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Keywords:

  • nonsmall cell lung cancer;
  • docetaxel;
  • cisplatin

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

There is increasing interest in the use of a weekly administration of docetaxel as a way of reducing its hematologic toxicity. The purpose of the current randomized study was to evaluate the toxicity and efficacy of docetaxel plus cisplatin combination on 2 schedules in patients with previously untreated, advanced nonsmall-cell lung cancer (NSCLC).

METHODS.

Consenting patients with advanced NSCLC were randomized to receive first-line chemotherapy with cisplatin 75 mg/m2 on Day 1, plus 3-weekly (75 mg/m2 on Day 1) or weekly (35 mg/m2 on Days 1, 8, and 15 of a 4-week cycle) docetaxel, for up to 6 cycles.

RESULTS.

Of 86 patients accrued, 41 patients were treated with 3-weekly and 43 with weekly docetaxel plus cisplatin. The most frequent grade 3/4 toxicity in the 3-weekly arm was neutropenia (56% of patients). In those receiving the weekly regimen, the frequent grade 3/4 toxicities were fatigue (44%) and nausea/vomiting (35%). The overall response rate was 40% with the 3-weekly and 39% with the weekly arm (P = .74). The median progression-free survival was 4.3 months in the 3-weekly arm and 3.9 months in the weekly arm (P = .08) and the median survival was 10.3 and 10.0 months, respectively (P = .76). Quality of life data showed no relevant difference between the arms.

CONCLUSIONS.

The weekly schedule of docetaxel plus cisplatin combination as first-line chemotherapy for advanced NSCLC, while feasible, has no clear advantage over the standard 3-weekly regimen. Cancer 2007. © 2007 American Cancer Society.

The benefit of palliative chemotherapy for advanced nonsmall-cell lung cancer (NSCLC), which is the leading cause of cancer-related death in Korea,1 is established.2 A number of randomized studies and meta-analyses have reported that cisplatin-based chemotherapy produces modest but significantly improved survival with better quality of life (QOL) compared with that of supportive care alone.2, 3 As a result, current American Society of Clinical Oncology (ASCO) guidelines have established 2-drug combination chemotherapy regimens as the standard of care for patients with advanced NSCLC.4 Although treatment options for NSCLC have expanded in recent years to include newer-generation agents such as vinorelbine, gemcitabine, paclitaxel, or docetaxel, the efficacy of platinum-based doublet therapy appears to have reached a therapeutic plateau, with a median survival of 8 to 10 months seen in patients with advanced disease.5, 6

In the TAX 326 study,7 which included chemotherapy-naive patients with advanced NSCLC, a combination of docetaxel and cisplatin significantly improved overall survival (OS) compared with a combination of vinorelbine and cisplatin combination (11.3 vs 10.1 months; P = .044) as first-line therapy. This led to the current use of docetaxel and cisplatin combination as one of the most important first-line chemotherapy regimens. Although initial Phase I studies suggested that docetaxel administered on a weekly basis was effective with low toxicity at doses up to 45 mg/m2,8, 9 the combination of docetaxel 75 mg/m2 and cisplatin 60–80 mg/m2 administered every 3 weeks is now one of the most commonly used regimens for the first-line treatment of advanced NSCLC.

Although the 3-weekly regimen is active and tolerated, it is associated with a significant incidence of severe neutropenia, often complicated by fever. Therefore, there has been increasing interest in the use of a weekly administration of docetaxel as a way of reducing its hematologic toxicity. In a Phase I study evaluating weekly docetaxel,9 significant alteration in the toxicity profile was observed, with fatigue being the dose-limiting toxicity. Myelosuppression was generally mild and severe neutropenia was uncommon. This altered toxicity profile suggested a potential for better tolerance and increased dose intensity, which was supported by recent randomized studies performed in a second-line setting.10–12

Likewise, weekly regimens of docetaxel in combination with cisplatin were developed in an attempt to increase the therapeutic index of this treatment when used for advanced NSCLC.13–15 In the first-line setting, most studies undertaken to date have been Phase II studies.16–19 Weekly docetaxel plus cisplatin produced minimal myelosuppression and showed activity in the treatment of chemotherapy-naive patients with NSCLC. Given the promising results, we designed the current randomized Phase II study in order to evaluate the safety profile and antitumor activity of two different schedules of docetaxel plus cisplatin given as first-line therapy in patients with advanced NSCLC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

For this single-center randomized Phase II study, eligible patients had histologically or cytologically confirmed AJCC stage IIIB/IV NSCLC. Other inclusion criteria were as follows: age less than 75 years; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; at least 1 bidimensionally measurable lesion or evaluable indicator lesion; adequate baseline bone marrow functions (neutrophil count >1,500/mm3 and platelet count >100,000/mm3); normal hepatic (aspartate aminotransferase [AST]/alanine transaminase [ALT] ≤2.5× upper limit of normal [ULN], bilirubin ≤1.5 mg/dL) and renal (creatinine clearance ≥60 mL/min or serum creatinine ≤ULN) functions; and the provision of a signed written informed consent. Patients were only enrolled if they had no prior chemotherapy, or if prior therapy consisted of adjuvant chemotherapy that had been completed more than 6 months before study entry. Patients were excluded from the study if they had severe comorbid illness, known history of anaphylaxis of any origin, or a history of other primary tumors except adequately treated in situ carcinoma of the uterine cervix and basal or squamous cell skin cancer. All registered patients were mentally capable of understanding the diagnosis and nature of the study. This study protocol was reviewed and approved by the Gil Medical Center (Incheon, Korea) Institutional Review Board.

Patients were stratified according to their performance status (0–1 vs 2) and were randomly assigned to receive either 3-weekly or weekly docetaxel, in addition to cisplatin 75 mg/m2 after adequate hydration on Day 1. The 3-weekly arm received 3-week cycles of docetaxel 75 mg/m2 as a 1-hour infusion on Day 1. Patients randomized to the weekly arm received 4-week cycles of docetaxel 35 mg/m2 on Days 1, 8, and 15. In both arms premedications included adequate antiemetic therapy and dexamethasone before each docetaxel infusion (15 mg given at −12, 0 and +12 hours of every docetaxel administration in the 3-weekly arm and at 0 hour in the weekly arm). Chemotherapy was administered for up to 6 cycles unless there was documented disease progression, unacceptable toxicity, or patient refusal. Second-line treatments were permitted at the investigators' discretion and the nature of any second-line treatments was recorded.

Dose adjustments at the start of a new cycle were based on the worst toxicity observed during the previous cycle. For hematologic toxicity, subsequent cycles were delayed for up to 2 weeks if grade ≥2 toxicities appeared. The dose of docetaxel was reduced if grade 4 myelosuppression or febrile neutropenia was present, and if myelosuppression or febrile neutropenia persisted an additional reduction of docetaxel dose was required. If there was a third such episode docetaxel was discontinued. In the case of grade ≥2 nonhematologic toxicity, treatment was delayed until recovery but not for more than 2 weeks. The dose was reduced in the case of severe nonhematologic toxicity that was not controllable with usual measures, and treatment was discontinued if the patient experienced a significant hypersensitivity reaction or unacceptable toxicity (eg, grade 4 stomatitis or diarrhea, grade ≥3 peripheral neuropathy, severe and persistent skin/nail changes). On the weekly arm, docetaxel administration could be omitted if 1 of the following toxicities was noted on Day 8 or Day 15: grade ≥2 hematologic or nonhematologic toxicities, fever ≥38°C, diarrhea of any grade, or a decreased performance status. Dose adjustment criteria for cisplatin were based on creatinine clearance, which was calculated before the beginning of each cycle, and neuropathy. The dose of cisplatin could be reduced for a reversible decrease of creatinine clearance. Cisplatin was also reduced if grade ≥2 neuropathy appeared.

The use of hematopoietic growth factors was not allowed during treatment, except for patients with febrile neutropenia or grade 4 myelosuppression at the investigators' discretion.

Efficacy and Safety Analyses

Baseline evaluation included a complete medical history, a physical examination, complete blood counts and serum chemistry, chest x-ray, computed tomography of the thorax and upper abdomen, and measurement of the measurable lesion(s). Safety evaluations, including the clinical assessment of any adverse events and laboratory tests, were performed before the start of subsequent cycles. In the weekly arm, clinical adverse events and blood counts were checked on Day 15. Objective tumor response was evaluated before every second cycle and graded using World Health Organization (WHO) criteria. Patients who showed a complete or partial response were reassessed at least 4 weeks later for confirmation of clinical response. All tumor measurements were recorded in millimeters by a pulmonary radiologist, with 2 dimensions in all measurable lesions. If the patient had only evaluable lesion, response was classified as complete response, stable disease, or progressive disease. Progression in nonmeasurable lesions that led to deterioration of the patient's status was classified as progressive disease, regardless of the status of the measurable lesions. Toxicities were evaluated according to the National Cancer Institute criteria (NCI-CTCAE) v. 3. The worst grade of toxicity occurred during the treatment was computed for each patient.

QOL was assessed using the validated Korean version of the European Organisation of Research and Treatment of Cancer questionnaire (EORTC QLQ-C30), which contains 30 questions addressing various aspects of QOL.20, 21 This self-administered questionnaire was completed by patients at baseline, every 2 cycles, and at the end of treatment. QOL scores were descriptively recorded as baseline values and changes from baseline. As a general criterion for a clinically significant improvement or deterioration, we defined a difference of 10 or more from baseline mean score as a clinically significant change.

Statistical Consideration

The objective of this study was to determine whether the weekly docetaxel plus cisplatin combination warranted further evaluation in a larger trial. Thus, this randomized Phase II study was treated for statistical purposes as 2 simultaneous Phase II studies and the Fleming's 1-stage design was applied separately for each treatment arm. Within each treatment arm the design was based on a test of a null hypothesis of 30% versus an alternative of 50%. With a significance level and power set at 0.1, 39 patients per arm were required.

The primary endpoint was to estimate the response rate to the given regimens, particularly to the weekly arm. A chi-square test was used for comparison of categorical variables, and QOL differences between treatment arms were calculated with paired t-tests. Progression-free survival (PFS) and OS were estimated according to the Kaplan-Meier method and the statistical significance of survival curves between the 2 arms was tested with a log-rank test. All P values were 2-sided, with P < .05 indicating statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

A total of 86 patients were entered in this study between January 2004 and December 2005: 42 in the 3-weekly arm and 44 in the weekly arm. One patient assigned to each arm did not receive protocol therapy because of the rapid deterioration of their general condition. However, in an intent-to-treat (ITT) analysis the patients were included in the denominator for treatment outcomes. Clinical characteristics were available for all patients and are listed in Table 1. Because of the stratification by their performance status, baseline characteristics are well balanced between the 2 arms. A majority of patients (73%) had stage IV disease.

Table 1. Patient Characteristics
 3-Weekly armWeekly arm
  • *

    Because patients could have metastases at multiple sites, the total numbers of metastases are greater than the number of patients.

  • ECOG indicates Eastern Cooperative Oncology Group.

No.of patients4244
Age, y
 Median6364
 Range37–7545–74
Sex
 Men2928
 Women1316
Histologic type
 Adenocarcinoma2331
 Squamous cell carcinoma1913
Disease status at registration
 Stage IIIb/recurrent1211
 Stage IV/metastatic3033
No. of involved site(s)
 196
 22118
 3 or more1220
Metastatic site(s)*
 Lung3136
 Malignant effusion1318
 Mediastinal lymph node1824
 Neck lymph node96
 Liver910
 Adrenal31
 Brain36
 Bone139
ECOG performance status31 
0128
12024
21012

Toxicity and Treatment Exposure

There was no significant difference in the number of chemotherapy cycles, with 153 cycles (median, 4; range, 1–6) given to patients in the 3-weekly arm and 144 cycles (median, 3; range 1–6) to the weekly arm (P = .37). Of the 84 patients who started treatment, 12 patients (29%) in the 3-weekly arm and 6 patients (14%) in the weekly arm completed 6 planned cycles. Other than the completion of all 6 planned treatment cycles, the main reasons for treatment discontinuation in the 2 arms were toxicity (38% vs 39%, respectively) and progressive disease (29% vs 39%, respectively). Dose reduction was required in 60 treatment cycles, which accounted for 18% and 22% of cycles, respectively (P = .40), for the 2 arms. In the 3-weekly arm, 17 patients had a treatment delay of >1 week at some time during therapy, and the total number of delayed cycles was 17 (11%). In the weekly arm, treatment delays were required in 15 patients and affected 21 (15%) cycles.

Patients treated with the 3-weekly regimen had a significantly higher incidence of thrombocytopenia (P < .01) and neutropenia (P < .01) of any grade compared with the weekly arm patients. Conversely, patients in the weekly arm experienced a significantly higher incidence of anemia (P < .01), fatigue (P = .04), peripheral neuropathy (P = .03), skin toxicity (P = .01), nail changes (P = .02), and lacrimation (P < .01) compared with patients in the 3-weekly arm. There was no difference in the incidence of stomatitis, nausea/vomiting, or peripheral edema. Diarrhea was noted in both arms, but was more severe in patients receiving the weekly regimen. A summary of toxicities is presented in Tables 2 and 3.

Table 2. Maximum Grade Hematologic Toxicity by Patient
 3-Weekly arm, n = 41Weekly arm, n = 43P
No. (%)No. (%)
Anemia  .01
 Grade 020 (49)7 (16) 
 Grade 110 (24)14 (33) 
 Grade 24 (10)10 (23) 
 Grade 36 (15)8 (19) 
 Grade 41 (2)4 (9) 
Thrombocytopenia  <.01
 Grade 022 (54)36 (84) 
 Grade 110 (24)5 (12) 
 Grade 26 (15)2 (5) 
 Grade 31 (2)0 (0) 
 Grade 42 (5)0 (0) 
Neutropenia  <.01
 Grade 03 (7)29 (67) 
 Grade 15 (12)2 (5) 
 Grade 210 (24)8 (19) 
 Grade 313 (32)3 (7) 
 Grade 410 (24)1 (2) 
Febrile neutropenia7 (17)1 (2).02
Table 3. Maximum Grade Nonhematologic Toxicity by Patient
 3-Weekly arm, n = 41Weekly arm, n = 43P
No. (%)No. (%)
Stomatitis  .13
 Grade 024 (59)18 (42) 
 Grade 16 (15)6 (14) 
 Grade 25 (12)9 (21) 
 Grade 35 (12)8 (19) 
 Grade 41 (2)2 (5) 
Fatigue  .04
 Grade 07 (17)2 (5) 
 Grade 15 (12)7 (16) 
 Grade 215 (37)15 (35) 
 Grade 314 (34)19 (44) 
Nausea/vomiting  .16
 Grade 00 (0)3 (7) 
 Grade 119 (46)14 (33) 
 Grade 212 (29)11 (26) 
 Grade 310 (24)15 (35) 
Peripheral neuropathy  .03
 Grade 020 (49)11 (26) 
 Grade 19 (22)14 (33) 
 Grade 25 (12)9 (21) 
 Grade 37 (17)9 (21) 
Diarrhea  .26
 Grade 033 (81)30 (70) 
 Grade 12 (5)3 (7) 
 Grade 25 (12)4 (9) 
 Grade 31 (2)6 (14) 
Skin  .01
 Grade 037 (90)29 (67) 
 Grade 13 (7)3 (7) 
 Grade 20 (0)2 (5) 
 Grade 31 (2)9 (21) 
Nail  .02
 Grade 035 (85)27 (63) 
 Grade 13 (7)3 (7) 
 Grade 21 (2)6 (14) 
 Grade 32 (5)7 (16) 
Peripheral edema  .51
 Grade 032 (78)36 (84) 
 Grade 16 (15)5 (12) 
 Grade 23 (7)2 (5) 
Lacrimation  <.01
 Grade 037 (90)26 (61) 
 Grade 13 (7)10 (23) 
 Grade 21 (2)4 (9) 
 Grade 30 (0)3 (7) 

The most frequent reasons for treatment delays were neutropenia (for the 3-weekly arm) and fatigue (weekly arm). The most frequent grade 3 or 4 toxicity in the 3-weekly arm was neutropenia (56% of patients) and overall 17% developed febrile neutropenia. In those receiving the weekly regimen, the most frequent grade 3 or 4 toxicities were fatigue (44%) and nausea/vomiting (35%). Hematopoietic growth factor was administered to 7 patients in the 3-weekly arm and to 1 patient in the weekly arm. Severe skin/nail changes and excessive lacrimation occurred almost exclusively in the weekly arm. No patient died of toxicity during treatment.

For patients treated with 3-weekly docetaxel plus cisplatin, the median dose intensity of docetaxel 24.3 mg/m2 per week corresponded to 97% of the scheduled dose, and the median duration of therapy was 3.1 months. For patients treated with weekly regimen, 21% of scheduled Day 15 docetaxel and 6% of Day 8 doses were omitted because of nonhematologic toxicity, as per the protocol criteria. Due to these skipped doses, the median dose of docetaxel in the weekly arm was only 23.1 mg/m2 per week, which corresponded to 88% of the scheduled dose, and the median treatment duration was 2.6 months. Relative dose intensities of cisplatin were 97% for patients in the 3-weekly arm and 98% for those in the weekly arm.

Efficacy

Treatment outcomes obtained in the study are summarized in Table 4. Disease control (objective response and stable disease) in the ITT population was achieved in 67% of patients in the 3-weekly arm and in 75% of patients in the weekly arm, and the overall response rate was 40% with the 3-weekly and 39% with the weekly regimen (P = .74). All responses occurred between 39 and 83 days after the initiation of treatment. At the time of analysis, 74% of the patients had died and the median follow-up duration was 15.4 months. The median PFS was 4.3 months (95% confidence interval [CI]: 2.5–6.1 months) in the 3-weekly arm and 3.9 months (95% CI: 3.1–4.7 months) in the weekly arm (P = .08; Fig. 1). Their median OS was 10.3 months (95% CI: 7.3–13.3 months) and 10.0 months (95% CI: 8.7–11.3 months) in the 3-weekly and weekly arms, respectively (P = .76; Fig. 2). Multivariate analysis revealed that only treatment arm (3-weekly vs weekly) had a significant effect on the hazard of disease progression (hazard ratio, 0.54; 95% CI: 0.33–0.88; P = .01). This effect did not, however, translate into OS benefit (hazard ratio, 0.70; 95% CI: 0.37–1.34; P = .28).

thumbnail image

Figure 1. Kaplan-Meier estimates for progression-free survival by treatment arm; 3-weekly docetaxel plus cisplatin (n = 41, solid line) versus weekly docetaxel plus cisplatin (n = 43, dotted line).

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thumbnail image

Figure 2. Kaplan-Meier estimates for overall survival by treatment arm; 3-weekly docetaxel plus cisplatin (n = 41, solid line) versus weekly docetaxel plus cisplatin (n = 43, dotted line). At the time of analysis the minimum follow-up of patients who were still alive (n = 22) was 10.3 months.

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Table 4. Treatment Outcomes
 3-WeeklyWeeklyP
  1. CR indicates complete response; PR, partial response; SD, stable disease; CI, confidence interval; PFS, progression-free survival; OS, overall survival.

Response rate, overall, %4039.74
 CR10 
 PR1617 
 SD1111 
Dose intensities, %
 Docetaxel97.088.0.07
 Cisplatin97.098.0.99
Dose reduction, per cycle2832.40
Delay >1 wk, per cycle1721.37
Treatment duration, mo
 Median3.12.7.22
 95% CI1.5–4.81.9–3.4 
PFS, mo
 Median4.33.9.08
 95% CI2.5–6.13.1–4.7 
OS, mo
 Median10.310.0.76
 95% CI7.3–13.38.7–11.3 

Second-Line Treatment

Salvage treatment was not specified in the protocol. Palliative radiotherapy was given to 12 patients with symptomatic progression in lung, bone, or brain. We offered second-line chemotherapy to 62 patients after failure. For reasons that are unknown, more patients in the weekly arm received second-line chemotherapy (23 patients in the 3-weekly arm vs 39 in the weekly arm). Second-line therapy after docetaxel plus cisplatin was mostly nonplatinum therapy: 22 patients (8 in the 3-weekly arm vs 14 in the weekly arm, respectively) received gemcitabine-based therapy, 9 patients (2 vs 7 patients in each arm, respectively) received irinotecan, 2 patients (in the weekly arm) received pemetrexed, and 29 patients (13 vs 16 patients, respectively) were treated with gefitinib or erlotinib. Nineteen patients received third-line treatment.

Quality of Life

Baseline QOL questionnaires were completed by 66 (77%) patients: 31 in the 3-weekly arm and 35 in the weekly arm (Table 5). The scores for the baseline QOL were similar in both arms. The baseline highest score of the symptoms scales was assigned to fatigue in both arms, and this was neither improved nor deteriorated after chemotherapy. Change in QOL was defined as the difference between the baseline and mean score reported for each subscale during and after chemotherapy. For both arms, the global QOL and functional scores were unchanged from baseline. When we considered as significant a change of 10 or greater in any of the symptoms scores, there was significant improvement in insomnia scores in the weekly arm. Nausea/vomiting and appetite scores were worsened in both arms. Over the whole treatment period, no relevant difference between arms was detected in the proportion of patients reporting QOL changes from baseline to posttreatment.

Table 5. Patients' Mean Scores on EORTC QLQ-C30
 Baseline, meanChange from baseline, mean
3-WeeklyWeeklyP3-WeeklyWeeklyP
  • EORTC QLQ-C30 indicates European Organisation of Research and Treatment of Cancer questionnaire.

  • *

    Scores range from 0 to 100, with a higher score representing a higher level of function.

  • Scores range from 0 to 100, with a higher score representing a higher level of symptoms.

Global health*66.968.8.79−2.6−4.2.86
Functional scales*
 Physical67.563.4.51−1.60.4.74
 Role68.368.1.98−8.7−7.0.81
 Emotional60.870.0.122.7−2.1.58
 Cognitive91.493.3.48−1.1−5.6.29
 Social53.855.2.79−1.7−1.2.66
Symptoms
 Fatigue49.851.7.776.12.5.60
 Nausea/vomiting5.48.6.2928.025.9.78
 Pain19.422.8.516.77.2.95
 Dyspnea38.734.3.52−1.53.3.49
 Insomnia47.343.8.597.7−11.1.70
 Loss of appetite21.525.7.5232.919.8.13
 Constipation20.833.3.51−5.60.61
 Diarrhea2.23.8.56−15.3−3.0.09
 Economic impact43.044.1.851.17.8.46

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The primary objective of this study was to compare weekly schedule with 3-weekly docetaxel plus cisplatin, the standard first-line chemotherapy for patients with advanced NSCLC. Both treatment schedules showed similar response rates but had different toxicity profiles. The most frequent grade 3 or 4 toxicities were neutropenia in the 3-weekly arm and fatigue in the weekly arm. Of the 84 patients who started treatment, only 18 patients (12 patients in the 3-weekly arm and 6 patients in the weekly arm) completed the 6 planned cycles. The main reason for treatment discontinuation was toxicity rather than progressive disease. The toxicity profiles suggested that the weekly regimen might not have a significant impact on tolerability when compared with the standard 3-weekly docetaxel plus cisplatin schedule.

Although the concept of weekly docetaxel administration was introduced as a way of reducing its hematologic toxicity, previous randomized studies comparing weekly with 3-weekly docetaxel in the treatment of NSCLC were mostly limited to the second-line setting.10–12 These studies showed similar efficacy and improved tolerability with weekly docetaxel compared with the 3-weekly regimen. In a Phase III study, Schuette et al12 concluded that weekly docetaxel at 35 mg/m2 could be recommended as a feasible second-line treatment option for patients with previously treated NSCLC. However, they reported that more patients in the weekly arm had to discontinue treatment due to toxicity than did those in the 3-weekly arm (9.7% vs 12.4%). The median number of treatment cycles delivered was 4 and 2 for the 3-weekly and weekly arms, respectively. Gridelli et al.11 focused on QOL issues and found similar efficacy and some QOL advantages in favor of a weekly treatment schedule. In contrast, Camps et al.22 reported that both 3-weekly and weekly docetaxel are effective and well-tolerated, but they concluded that in general there is no indication to recommend the weekly schedule. Another randomized Phase II study, in which the relative dose intensity delivered was similar for both treatment arms, reported similar efficacy despite a higher rate of severe fatigue with the weekly regimen.10

In our study a weekly docetaxel dose of 26 mg/m2/week was employed, which was comparable to the dose intensity of the standard 3-weekly docetaxel (25 mg/m2/week). However, the true dose intensity of docetaxel in the weekly arm was lower because weekly doses were sometimes omitted due to nonhematologic toxicity. Differences between the 3-weekly and weekly regimens found in the present study are not due to an uneven distribution of patient characteristics (Table 1) or to the number of cycles given. The only bias was that dose omission on Day 15, and even on Day 8, in the weekly arm was necessary for some patients. This dose omission resulted in reduced overall dose intensity for weekly docetaxel. The median relative dose intensity for docetaxel in the weekly arm was 88%, whereas in the 3-weekly arm it was higher at 97%.

While there was no relevant difference in overall survival between the 2 arms, it is worth considering the possible role that salvage treatment could have had on survival, and the administration of epidermal growth factor receptor (EGFR) inhibitors after treatment failure could have influenced survival results. Thirty-one percent of the 3-weekly arm patients received EGFR inhibitors as second-line treatment, and in the weekly arm 36% received gefitinib or erlotinib. It is also possible that the greater incidence of neutropenia in the 3-weekly arm is associated with improved efficacy.23 A previous investigation by Di Maio et al.24 demonstrated that neutropenia during chemotherapy was associated with increased survival of patients with advanced NSCLC. In addition, differences in baseline factors may have contributed to the different results. Current ASCO guidelines recommend that second-line chemotherapy with docetaxel should be confined to patients with adequate performance status,4 thus only patients with a good performance status who had responded to first-line treatment are candidates for second-line chemotherapy. Possible selection of only patients who were eligible for further treatment could influence outcome parameters in previously performed randomized studies.

The overall response rate of 40% and the median OS of 10.3 months obtained with the 3-weekly treatment schedule are consistent with those reported in previous Phase III studies applying the same regimen.6, 7, 25 The comparison of both treatment schedules revealed similar treatment outcomes. This was rather unexpected, considering the results from earlier randomized studies performed in a second-line setting,10–12 and those from nonrandomized studies in first-line setting.16–19 One possible explanation might be the combination with cisplatin. Randomized studies have shown that cisplatin-containing regimens are significantly more toxic than those without cisplatin, due to excessive nonhematologic toxicity of cisplatin.26, 27 A meta-analysis also demonstrated that combination chemotherapy increased toxicity significantly, including a 3.6-fold increase in the risk of treatment-related death compared with single-agent chemotherapy in patients with NSCLC.28 Rather than indicating decreased nonhematologic toxicity of 3-weeks docetaxel plus cisplatin, the difference in toxicity profile is probably a consequence of the combination with cisplatin, as the incidence and severity of toxicities observed in the 3-weekly arm are consistent with the known profiles of standard 3-weekly docetaxel plus cisplatin combination. A randomized Phase II study performed in elderly and/or poor performance patients with advanced NSCLC showed that weekly docetaxel monotherapy had equivalent efficacy but lower hematologic toxicity than 3-weekly docetaxel.29 In the current study, that more patients in the weekly arm experienced severe nonhematologic toxicity, leading to Day 15 dose omission, makes this a likely explanation. Moreover, severe (grade 3) skin/nail changes and excessive lacrimation occurred almost exclusively in the weekly arm. These chronic toxicities that develop and increase with successive treatment were more prominent with weekly dosing. It is also noteworthy that the latest version of NCI-CTCAE (v. 3) includes grade 3 nail changes, whereas in version 2 the rating scale extended only up to grade 2. It is likely that previously reported severities of nail changes were underestimated because of the lack of more specific rating.

Our study is limited in that we performed laboratory tests (ie, complete blood counts) once per chemotherapy cycle in the 3-weekly arm (on Day 1) and twice in the weekly arm (on Days 1 and 15). Lower incidence of grade 3 or 4 neutropenia was in part due to the fact that weekly blood counts were not done for the 3-weekly arm. However, hematologic adverse events including neutropenia and thrombocytopenia were observed more frequently in the 3-weekly arm. More frequent evaluation of these hematologic parameters would likely strengthen rather than weaken our results. We found that the toxicity profiles for the 3-weekly arm were generally consistent with those reported in other Phase III studies.6, 7

We designed the present study to test the hypothesis that weekly docetaxel plus cisplatin is better tolerated than chemotherapy every 3 weeks, especially in the first-line setting. The underlying presumption with a weekly schedule is that it can reduce toxicity and thus allow intensification of the dose without increasing adverse events. However, we find that the weekly schedule, while feasible, has no clear advantage over the standard 3-weekly regimen. Chemotherapy given at intervals of 3 weeks is more efficacious and convenient for most patients, and we believe that this should remain the standard first-line docetaxel schedule. The weekly docetaxel plus cisplatin combination can only be applied to specific patient population who are not expected to tolerate certain toxicities such as febrile neutropenia, including those with a poor performance status, multiple comorbidities, or old age. Additionally, modifications of the weekly regimen, such as docetaxel 35 mg/m2 on Days 1 and 8 every 3 weeks, which is quite similar to the actual dose intensity in the present study and is more convenient, could affect the tolerability or outcome in this setting.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Supported in part by an unrestricted grant from the Gachon University of Medicine and Science Research Fund, Incheon, Korea.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Bae JM, Won YJ, Jung KW, Park JG. Annual report of the Korean central cancer registry program 2000. Cancer Res Treat. 2002; 34: 7783.
  • 2
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