First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial.

Abstract

The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n=240) were randomised to receive gemcitabine 1125 mg x m(-2) (days 1 and 8) plus either cisplatin 80 mg x m(-2) (day 2) or epirubicin 100 mg x m(-2) (day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status <or=2. QOL was measured with European Organisation for Research and Treatment of Cancer QLQ-C30 and LC13 questionnaires. There were no significant differences in median progression-free survival (CG 26 weeks, EG 23 weeks), median overall survival (CG 43 weeks, EG 36 weeks), or tumour response rates (CG 46%, EG 36%). Toxicity was mainly haematologic. In the EG arm granulocytopenia occurred more frequently, leading to more febrile neutropenia. Also, elevation of serum transaminases, mucositis, fever, and decline in LVEF were more common in the EG arm. In the CG arm, more patients experienced elevated serum creatinine levels, sensory neuropathy, nausea, and vomiting. Global QOL was not different in both arms. Progression-free survival, overall survival, response rate, and QOL were not different between both arms; however, overall toxicity was more severe in the EG arm.

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First-line gemcitabine with cisplatin or epirubicin in advanced
non-small-cell lung cancer: a phase III trial
FM Wachters1, JWG van Putten1, H Kramer1, Z Erjavec2, P Eppinga3, JH Strijbos3, GPJ de Leede4, HM Boezen5,
EGE de Vries6and HJM Groen*,1
1Department of Pulmonary Diseases, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands;2Department of Internal
Medicine, Delfzicht Hospital, Jachtlaan 50, 9934 JD Delfzijl, The Netherlands;3Department of Pulmonary Diseases, Nij Smellinghe Hospital,
Compagnonsplein 1, 9202 NN Drachten, The Netherlands;4Department of Pulmonary Diseases, Bethesda Hospital, Amshoffweg 1, 7909 AA
Hoogeveen, The Netherlands;5Department of Epidemiology and Statistics, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The
Netherlands;6Department of Medical Oncology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin–gemcitabine (CG) or
epirubicin–gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n¼240) were
randomised to receive gemcitabine 1125mgm?2(days 1 and 8) plus either cisplatin 80mgm?2(day 2) or epirubicin 100mgm?2
(day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology
Group performance status p2. QOL was measured with European Organisation for Research and Treatment of Cancer QLQ-C30
and LC13 questionnaires. There were no significant differences in median progression-free survival (CG 26 weeks, EG 23 weeks),
median overall survival (CG 43 weeks, EG 36 weeks), or tumour response rates (CG 46%, EG 36%). Toxicity was mainly
haematologic. In the EG arm granulocytopenia occurred more frequently, leading to more febrile neutropenia. Also, elevation of
serum transaminases, mucositis, fever, and decline in LVEF were more common in the EG arm. In the CG arm, more patients
experienced elevated serum creatinine levels, sensory neuropathy, nausea, and vomiting. Global QOL was not different in both arms.
Progression-free survival, overall survival, response rate, and QOL were not different between both arms; however, overall toxicity
was more severe in the EG arm.
British Journal of Cancer (2003) 89, 1192–1199. doi:10.1038/sj.bjc.6601283
& 2003 Cancer Research UK
www.bjcancer.com
Keywords: non-small-cell lung cancer; cisplatin; epirubicin; gemcitabine; phase III trial; chemotherapy
?????????????????????????????????????????????????????
Platinum-based chemotherapy is the standard treatment for
patients with advanced non-small-cell lung cancer (NSCLC) who
have a good performance status (American Society of Clinical
Oncology, 1997). A meta-analysis published in 1995 showed that
cisplatin-based chemotherapy induces 27% reduction in the risk of
death, 10% improvement in survival at 1 year, and an absolute
increase in median survival of 1.5 months compared to best
supportive care (Non-small Cell Lung Cancer Collaborative Group,
1995). Since then, several new chemotherapeutic agents in
combination with platinum have been investigated for their
beneficial effect in patients with NSCLC. Phase II studies of new
drugs in combination with platinum, published between 1992 and
1997 and reviewed by Bunn and Kelly, showed a prolonged
survival from about 4 to 10 months, a prolonged 1-year survival
rate from 10 to 40–50%, and an improved quality of life (QOL)
(Bunn and Kelly, 1998).
In spite of the fact that cisplatin-containing regimens are
currently considered the treatment of choice for advanced NSCLC,
cisplatin has several disadvantages such as nephro-, neuro-, and
ototoxicity. Therefore, nonplatinum-containing regimens have
been studied to find less toxic therapies with similar efficacy.
Phase III studies have reported similar response rates and overall
survival in cisplatin and noncisplatin-based regimens. However, in
the majority of these trials the nonplatinum regimens had a more
favourable toxicity profile (Gatzemeier et al, 1991; Gridelli et al,
1996; Georgoulias et al, 2001; Kosmidis et al, 2002; Sculier et al,
2002).
Gemcitabine, a nucleoside analogue, has shown activity against
NSCLC as a single agent. Phase II studies showed response rates
between 18–26% and a mild toxicity profile (Anderson et al, 1994;
Gatzemeier et al, 1996; Halme et al, 1997; Yokoyama et al, 1997;
Perng et al, 1997; Takada et al, 1998; Zatloukal et al, 1998; Ten
Bokkel Huinink et al, 1999). The combination of cisplatin and
gemcitabine in NSCLC has been evaluated in phase III trials,
reporting response rates of 22–41% and median survival between
8.1 and 9.7 months (Cardenal et al, 1999; Crino et al, 1999; Comella
et al, 2000; Sandler et al, 2000; Schiller et al, 2002).
As a single-agent epirubicin, the 40epimer of the anthracycline
antibiotic doxorubicin, showed tumour response rates from 17 up
to 36% in NSCLC (Wils et al, 1990; Feld et al, 1992; Smit et al,
1992). The main toxicities of epirubicin are myelosuppression,
mucositis, and cardiomyopathy (Wils et al, 1990; Feld et al, 1992;
Smit et al, 1992). In our institution, the activity of epirubicin
combined with gemcitabine was studied in phases I and II study
(Van Putten et al, 2000). In this trial, a dose of 1125mgm?2
gemcitabine on days 1 and 8 of each 21-day cycle was chosen since
Received 6 March 2003; revised 30 June 2003; accepted 21 July 2003
*Correspondence: Dr HJM Groen; E-mail: h.j.m.groen@int.azg.nl
British Journal of Cancer (2003) 89, 1192–1199
& 2003 Cancer Research UKAll rights reserved 0007– 0920/03$25.00
www.bjcancer.com
Clinical

Page 2

this dose leads to a dose intensity of 750mgm?2week?1, which is
similar as the schedule in which single-agent gemcitabine
1000mgm?2is given weekly for 3 consecutive weeks in a 28-day
schedule. The nadir of epirubicin is expected 12–15 days after
administration; therefore, gemcitabine was omitted on day 15. The
phase II trial continued with a dose of 100mgm?2epirubicin
because in the preceeding phase I dose-escalation trial, a
maximum tolerated dose of 120mgm?2
haematologic toxicity of this regimen was acceptable with
granulocytopenia grade 4 in 33% and thrombocytopenia grade 4
in 12% of the cycles. Febrile neutropenia occurred in 14% of
patients. Nonhaematologic toxicity was mainly mucositis grade 2
and 3 in 35% of patients. Cardiotoxicity measured as a significant
decrease of left-ventricular ejection fraction (LVEF) was observed
in 7% of patients. The tumour response rate was 49% and the
median survival time was 42 weeks (Van Putten et al, 2000).
Manageable toxicity and high response rates of the epirubicin–
gemcitabine regimen were the background for initiating this phase
III trial. The aim of this phase III trial was to compare the efficacy
and safety of gemcitabine in combination with either cisplatin
(standard arm) or epirubicin. Epirubicin in combination with
gemcitabine (EG) was administered as an outpatient regimen, the
cisplatin–gemcitabine (CG) combination was given as a short
inpatient regimen as is often done in European countries. The
American Society of Clinical Oncology guidelines (published in
1997) recommended two to eight cycles of platinum-based
treatment in advanced NSCLC. We chose a maximum of five
cycles. Progression-free survival was the primary end point of the
study. Overall survival, response rate, toxicity, and QOL were
secondary end points.
was reached. The
PATIENTS AND METHODS
Patient selection
Patients were included if they had histological or cytological
diagnosis of unresectable stage III or stage IV NSCLC and at least
one measurable or evaluable tumour lesion on physical examina-
tion, chest X-ray, or chest CT. No prior chemotherapy was allowed
and radiotherapy was permitted as long as no more than 25% of
the bone marrow was irradiated. Radiotherapy should have been
completed at least 4 weeks before inclusion, and patients should
have recovered from any toxic side effect. The irradiated area was
excluded from tumour measurements. All patients had to have a
performance status p2 according to the Eastern Cooperative
Oncology Group (ECOG) scale and a life expectancy of at least 12
weeks.An adequatebone
X3.0?109l?1,
X100?109l?1, haemoglobin X6.2mmoll?1), normal renal (ser-
umcreatinine
p120mmoll?1
X60mlmin?1) and liver function (serum bilirubin p35mmoll?1,
serum alanine aminotransferase (ALAT), and serum aspartate
aminotransferase (ASAT) less than three times the upper limit of
normal) were required. Patients were excluded if they had active
infections, second primary malignancies (except carcinoma in situ
of the cervix, adequately treated basal cell carcinoma of the skin,
and adequately treated upper respiratory tract malignancy),
uncorrected hypercalcaemia, or an LVEF p45% measured by
multiple gated acquisition (MUGA) scan. Local medical ethics
committees of all hospitals approved the protocol. All patients gave
informed consent before study entry.
marrow
X1.5?109l?1,
reserve (leucocytes
platelets neutrophils
or creatinineclearance
Treatment
Eligible patients were randomised by telephone to receive either
cisplatin or epirubicin both with gemcitabine. Gemcitabine
(1125mgm?2) was administered in 250ml 0.9% NaCl by a
30min infusion on days 1 (before cisplatin or epirubicin) and 8.
Cisplatin 80mgm?2(in 1000ml 0.9% NaCl) was administered
intravenously during 3h after prehydration with 0.9% NaCl on day
2 of each 21-day treatment cycle. Epirubicin 100mgm?2(in 50ml
0.9% NaCl) was administered as an intravenous bolus injection
within 5min on day 1 of each 21-day cycle. For prehydration,
patients in the CG arm were admitted to hospital for 2 days.
Epirubicin–gemcitabine was administered as an outpatient regi-
men. Anti-emetics consisted of ondansetron 8mg and dexametha-
sone 8mg twice a day on days 1, 2, and 8. The treatment consisted
of a maximum of five cycles and was stopped earlier in case of
tumour progression, intolerable toxicity, or patient’s wish. No
treatment with G-CSF was foreseen. In case of Hbo5.0mmoll?1or
symptomatic anaemia in combination with Hbo6.0mmoll,
patients were treated with red blood cell transfusion. Platelet
transfusion was given in the event of platelets o10?109l?1or
persistent bleeding in combination with platelets o20?109l?1.
Dose adjustments
Drug administration was postponed to a maximum of 2 weeks if
there was no haematologic recovery on day 22 (neutrophils
o1.5?109l?1and/or platelets o100?109l?1) or in case of
persistent common toxicity criteria (CTC) grade 2 or more
nonhaematologic toxicity (except alopecia). The dose of cisplatin
or epirubicin for subsequent cycles was reduced to 75% in case of a
nadir of neutrophils below 0.5?109l?1exceeding 7 days, a nadir
of platelets below 25?109l?1, thrombocytopenia associated with
bleeding, febrile neutropenia, or CTC grade 3 nonhaematologic
toxicity (except nausea and vomiting). The cisplatin dose was
reduced by 50% for a calculated creatinine clearance between 50
and 70mlmin?1, and in case of a creatinine clearance less than
50mlmin?1cisplatin was not administered (Cockcroft and Gault,
1976). The dose of gemcitabine on day 8 was reduced to 50% in
case of neutrophils between 0.5 and 1.5?109l?1, platelets between
50 and 100?109l?1or grade 3 nonhaematologic toxicity on day 8.
Gemcitabine was omitted on day 8 in case of neutrophils
o0.5?109l?1, platelets o50?109l?1or grade 4 nonhaematologic
toxicity. The mean relative dose intensity was calculated by
dividing the delivered dose (mgm?2week?1) by the planned dose
(mgm?2week?1) for the number of cycles each patient received.
Treatment evaluation
Complete blood cell counts were performed at least on days 1 and
8 of each cycle. On day 1 of each cycle, patient evaluation also
included liver and renal functions, performance status, and
toxicity scoring according to the CTC of the National Cancer
Institute. The LVEF was measured by the MUGA scan before and
6–12 weeks after treatment. All patients were evaluable for
toxicity. The tumour response was evaluated by the treating
physician, at least after three and five cycles, according to the
World Health Organisation (WHO) criteria (WHO, 1979). After
treatment, tumour responses were evaluated by an independent
observer.
After discontinuation of treatment, patients were evaluated
every 6 weeks with physical examination, laboratory tests, chest X-
ray or CT-scan of the chest, and additional imaging tests on
clinical indication to assess tumour progression.
At the start of treatment, after three cycles of chemotherapy, and
6 weeks after the end of treatment, QOL was measured with the
European Organisation for Research and Treatment of Cancer
(EORTC) QLQ-C30, supplemented by a 13-item lung-cancer-
specific questionnaire module, the EORTC QLQ-LC13. This
validated questionnaire was filled in at home and is composed of
a core QOL questionnaire covering general aspects of health-
related QOL and disease- and treatment-specific symptoms
(Aaronson et al, 1993; Bergman et al, 1994).
Nonplatinum combination in advanced NSCLC
FM Wachters et al
1193
British Journal of Cancer (2003) 89(7), 1192–1199
& 2003 Cancer Research UK
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Statistical analysis
The primary end point of the study was progression-free survival.
The study was designed to detect a 20% increase in 6-month
progression-free survival, from 40% in the CG arm to 60% in
the EG arm. To detect such an increase using a two-sided 0.05
alpha-level test with 85% power, the required accrual was
determinedto be 120 patients
was performed on the intention-to-treat principle. The time from
the date of randomisation to the date of first documented
progression was defined as progression-free survival. Overall
survival was defined as the interval between the date of
randomisation to the date of death. Progression-free and overall
survivals for both treatment arms were compared by Kaplan–
Meier curves using the log-rank test. Quality of life was analysed by
ANOVA for the different functional areas and symptoms at all
three points of measurement. To identify potential prognostic
factors, a multivariate analysis was performed using a logistic
regression model for response rate and a Cox regression model for
progression-free and overall survivals. A Po0.05 was considered
statistically significant.
inbotharms. Analysis
RESULTS
Patient characteristics
Between November 1998 and February 2002, 240 patients from
four hospitals in the Northern part of the Netherlands were
recruited. Patients were randomised to CG (n¼119) or EG
(n¼121). Patient characteristics were not significantly different
between both treatment arms (Table 1). Seven patients had been
treated with prior radiotherapy on the primary tumour. Three
randomised patients did not receive chemotherapy because of
rapidly deteriorating performance status due to progression of
disease before treatment initiation. These patients were included in
all analyses.
Toxicity
Haematologic toxicity is shown in Table 2. In the EG arm, grade 3
or 4 leukopenia and granulocytopenia occurred more frequently as
compared to the CG arm. Epirubicin–gemcitabine patients were
more often hospitalised for febrile neutropenia than patients in the
CG arm (11 vs 2% of patients, P¼0.006). In both arms, two
patients died due to septicaemia (EG arm after one and three
cycles, CG arm after three and five cycles). In the CG arm, 56% of
patients had one or more red blood cell transfusions during
treatment, compared to 51% of patients in the EG arm (P¼0.433).
At the time of study, erythropoietin was not routinely adminis-
tered. The number of red blood cell transfusions per patient was
also not different between both treatment arms.
The worst nonhaematologic toxicity per patient is listed in
Table 3. Gemcitabinecan induce
of transaminases, this was experienced more frequently in the
EG arm (P¼0.001). Patients in the EG arm also had more often
short-lasting fever (in the absence of neutropenia). Nausea,
vomiting, and fatigue frequently occurred in both arms, but more
often in the CG arm. Significantly more patients in the EG arm had
a grade 1 (16% in the CG arm vs 42% in the EG arm) and grade 2
(7% in the CG arm vs 13% in the EG arm) decline in LVEF
(P¼0.006, n¼69). Clinically evident cardiac failure was not
observed during follow-up. In this trial, 28 elderly patients (X70
years) were included. In these patients, grade 3 or 4 thrombocy-
topenia occurred more frequently compared to younger patients,
in 78 vs 46% of patients, respectively (P¼0.029). No differences in
other toxicities were found when comparing them to younger
patients.
short-lasting elevation
Table 1Patient characteristics
Cisplatin–gemcitabine Epirubicin–gemcitabine
No.% No.%P
Patients entered119 50121 50 ns
Sex ns
Male
Female
94
25
79
21
85
36
70
30
Age, years
Median
Range
6060
29–8032–76ns
Stage
IIIa
IIIb
IV
ns
8787
43
68
36
57
44
69
36
57
Performance status
0
1
2
ns
36
66
17
30
55
14
37
73
11
31
60
9
Histology
Squamous cell carinoma
Adenocarcinoma
Large cell carcinoma
Other
ns
41
41
36
35
35
30
32
50
38
1
26
41
31
111
Weight loss (last 3 months)
o5%
X5%
ns
82
37
69
31
80
41
66
34
Liver metastases
Absent
Present
ns
109
10
92 111
10
92
88
ns¼Not significant.
Table 2Worst haematologic CTC toxicity grade per patient
Cisplatin–gemcitabine Epirubicin–gemcitabine
Toxicity No.%No.%P
Anaemia
1
2
3/4
ns
20
77
20
17
66
17
18
68
26
16
60
23
Leukopenia
1
2
3/4
o0.01
24
48
27
21
41
23
98
31
68
27
60
Granulocytopenia
1
2
3/4
o0.01
18
22
31
19
23
32
10
8
55
12
10
65
Thrombocytopenia
1
2
3/4
ns
19
22
66
16
19
56
35
24
48
31
21
42
Transfusions
Red blood cellsa
Plateletsa
665661
11
50ns
ns989
Febrile neutropenia2213 11
o0.01
aPatients receiving at least one red blood cell or platelet transfusion.
ns¼Not significant.
Nonplatinum combination in advanced NSCLC
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& 2003 Cancer Research UK
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Treatment
The median (range) number of cycles per patient was 4 (0–5) for
both arms. The maximum of five cycles was completed in 58 (49%)
patients in the CG arm and in 49 (41%) patients in the EG arm
(Table 4). The reasons for treatment discontinuation between both
arms were not different (Table 5).
The mean relative dose intensity for cisplatin and epirubicin was
94 and 95%, respectively. The mean relative dose intensity of
gemcitabine was not significantly different between both treatment
arms; 89% for the EG arm and 92% for the CG arm. Cisplatin,
epirubicin, and gemcitabine doses were reduced in, respectively, 6,
5, and 12% of cycles (for gemcitabine, days 1 and 8 were taken
together).
Tumour response
The overall response rate was 46% (95% CI, 37–55) for the CG arm
and 36% (95% CI, 28–45) for the EG arm (P¼0.121) (Table 6). In
all, 13 patients were not evaluable for tumour response due to early
death from toxicity (n¼1), death from other causes (n¼4),
discontinuation of treatment at patient’s request after one cycle
(n¼4), toxicity (n¼2), and for other reasons (n¼2). Three
patients did not receive chemotherapy at all and were, therefore,
not evaluable for response. For the analysis, these patients were
considered as nonresponders. The response rates for patients with
stage III vs stage IV disease were 55% (95% CI, 41–69) and 40%
(95% CI, 28–51) in the CG arm, and 44% (95% CI, 31–58) and
30% (95% CI, 20–41) in the EG arm, respectively. All these
differences were not statistically significant. The tumour response
rate in patients with a performance status of 0 or 1 was 43%
compared to 36% in patients with a performance status of 2
(P¼0.443). Elderly patients (X70 years) had a similar tumour
response rate compared to younger patients. However, patients
with liver metastases (n¼20) had a lower response rate (15%)
compared to patients without these metastases (44%) (P¼0.013).
A logistic regression model with potential prognostic factors
Table 3 Worst nonhaematologic CTC toxicity grade per patient
Cisplatin–gemcitabine Epirubicin–gemcitabine
Toxicity No.% No.%P
Bilirubin
1
2
3/4
ns
5
0
0
4
0
0
10
1
2
10
1
2
ASAT
o0.01
1
2
3/4
3127
0
0
43
8
4
40
0
0
7
4
ALAT
o0.01
1
2
3/4
50
12
44
10
2
46
27
14
43
25
132
Creatinine
1
2
3/4
o0.01
5345
8
0
10
4
0
9
4
0
9
0
Mucositis
1
2
3/4
o0.01
15 13
6
0
23
46
14
20
40
12
7
0
Nausea
1
2
3/4
o0.01
36
51
31
44
4
46
27
1
40
24
51
Vomiting
1
2
3/4
o0.01
37
27
32
23
2
28
11
1
25
10
21
Diarrhoea
1
2
3/4
ns
6
4
3
5
3
3
15
2
1
13
2
1
Fever
o0.01
1
2
3/4
119
2
1
22
12
3
19
102
13
Infections
1
2
3/4
ns
0
2
9
0
2
8
1
3
1
3
1311
Skin reactions
1
2
3/4
ns
9
7
1
8
6
1
14
1
2
12
1
2
Sensory neuropathy
1
2
3/4
o0.01
16 14
6
0
2
1
0
2
1
0
7
0
Motoric neuropathy
1
2
3/4
ns
0
2
1
0
2
1
0
2
1
0
2
1
Anorexia
1
2
3/4
ns
50
27
43
23
2
46
38
0
40
33
20
Fatigue
1
2
3/4
o0.05
41
54
35
46
4
22
57
5
19
50
54
ns¼Not significant.
Table 4 Number of chemotherapy cycles per patient
Cisplatin–gemcitabine Epirubicin–gemcitabine
No. of cyclesNo.%No.%
0
1
2
3
4
5
Median (range)
11
9
7
22
11
8
18
23
58
19
11
20
20
49
16
9
17
17
41
15
19
49
4 (0–5)4 (0–5)
Table 5Reasons for chemotherapy discontinuation
Cisplatin–gemcitabine Epirubicin –gemcitabine
Reason for
discontinuationNo.% No.%
Progressive disease
Toxicity
Death due to toxicity
Unrelated death
Patient’s request
Other
Total discontinuations
18
21
15
18
1
2
6
10
51
24
27
2
3
5
11
72
20
22
1
2
7
2
3
4
9 12
6160
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& 2003 Cancer Research UK
Clinical

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(disease stage, histology, sex, age, performance status, weight loss,
and liver metastases) showed that the presence of liver metastases
was a significant independent negative prognostic factor for
tumour response.
A total of 38 patients in the CG arm (32%) and 39 patients in
the EG arm (32%) received second-line chemotherapy, consisting
of docetaxel alone or docetaxel combined with carboplatin
or irinotecan. A partial response to second-line therapy was
observed in 20% of patients, without a difference between CG
and EG. In all, 24% of responders and 14% of nonresponders
on first-line therapy achieved a partial response to second-line
therapy; this difference was also not significant. Median survival
after start of second-line chemotherapy (n¼77) was 28 weeks
(95% CI, 22–34).
Progression-free survival and overall survivals
On August 2002, 47 patients were still alive. The median
progression-free survival was not significantly different between
both treatment arms; 26 (95% CI, 20–31) vs 23 (95% CI, 20–26)
weeks for the CG and EG arm, respectively (P¼0.247). Progres-
sion-free survival (7s.e.) at 6 months follow-up was 49% (75%)
vs 40% (75%) for the CG and EG arm, respectively (P¼0.134)
(Figure 1). The median overall survival was 43 (95% CI, 30–57)
weeks in the CG arm, vs 36 (95% CI, 30–42) weeks in the EG arm,
which was not different between both arms (P¼0.143). The 1-year
survival rate (7s.e.) was 45% (75%) vs 35% (75%) in the CG and
EG arm, respectively (P¼0.123) (Figure 2). Progression-free and
overall survivals were not different in elderly patients (X70 years)
when compared to younger patients.
A Cox regression model was used to find independent
prognostic factors for progression-free and overall survivals.
The factors disease stage, histology, sex, age, performance
status, weight loss, and liver metastases were used in this
model. Performance status p1, absence of liver metastases,
and weight loss o5% were associated with prolonged progres-
sion-free and improved overall survivals. Stage III disease
was, compared to stage IV disease, associated with longer
progression-free survival.
Quality of Life
The questionnaires filled in at the patient’s home at the start of
treatment, after three cycles of chemotherapy, and 6 weeks after
the end of treatment were returned to the datacenter by 70, 47, and
45% of patients, respectively. Between both treatment arms, no
significant differences were found in global health status and
functional scales (physical, role, emotional, cognitive, and social
functioning), at all three moments of measurement (Table 7a). On
symptom scales, differences were found in the occurrences of
nausea and vomiting, that were more common in the CG arm. A
sore mouth and dysphagia were more frequently noted in the EG
arm. Fatigue did not score different between both treatment arms.
A selection of scores on symptom scales from the EORTC QLQ-
C30 and QLQ-LC13 is shown in Table 7b.
DISCUSSION
The efficacy of epirubicin and cisplatin both combined with
gemcitabine is not significantly different in terms of progression-
free survival and tumour response rates. Since overall survival was
not the primary end point of this trial and our power analysis was
not performed to detect differences in overall survival, no
definitive conclusions in terms of overall survival can be drawn
although we found no significant differences in overall survival
between both arms. The overall toxicity was different and more
severe in the epirubicin combination. Neutropenia, febrile
neutropenia, elevation of serum transaminases, mucositis, and
fever occurred more frequently in the EG arm while nausea,
Table 6 Tumour response
Cisplatin–gemcitabine Epirubicin–gemcitabine
ResponseNo.% No.%P
Complete response
Partial response
Stable disease
Progressive disease
Not assessable
1100
54
40
22
2
45
34
19
2
44
37
26
14
36
31
22
12
Overall response
(95% CI)
46 (37–55) 36 (28–45)0.121
180160 140120 100 806040200
1.0
0.8
0.6
0.4
0.2
0.0
Cisplatin - Gemcitabine (n = 119)
Epirubicin - Gemcitabine (n = 121)
Log-rank: P = 0.247
Time (weeks)
Progression-free survival
Figure 1Kaplan–Meier curve for progression-free survival
180160140120100 80 6040 200
1.0
0.8
0.6
0.4
0.2
0.0
Cisplatin - Gemcitabine (n = 119)
Epirubicin - Gemcitabine (n = 121)
Log-rank: P = 0.143
Time (weeks)
Survival probability
Figure 2 Kaplan–Meier curve for overall survival
Nonplatinum combination in advanced NSCLC
FM Wachters et al
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& 2003 Cancer Research UK
Clinical

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vomiting, nephrotoxicity, and sensory neuropathy were more
common in the CG arm. The decline in LVEF after treat-
ment, especially grade 1, was more evident in the EG arm,
but was not associated with clinical signs of heart failure during
follow-up. In line with CTC toxicity evaluation, the symptom scales
of EORTC questionnaires showed a different spectrum of toxicity
in both arms. The global health status and scores on functional
scales were similar in both arms in all three moments of
measurement, although the number of patients who returned their
questionnaires was limited and therefore no firm conclusions can
be drawn.
Although in this trial efficacy was similar in both arms in
terms of progression-free survival, overall survival, and response
rate, this trial failed to show benefits in terms of less toxicity
for the nonplatinum-based regimen. Other trials showed similar
response rates and survival, and less toxicity in patients treated
with nonplatinum-based schedules compared to platinum-contain-
ing combinations (Gatzemeier et al, 1991; Gridelli et al,
1996; Georgoulias et al, 2001; Sculier et al, 2002). A recently
publishedstudycomparedfour
for advanced NSCLC (cisplatin with either paclitaxel, gemcitabine,
or docetaxel, and carboplatin with paclitaxel), and showed
no difference in survival (the median survival was 7.9 months
for all patients) and response rate (19% for all patients). How-
ever, progression-free survival was longer in the group of patients
who received cisplatin and gemcitabine (4.2 months). On the
other hand, treatment with cisplatin and gemcitabine was
associated with more renal toxicity (Schiller et al, 2002). Recently,
Rosell et al (2002) compared two platinum-based regimens and
showed that a cisplatin-based therapy was associated with a
significantly longer median survival. However, in our trial,
response rates and survival were similar in both arms, but the
nonplatinum-containing regimen had a less favourable toxicity
profile. Based on these data, we conclude that a platinum-based
combination therapy remains the standard treatment for advanced
NSCLC.
A performance status of 2, liver metastases, and weight loss of
morethan5% were associated
An unfavourable survival outcome for patients with a poor
performance status has also been reported in other studies
(Comella et al, 1996; Cullen et al, 1999; Le Chevalier et al, 2001;
Sweeney et al, 2001). Whether chemotherapy in patients with a
performance status of 2 should be advocated is still a matter of
debate. For these patients, a new therapeutic approach, for
example, with biologicals with hardly any toxicity, may be a more
attractive treatment option. Further trials are required to
investigate these modalities.
In the 28 elderly patients (X70 years) included in this
trial toxicity (except thrombocytopenia), the tumour response
rate, progression-free and overall survivals were not different
compared to younger patients. However, in contrast to the fact
that 35–43% of all lung cancers arise beyond the age of 70 years
(Fry et al, 1999), in this trial only 12% of patients were over
70 years of age. It is possible that we cannot demonstrate
differences between elderly and younger patients due to exclusion
of elderly patients with a poor performance status or comorbidity.
Generally, elderly patients are thought to be less able to tolerate
polychemotherapy (Frasci, 2002). However, to date prospective
randomised trials on the beneficial role of platinum-based
chemotherapy in elderly NSCLC patients are not available (Frasci,
2002).
Shepherd et al (2000) have shown that second-line treatment
with single-agent docetaxel, compared to best supportive care, is
associated with prolongation of survival. The tumour response rate
of single-agent docetaxel in this trial was 7.1%. However, in our
study the observed tumour response rate after predominantly
docetaxel-containing doublets as second-line chemotherapy regi-
mens was 20%, suggesting that a combination regimen may be
platinum-basedregimens
withaworse survival.
Table 7 Mean quality of life scores before, during, and after treatment
Cisplatin–gemcitabineEpirubicin–gemcitabine
ItemsMean s.e. Mean s.e.P
(a)
Global health statusa
Before
During
After
53.1
53.4
52.0
2.7
2.7
2.9
58.1
53.5
51.7
2.4
3.0
3.1
ns
ns
ns
Functional scalesa
Physical
Before
During
After
59.1
56.3
57.0
3.5
3.6
3.9
67.3
51.2
47.1
2.9
3.8
3.6
ns
ns
ns
Role
Before
During
After
53.2
48.0
45.9
3.7
3.8
3.7
59.3
37.7
43.0
3.3
4.2
4.1
ns
ns
ns
Cognitive
Before
During
After
82.1
80.4
79.9
2.5
3.0
3.0
82.7
77.7
81.2
2.6
3.6
2.8
ns
ns
ns
Emotional
Before
During
After
62.4
72.4
72.5
2.6
3.3
2.6
64.0
69.6
72.9
2.6
3.3
2.8
ns
ns
ns
Social
Before
During
After
73.6
64.9
67.3
2.8
3.9
3.8
74.0
65.7
65.2
3.0
4.0
4.1
ns
ns
ns
(b)
Symptom scalesb
Fatigue
Before
During
After
40.2
49.2
46.5
3.3
3.2
3.5
37.3
56.4
52.0
3.0
3.7
3.8
ns
ns
ns
Nausea and vomiting
Before
During
After
11.0
32.5
31.5
2.1
4.3
4.5
7.3
16.7
12.7
1.4
2.9
3.5
ns
0.003
0.001
Pain
Before
During
After
25.4
16.7
22.2
3.1
3.3
3.9
27.8
26.2
32.4
3.1
4.3
4.4
ns
ns
ns
Appetite loss
Before
During
After
24.4
36.2
30.8
3.5
4.6
4.3
21.6
37.0
30.2
3.2
4.6
4.6
ns
ns
ns
Sore mouth
Before
During
After
8.2
16.7
9.4
2.3
3.4
3.2
9.4
42.3
35.2
2.5
5.3
5.6
ns
0.001
0.001
Dysphagia
Before
During
After
8.5
13.6
9.4
2.1
3.4
2.9
11.0
31.4
27.2
2.5
5.0
4.8
ns
0.003
0.002
Peripheral neuropathy
Before
During
After
11.0
16.4
19.5
2.4
3.3
4.0
7.1
14.0
12.6
1.9
3.2
3.0
ns
ns
ns
aScores range from 0 to 100, with a higher score representing a higher level of
functioning.
bScores range from 0 to 100, with a higher score representing a greater degree of
symptoms.
ns¼Not significant.
Nonplatinum combination in advanced NSCLC
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& 2003 Cancer Research UK
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Page 7

more effective than a single agent one. Other trials on second-line
chemotherapy in NSCLC, reviewed by Huisman et al (2000), also
report higher response rates.
In conclusion, we found no differences in efficacy and
global QOL between cisplatin and epirubicin, both in combina-
tion with gemcitabine as first-line treatment for advanced
NSCLC. However, the observed differences in toxicity profile
are in favour of cisplatin. Therefore, a platinum-based combina-
tion regimen remains the recommended treatment for advanced
NSCLC.
ACKNOWLEDGEMENT
This study was supported by Eli Lilly, Nieuwegein, The Nether-
lands.
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