A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC)

Lung Cancer 27 (2000) 145 – 157 www.elsevier.nl/locate/lungcan

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A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC) Kazimierz Roszkowski a,*, Anna Pluzanska b, Maciej Krzakowski c, Alexander Peter Smith d, Eugeni Saigi e, Ulf Aasebo f, Annamaria Parisi g, Ngoc Pham Tran h, Robert Olivares h, Jocelyne Berille h a

National Tuberculosis and Lung Diseases Research Institute, ul. Plocka 26, 01 -138 Warszawa, Poland b Chemotherapy Department, Oncology Centre, ul. Paderewskiego 4, 93 -509 Lodz, Poland c Institute of Oncology, ul. Findera 101, 02 -781 Warszawa, Poland d Llandough Hospital, Penlan Road, Penarth, South Glamorgan CF64 2XX, Wales, UK e Ser6izio de Oncologia, Parc Tauli, 08208 Sabadell, Barcelona, Spain f Medical Department — Lung Section, 9038 Tromso, Norway g Responsabile XII Di6isione, Ospedale C., Forlanini, 00159 Roma, Italy h Rhoˆne-Poulenc Rorer, 20, A6enue Raymond Aron, 92165 Antony Cedex, France Received 23 November 1999; received in revised form 23 December 1999; accepted 3 January 2000

Abstract This was an open-label randomized Phase III study of 207 patients with either unresectable or metastatic non-small cell lung cancer (NSCLC) who were treated with docetaxel plus best supportive care (BSC) or best supportive care alone. Patients in the chemotherapy arm of the study received docetaxel 100 mg/m2 as a 1 h intravenous infusion every 21 days until they showed evidence of progressive disease, or estimated maximum benefit obtained or unacceptable side effects. Patients who received docetaxel were pretreated with oral dexamethasone. Patients in the BSC arm should not receive chemotherapy or anticancer therapy except for palliative radiotherapy. Overall survival obtained in the docetaxel arm was significantly longer than in the BSC arm (P =0.026). Two-year survival in the docetaxel arm was 12%, whereas none of the BSC patients survived after 20 months. The response rate was 13.1% (95% CI, 7.5 – 18.8%). There was a significantly longer time to progression in the docetaxel versus the BSC arm (P B0.001), and statistically significant improvement of clinical symptoms with docetaxel compared to BSC. The quality-of-life descriptors were in favor of docetaxel, and the difference was significant for pain, dyspnea and emotional functioning. The safety profile of docetaxel for this study was similar to that already reported in this patient population. © 2000 Elsevier Science Ireland Ltd. All rights reserved. * Corresponding author. Tel.: + 48-22-6912100; fax: + 48-22-6912453. 0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 0 ) 0 0 0 9 4 - 5

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Keywords: Non-small cell lung cancer; Docetaxel; Best supportive care; Survival; Quality of life; Efficacy; Safety

1. Introduction Non-small cell lung cancer (NSCLC) accounts for 75–80% of lung cancer cases and carries a 5 year survival of 14% for all stages. Cases detected while the disease is still localized have a survival rate of 50%, but only 15% of lung cancers are discovered that early. The 5 year survival for stage IIIA/IIIB NSCLC is 4 – 8% and for stage IV disease it isB 1% [10,12]. Surgery is the treatment of choice for localized cancers. A combination of chemotherapy and radiation has been shown to prolong survival in-patients with stage III disease. Chemotherapy alone is the treatment of choice in-patients with stage IV disease [3]. Although, a large number of randomized trials of chemotherapy versus best supportive care (BSC) in the treatment of inoperable lung cancer have been conducted [5,7,11,15,16,21,22], the majority have failed to show a statistically significant improvement in survival. Several meta-analyses of these studies, using a population of : 1200 patients, have concluded that chemotherapy can significantly increase median survival, by 1 – 2 months with a 10% increase in 1 year survival [9,13,14,18] but there are scarce data on quality of life. New Agents are therefore needed to improve the survival of patients with NSCLC and their quality of life. The Non-Small Cell Lung Cancer collaborative group [14] concluded that ‘Modern chemotherapy regimens may have a role in treating all stages of non-small cell lung cancer, although further research is needed to confirm the suggestion of benefit’. A previous phase II trial showed that docetaxel is an active drug for the treatment of unresectable or metastatic NSCLC in chemotherapy-naive patients. The response rate for docetaxel in this population was 27%, with a median duration of response of 6 months. The median survival was 9.2 months and the 1 year survival was 39% [17]. The aim of this study was to demonstrate the impact of docetaxel on overall survival and its

impact on quality of life compared to best supportive care in chemotherapy-naive NSCLC patients.

2. Materials and methods

2.1. Patient selection Patients between 18 and 75 years of age were enrolled if they met the following criteria: (1) histologically or cytologically confirmed nonsmall cell carcinoma; (2) unresectable locally advanced (stage IIIB not amenable to curative chemoradiotherapy or relapse after surgery or radiotherapy) disease or metastatic (stage IV) disease; (3) uni- or bi-dimensionally measurable disease, at least one area of which had not been subject to prior irradiation; (4) World Health Organization (WHO) performance status of 0, 1, or 2; (5) adequate organ function as documented by absolute neutrophil count ]2.0× 109/l, platelet count]100× 109/l, hemoglobin] 100 g/ l, creatinine5 1.5× upper limit of normal (ULN), bilirubin5 ULN, aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT)5 1.5× ULN, alkaline phosphatases5 5×ULN; (6) no prior chemotherapy or immunotherapy even as neoadjuvant and adjuvant therapy; and (7) previous radiation therapy limited to 525% of the bone marrow and completed more than 4 weeks prior to enrollment; patient had to have recovered fully from any toxic effects. Patients were not eligible for the study if they met any of the following criteria: (1) presence or history of symptomatic central nervous system (CNS) metastases; (2) pre-existing neuromotor or neurosensory toxicity]National Cancer Institute (NCI) grade 2; (3) serious illnesses or medical conditions including (a) active infection requiring intravenous (IV) antibiotics; (b) severe hypercalcemia requiring IV treatment; (c) active cardiac disease (uncontrolled hypertension, angina pectoris, congestive heart failure, myocardial infarction within the previous 12 months, and serious

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arrhythmias); (d) untreated superior vena cava syndrome; (e) history of significant neurologic or psychiatric disorders; (f) other serious underlying medical conditions that would impair ability to participate in the study; (4) pregnancy or lactation; (5) past or present history of neoplasm other than lung carcinoma, except for curatively treated non-melanoma skin cancer, cervical carcinoma in situ, or other cancer curatively treated with no evidence of disease for the past 5 years; (6) pre-existing ascites or pericardial effusion; (7) concurrent treatment with other experimental drugs or anticancer therapy; (8) definite contraindications to use of corticosteriods as premedication; and (9) treatment in a clinical trial within the previous 30 days. The study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki (Hong Kong Amendment, 1989). All patients were required to provide written informed consent as approved by local institutional review boards before initiation of any study procedures.

2.2. Study treatment Docetaxel (Taxotere® — Rhoˆne-Poulenc Rorer, Antony, France) was supplied in a singledose vial (40 mg/ml) as a sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic diluent vial (7.33 ml of 13% w/w ethanol in water for injection). All the diluent was aseptically added to the docetaxel vial producing a solution containing 80 mg/8 ml of docetaxel. The drug vial was mixed by gentle hand shaking and let stand a few minutes to allow any foam to dissipate. The quantity of drug necessary for patient administration was then extracted and added to an infusion bag or bottle containing either 0.9% sodium chloride solution or 5% dextrose solution to produce a final concentration of 0.3 – 0.9 mg/ml. Docetaxel was administered at a dose of 100 mg/m2 as a 1 h intravenous injection every 3 weeks. Patients were pretreated with 8 mg dexamethasone p.o. twice a day for 5 days starting 1 day prior to each docetaxel infusion. Preventive granulocyte colony stimulating factor (G-CSF) was

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not permitted at the first cycle. Anti-allergic measures and antiemetics (except steroids) were permitted except at the first cycle. Preventive oral or intravenous antibiotics were not recommended. Docetaxel dose reductions were planned in the event of severe hematological and/or non-hematological toxicity. Dose adjustments were made according to the organ system showing the greatest degree of toxicity. Patients in the two arms of the study were to receive the best supportive care available as judged by their treating physician, according to institutional standards. This might have included antibiotics, analgesics, transfusions, or any other symptomatic therapy as medically indicated. Localized radiation therapy to alleviate symptoms such as pain, cough, dyspnea, or hemoptysis was allowed, provided that the total dose delivered was in the palliative range according to institutional standards. Patients requiring palliative radiation therapy were counted as having progressive disease at the time of radiation. Best supportive care should not have included any chemotherapy or other systemic anticancer therapy. Docetaxel was administered until progressive disease was documented or until the physician judged that the maximum benefit was obtained, or until unacceptable side effects occurred. All patients were followed for 36 months.

2.3. Quality of life Quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire [1] which included one global health status scale, five functional scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties).

2.4. Study e6aluations Prior to treatment, a medical history was taken and patients underwent a physical examination (including clinical tumor assessment, WHO performance status, vital signs, concomitant medica-

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tions, baseline signs and symptoms), neurologic examination, laboratory evaluation (white blood cell, neutrophil count, platelet count, hemoglobin); and serum chemistry evaluation (alkaline phosphatases, bilirubin, ASAT, ALAT, serum creatinine, creatinine clearance (if indicated), sodium, calcium, potassium, protein). Patients had an ECG and radiological examinations to document all lesions. CT scans were performed if clinically indicated. After every cycle, docetaxel patients had a physical examination (including clinical tumor assessment, WHO performance status, vital signs, concomitant medications, and adverse events) and hematology evaluation as described above. Docetaxel patients had chemistry evaluations every other cycle. X-rays and CT scans were done every three cycles until progression. Every 3 weeks, BSC patients had a physical examination (including clinical tumor assessment, WHO performance status, vital signs, concomitant medications, and adverse events), and every 6 weeks they had hematology and chemistry examinations. Every 9 weeks, BSC patients had radiology examinations and CT scans. After the last treatment, docetaxel patients had the same assessments as those made prior to treatment. Throughout the study, both docetaxel patients and BSC patients had neurological examinations and bone scans as clinically indicated. The QoL instruments were to be completed at baseline, then at every other cycle during the treatment period for the docetaxel arm, or every 6 weeks during the first 18 weeks on study for the BSC arm. During the follow-up period (after treatment discontinuation for the docetaxel arm and after the first 18 weeks on study for the BSC arm), the questionnaires were to be completed every 3 months over a 36 month period. The intent-to-treat (ITT) population was defined as all randomized patients analyzed in the randomization group they were assigned to. Survival was measured in the ITT population from the randomization date to the date of death or date of last contact. Time to progression was assessed in the ITT population and was calculated from the date of randomization until progression. Patients receiving any antitumor treatment from

the last cycle of study drug up to the first progression were censored at the date of last tumor assessment before the start of the new antitumor treatment. Objective response rate and duration of response were assessed only in docetaxel-randomized patients, both in ITT and evaluable for response population. Patients receiving two or more cycles with at least one follow-up visit were considered evaluable for response provided that the tumor lesions were properly assessed as per protocol. Patients developing progressive disease after receiving less than two cycles were considered evaluable with a response of early progression. WHO criteria [23] were followed to evaluate the response to treatment. Safety was analyzed in all patients in the treatment group they actually received. Clinical and laboratory toxicities were graded according to NCI criteria. Adverse events not gradable with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) were graded as mild, moderate, severe, or life-threatening using the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) dictionary. Patients having at least one cycle with a blood count between day 2 and the next cycle were evaluable for hematologic toxicity.

2.5. Statistical analysis The sample size of the study was based on the assumption that the expected median survival of locally advanced/metastatic NSCLC patients was 5 months, whereas in the available phase II experience with docetaxel, it is 8 months. A total of 200 patients were necessary to allow the detection of a survival advantage in the docetaxel arm versus the BSC arm, with an alpha level of 5 and 85% power, assuming an accrual period of 21 months and a follow-up period of 12 months. After stratification by stage (unresectable locally advanced disease (stage IIIB) or metastatic disease (stage IV)), patients were centrally randomized, so that two-thirds of the patients were allocated in the docetaxel arm and one-third in the BSC arm.

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The primary efficacy analysis was overall survival in the ITT population. Survival and time to progression were calculated in the two treatment groups by the Kaplan – Meier method. The two groups were compared using a log-rank test. Response rates were provided with the exact 95% confidence interval (CI) in the ITT and evaluable for response populations. Analyses of hemoptysis, pulmonary symptoms, cough, and pain not related to the study drug were described for each treatment group with number of patients and percentages throughout the study visits (or cycles) in four categories: no symptom (absent at baseline/absent at visit), stable (same grade or severity at visit as baseline), improved (lower grade or severity at visit than at baseline or disappearance at visit), worsened (higher grade or severity at visit than at baseline or appearance at visit). An exploratory analysis on tumor-related medications for pain (number of patients having had a opiate analgesic, number of patients having had a non-opiate analgesic, number of days with opiate analgesic relative to the total number of days on study) and other symptoms (number of patients with tumor-related medication except analgesics) was performed to confirm the findings of the analysis on symptoms. Safety analysis was mainly descriptive The QoL analyses were performed in the ITT population. The global health status/QoL, physical functioning, and emotional scores were considered as primary QoL dimensions and thus, analyzed using four methods: a longitudinal mixed model, a worst score, an AUC analysis, and a pattern mixture model based on completers and non-completers. Completers were defined as patients with follow-up data for QoL after treatment period 5. Non-completers were defined as patients with follow-up data for QoL ending at or before treatment period 5. Worst score during study and area under curve (AUC) were compared using a non-parametric Wilcoxon test. To avoid multiplicity, only the AUC analysis was used to analyze the QLQ-C30 functional and symptomatic dimensions non considered as primary. Nevertheless, when a dimension was found

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to be significantly different between treatment groups with the AUC method, the others methods were employed as sensitivity analyses to explore the robustness of the result.

3. Results

3.1. Patient characteristics Patients were enrolled in 18 centers (15 in Europe, two in Mexico, and one in the US) beginning in October 1995. There were 137 patients randomized to the docetaxel arm and 70 patients randomized to the BSC arm; however, one patient initially randomized to the BSC arm received docetaxel by error. This patient is included in the docetaxel arm for the analysis of safety only but was kept in the BSC arm for all the other analyses (efficacy, clinical benefit, and QoL analysis), to stick to the ITT principle. Patient characteristics are presented in Table 1. Demographic characteristics were well balanced across the two treatment arms. Sixteen patients (12%) in the docetaxel arm and 11 patients (16%) in the BSC arm received at least one course of off-protocol chemotherapy. Among the 11 patients in the BSC arm, four received cisplatin/ etoposide, two received carboplatin, one received methotrexate, three received vinorelbine in combination with either cisplatin or carboplatin, and one patient received docetaxel and cisplatin followed by fluorouracil, adriamycin, and mitomycin. Twelve docetaxel patients received platinum-containing combination chemotherapy, and four docetaxel patients received single-agent therapy with either carboplatin, etoposide, or gemcitabine. A total of 649 cycles of docetaxel were administered to the 138 patients having received docetaxel (median: three cycles; range, 1–22 cycles); 47% of the patients received four cycles or more. Approximately 90% of the treatment cycles were administered at the initial planned dose of 100 mg/m2. Dose modifications, mostly due to toxicity, occurred in only 5% of cycles. Treatment delays occurred in 9% of cycles. Most delays were between 3 and 7 days.

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Table 1 Baseline patient and tumor characteristics ITT population Docetaxel

Total number of patients Sex Male Female Age (years) B35 35–49 50–65 \65 Median Range (min–max) Performance status (WHO score) 0–1 2

BSC

n

%

n

%

137

100.0

70

100.0

110 27

80.3 19.7

59 11

84.3 15.7

1 9 40 20 60.0 31–74

1.4 12.9 57.1 28.6

0 20 79 38 59.0 36–75

0.0 14.6 (57.7) 27.7

111 26

81.0 19.0

54 16

77.2 22.9

Histological subtype Squamous cell carcinoma NOS Adenocarcinoma NOS Carcinoma NOS or undifferentiated Large cell carcinoma NOS

74 36 18 9

54.0 26.3 13.2 6.6

33 24 9 4

47.1 34.3 12.8 5.7

Baseline Opiate analgesic Non-opiate analgesic Tumor-related medication other than for pain

27 29 41

19.7 21.2 29.9

12 17 18

17.1 24.3 25.7

Extent of disease Locally advanced Metastatic

77 60

56.2 43.8

33 37

47.1 52.9

Number of organs in6ol6ed 1 2 ]3

43 69 25

31.4 50.4 18.2

18 42 10

25.7 60.0 14.3

Organ in6ol6ement (]5%) Lung Lymph nodes Liver Pleura Adrenal glands Bone

134 75 11 9 9 13

97.8 54.7 8.0 6.6 6.6 9.5

65 36 9 7 8 4

92.9 51.4 12.9 10.0 11.4 5.7

Prior anticancer therapy No prior treatment Radiotherapy only Surgery onlya Radiotherapy+surgery

120 9 5 3

87.6 6.6 3.6 2.2

61 1 3 5

87.1 1.4 4.3 7.1

a

Including lung surgery with curative intent.

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Fig. 1. Overall survival analysis — ITT population.

3.2. Efficacy

3.2.1. O6erall sur6i6al Kaplan–Meier survival curves displayed in Fig. 1 show a separation after 6 months of follow-up, sustained over time and leading to a statistically significant difference in the overall survival in favor of docetaxel (P = 0.026 for the log-rank test and P=0.040 log rank test stratified on the extent of disease). Median survival was 6.0 months (95% CI, 5.0–8.0) for patients in the docetaxel arm and 5.7 months (95% CI, 4.4 – 6.8) for patients in the BSC arm. The 1-year survival rate for the docetaxel patients was 25%, versus 16% for the BSC group. After 2 years, the survival rate in the docetaxel arm was 12%, whereas none of the BSC patients remained alive after only 20 months of follow-up. Since 27 patients received off-protocol chemotherapy (16 patients (12%) in the docetaxel arm and 11 patients (16%) in the BSC arm), a Kaplan–Meier curve for survival analysis was performed (figure not shown) censoring patients at subsequent chemotherapy to check whether off-protocol chemotherapy may have had an impact on the overall survival. The trend and the conclusion are similar to the overall survival curve.

3.2.2. Secondary parameters The time to progression was significantly longer (PB 0.001) in the docetaxel arm than in the BSC arm in the ITT population, being 12.6 weeks (95% CI, 9.9–16.6) and 8.9 weeks (95% CI, 7.7–9.7), respectively. The response rate in the ITT population was 13.1% (95% CI, 7.5–18.8) and in the evaluable for response population 19.6% (95% CI, 12.0–29.1), respectively. There were 18 confirmed responses including two complete responses. Durations of response ranged from 14 weeks to 90 weeks with a median of 37.1 weeks (95% CI, 30.9–69.9). In the ITT population, 31.4% of docetaxel treated patients experienced disease stabilization. This rate was 42.4% in evaluable for response patients. Patients treated with docetaxel had statistically significant improvements in clinical benefit (Table 2). In the docetaxel group, there was less use of opiate analgesics (PB 0.001), non-opiate analgesics (PB 0.001), tumor-related medications other than for pain (PB 0.01), and palliative radiotherapy (PB 0.01). There was a significantly higher use of anti-infective drugs (P= 0.027) in patients treated with docetaxel. There was an improvement of dyspnea symptoms and pain symptoms in the docetaxel group compared to BSC. The incidence of hemoptysis and cough was

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between the two treatment groups for the remaining dimensions, but all the estimates were in favor of the docetaxel group except for diarrhea.

similar in the two treatment groups (figure not shown).

3.3. Quality of life 3.4. Safety The number of missing questionnaires at baseline was high in the BSC arm (41%) compared to the docetaxel group (7%). This may have been due to the inability of investigators to differentiate between baseline and treatment period 1 in the BSC arm. The proportion of questionnaires filled in was comparable between the two groups throughout the study period and does not seem to be linked to patient condition. The emotional functioning was significantly different in favor of docetaxel in three of the four analyses, longitudinal mixed model (P = 0.01), pattern mixture model (P =0.04), and worst score (P= 0.01),but not in the AUC analysis. Although not statistically significant, there was a trend in favor of docetaxel for global health status/QoL and physical functioning scores. For other dimensions (QLQ-LC30) analyzed through AUC, nausea/vomiting (P =0.04), pain (PB 0.001), and dyspnea (P =0.02) were significantly better in docetaxel patients. A sensitivity analysis using mixed model, pattern mixturemodel, and worst score analysis confirmed that differences were significant with all methods for pain and dyspnea but not for nausea/vomiting (Table 3). There were no significant differences

Table 4 shows the incidence of grade 3 or 4 (NCI-CTC) or severe (COSTART) adverse events regardless of relationship. Patients in the BSC arm experienced a higher incidence of pulmonary events, neurocortical events, and pain than did patients receiving docetaxel. Patients treated with docetaxel had a higher incidence of asthenia, infection, and neurosensory events. Grade 3 or 4 neutropenia occurred in 36 docetaxel-treated patients (28%). Febrile neutropenia occurred in five patients (3.6%) and eight cycles (1.2%). Infections during grade 3 or 4 neutropenia were seen in nine patients (6.5%) and nine cycles (1.4%). Grade 3 or 4 anemia occurred in six patients (4.6%), and grade 3 or 4 leukopenia occurred in 29 patients (21.9%). These toxicities are expected with docetaxel. Adverse events reported for the BSC group reflect the complications of the patient’s cancer and underlying medical conditions, as well as any adverse events from supportive medications or sequelae from radiation or surgical procedures. A high rate of anemia (33%) was noted in-patients in the BSC arm with 3.4% of grade 3/4 anemia. Fluid retention related to docetaxel treatment was seen in 31 patients (23%). Most fluid reten-

Table 2 Clinical benefit — tumor related medications Parameter

Docetaxel

BSC

P-value

n

%

n

%

Total number of patients

137

100.0

70

100.0

Patients with palliati6e radiotherapy during the study At least one dose None

33 104

24.1 75.9

29 41

41.4 58.6

PB0.01

56 44 75 79

40.9 32.1 54.7 57.7

48 43 52 29

68.6 61.4 74.3 41.4

PB0.001 PB0.001 PB0.001 P =0.027

Patients with tumor-related medication during the study Opiate analgesic Non-opiate analgesic Tumor-related medication other than for pain Anti-infective medication

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Table 3 QoL analysis: longitudinal mixed model, worst score, AUC, and pattern mixture model Dimension/item

Mixed model

Worst score

AUC

Pattern mixture model

Global health status/QoL Physical functioning Emotional functioning Role functioning Cognitive functioning Social functioning Fatigue Nausea/vomiting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhea Financial difficulties

0.16 0.14 0.01a NAc NA NA NA 0.03a,b B0.001a,b 0.005a,b NA NA NA NA NA

0.09a 0.08a 0.01a NA NA NA NA 0.08a,b B0.001a,b 0.03a,b NA NA NA NA NA

0.36 0.52 0.42 0.38 1.00 0.52 0.42 0.04a B0.001a 0.02a 0.13 0.27 0.41 0.49 0.12

0.13 0.22 0.04a NA NA NA NA 0.10a,b B0.001a,b 0.02a,b NA NA NA NA NA

a

Difference in favor of docetaxel at P50.10 level. Sensitivity analysis performed to confirm the results of the AUC analysis. c NA, not done to avoid multiplicity in statistical tests. b

tion (84%) was in the form of peripheral edema. None of the fluid retention events was classified as serious. New onset peripheral edema also was seen in 12% of patients in the BSC treatment arm. Fluid retention was not considered a dose-limiting toxicity of docetaxel because the median cumulative dose to onset of fluid retention was above 800 mg/m2, as the lower bound of the 95% Cl for the median was 795 mg/m2. Two patients in the docetaxel arm died from study drug toxicity — one patient from febrile neutropenia and diarrhea and one patient from heart failure and pulmonary edema. A third patient died from a combination of malignant disease and infection. Adverse events leading to hospitalization were reported for 70 patients (51%) in the docetaxel arm and 21 patients (30%) in the BSC arm. Forty-one docetaxel-treated patients (30%) had serious adverse events that were related to study treatment. The most commonly occurring treatment-related serious events were infection (8.7%), allergy, diarrhea, fever in absence of infection, and febrile neutropenia (4% each). Twenty-six patients (19%) treated with docetaxel discontinued the study due to adverse events. The most common reasons for discontinuations were neurological events (nine

patients) and allergic reactions (six patients) that occurred during the first or second cycle. Among the patients who discontinued for neurological events, the median number of cycles received before discontinuation was 6 (range, 3–18).

4. Discussion Docetaxel has already demonstrated to improve overall survival in patients with advanced NSCLC, with relapsed after previous chemotherapy [2]. Treatment with docetaxel improved long term survival Although median survival in the docetaxel treatment group was similar to that in the BSC group, the two curves clearly separated after the sixth month of follow-up, leading to a statistically significant difference in overall survival in favor of docetaxel (P= 0.026), resulting in the 1 year survival rate of 25% in patients treated with docetaxel versus 16% in patients treated with BSC. None of the BSC patients remained alive after 20 months of follow-up, while 12% of docetaxel patients were alive at 2 years. This study demonstrates that results similar to those for the 1200 patients in the NSCLC SG 1200 patient meta-analysis of CDDP combination

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154

chemotherapy versus BSC (10% increase in 1 year survival) can be detected with docetaxel treatment versus BSC [19]. When survival was censored at further chemotherapy, the median remained 6 months for docetaxel, whereas for the BSC group, the median became similar to the results observed for BSC in other trials, around 5 months [4,8,20] suggesting that the BSC patients greatly benefited from the institution of chemotherapy after the study. These significant results in survival with docetaxel treatment versus BSC are reinforced by the secondary end points. The median time to progression for docetaxel patients is significantly longer than in the BSC group (12.6 weeks doc-

Table 4 Number of patients with most frequently incidence\2.5% reported grade 3/4 (NCI-CTC) or severe (COSTART) adverse events by treatment group regardless of relationship

Pulmonary Astheniab Neutropenia Leukopenia Painb Infection Neuromotor Cough increasedb Neurosensory Nausea Anemia Allergy Peripheral edemab Hemoptysisb Neuroconstipation Stomatitis Neurocortical

Docetaxel

BSC

Grade 3/4 or severe N = 138a

Grade 3/4 or severe N= 69

31 39 36 29 29 15 13 12 9

(22.5) (28.3) (27.7) (21.9) (21.0) (10.9) (9.4) (8.7) (6.5)

24 16 0 0 23 2 0 3 0

7 6 5 5 4 5

(5.1) (4.6) (3.6) (3.6) (2.9) (3.6)

1 2 0 1c 1 0

(1.4) (3.4) – (1.4) (1.4) –

5 3

(3.6) (2.2)

0 5

– (7.2)

(34.8) (23.2) – – (33.3) (2.9) – (4.3) –

a Including the patient randomized to BSC but receiving docetaxel treatment. b COSTART. c Peripheral edema related to a deep thrombophlebitis.

etaxel vs. 8.9 weeks BSC). The time to progression is an important factor, measuring impact of the drug on the tumor. The ITT response rate of 13.1% and evaluable response rate of 19.6% for docetaxel patients are lower than the typical response rates reported in docetaxel phase II studies [6]. Because phase II trials are often single-institution studies with smaller carefully selected patient populations, the response rate is usually higher in phase II compared to phase III trials. In addition, the assessment of tumor response at each cycle is usually less rigorously performed in phase III than in phase II studies, for which response rate is the primary endpoint. The response rate among evaluable patients treated with docetaxel (19.6%) is similar to the 20% with vinorelbine [8], 17.4% with gemcitabine [1], and 15% with paclitaxel [20] when these treatments were compared in phase III versus BSC. It is noteworthy that 31.4% (ITT) and 42.4% (evaluable) of the docetaxel patients experienced disease stabilization. When the responses are evaluable, their durations are also striking, with a median duration of approximately 8 months. In addition to the clear improvement on survival and time to progression, docetaxel treatment leads to significant improvement of clinical benefit versus BSC. Among docetaxel patients, there was significantly less use of opiate medications, nonmorphine analgesics, other tumor-related medications except for pain, and palliative radiotherapy. Conversely, there was significantly higher use of prophylactic or curative anti-infective drugs in docetaxel patients versus BSC patients. This is not unexpected with myelosuppressive agents such as docetaxel. There was also a clear improvement of dyspnea and pain symptoms for docetaxel patients compared with BSC patients, while for cough and hemoptysis symptoms, the evolution throughout the study is similar within the two groups. These improvements in clinical benefit are confirmed and strengthened by the QoL data. The consistent findings in QoL analyses were particularly important because they confirm the better clinical benefit data for docetaxel from the patient’s point of view. The better clinical benefit is

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reported despite the drug related adverse events and the higher rate of hospitalization mainly due to rather strict intervention rules followed when a new drug is investigated. Analyses suggested a statistical difference or a trend in favor of docetaxel patients versus BSC patients for all the dimensions except diarrhoea. The significantly better QoL scores of the docetaxel group compared to the BSC group for dyspnea and pain confirm the clinical benefit results, from the patient’s point of view. The differences in the emotional functioning score, pain, and dyspnea symptom scores were statistically significant in favor of docetaxel using various statistical methods. The emotional functioning has to be emphasized: it means that the patient felt significantly better by receiving docetaxel treatment than by having only BSC. In addition, docetaxel did not lead to a significant worsening compared to BSC in any of the QoL analyses, which confirmed that docetaxel-related adverse events had very little or no impact on the QoL of the docetaxel treated patients. Other new generation drugs have also been tested versus BSC. A study comparing gemcitabine versus BSC [1] did not demonstrate any difference in survival (median: 4 months each arm), although an improvement in QoL was demonstrated in favor of gemcitabine. Vinorelbine versus BSC [8] displays similar results to docetaxel versus BSC in an elderly population. However, the results are reported in a restricted population, not in an ITT population. Paclitaxel demonstrates a transient overall survival improvement [20] during the early months but the two curves overlap at a 12 month followup, while the docetaxel study demonstrates a benefit in the long term survival. It is also important to note that the overall survival was better for the BSC arm in our study (5.7 months) than in the vinorelbine (4 – 9 months) [9], gemcitabine (4 months) [1], and paclitaxel (4.8 months) [20]. However, when the survival is censored for further therapy, the median survival in our study became consistent with the results observed for BSC in historical studies [14] as well as with the above studies (4.6 months).

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5. Conclusions This study demonstrated that docetaxel at the dose of 100 mg/m2 given intravenously every 21 days significantly improves the overall survival of patients with locally advanced or metastatic NSCLC who were not previously treated with chemotherapy. Docetaxel significantly improves the QoL of patient for pain, dyspnea and emotional functioning. A non-significant trend in favor of docetaxel is observed for other QoL dimensions. Therefore, this study has addressed positively the issue raised in the 1995 meta-analysis of whether survival improvement with chemotherapy is related to improvement in QoL and whether or not chemotherapy should be considered as a standard of care. Now, the scientific community has to be convinced that stage IIIB/IV NSCLC must be treated with active chemotherapy. A controversy remains whether or not combination therapies with newer drugs and platinum are more efficient than single newer drugs. 6. List of participants Ireland

William Ian Fraser, MD St Luke’s Hospital Dublin

Italy

Professor Ignazio CARRECA Oncoligia clinica policlinico ‘Paolo Giaccone’ Palermo

Mexico

Laura Torrecillas Torres Centro Medico de Especialidades Mexico Dr Maria De Los Dolores Gallardo Rincon Instituto Nacional de Cancerologia Mexico City

Spain

Dr R. Blanco Consorci Sanitari De Terrassa Torebonica Barcelona

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Dr Luis Cirera Nogueras Mutua de Terrassa Barcelona Dr Montserrat Gay Pastor Hospital General de Vic Barcelona Dr Eugeni Saigi-Grau Parc Tauli Sabadell(Barcelona) UK

Dr A.P. Smith Llandough Hospital South Glamorgan Dr Edward Gerald Anderson Newport Chest Clinic Gwent Dr David Gilligan Oncology Center Cambridge Dr Nicholas Thatcher CRCD Christie Hospital Crcc Research Centre Manchester

United States

Dr J.H Schiller University of Wisconsin Madison WI

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