19% and 17% in the D100 and D75 groups, respectively, v 8% in the control group).
Furthermore, this trial also demonstrated an objective improvement in quality of life. These data will be detailed in a separate publication. However, a preliminary quality-of-life analysis of this trial reported by Miller et al30 demonstrated a clinical benefit to treatment with docetaxel. Eighty-four percent of patients in the D100 group and 73% of patients in the D75 and V/I groups completed the LCSS quality-of-life questionnaire at baseline and at least once during treatment and were thus assessable for quality-of-life assessment. In an analysis of covariance performed on paired assessments from baseline to last assessment, the descriptors of patient-rated total score, lung cancer symptoms, and observer-rated total score all statistically favored treatment with D100 when compared with the control group (P < .05).
This study included a large number of patients who had received paclitaxel before enrollment: 31% in the D100 group and 42% in the D75 group. It is notable that prior paclitaxel exposure had no bearing on the likelihood of response to docetaxel at either dose level. This suggests that there is no cross-resistance between these two taxanes.
The results of this trial are strongly supported by the preliminary data of another phase III trial reported by Shepherd et al.31 In that multicenter international trial, patients with advanced NSCLC that had progressed on or after at least one prior platinum-containing regimen were randomized to receive docetaxel or best supportive care. The initial docetaxel dose was 100 mg/m2, but this dose was changed midway into the trial to 75 mg/m2 because of toxicity. A total of 204 patients were enrolled onto that trial: 49 received D100, 55 received D75, and 100 received best supportive care. One quarter of the patients had performance status of 2, and approximately 80% had stage IV disease. The partial response rate was 6% with docetaxel, and the median response duration was 6 months. Overall survival favored treatment with D75. In the D75 group, median survival was 9.0 months versus 4.6 months with best supportive care (P = .016), and 1-year survival was 40% with docetaxel versus 16% with best supportive care (P = .016). With the exception of grade 3 or 4 neutropenia, which was observed in 66% of patients, no significant differences in side effects were observed between the D75 arm and the best supportive care arm. Quality-of-life analysis also showed statistically significant improvement in the global quality of life and in pain control for D100 compared with best supportive care.32
The favorable response rate, progression-free survival, 1-year survival, and impact on quality of life noted in this trial suggest that docetaxel has clinically meaningful activity in this group of patients with NSCLC that has progressed after first-line platinum-based treatment. Any future randomized trials that evaluate second-line chemotherapy should include docetaxel as the reference control regimen.
The data from this large phase III study support the practice of offering a trial of second-line chemotherapy with docetaxel to patients with NSCLC who maintain a good performance status. Based on the observed response rates, survival, impact on quality of life, and toxicity profile, the optimal dose of docetaxel in this heavily pretreated population is 75 mg/m2 every 3 weeks.
APPENDIX
The TAX 320 Non–Small-Cell Lung Cancer Study Group included the following: F.V. Fossella and J.S. Lee (University of Texas M.D. Anderson Cancer Center, Houston, TX); R. DeVore (Vanderbilt University Medical School, Nashville, TN); R. Kerr (Texas Oncology, Dallas, TX); J. Crawford (Duke University, Durham, NC); R. Natale (University of Southern California/Norris Cancer Center, Los Angeles, CA); F. Dunphy (St Louis University Health Sciences Center, St Louis, MO); L. Kalman (Oncology-Hematology Group of South Florida, Miami, FL); V. Miller and M. Kris (Memorial Sloan-Kettering Cancer Center, New York, NY); M. Moore (Cancer Specialists of Georgia, Atlanta, GA); D. Gandara (University of California-Davis Cancer Center, Sacramento, CA); D. Karp (New England Medical Center Hospital, Boston, MA); E. Vokes (University of Chicago, Chicago, IL); R. Comis (Jefferson Medical Center, Philadelphia, PA); M. Levitt (Medical College of Pennsylvania, Pittsburgh, PA); M. Kies (Northwestern University Medical School, Chicago, IL); H. Kindler (Roswell Park Cancer Institute, Buffalo, NY); A. Wozniak (Harper Hospital, Detroit, MI); M. Kolodziej (University of Oklahoma Health Science Center, Oklahoma City, OK); J. Reeves (Leecoast Research Center, Fort Myers, FL); L. Stolbach (St Vincent’s Hospital, Worcester, MA); V. Stark-Vancs (M.D. Anderson Cancer Center Network-Tarrant County, Fort Worth, TX); T. Banerjee (Marshfield Clinic, Marshfield, WI); K. Hunt (University of Washington, Seattle, WA); and Y. Kim, F. Gamza, and L. Hammershaimb (Rhône-Poulenc Rorer, Collegeville, PA).
- Received August 31, 1999.
- Accepted February 22, 2000.
