Two phase III trials were conducted using docetaxel (Taxotere), administered every 3 weeks, as second-line treatment of non-small-cell lung cancer (NSCLC) in patients previously treated with platinum-based chemotherapy. In the TAX 317 trial, 204 patients were randomized to receive either docetaxel (49 received 100 mg/m² and 55 received 75 mg/m²) or best supportive care (100 patients). Median survival was 7.5 months with docetaxel at 75 mg/m² (D75) vs 4.6 months for best supportive care (P = .010); and 1-year survival was 37% for D75 vs 11% for best supportive care (P = .010).
ABSTRACT: Two phase III trials were conducted using docetaxel (Taxotere), administered every 3 weeks, as second-line treatment of non-small-cell lung cancer (NSCLC) in patients previously treated with platinum-based chemotherapy. In the TAX 317 trial, 204 patients were randomized to receive either docetaxel (49 received 100 mg/mÂ² and 55 received 75 mg/mÂ²) or best supportive care (100 patients). Median survival was 7.5 months with docetaxel at 75 mg/mÂ² (D75) vs 4.6 months for best supportive care (P = .010); and 1-year survival was 37% for D75 vs 11% for best supportive care (P = .010). Quality-of-life analysis also showed statistically significant improvement in disease-related symptoms with docetaxel vs best supportive care. In the TAX 320 study, 373 patients were randomized to receive docetaxel at 100 mg/mÂ² (D100), docetaxel at 75 mg/mÂ² (D75), or a control arm of either vinorelbine (Navelbine) or ifosfamide (Ifex) (V/I). Partial response rates were 11.9% with D100 and 7.5% with D75 vs 1% with V/I (P values: .001 [D100] and .036 [D75]). Median response duration was over 7 months. One-year survival was 32% with D75 vs 19% in V/I (P = .025). Prior paclitaxel exposure had no bearing on the response rate and survival advantage of second-line treatment with docetaxel. Response rates to docetaxel were equivalent in the cohort of patients who had received prior paclitaxel (10.5%) and the group of patients who had not received prior paclitaxel (8.5%). The 1-year survival rates for patients with no prior paclitaxel therapy were 33% (D75) vs 20% (V/I); and the 1-year survival rates for patients who had received prior paclitaxel were 30% (D75) vs 17% (V/I). In conclusion, two large randomized phase III trials of second-line chemotherapy for NSCLC have shown significant differences favoring docetaxel for response rate, time to progression, survival, and quality of life. Prior paclitaxel did not decrease the likelihood of response to docetaxel, nor did it lessen the survival advantage seen with docetaxel. Docetaxel offers a clinically meaningful benefit in this setting, with manageable toxicity. Based upon the observed response rates, survival, impact on quality of life, and toxicity profile, the optimal dose of docetaxel in this pretreated population is 75 mg/mÂ² every 3 weeks. [ONCOLOGY 16(Suppl 6):45-51, 2002]
In the past several years, medicaloncologists have become increasingly aware that a subset of patients withadvanced non-small-cell lung cancer (NSCLC) may benefit from second-linechemotherapy after the failure of first-line therapy. Most of the data insupport of the use of second-line chemotherapy has been with docetaxel (Taxotere).
Docetaxel as a first-line agent for advanced NSCLC showedconsistent response rates in phase II trials that ranged from 23% to 38%.[1-5]Average median survival is 39 weeks and 1-year survival is 34%. Docetaxel alsohas been systematically evaluated in the second-line setting for NSCLC patientswhose disease has progressed or failed to respond to first-line platinum-basedchemotherapy. Objective radiographic responses were consistently seen in fourphase II studies of docetaxel in the second-line setting, and ranged from 16% to22%.[4-8] Favorable survival rates were noted as well in these trials; themedian survival rate ranged from 5.8 to 9.8 months, and the estimated 1-yearsurvival rate ranged from 25% to 44% (Table 1).[4,6-8]
The most compelling evidence to support docetaxel’sactivity in the second-line treatment of NSCLC comes from two large randomizedphase III trials that compared docetaxel with either best supportive care (TAX317)  or a comparator regimen of chemotherapy (TAX 320)  (Figure1).
The TAX 317 trial was a multicenter international trial ofsecond-line chemotherapy with docetaxel reported by Shepherd.[9,11] Eligiblepatients had advanced NSCLC that had progressed during or after one or moreplatinum-containing chemotherapy regimens. There was no restriction on thenumber of prior chemotherapy cycles or regimens, and there was no restriction onthe prior chemotherapy agents permitted (with the exception that patients withprior paclitaxel exposure were excluded). Patients were required to have anEastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patientswith treated brain metastases were included in the trial.
Eligible patients were stratified by their best response toprior platinum-based chemotherapy and performance status and then randomlyassigned to receive either docetaxel every 3 weeks or best supportive care.The initial trial design called for a docetaxel dose of 100 mg/m² (D100) as a1-hour IV infusion every 3 weeks. However, because of an unexpectedly highoccurrence of adverse events occurring at this dose level, the protocol wassubsequently modified to a docetaxel dose of 75 mg/m² (D75) every 3 weeks.
A total of 204 patients were enrolled in this trial: 49received docetaxel at 100 mg/m², 55 received docetaxel at 75 mg/m², and 100received best supportive care. Patient characteristics and updated results aresummarized in Table 2. About 80% of patients had stage IV disease, and nearly25% of patients had a performance status of 2. The demographics with regard toage and gender were typical for this patient population and were well balancedamong the treatment groups. The predominant histology was adenocarcinoma.One-quarter of patients had received two or more prior chemotherapy regimensbefore enrollment.
Partial response was observed in 6% of patients treated withdocetaxel (either dose level), and another 40% of patients had stable disease.The median response duration was 26 weeks. Time to progression favoredtreatment with docetaxel vs best supportive care. The median time to progressionwas 12.3 weeks with D75 vs 7 weeks with best supportive care (P = .004).
In an intent-to-treat analysis, overall survival also favoredtreatment with docetaxel. For the entire docetaxel group (ie, patients treatedat both D100 and D75), median survival was 7 months (docetaxel) vs 4.6 months(best supportive care). Considering only those patients in the D75 group, themedian survival was 7.5 vs 4.6 months (P = .010), and the 1-year survival ratewas 37% vs 11% (P = .010, Figure 2).
With the exception of grade 3/4 neutropenia, there were noother significant differences in side effects between the D75 arm and bestsupportive care (Table 3).
To support the promising results of the TAX 317 trial, amulticenter US trial (TAX 320) was conducted.[10,12] Eligible patients hadadvanced NSCLC that had progressed during or after one or moreplatinum-containing chemotherapy regimens. There was no restriction on thenumber of prior chemotherapy cycles or regimens, and, in contrast to the TAX 317trial, there was no restriction on the prior chemotherapy permitted.Specifically, patients treated with prior paclitaxel were eligible for thestudy. Patients were required to have an ECOG performance status of 0 to 2.Patients with treated brain metastases were included in the TAX 320 trial.
After stratification by best response to prior platinum-basedchemotherapy and performance status, patients were randomized to eitherdocetaxel at 100 mg/m² every 3 weeks (D100), docetaxel at 75 mg/m² every 3 weeks(D75), or a comparator arm of either vinorelbine (Navelbine) at 30 mg/m²/wk orifosfamide (Ifex) at 2 g/m² × 3 days every 3 weeks. (For patients who wererandomized to arm 3, the choice of either vinorelbine or ifosfamide wasleft to the treating physician.)
A total of 373 patients were enrolled in this trial: 125received docetaxel, 100 mg/m²; 125 received docetaxel, 75 mg/m²; and 123received either vinorelbine or ifosfamide. Patient characteristics and resultsare summarized in Table 4. About 90% of patients had stage IV disease, and 16%of patients had a performance status of 2. The age and gender were typical for alung cancer population and were similar across the three groups. The predominanthistology was adenocarcinoma. Nearly one-third of patients had received two ormore prior chemotherapy regimens before enrollment, and almost 40% of patientshad received prior paclitaxel.
The partial response rate was 12% for patients in the D100group, 8% for those in the D75 group, and 1% for the vinorelbine/ifosfamidecontrol group. The differences in response rates favoring docetaxel over thecontrol group were highly significant (P value of .002). An additionalone-third of patients (in either group) had stable disease. The median responseduration was 9.1 months with D75. Overall time to progression favored treatmentwith docetaxel vs vinorelbine/ifosfamide. Although the median time toprogression was equivalent between the three groups (at about 8 weeks), the26-week progression-free survival was 8% in the vinorelbine/ifosfamide groupcompared with 19% in the D100 group (P = .013) and 17% in the D75 group (P =.031).
In an intent-to-treat analysis, overall survival also favoredtreatment with docetaxel. Although the median survival was equal across thethree arms of the study, at about 5.5 months, the 1-year survival rate wassignificantly higher among patients treated with docetaxel at 75 mg/m² (32% inpatients treated with D75 vs 21% in D100 and 19% in the vinorelbine/ifosfamidegroup). The improvement in 1-year survival for patients randomized to D75 wasstatistically significant (P = .025, Figure3A).
More than one-third of patients in each group receivedsubsequent chemotherapy upon removal from this trial, including taxane therapyin 21% of patients in the control group. Because of the potential impact suchsubsequent therapy may have had on survival, we generated an intent-to-treatsurvival curve in which survival observations were censored at the point atwhich patients received subsequent chemotherapy treatment (Figure3B). In thisintent-to-treat analysis, we observed that 1-year survival significantly favoredtreatment with either docetaxel arm. The 1-year survival was 32% with eitherdocetaxel dose, compared with the 10% 1-year survival in thevinorelbine/ifosfamide group. These differences were highly statisticallysignificant (P =.002).
Grade 4 neutropenia and febrile neutropenia occurred withgreater frequency in both docetaxel arms compared with the control group;documented infection and grade 4 thrombocytopenia, however, were equivalentacross all three arms. Granulocyte colony-stimulating factor (G-CSF [Neupogen])use was greatest in the D100 group (in 28% of the cycles), but was comparablebetween the D75 and vinorelbine/ifosfamide groups. Severe nonhematologic sideeffects, including treatment-related death, were equivalent across the threearms (Table 5).
As previously noted, many patients in this trial had receivedpaclitaxel prior to enrollment into this study: 31% of patients in D100, 42% ofpatients in D75, and 41% of patients in the vinorelbine/ifosfamide group.Although this trial was not designed to assess the clinical benefit of docetaxelin this particular subset of patients, the available data suggest that priorpaclitaxel exposure did not have any bearing on response rate and survivaldata. For example, with regard to objective radiographic response todocetaxel, the partial response rates were equivalent in the cohort of 91patients who had received prior paclitaxel (10.5%) and the group of 159 patientswho had not received prior paclitaxel (8.5%). This finding suggests that priorpaclitaxel therapy had no impact on response rate (Table6).
In a similar analysis of the survival data, we found thatprior paclitaxel therapy had no bearing on the survival advantage seen withdocetaxel. As noted, Figure 3A shows the overall intent-to-treat survival forthe entire study population, showing a 1-year survival of 32% in the D75 groupcompared with 19% in the vinorelbine/ifosfamide group (P = .025). Thissurvival curve is compared with the intent-to-treat survival curves for thesubset of patients with no prior paclitaxel therapy (Figure4A). Overallsurvival is comparable among the three groups, but the 1-year survival againfavors D75 (at 33%) vs the vinorelbine/ifosfamide group (at 20%). (The P valueof .08 is a favorable indication in subgroups of patients with small samplesizes.) Similarly, Figure 4B shows the survival curves for the cohort ofpatients who did receive prior paclitaxel treatment. Again, the curves lookssimilar to the overall survival curves (Figure3A), with the 1-year survivalagain favoring D75 (at 30%) vs vinorelbine/ifosfamide (at 17%). (The P value is.13, which again is a favorable indication in subgroups of patients with smallsample sizes.)
Impact of Second-Line Treatment With Docetaxel on Quality of Life
Both the TAX 317 and TAX 320 trials prospectively evaluatedquality-of-life parameters. Both trials demonstrated clear trends favoringquality of life for the patients treated with docetaxel.
The TAX 317 trial employed the Lung Cancer Symptom Scale (LCSS)and the EORTC-QLQ-C30. All of the quality-of-life parameters that wereconsidered favored the patients treated with docetaxel vs best supportive care.With regard to change in performance status and pain, there was a clear trend(though not statistically significant) in favor of docetaxel. The differences inthe pain control and fatigue scales favoring docetaxel did reach statisticalsignificance (P = .006 and P = .06, respectively).
The TAX 317 patients receiving docetaxel were also noted touse significantly fewer medications for control of tumor-related symptoms. Forexample, 62% of docetaxel patients required "any medication" fortumor-related symptoms, compared with 77% of patients in the best supportivecare group (P = .02). The use of analgesics was significantly less in thedocetaxel-treated patients. Opioid narcotics for pain control were required by32% of patients receiving docetaxel vs 49% of the best supportive care patients(P = .01). Similarly, 39% of docetaxel patients vs 55% of the bestsupportive care patients required nonopioid analgesics for pain (P = .03).
TAX 320 showed similar favorable findings with regard toquality of life using the LCSS. The quality-of-life parameters consideredincluded pain, dyspnea, cough, hemoptysis, fatigue, appetite, activity, symptomdistress, evolution of performance status during treatment, and overall qualityof life. Patients treated in the docetaxel 75 mg/m² arm showed a statisticallysignificant improvement in appetite, symptom distress, performance status, andoverall quality of life as compared with the vinorelbine/ifosfamide controlgroup; and the D75 patients showed a trend (though not statisticallysignificant) favoring pain, dyspnea, fatigue, and activity compared with thecontrol patients. While the data from TAX 320 showed only a modest trendfavoring improvement in quality of life, it is encouraging, nonetheless, thatthe beneficial results with regard to time to progression and survival seen withdocetaxel could be achieved with at least no decrement in quality of life.
Two large randomized phase III trials of second-linechemotherapy for NSCLC have shown significant differences favoring docetaxelwith regard to response rates, time to progression, and duration of survival ascompared with either best supportive care (TAX 317) or a comparator chemotherapyregimen (TAX 320). Quality-of- life analysis also showed a strong trend favoringdocetaxel.
Furthermore, in an updated analysis focusing on the patientswho had received prior paclitaxel treatment before enrollment in the TAX 320trial, it was noted that prior exposure to paclitaxel did not decrease thelikelihood of response to docetaxel, nor did prior paclitaxel treatment seem tolessen the survival advantage of docetaxel in the second-line treatment.
Given these data, a reasonable practice at this time would beto offer a trial of second-line chemotherapy with docetaxel, 75 mg/m² every 3weeks, to patients with NSCLC who have failed first-line chemotherapy. Of note,the majority of the subjects enrolled in the positive trials were in goodcondition, with an ECOG performance status of 0 or 1. Therefore, patientperformance status must be taken into consideration when choosing therapy in thesecond-line setting.
1. Fossella FV, Lee JS, Murphy WK, et al: Phase II study ofdocetaxel for recurrent or metastatic non-small-cell lung cancer. J Clin Oncol12:1238-1244, 1994.
2. Francis PA, Rigas JR, Kris MG, et al: Phase II trial ofdocetaxel in patients with stage III and IV non-small-cell lung cancer. J ClinOncol 12:1232-1237, 1994.
3. Cerny T, Kaplan S, Pavlidis N, et al: Docetaxel (Taxotere)is active in non-small-cell lung cancer: A phase II trial of the EORTC earlyclinical trials group (ECTG). Br J Cancer 70:384-387, 1994.
4. Burris HA, Eckardt J, Fields S, et al: Phase II trials ofTaxotere in patients with non-small-cell lung cancer. [abstract] Proc Am SocClin Oncol 12:335a, 1993.
5. Fossella FV, Lee JS, Berille J, et al: Summary of phase IIdata of docetaxel (Taxotere), an active agent in the first- and second-linetreatment of advanced non-small-cell lung cancer. Semin Oncol 22(2 suppl4):22-29, 1995.
6. Fossella FV, Lee JS, Shin DM, et al: Phase II study ofdocetaxel for advanced or metastatic platinum refractory non-small-cell lungcancer. J Clin Oncol 13:645-651, 1995.
7. Gandara DR, Vokes E, Green M, et al: Activity of docetaxelin platinum-treated non-small-cell lung cancer: Results of a phase IImulticenter trial. J Clin Oncol 18:131-135, 2000.
8. Robinet G, Kleisbauer JP, Thomas P, et al: Phase II studyof docetaxel (Taxotere) in first- and second-line non-small-cell lung cancer(abstract 1726). Proc Am Soc Clin Oncol 16:480a, 1997.
9. Shepherd FA, Dancey J, Ramlau R, et al: Prospectiverandomized trial of docetaxel vs best supportive care in patients with non-small-celllung cancer patients previously treated with platinum-based chemotherapy. J ClinOncol 18:2095-2103, 2000.
10. Fossella FV, DeVore R, Kerr RN, et al: Randomized phaseIII trial of docetaxel vs vinorelbine or ifosfamide in patients with advancednon-small-cell lung cancer previously treated with platinum-containingchemotherapy. J Clin Oncol 18:2354-2362, 2000.
11. Shepherd FA, Fossella FV, Lynch T, et al: Docetaxel (Taxotere)shows survival and quality-of-life benefits in the second-line treatment of non-small-celllung cancer: A review of two phase III trials. Semin Oncol 28(suppl 2):4-9,2001.
12. Fossella FV: Second-line chemotherapy for non-small-celllung cancer, in DeVita V, Hellman S, Rosenberg A (eds): Lung Cancer Principlesand Practice Updates 2001 1st ed, vol 1, pp 1-7. New York, Lippincott Williams& Wilkins; 2001.