Sequential administration of docetaxel followed by maintenance gefitinib, as salvage treatment in patients with advanced NSCLC: A multicenter phase II trial

2.1. Patients 

Patients with histologically or cytologically confirmed, unresectable locally advanced (stage IIIB with pleural effusion) and/or metastatic (stage IV) NSCLC, aged >18 years were enrolled in this study. Furthermore, other inclusion criteria were: bidimensionally measurable disease, life expectancy of more than 3 months and a World Health Organization (WHO) performance status of ≤2. All patients had to have at least one prior chemotherapy regimen (platinum- or taxane-based). Previous radiotherapy, either in the adjuvant setting or for the treatment of bone metastases, was allowed provided that the measurable lesions were outside the radiation fields. Patients with known, symptomatic central nervous system metastases were ineligible. Patients had to have adequate liver [serum bilirubin ≤1.5 times the upper normal limit (UNL); AST and ALT ≤2.5UNL in the absence of demonstrable liver metastases, or ≤5UNL in the presence of liver metastases], renal (serum creatinine ≤1.5 times the UNL), and bone marrow (neutrophils ≥1.5×109L−1, and platelets ≥100×109L−1) function. Other eligibility criteria were: absence of active infection, history of significant cardiac disease (unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, ventricular arrhythmias) or malnutrition (loss of ≥20% of the original body weight). All patients gave written informed consent to participate in the study and the trial was approved by the Ethics and Scientific Committees of the participating centers. The study was conducted according to the Helsinki Declaration and Good Clinical Practice guidelines. Gefitinib was administered in the context of the Iressa Expanded Access Program.

2.2. Patient evaluation 

Baseline assessment comprised of a complete medical history, physical examination and vital signs, evaluation of performance status, 12-lead ECG, complete blood cell count with differential and blood chemistry, chest X-rays and computed tomography scans of the chest, abdomen and brain and a whole-body radionuclide bone scan. Baseline evaluation had to be performed within 2 weeks prior to therapy initiation. All measurable lesions were identified at baseline and were monitored throughout. A complete medical history and a detailed physical examination with complete blood cell count with differential and blood chemistry, ECG and a chest X-ray were performed before each treatment administration to assess the disease status and treatment toxicity. After completion of study treatment, patients were followed every 1 month until the development of disease progression. Third-line therapy included best supportive care, palliative radiotherapy, or chemotherapy according to the discretion of the responsible physician.

2.3. Treatment 

Treatment consisted of three cycles of docetaxel 30mg/m2, administered as a 1-h IV infusion, on days 1, 8 and 15 of each 4-week cycle. Standard pre- and post-medication with 8mg oral dexamethasone, at 7 and 1h before the docetaxel infusion, and 8mg twice daily for a further 3 days, was used to reduce the risk of allergic reactions and fluid-retention syndrome that can be associated with docetaxel administration. The weekly schedule of docetaxel administration was selected due to its favorable toxicity profile [14], [15], [16]. After the administration of three cycles of docetaxel all patients [those with complete (CR) or partial (PR) response as well as those with stable (SD) and progressive (PD) disease], received gefitinib 250mg daily po. Gefitinib treatment was continued until disease progression, the development of unacceptable toxicity, or withdrawal of patients’ consent. Patients with early evidence of disease progression, before completing three cycles of docetaxel, were switched immediately to gefitinib treatment.

2.4. Assessment of antitumor activity and toxicity 

Response assessment was evaluated after three chemotherapy cycles, and every 2 months for patients receiving gefitinib maintenance. Objective tumor responses were evaluated according to WHO response criteria [17] with the same method on each occasion and all objective responses were confirmed by repeating the evaluation 4 weeks later. All CT scans were reviewed by an independent radiologist. Toxicity was reported according to National Cancer Institute Common Toxicity Criteria, Version 2 [18].

2.5. Statistical design 

A Simon's optimal two-stage design was used to estimate the appropriate sample size [19], [20]. A total of 42 patients were planned for both stages, while more than three patients with disease control (CR+PR+SD) were required out of the first 18 consecutive patients. A disease control rate greater than 0.35 was expected, while Types I and II error were set at 0.05 and 0.10, respectively. The primary end point of this study was disease control rate (DCR); secondary objectives included overall survival (OS), time to tumor progression (TTP) and safety. All patients who received at least two chemotherapy cycles were assessable for response and all patients who received at least one cycle were evaluated for toxicity. The time to disease progression (TTP) was measured from the enrollement to the study until the day of the first evidence of disease progression. The duration of response was calculated from the day of the first documentation of response to disease progression while overall survival was measured from entry into the study until death; 1-year survival was estimated using the Kaplan–Meier method [21]. Descriptive statistics for the patient group are reported as mean, median, and range. Statistical comparisons between group rates (proportions) were assessed by Pearson's χ2-test, or Fisher's test where appropriate [22].

3.1. Patient characteristics 

A total of 41 patients were enrolled onto the study. The median interval from previous treatment was 2.6 months (min–max: 1–19.2). All patients were evaluable for toxicity and response. Thirty-five (85.3%) patients completed treatment as per protocol whereas early treatment discontinuation occurred in six patients for the following reasons: (i) adverse events (n=1; one patient with grade III hypersensitivity reaction to docetaxel) and (ii) early death (due to disease progression; n=5); these patients were considered to have progressive disease in the intention-to-treat analysis. Patients’ characteristics are presented in Table 1.

Table 1. Patients’ characteristics

		N	%
	Age
	Median	59
	Min–max	43–78
	Sex
	Male	38	93
	Female	3	7
	PS (WHO)
	0–1	32	78
	2	9	22
	Smoking status
	Smoker	17	41
	Ex-smoker	11	27
	Never-smoker	13	32
	Histology
	Adeno	25	61
	Squamous	12	29
	Large cell	4	10
	Stage
	IIIB	6	15
	IV	35	84
	Line of therapy
	2nd	15	37
	≥3rd	26	63
	Type of prior chemotherapy
	Platinum-based	5	12
	Taxane-based	13	32
	Both	23	56
	Response to 1st line
	CR	1	2
	PR	10	24
	SD	10	25
	PD	20	49
	No. of organs involved
	1	14	34
	2	20	49
	≥3	7	17
	Median	2
	Min–max	1–4

3.2. Treatment 

A total of 128 chemotherapy cycles were administered; the median number of cycles received per patient was 3.0 (range 1–4). The median cycle duration was 28 days (range, 28–36 days). Treatment administration was delayed in 13 (10%) cycles. All cycles were delayed for reasons not related to treatment or toxicity (i.e. patient's request for personal reasons, pending imaging studies for response assessment). Dose reduction was required in 10 (8%) cycles, mainly because of non-haematologic (diarrhea and peripheral neuropathy, n=9 cycles) but also haematological toxicity (neutropenia and thrombocytopenia, n=3 cycles). The median dose intensity of docetaxel was 21mg/m2week (range: 11–22mg/m2week; 92.9% of planned dose). Thirty-six (87.8%) patients received gefitinib (five patients did not receive gefitinib because they had an early disease-related death, while on docetaxel treatment). The median duration of gefitinib therapy was 2.8 months (range: 1–38.3). There was no difference regarding duration of gefitinib administration in patients who developed rash compared with those who did not (p=0.694). The reason for gefitinib discontinuation was disease progression in all but one patient who developed a serious adverse event (grade III diarrhea).

3.3. Response to treatment 

Responses and survival are based on the intention-to-treat analysis. No patient achieved a complete response (CR), while two (4.9%) achieved a partial response (PR) and 10 (24.4%) stable disease (SD), for a disease control rate (DCR) of 29.3% (95% CI: 15,3%–43.2%) while on weekly docetaxel treatment. Additionally, progressive disease (PD) was observed in 29 (70.7%). Among those 18 patients who were first enrolled one (5.6%) achieved PR and four (22.2%) SD. No objective responses were observed during the gefitinib maintenance therapy; however, a total of 17 (41.5%) patients presented stable disease maintained for more than 2 months. There was no clear association between DCR and any of the following prognostic factors: adenocarcinoma histology (p=0.674), disease stage (p=0.587), number of prior regimens (p=0.271), response to prior regimens (p=0.456), PS (0–1 versus 2; p=0.599) and smoking (p=0.096). However, the small number of female patients (n=3) included in this study, precludes any conclusions in relation to patients’ sex.

After a median follow-up time of 6.7 months (range 1.2–40.2), the median time to tumor progression (TTP) was 3.0 months (range: 1–38.3 months; 95% CI: 2.4–3.6) (Fig. 1); the 1-year survival without progression was 13.9% (two patients who had this regimen ≥3rd line, had not progressed after 12 months of follow-up); there was no difference in TTP between patients who received this regimen as second or third-line treatment (2nd line versus ≥3rd line; 3 months versus 2.7 months, p=0.361). Median overall survival (OS) was 6.9 months (range: 1.2–40.2 months; 95% CI: 5.34–8.52) (Fig. 2); while the overall 1-year survival was 28.8%. Similarly, there was no difference in OS and 1-year survival in connection with number of prior regimens (OS: 2nd line versus ≥3rd line; 7.5 months versus 6.7 months, p=0.431; 1-year survival: 2nd line versus ≥3rd line; 30% versus 27%, p=0.461) (Fig. 3). It is noteworthy that 24 (58.5%) patients survived for ≥6 months.

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Fig. 1. Time to tumor progression of all patients enrolled in the study.

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Fig. 2. Kaplan–Mayer survival curve of all patients enrolled in the study.

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Fig. 3. Survival of patients receiving docetaxel/gefitinib regimen as 2nd or ≥3rd line treatment.

3.4. Toxicity 

Toxicity was assessed in all chemotherapy cycles and in all patients. Table 2 summarizes all treatment-related grade III/IV toxicities. Grade III/IV hematologic toxicity was in general rare; neutropenia and thrombocytopenia occurred in 2.4% of patients each. Two (4.8%) patients developed grade II peripheral neuropathy, three (7.3%) grade III diarrhea and one of them required hospitalisation. One (2.4%) patient experienced a docetaxel-related grade III hypersensitivity reaction, and treatment with docetaxel was permanently stopped. This particular patient continued treatment with gefitinib. Finally, three (7.3%) patients experienced grade III asthenia. There was no treatment-related death. All other hematologic and non-hematologic toxicities were relatively infrequent. Five (13.9%) and one (2.8%) patients on gefitinib therapy developed grades II and III diarrhea, respectively. In the latter patient, gefitinib was interrupted for 2 weeks and patient was hospitalised for iv hydration and treatment with wide spectrum antibiotics. Re-administration of gefitinib in this particular patient resulted in the recurrence of severe diarrhea and the drug was permanently stopped. Eight (22.2%) and one (2.8%) patients, had grades II and III achneiform rash, respectively. Although 18 (50.0%) patients developed skin rash, in nine (25%) of them it was grade I and transient. The median time to rash appearance was 2 weeks (range 1–3). In those patients who remained on treatment for several weeks the rash was observed to decrease over the treatment period. One (2.8%) patient developed grade III skin rash. Gefitinib was discontinued for 1 week and the patient was treated with dimethidine 2.5mg bid per os and doxycycline 200mg per os qd.

Table 2. Treatment-related grade III/IV toxicity (per patient)

		Docetaxel (n=41)		Gefitinib (n=36)
		Gr III	Gr IV	Gr III	Gr IV
	Hematologic
	Neutropenia	1 (2.4%)	–	–	–
	Febrile neutropenia	–	–	–	–
	Anemia	–	–	–	–
	Thrombocytopenia	1 (2.4%)	–	–	–
	Non-hematologic
	Nausea/vomiting	2 (4.8%)	–	–	–
	Diarrhea	3 (7.3%)	–	1 (2.8%)	–
	Asthenia	3 (7.3%)	–	–	–
	Peripheral neuropathy	2 (4.8%)*	–	–	–
	Hypersensitivity reaction	1 (2.4%)	–	–	–
	Acneiform rash	–	–	1 (2.8%)	–

*Grade II; five (13.9.3%) patients on gefitinib maintenance developed grade II diarrhea; eight (22.2%) patients on gefitinib maintenance developed grade II achneiform rash.