Comparison of docetaxel and docetaxel–irinotecan combination as second-line chemotherapy in advanced non-small-cell lung cancer: a randomized phase II trial

D. Pectasides1,*, M. Pectasides1, D. Farmakis2, V. Kostopoulou2, M. Nikolaou2, A. Gaglia2, M. Koumpou2, N. Mylonakis2, N. Xiros1, T. Economopoulos1 and S. A. Raptis1

1 Second Department of Internal Medicine – Propaedeutic, Athens University Medical School, Attikon University Hospital, Athens; 2 Second Department of Medical Oncology, Metaxas Memorial Cancer Hospital, Piraeus, Greece

* Correspondence to: Dr D. Pectasides, Gravias 5B, Aghia Paraskevi, Athens 15342, Greece. Tel/Fax: +30-210-600-8610; Email: pectasid{at}otenet.gr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The aim of this study was to evaluate whether docetaxel (taxotere) treatment with or without irinotecan improved patient outcomes with similar toxicity in recurrent non-small-cell lung cancer (NSCLC).

Patients and methods: Patients with recurrent platinum-refractory NSCLC with Eastern Cooperative Oncology Group performance status of 0–2 were randomized to either docetaxel 30 mg/m2 and irinotecan 60 mg/m2 (days 1 and 8) or docetaxel 75 mg/m2 (day 1), both administered every 3 weeks.

Results: A total of 130 patients were randomized. The response rate (RR) (20% versus 14%), overall survival (6.5 months versus 6.4 months) and 1-year survival (37% versus 34%) were similar in the combination and docetaxel arms, respectively. The combination arm demonstrated a longer time to tumor progression (TTP) (5.6 versus 4.8 months; P=0.065). Grade 3–4 neutropenia and anemia were similar in the combination and docetaxel arms. Grades 3–4 non-hematological toxicity (except diarrhea) was mild and was similar in the two groups. Grade 3–4 thrombocytopenia (17% versus 6%; P=0.04) and diarrhea (12% versus 3%; P=0.05) occurred more frequently in the combination arm.

Conclusions: The administration of irinotecan with docetaxel in platinum-refractory NSCLC prolonged TTP, but did not improve significantly RR, median survival or 1-year survival. Second-line docetaxel monotherapy offers significant and reproducible efficacy in platinum-refractory NSCLC.

Key words: docetaxel, irinotecan, non-small-cell lung cancer, platinum-refractory, salvage regimen, second-line chemotherapy


    Introduction
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 Abstract
 Introduction
 Patients and methods
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Patients with non-small-cell lung cancer (NSCLC) frequently relapse after first-line and require second-line chemotherapy. Many investigators claim that non-elderly patients with a good performance status (PS) who have relapsed after first-line cisplatin-based chemotherapy require treatment for the relief of tumor-related symptoms [1Go]. Early reviews of second-line chemotherapy for NSCLC reported disappointing results in the treatment of recurrent cisplatin-refractory NSCLC, with response rates (RRs) of <15% in small phase II trials [2Go].

Docetaxel is a semisynthetic taxoid derivative administered as first-line treatment of advanced NSCLC. In a study that examined patients with advanced NSCLC, the observed RR was 30%, the median survival time was 9 months and neutropenia was the primary dose-limiting adverse event [3Go]. Reproducible activity was noted in eight phase II trials [4Go–11Go] of single-agent docetaxel in platinum-pretreated patients with NSCLC, resulting in RRs ranging from 16% to 31% and a median survival of >7 months. In two subsequent randomized trials, docetaxel 75 mg/m2 administered every 3 weeks resulted in a survival benefit over either vinorelbine or ifosfamide [12Go], or best supportive care [13Go]. Thus, single-agent docetaxel is effective in the salvage treatment of recurrent platinum-refractory NSCLC.

Irinotecan is a semisynthetic camptothecin derivative with single-agent activity in NSCLC cell lines [14Go,15Go]. In chemotherapy-naïve patients with NSCLC, irinotecan induced an objective RR of 15% to 34% [16Go–18Go]. Irinotecan produced an overall clinical RR of 16% in patients with advanced NSCLC pretreated with platinum and taxanes [19Go]. Principal toxic effects observed with irinotecan included myelotoxicity, nausea, vomiting and diarrhea [17Go].

In addition to the observed activity of docetaxel and irinotecan in NSCLC, these compounds possess different mechanisms of action, non-overlapping toxic effects, good general tolerance and easy administration in an outpatient setting. Our study investigated whether the combination of docetaxel and irinotecan demonstrates superiority over docetaxel monotherapy as salvage treatment in patients with advanced NSCLC who have previously failed platinum-based chemotherapy.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Eligible patients over 18 years of age presented with histological or cytological proof of NSCLC, failure of first-line platinum-based chemotherapy and an Eastern Cooperative Oncology Group (ECOG) PS of 0–2. Other eligibility criteria were measurable disease area not subject to irradiation, a predicted life expectancy of at least 12 weeks, no prior chemotherapy with docetaxel or irinotecan, and completion of previous chemotherapy at least 4 weeks before enrollment. Only one prior (first-line) regimen was allowed. Adequate bone marrow reserve [white blood cell count ≥4000/ml, absolute neutrophil count (ANC) ≥2000/ml, platelet count ≥100 000/ml], and adequate renal (serum creatinine ≤2 mg/dl) and hepatic (total serum bilirubin ≤1.5 mg/dl, serum transaminases <3x the institutional upper normal limit) functions were required of all patients.

Exclusion criteria included active infections, heart disease and a history of previous malignancies other than adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix. Patients with grade 2 neurotoxicity on the WHO scale, or those receiving antiseizure medication, were also excluded. Informed consent was obtained for all patients and the local ethics committee approved the protocol.

Response and toxicity evaluation
Pretreatment evaluations included complete patient history, physical and neurological examinations, assessment of ECOG PS, and routine laboratory tests. Tumor measurements were assessed by computed tomography and bone scans performed within 3 weeks preceding enrollment. Clinical benefit response was evaluated by a specially designed questionnaire that assessed eight symptoms (pain, cough, dyspnea, hemoptysis, nausea, vomiting, weakness and appetite), each on a scale from 0 (best) to 10 (worst), along with body weight, ECOG PS and the patient's general feeling (classified as very good, good, moderate or poor). Each patient was asked to complete this questionnaire at baseline, every second chemotherapy cycle and at the end of treatment.

Randomization and treatment
Patients who fulfilled the eligibility criteria and underwent staging procedures were randomized to either docetaxel 75 mg/m2 (1-h infusion with steroid premedication) on day 1 or docetaxel 30 mg/m2 (1-h infusion with steroid premedication) and irinotecan 60 mg/m2 (90-min infusion) on days 1 and 8, both administered every 3 weeks [20Go]. Doses were modified according to any hematological and non-hematological toxic effects detected. If the ANC was ≤1500/ml and/or the platelet count was ≤75 000/ml at nadir, both drug doses were reduced by 20%. If the ANC was <500/ml and/or the platelet count was <50 000/ml at nadir, both drug doses were reduced by 30%. For subsequent courses, full doses were administered if on the day of treatment the ANC was ≥1500/ml, the platelet count was ≥100 000/ml and non-hematological toxicity was grade <2. For non-hematological toxic effects of grade 3–4, treatment was delayed until recovery to grade 1, and the doses were reduced by 30%.

Statistical analysis
Sample size was based on overall RR. Assuming a baseline RR of 20%, a sample of 124 patients would suffice to detect a difference of ±25% with an 80% power at the 5% level of significance. Assuming a withdrawal rate of 3%, a minimum of 128 patients needed to be enrolled in the study. Toxic effects and response were graded according to WHO criteria. Response duration was documented from evidence of response to first disease progression. Survival was calculated from date of treatment initiation to the day of death. Time to tumor progression (TTP) was determined by the interval between treatment initiation and first evidence of tumor progression. Response was evaluated every second cycle or whenever disease progression was suspected. Patients with non-progressive disease continued treatment for at least six cycles, or more if found beneficial. Patients with disease progression, unacceptable toxic effects and treatment delays of >2 weeks discontinued treatment. A log-rank test was used to compare Kaplan–Meier curves for survival and TTP.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient demographics
One hundred and thirty patients were enrolled in the study, 65 in each arm (Table 1). Most of these patients had an ECOG PS of 0–1, despite their extensive tumor disease. All patients had received first-line platinum-based chemotherapy and were well balanced for best response (response/stable disease, 62%/60%) and prior exposure to other agents. Platinum-refractory disease, defined as disease progression during therapy or within 60–90 days of completing therapy, was present with a similar occurrence in both treatment arms (78% in monotherapy arm and 77% in combination arm). One patient in the combination arm withdrew after the first cycle upon experiencing severe asthenia and fatigue. One patient in the docetaxel arm had a myocardial infarction and two patients (one in each arm) died soon after the initiation of treatment due to rapid disease progression.


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Table 1. Patient characteristics

 
Chemotherapy administration
The median number of cycles administered per patient was three in each arm (range: docetaxel arm 1–14, combination arm 1–9). The median relative dose intensity was 89% in the docetaxel arm versus 86% for docetaxel and 85% for irinotecan in the combination arm.

Efficacy
Sixty-three patients in each arm were assessed for response (Table 2). On intention-to-treat analysis, nine patients [14%; 95% confidence interval (CI) 5.5% to 22%] in the docetaxel arm and 13 (20%; 95% CI 10% to 29%) in the combination arm achieved a partial response (P=0.36). Twenty-three patients (35%; 95% CI 23% to 46%) in the docetaxel arm and 24 patients (37%; 95% CI 25% to 48%) in the combination arm had stable disease (P=0.81). The combination arm demonstrated longer TTP (5.6 versus 4.8 months; P=0.065), while overall survival (6.5 versus 6.4 months) and 1-year survival (37% versus 34%) were not significantly different in the two arms (Figure 1). Patients with an ECOG PS of 0 and 1 responded to this second-line chemotherapy. Of the nine responders in the docetaxel arm, five had responded to prior chemotherapy, three had achieved stable disease and one had progressed while receiving carboplatin and etoposide. In the combination arm, seven had responded to prior chemotherapy, five had achieved stable disease and one had progressed while receiving carboplatin and etoposide. Responses in both treatment arms were not affected by prior paclitaxel exposure.


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Table 2. Objective response to treatment (n=130)

 


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Figure 1. (A) Kaplan–Meier curves for time to tumor progression in both treatment arms (log-rank test, P=0.065). (B) Kaplan–Meier survival curves in both treatment arms (log-rank test, P=0.49).

 
Both treatment arms demonstrated equivalent clinical benefit response, including an improved PS, improvement in dyspnea, cessation of hemoptysis, and improvement in anorexia and fatigue (Table 3).


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Table 3. Clinical benefit

 
Safety and tolerability
One hundred and thirty patients were assessed for toxicity (Table 4). Toxic effects included grade 3–4 neutropenia and anemia, which were similar in the two arms, and grade 3–4 thrombocytopenia (17% versus 6%; P=0.04) and diarrhea (12% versus 3%; P=0.05), which were different in the two arms. Three patients (5%) in each arm developed febrile neutropenia and, except for one patient who died of sepsis, were treated with broad-spectrum antibiotics and granulocyte colony-stimulating factor (G-CSF). Therapeutic or prophylactic administration of G-CSF for grade 4 or febrile neutropenia was required in 18 patients (28%) in the docetaxel arm and 22 patients (34%) in the combination arm. Myelosuppression and diarrhea resulted in dose reductions and treatment delays. A delay in treatment occurred in 8% and 10% of the courses administered in the docetaxel and combination arm, respectively. Two patients were hospitalized for diarrhea while one patient in the combination arm discontinued treatment due to grade 4 asthenia. There was one treatment-related death resulting from myelotoxicity in the docetaxel arm.


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Table 4. Toxicity

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Palliative chemotherapy following the failure of first-line treatment is increasingly recognized as an important treatment modality in advanced NSCLC. Although earlier reviews of treatment options in recurrent platinum-failed NSCLC were disappointing [2Go], agents such as paclitaxel, docetaxel, gemcitabine and irinotecan [1Go] have shown promising results. Their availability provides an opportunity to identify new combinations capable of inducing a response in platinum-refractory NSCLC.

Docetaxel has been studied extensively and has been approved as an effective second-line agent in the treatment of NSCLC. In eight phase II trials in platinum-treated NSCLC, docetaxel doses of 100 mg/m2 every 3 weeks produced RRs ranging between 16% and 31% [4Go–11Go]. Shepherd et al. [13Go] compared second-line docetaxel with best supportive care, showing survival prolongation using docetaxel and a 1-year survival rate of 37%, in line with survival rates observed using first-line chemotherapy. A dose of 75 mg/m2 was recommended, since the dose of 100 mg/m2 resulted in five deaths. In a phase III randomized study, Fossella et al. [12Go] compared two doses of docetaxel (100 and 75 mg/m2) administered 3-weekly with a control regimen of vinorelbine or ifosfamide, demonstrating RRs of 10.8% and 6.7% for the two doses of docetaxel, respectively, compared with a RR of 0.8% observed with vinorelbine or ifosfamide. In addition, a 1-year survival rate of 32%, observed in both docetaxel arms, was significantly greater than the 10% survival rate observed in the vinorelbine or ifosfamide arm (P <0.01). With the above amassed knowledge, it is recommended that future trials investigating second-line regimens for NSCLC include docetaxel as the control regimen.

Studies assessing combinations of docetaxel with irinotecan are justified due to each drug's striking single-agent activity in a variety of solid tumors. The effects of combining taxanes with camptothecins in animal and human cell lines are either synergic [21Go, 22Go] or antagonistic [23Go], the effect induced depending upon dosing, sequencing and/or cell type. Although the administration of irinotecan before docetaxel may be expected to decrease docetaxel clearance, as both drugs are metabolized by cytochrome P450 3A4 (CYP3A4), studies carried out using these two drugs did not demonstrate clinically significant pharmacokinetic interactions [20Go, 24Go].

Phase I trials have evaluated irinotecan plus docetaxel combination therapy in NSCLC by varying the frequency and order of drug administration [20Go, 24Go–26Go]. In one such study [20Go], the maximum tolerated combination dose was docetaxel 50 mg/m2 and irinotecan 60 mg/m2, with a partial response of 37%, median survival of 48 weeks and a 1-year survival rate of 45%. As the administration of irinotecan and docetaxel every 3 weeks resulted in a high incidence of neutropenia and delayed diarrhea [25Go], a weekly dose of docetaxel and irinotecan was recommended to lower the incidence of toxic effects and to allow the option of dosage withdrawal based on reduced neutrophil counts [25Go, 27Go, 28Go].

This was the first randomized trial to compare the efficacy of the established second-line docetaxel regimen with docetaxel–irinotecan combination therapy in patients with platinum-refractory NSCLC. The two regimens had comparable efficacy and were well tolerated. The overall RR was higher in the combination arm (20% versus 14%), and patients with PS ≥2 did not respond to either line of treatment. TTP showed a tendency of being higher in the combination arm (5.6 versus 4.8 months; P=0.065). The median survival time and the 1-year survival rate were 6.4 months (34%) in the docetaxel arm and 6.5 months (37%) in the combination arm. In terms of RR and survival, the results were consistent with those reported in eight phase II trials [4Go–11Go], and also by Fossella et al. [12Go] and Shepherd et al. [13Go]. Overall toxicity was moderate in both arms. Grade 3–4 neutropenia and G-CSF administration were similar in the two arms. Febrile neutropenia occurred in three patients in each arm, necessitating hospitalization. Grade 3–4 thrombocytopenia was significantly more frequent in the combination arm, although no bleeding episodes occurred. Grade 3–4 anemia and diarrhea also showed a trend towards being higher in the combination arm. Grade 3–4 fatigue and asthenia were identical in both arms, with one patient in the combination arm discontinuing treatment after the first cycle due to grade 4 asthenia. Two patients died due to rapid disease progression, one in the docetaxel arm due to sepsis that resulted from myelotoxicity. The toxicity encountered with docetaxel 75 mg/m2 in this study was in line with that reported by others [12Go, 13Go].

Conclusions
The addition of irinotecan to docetaxel in the second-line therapy of NSCLC shows a trend for significantly higher TTP. However, the combination regimen is not associated with any additional benefits in terms of RR, duration of response, median survival time or 1-year survival rate. Both treatment regimens have been shown to be well tolerated, but thrombocytopenia, anemia and diarrhea appear more frequently in the docetaxel–irinotecan arm. As it has been demonstrated by previous studies, docetaxel monotherapy should currently be considered the reference regimen for the second-line treatment of NSCLC, while a further investigation of the docetaxel–irinotecan combination does not seem warranted in this setting.

Received for publication May 19, 2004. Revision received September 26, 2004. Accepted for publication September 27, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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