Gemcitabine and cisplatin treatment of advanced-stage non

Gemcitabine and cisplatin treatment of advanced-stage non

Tumori, 94: 474-480, 2008
Gemcitabine and cisplatin treatment
of advanced-stage non-small-cell lung cancer
in patients given cisplatin on day 8
Zafer Akcali, Zuleyha Calikusu, Hakan Sakalli, and Ozgur Ozyilkan
Department of Medical Oncology, Baskent University Faculty of Medicine, 06490, Ankara, Turkey
ABSTRACT
Aims and background. Gemcitabine and cisplatin treatment were administered to
patients with advanced-stage, non-small-cell lung cancer. During phase II studies,
the treatment is performed using a 28-day cycle, with gemcitabine administered on
days 1, 8, and 15. Although it is advised that cisplatin not be administered on the first
day, gemcitabine and cisplatin treatment is usually performed using a 21-day cycle,
with gemcitabine administered on days 1 and 8, and cisplatin is given on the first day
in most phase III studies. In contrast with previous phase III studies, cisplatin was administered on day 8 in our study. Dose density, drug toxicity, and efficacy were analyzed.
Methods and study design. Chemonaive patients with stage IIIB or stage IV nonsmall-cell lung cancer received gemcitabine (1250 mg/m2) on days 1 and 8 plus cisplatin (75 mg/m2) on day 8 every 3 weeks (1 cycle contained 2 applications).
Results. Sixty-seven patients received a total of 293 applications. Dose densities were
92.3% for gemcitabine and 93.9% for cisplatin. The types and rates of grade 3 and
grade 4 hematologic toxicities were anemia (6%), granulocytopenia (46%), and
thrombocytopenia (6%). Complete remission was seen in 2 patients (3%); partial remission was 40%, stable disease was 39%, and progression of disease, 10%. The median overall survival time was 13 months. The median progression-free survival time
was 9.5 months. One-year survival rate was 54% and 2-year survival, 10.4%.
Conclusions. In this 21-day treatment regimen, overall survival was longer than 1 year
and the 1-year survival rate was more than 50%. Both the severity and rate of observed thrombocytopenia in the study were very low. Other adverse effects in the current study were comparable to those reported in the literature.
Introduction
Chemotherapy treatment in advanced stage (stage IIIB/IV) non-small-cell lung
cancer (NSCLC) has favorable effects on patient survival and quality of life1. One platinum drug, usually cisplatin or carboplatin, combined with another antineoplastic
drug comprises the first-line treatment. Although three-drug combinations have
been used in recent trials and most of them demonstrated high response rates, their
survival rates were similar to two-drug combinations, and more toxicities have been
shown. Therefore, two-drug combinations are usually preferred2,3. However, it should
be noted that Paccagnella et al.4 demonstrated a survival advantage by adding gemcitabine to the paclitaxel/carboplatin combination. A combination of cisplatin plus
gemcitabine has been found to be superior to the previous combination of cisplatin
plus etoposide5. Other two-drug combinations using cisplatin with gemcitabine, vinorelbine, paclitaxel or docetaxel in advanced-stage NSCLC patients have been tried,
but all of the combinations demonstrated nearly the same effect on tumor dimensions and patient survival6,7. Some meta-analyses suggested that the gemcitabine
Key words: cisplatin, gemcitabine,
non-small-cell lung cancer.
Correspondence to: Dr Zafer Akcali,
Baskent University Faculty of Medicine,
Department of Medical Oncology, 12.
Sokak No: 7/5 Bahcelievler, 06490
Ankara, Turkey.
Tel +90-312-212- 0434;
fax +90-312-212-7572;
e-mail [email protected]
Received October 3, 2007;
accepted January 28, 2008.
A DIFFERENT SCHEDULE OF GEMCITABINE AND CISPLATIN
475
plus platinum drug combination has a small survival
advantage over other combinations. According to one
meta-analysis of advanced-stage NSCLC, overall survival was 9 months, median progression-free survival
(PFS) was 5.1 months, and the 1-year survival rate was
40% for gemcitabine-based treatments8. Usually, a gemcitabine-platinum combination is less expensive than
other combinations9,10. Gemcitabine is infrequently
combined with carboplatin11 and more recently with
oxaliplatin12. Consequently, gemcitabine plus platinum
is frequently used as an effective and inexpensive combination as a first-line treatment for NSCLC.
Different schedules of platin plus gemcitabine combinations have been used to minimize toxic effects without compromising antitumor effects. In phase II trials,
cycle lengths have been 28 days with gemcitabine (1000
mg/m2) administered on days 1, 8 and 15. These studies
were analyzed in separate publications13,14. Shepherd et
al.13 suggested that gemcitabine be administered on the
first day and that the platinum be administered on another day of the cycle to ensure better survival rates.
However, in later phase III studies, the cycle length was
21 days, gemcitabine was administered on days 1 and 8,
and the platinum was usually administered on the first
day.
In one phase III trial, gemcitabine plus cisplatin was
compared with cisplatin plus etoposide; cisplatin (100
mg/m2) was administered on day 1, and gemcitabine
(1250 mg/m2) was administered on days 1 and 8. Response rates and PFS were better in the gemcitabinecisplatin arm5. After this trial, cisplatin was administered at a dosage lower than 100 mg/m2, and a cycle
length of 21 days was used in phase III trials. Some of
these trials are summarized in Table 13,5-6,15-21. Except for
one Korean study20, overall survival ranged from 8.7 to
11 months, and 1-year survival rates were 32%-44%.
Additional studies were found in which gemcitabine
and a platinum drug were administered on day 8 but
combined with carboplatin instead of cisplatin. In one
of these studies, gemcitabine (1100 mg/m2) was administered on days 1 and 8, and carboplatin was administered at an AUC of 5 on day 822. In another study, gemcitabine (1000 mg/m2) was administered on days 1 and 8,
and carboplatin was administered at an AUC of 5 on day
823. The response rates were similar in these two studies,
but the reported severity of thrombocytopenia was lower than with the previous gemcitabine plus carboplatin
studies.
In our study, for advanced-stage NSCLC patients, we
followed the advice of Shepherd et al.13 and did not administer cisplatin in combination with gemcitabine on
day 1. Instead, we administered cisplatin (75 mg/m2) on
day 8 and gemcitabine (1250 mg/m2) on days 1 and 8,
every 21 days. We thought that this application was the
best replacement for the schedule that Abratt et al.24
published in 1997, which was every 28 days. Abratt et
al.24 combined gemcitabine (1000 mg/m2) on days 1, 8
and 15 with cisplatin on day 15, and the phase II study
demonstrated some of the best survival and tumor response rates24. Both the study of Abratt et al.24 and ours
used gemcitabine alone for 1 week prior to cisplatin; patients received no treatment for 14 days between the
second cycle and cisplatin administration.
Patients and methods
Patients
Histologically or cytologically confirmed NSCLC patients, whose disease was staged as IIIB or IV according to
the American Joint Committee on Cancer staging system
(AJCC, 1997), whose performance status was between 0
Table 1 - Cisplatin + gemcitabine schedules and results of phase III studies
Gemcitabine
Cisplatin
Dose
(mg/m2) Day
Dose
(mg/m2) Day
1250
1250
1250
1250
1200
1200
1250
1000
1250
1200
1+8
1+8
1+8
1+8
1+8
1+8
1+8
1+4
1+8
1+8
100
100
75
80
80
75
50
70
75
80
1
1
2
1
1
1
1+8
2
1
2
First drug
NR
Cisplatin
NC
Gemcitabine
NR
Gemcitabine
NR
NC
Cisplatin
NC
No.
cases
OS
(mo)
RR
(%)
SR
(%)
DRM
(%)
182
69
205
160
125
135
78
34
40
62
9.3
8.7
9.8
8.9
9.5
11
NC
10
18.3
10.4
42
41
30
37
29
26
NC
44
52
42
38
32
37
33
37
44
NC
NR
69
43
1.6
1.4
3.9
1.2
4.4
0.7
0.0
0.0
0.0
0.0
Plt
(%)
Grn
(%)
Ref.
No.
19
55
36
36
NC
9.3
5
13
18
6.5
32
64
38
43
NC
18
32
18
48
4
3
5
6
15
16*
17
18†
19
20
21‡
First drug, which drug was delivered first when gemcitabine and cisplatin were administered the same day; No., no of patients; OS, overall
survival; RR, response rate; SR, one-year survival rate; DRM, drug-related mortality; Plt, grade 3-4 thrombocytopenia; Grn, grade 3-4 granulocytopenia; NC, not comparable with other studies; NR, not reported.
*Combined results with both gemcitabine-cisplatin and cisplatin-vinorelbine arm.
†
Includes only stage IIIA and IIIB patients.
‡
Grn and Plt rate is calculated per cycle, according to WHO criteria.
476
and 2 according to the Eastern Cooperative Oncology
Group, treated with the gemcitabine plus cisplatin protocol between 2000-2006 at the Department of Medical Oncology, Baskent University Faculty of Medicine, were retrospectively analyzed. Additional requirements were adequate bone marrow reserve (white blood cell count
≥ 3.5×109/L-1, platelets ≥100×109/L-1, hemoglobin ≥10
g/dL, hematocrit ≥ 30%) and liver and renal function
(bilirubin < 1.5 mg/dL, serum transaminase levels less
than 3 times the upper limit of normal, and serum creatinine ≤ 1.4 mg/dL). Some patients received prior palliative
radiotherapy for brain or bone metastases, which was
completed 2 weeks before the start of chemotherapy. All
patients had bidimensionally measurable masses. These
masses (assigned as follow-up criteria) had not been previously treated with radiotherapy or chemotherapy. Patients with active infection, serious concomitant systemic disorders, second primary malignancies (except in
situ carcinoma of the cervix or nonmelanomatous skin
cancers), or pregnancy were excluded from the study.
Written informed consent was obtained from each patient before administering chemotherapy. The treatment
schedule was approved by the local research and ethics
committee at Baskent University.
Treatment schedule
Patients received gemcitabine (1250 mg/m2) in an intravenous infusion during 30 min on days 1 and 8, and
cisplatin (75 mg/m2) was administered over 120 min
with appropriate hydration and antiemetic medications
on day 8 after gemcitabine infusion. Cycles were repeated every 21 days. No treatment application was given
unless the absolute granulocyte count was ≥1.5×109/L-1,
the platelet count was ≥100×109/L-1, and the hemoglobin
level was ≥10 g/dL on day 1 or day 8. The dose of cisplatin was not reduced unless grade 2 neuropathy was
encountered or if the serum creatinine level was ≥1.25
times the upper normal limit. The gemcitabine dose was
reduced 10% to 25%, in subsequent applications, after
one week rest, if the absolute granulocyte count or
platelet count was below the aforementioned limits.
Granulocyte colony-stimulating factors were used to
treat granulocytopenia if it persisted more than a week,
but also the gemcitabine dose was reduced in subsequent
administrations after one of week rest. Treatment was terminated if thrombocytopenia or granulocytopenia persisted, even after a 25% dose reduction of gemcitabine. If
the hemoglobin level was <10 g/dL, then erythrocyte
transfusions were given. The use of erythropoietin was not
permitted for cancer patients in our country at that time.
In stage IIIB patients, if curative resection was applicable, a maximum of 4 cycles of chemotherapy was given. Some stage IIIB patients received radiotherapy for
the primary tumor either concurrently or sequentially
with chemotherapy. In stage IV patients, chemotherapy
was continued for a maximum of 6 cycles if an objective
Z AKCALI, Z CALIKUSU, H SAKALLI, O OZYILKAN
response (partial or complete remission) was obtained,
or for 4 cycles if a stable response was obtained. Some
patients were given second- or third-line chemotherapy
protocols. Palliative radiotherapy was used for brain
and symptomatic bone metastases. Treatment was
stopped if the patient decided to stop treatment, if a
major toxicity occurred, if the clinician thought that a
different therapy was required, or if an ongoing treatment was delayed for more than 3 weeks. All patients
were evaluated for toxicity and survival if they were given one application of gemcitabine.
Response evaluation and follow-up
Medical history, physical examination, complete
blood count, electrocardiography, chest radiograph,
blood chemistries, and calculated creatinine clearance
were assessed in all patients. Additional assessments included computed tomography (CT) of the chest, bone
scintigraphy, and abdominal ultrasonography or CT to
detect liver and suprarenal metastases. CT or magnetic
resonance imaging of the brain was obtained if brain
metastases were suspected. Tumor responses were defined as complete response (CR; complete disappearance of all clinically detectable malignant disease on 2
occasions at least 4 weeks apart), partial response (PR; a
reduction of at least 50% of the tumor size as determined
on 2 occasions at least 4 weeks apart with no appearance
of new lesions or progression of any lesion), progressive
disease (PD; an increase in the size of 1 or more lesions
of 25% or more or the appearance of a new lesion), and
stable disease (SD; no response or progressive disease
demonstrated during the first 8 weeks of treatment). Response durations were measured from the date of diagnosis to progression date if the response was SD, and
from the observation of response to progression date if
the response was a PR or a CR. Overall survival was calculated as the interval between date of diagnosis and
death. PFS was measured from the date of diagnosis until observation of PD. Toxicities were scored between 0
and 5 (5 meaning death due to toxicity) according to the
National Cancer Institute Common Toxicity Criteria for
Adverse Events Version 3 (CTCAE V3). Complete blood
count, blood urea nitrogen and creatinine levels were
measured before every application. Complete biochemistry profiles were assessed prior to chemotherapy administration during every cycle. Chest radiographs were
obtained and assessed every 2 cycles if there were no
lung symptoms. Chest CT was performed after cycle 3
and cycle 6, or prior to radiotherapy or curative surgery.
Statistics
There was no control group; all patients were given
the same treatment. Patient and disease characteristics,
response rates, survival rates, and toxic effects are presented as percentages. Age and survival times are presented as median values with lower and upper limits.
A DIFFERENT SCHEDULE OF GEMCITABINE AND CISPLATIN
Survival curves were plotted according to the KaplanMeier method using SSPS software (Statistical Package
for the Social Sciences, version 11.5, SSPS Inc, Chicago,
Ill, USA). Ninety-five percent confidence intervals (CI)
are given where appropriate.
477
From December 2000 to February 2006, 67 patients
were treated and evaluated. Patient characteristics are
summarized in Table 2. The median follow-up was 13
months (range, 1.5-48; 95% CI, 11.42-14.58). Fifty-eight
patients (86.5%) died, and 9 (13.5%) were alive at the
time of this writing. Thirteen bone, 10 brain, 2
suprarenal gland, 1 pericardial, and 1 leptomeningeal
metastases occurred during follow-up. Median age was
62 years (range, 44-78).
delay. Treatment was delayed 1 time in 16, 2 times in 15,
3 times in 4, and 4 or more times in 7 patients.
Fourteen stage IIIB patients (53%) received radiotherapy for a primary lung mass, one (3.5%) stage IIIB patient was operated with a curative intent, and one patient was treated with both radiotherapy and surgery.
Responses to gemcitabine plus cisplatin were assessed
and reported before radiotherapy in these patients.
These 16 patients were excluded from PFS analysis.
Forty patients (60%) received second-line chemotherapy
after the disease had progressed. These schedules were cisplatin plus docetaxel in 18 (27%), docetaxel only in 15
(22%), cisplatin plus vinorelbine in 3 (4.5%), and other
schedules in 4 (6%) patients. Five patients (7%) received
third-line chemotherapy. Twenty-two patients received cisplatin-containing salvage regimens. Four of them were not
responsive to gemcitabine-cisplatin, 16 of them had SD or
PR duration of at least 3 months. Overall survival of 4 unresponsive stage IV patients was 5, 6, 14 and 17 months.
Treatment administration
Responses
The mean dose for gemcitabine was 1154 mg/m2
(92.3% of the planned dose). The mean dose for cisplatin was 70 mg/m2 (93.9% of the planned dose). Six
cycles were planned for 49 patients (73%), 4 cycles were
planned for 14 patients (21%), and 3 cycles were
planned for 4 patients (6%). A median of 4 chemotherapy cycles was given (mean, 4.3; 95% CI, 0.5-6) at a median of 13.5 weeks. A total of 288 cycles was performed in
67 patients. Drugs were given to 25 patients without any
Two (2%) radiological CR and 27 (40%) PR were obtained. Responses were SD in 26 patients (39%) and PD
in 7 (10%). Five patients (7.5%) could not be assessed for
the responses – 4 owing to toxicity and 1 because of
death at home for unknown reasons prior to the second
cycle. Responses according to stages are given in Table 3.
Results
Patient and disease characteristics
Table 2 - Patient and disease characteristics at the time of
diagnosis
Characteristic
No. of patients
%
Table 3 - Responses according to stage
Stage
CR
PR
SD
PD
IIIB
IV
Total
1 (3.5)
1 (2.5)
2 (3)
11 (39.5)
16 (41)
27 (40)
14 (50)
12 (31)
26 (39)
1 (3.5)
6 (15.5)
7 (10.5)
Unknown
1 (3.5)
4 (10)
5 (7.5)
CR, complete remission; PR, partial remission; SD, stable disease;
PD, progressive disease. In parenthesis, percentage.
Sex
Male
Female
65
2
97%
3%
Histopathology
Adenocarcinoma
Epidermoid carcinoma
Other
30
27
10
40%
45%
15%
Stage
IIIB
IV
28
39
42%
58%
Treatments were terminated in 9 patients (13.4%) owing to toxicity. Three of these patients (4.5%) died. The
reasons for death were neutropenic infection, nonneutropenic sepsis, and cerebral infarction after orthopedic
surgery for a traumatic (nonmetastatic) bone fraction.
Hematologic toxicities are shown in Table 4. Only 1 pa-
Performance status
0
1
2
3
55
9
4.5
82
13.5
Table 4 - Hematologic toxicity (according to CTC V3)
Metastases (invasion)
Brain
Suprarenal gland
Lung
Pleura
Bone
Liver
Pulmonary artery
Trachea (carina)
12
11
11
7
7
5
1
1
18
16
16
10
10
7
1.5
1.5
Toxicity
Toxicity
Grade 2
Grade 3
Grade 4
Grade 5
(death)
Anemia
Granulocytopenia
Thrombocytopenia
Neutropenic infection
21 (31)
11 (16)
2 (3)
-
4 (6)
24 (36)
2 (3)
1 (1.5)
7 (10)
2 (3)
-
1 (1.5)
In parenthesis, percentage.
478
Z AKCALI, Z CALIKUSU, H SAKALLI, O OZYILKAN
Table 5 - Nonhematologic toxicity (according to CTC V3)
Toxicity
Renal
Hepatic
Heart failure
Venous thrombosis
Non-neutropenic
infection
Alopecia
Neuropathy
Dermatologic
Mucositis
Diarrhea
Grade 1 Grade 2 Grade 3
5
2
1
1
6
(7.5)
(3)
(1.5)
(1.5)
(9)
7
9
1
1
1
(10)
(13)
(1.5)
(1.5)
(1.5)
-
Grade 4
Grade 5
(death)
-
1 (1.5)
1 (1.5)
1 (1.5)
-
-
-
1.2
1.0
Cumulative survival
tient experienced long-term hematologic toxicity requiring 4 units of platelets and 6 units of erythrocytes.
Nonhematologic toxicities are shown in Table 5. Additionally, nausea and vomiting occurred: grade 2 in 6
(9%), grade 3 in 5 (7.5%), and grade 4 in 3 (4%) patients.
.8
.6
.4
.2
0.0
0
3
3
3
1
1
(4)
(4)
(4)
(1.5)
(1.5)
10
30
20
40
50
Months
Figure 1 - Overall survival (months) of 51 patients who were treated with chemotherapy only, Kaplan-Meier curve.
In parenthesis, percentage.
1.2
PFS and response duration
Cumulative survival
Median PFS for 46 patients who had known responses
(5 patients were not assessed for the response) and who
were treated with chemotherapy only (16 patients were
also treated with radiotherapy or surgery) was 8.0
months (95% CI, 7.11-8.89). Median response duration
was 6.0 months (mean, 6.4; 95% CI, 7.3-10.3). According
to the responses, median response duration was 7.0
months for CR (1 patient), 6.5 months (mean, 7.8; 95%
CI, 5.5 -10.2) for PR (20 patients), and 6.5 months
(mean, 7.3; 95% CI, 4.9-9.9) for SD (18 patients).
1.0
.8
.6
Stage IIIB
Stage IV
.4
.2
0.0
Survival time
The median overall survival was 13 months (95% CI,
11.5-14.5). For 51 patients treated with chemotherapy
only, the median overall survival was 12.0 months (95%
CI, 10.2-13.7) (Figure 1). When ranked according to
stages, the median overall survival was 15 months (95%
CI, 9-21) for stage IIIB and 12.0 months (95% CI, 10.014.0) for stage IV patients (Figure 2). The 1-year survival
rate was 54% for all patients (36 patients). When ranked
according to stages, the 1-year survival rate was 61% (17
patients) for stage IIIB and 49% (19 patients) for stage IV
patients. The 2-year survival rate was 10.4% (a total of 7:
4 stage IIIB and 3 stage IV patients) for all patients.
Discussion
Our survival rates – more than 1-year overall survival
and more than 50% 1-year survival rates – indicate a
highly effective schedule. Docetaxel-containing secondand even third-line antineoplastic drugs may have con-
0
10
20
30
40
50
Months
Figure 2 - Overall survival (months) for 28 stage IIIB and 39 stage
IV patients, Kaplan-Meier curve.
tributed to these survival results. A long PFS of 8.0
months independent of second- and third-line drugs also shows the effectiveness of this schedule. There are few
publications demonstrating activity of platinum-containing regimens in a second-line setting. Platinum sensitivity was required in the study of Song et al.25 but not
required in that of Hamada et al.26 Two of 4 patients who
were unresponsive to gemcitabine-cisplatin but who received platinum-containing second-line treatments
lived longer than 1 year in our study. Grade 3 or 4 thrombocytopenia reached 50% in other gemcitabine-cisplatin studies; our rate of 6% is lower. Thrombocytopenia also was not clinically important, because our patients did not experience bleeding or petechiae. We de-
A DIFFERENT SCHEDULE OF GEMCITABINE AND CISPLATIN
layed administration when the platelet count was below
100×109/L-1, but some authors have administered gemcitabine with18 or without17 reduced doses when the
platelet count was above 75×109/L-1. If we had done this,
our delay rates would have been much lower. Our grade
3 and 4 granulocytopenia rates are consistent with those
of other studies. Only 1 patient died for a neutropenic infection. One patient died because of a nongranulocytopenic infection. One patient had a nonmetastatic femur fracture during chemotherapy administration and
then died after experiencing a deep vein thrombosis and
cerebral infarction. It is unlikely that this patient died
owing to the direct toxic effects of chemotherapy.
Drug-related mortality was thus 3% and was comparable
with other studies (Table 1).
Cycle lengths were 28 days in the first gemcitabinecisplatin combination studies, and gemcitabine was administered on days 1, 8, and 15. When cisplatin was administered on day 1, gemcitabine was frequently omitted on day 8 or 15 because of hematologic (mainly
thrombocytopenia) toxicity. The best survival results
were obtained if cisplatin was administered on day 2 or
day 15 in these phase II studies24,27. Shepherd et al.13
and Abratt et al.14 believed that the optimal way to administer these two agents was with a loading course of
gemcitabine followed later in the treatment cycle by cisplatin13,14. Unfortunately, most randomized trials of
gemcitabine and cisplatin using either a 28- or 21-day
cycle administered gemcitabine and cisplatin together
on day 1. Practically, it was difficult to administer cisplatin on day 2, but there are no published data about
administering the two drugs together on day 8.
Gemcitabine pretreatment negatively affects the intracellular pharmacokinetics of cisplatin when administered 4 hr before cisplatin. Moreover, treatment of
cancer patients with cisplatin 24 hr before gemcitabine
led to the highest active gemcitabine accumulation in
WBC and total platinum in plasma28. The schedule may
increase tumor response but also worsens side effects.
There is no consensus on the sequence of the drugs, and
some authors also administered gemcitabine first, similar to our study (Table 1).
References
1. le Chevalier T: Chemotherapy for advanced NSCLC. Will
meta-analysis provide the answer? Chest, 109 (Suppl 5):
S107-109, 1996.
2. Comella P, Filippelli G, De Cataldis G, Massidda B, Frasci
G, Maiorino L, Putzu C, Mancarella S, Palmeri S, Cioffi R,
Roselli M, Buzzi F, Milia V, Gambardella A, Natale D, Bianco M, Ghiani M, Masullo P: Efficacy of the combination of
cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase
III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101). Ann Oncol, 18: 324-330,
2006.
479
3. Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C,
Bover I, Ruiz-Casado A, Azagra P, Jimenez U, Gonzalez-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S,
Sanchez JJ, de las Penas R, Felip E, Lopez-Vivanco G: Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non
small-cell lung cancer: a Spanish Lung Cancer Group phase
III randomized trial. J Clin Oncol, 21: 3207-3213, 2003.
4. Paccagnella A, Oniga F, Bearz A, Favaretto A, Clerici M, Barbieri F, Riccardi A, Chella A, Tirelli U, Ceresoli G, Tumolo S,
Ridolfi R, Biason R, Nicoletto MO, Belloni P, Veglia F, Ghi MG:
Adding gemcitabine to paclitaxel-carboplatin combination
increases survival in advanced non-small-cell lung cancer:
results of a phase II-III study. J Clin Oncol, 24:681-687, 2006.
5. Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, Garcia M, Lianes P,
Montalar J, Vadell C, Gonzalez-Larriba JL, Nguyen B, Artal
A, Rosell R: Randomized phase III study of gemcitabinecisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non small-cell lung cancer. J
Clin Oncol, 17: 12-18, 1999.
6. Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C,
Ricci S, Matano E, Boni C, Marangolo M, Failla G, Altavilla
G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, Frontini
L, Tonato M: Phase III randomized trial comparing three
platinum-based doublets in advanced non small-cell lung
cancer. J Clin Oncol, 20: 4285-4291, 2002.
7. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A,
Krook J, Zhu J, Johnson DH: Comparison of four
chemotherapy regimens for advanced non small-cell lung
cancer. N Engl J Med, 346: 92-98, 2002.
8. Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R,
Stahel R, Thomas P, Rudd RM, Vansteenkiste J, Thatcher N,
Manegold C, Pujol JL, van Zandwijk N, Gridelli C, van Meerbeeck JP, Crino L, Brown A, Fitzgerald P, Aristides M, Schiller
JH: Efficacy of gemcitabine plus platinum chemotherapy
compared with other platinum-containing regimens in advanced non small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer, 47: 69-80, 2005.
9. Novello S, Kielhorn A, Stynes G, Selvaggi G, De Marinis F,
Maestri A, Foggi P, Tilden D, Tonato M, Crino L, Rinaldi M,
Migliorino AM, Scagliotti GV: Cost-minimisation analysis
comparing gemcitabine/cisplatin, paclitaxel/carboplatin
and vinorelbine/cisplatin in the treatment of advanced
non small cell lung cancer in Italy. Lung Cancer, 48: 379387, 2005.
10. Pimentel FL, Bhalla S, Laranjeira L, Guerreiro M: Cost-minimization analysis for Portugal of five doublet chemotherapy regimens from two phase-3 trials in the treatment of
advanced non small cell lung cancer. Lung Cancer, 52: 365371, 2006.
11. Cullen M: The development of gemcitabine and carboplatin in the treatment of non small-cell lung cancer. Lung
Cancer, 50 (Suppl. 1): S5-7, 2005.
12. Bidoli P, Zilembo N, Cortinovis D, Mariani L, Isa L, Aitini E,
Cullura D, Pari F, Nova P, Mancin M, Formisano B, Bajetta
E: Randomized phase II three-arm trial with three platinum-based doublets in metastatic non small-cell lung
cancer. An Italian Trials in Medical Oncology study. Ann
Oncol, 18: 461-467, 2007.
13. Shepherd FA, Abratt R, Crino L, Green M, Sandler A, Steward W, Iglesias J, Anglin G: The influence of gemcitabine and
cisplatin schedule on response and survival in advanced
non small cell lung cancer. Lung Cancer, 30: 117-125, 2000.
14. Abratt RP, Sandler A, Crino L, Steward WP, Shepherd FA,
Green MR, Nguyen B, Peters GJ: Combined cisplatin and
gemcitabine for non small cell lung cancer: influence of
scheduling on toxicity and drug delivery. Semin Oncol,
25(Suppl. 9): S35-43, 1998.
480
15. Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand
C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C,
Neymark N, Giaccone G: Three-arm randomized study of
two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non small-cell lung cancer: a phase III
trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group – EORTC 08975. J Clin
Oncol, 21: 3909-3917, 2003.
16. Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B,
Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava
S, Hirsh V, Bezjak A, Seymour L, Perrone F: Gemcitabine plus
vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non small-cell lung
cancer: a phase III trial of the Italian GEMVIN Investigators
and the National Cancer Institute of Canada Clinical Trials
Group. J Clin Oncol, 21: 3025-3034, 2003.
17. Martoni A, Marino A, Sperandi F, Giaquinta S, Di Fabio F,
Melotti B, Guaraldi M, Palomba G, Preti P, Petralia A, Artioli
F, Picece V, Farris A, Mantovani L: Multicentre randomised
phase III study comparing the same dose and schedule of
cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non small cell lung cancer. Eur J Cancer, 41: 81-92, 2005.
18. Esteban E, de Sande JL, Villanueva N, Corral N, Muniz I,
Vieitez JM, Fra J, Fernandez Y, Estrada E, Fernandez JL,
Luque M, Jimenez P, Mareque B, Capellan M, Buesa JM, Lacave AJ: Cisplatin plus gemcitabine with or without vinorelbine as induction chemotherapy prior to radical locoregional treatment for patients with stage III non smallcell lung cancer (NSCLC): Results of a prospective randomized study. Lung Cancer, 55: 173-180, 2007.
19. Parra HS, Cavina R, Latteri F, Campagnoli E, Morenghi E,
Torri W, Brambilla G, Alloisio M, Santoro A: Cisplatin plus
gemcitabine on days 1 and 4 every 21 days for solid tumors: result of a dose-intensity study. Invest New Drugs,
25: 57-62, 2006.
20. Kim JH, Kim SY, Jung KH, Park K, Suh CW, Lim HY, Kim YH,
Ryoo BY, Cho EK, Park BJ, Heo DS: Randomized phase II
study of gemcitabine plus cisplatin versus etoposide plus
cisplatin for the treatment of locally advanced or metastatic non small cell lung cancer: Korean Cancer Study Group
experience. Lung Cancer, 52: 75-81, 2006.
Z AKCALI, Z CALIKUSU, H SAKALLI, O OZYILKAN
21. Mazzanti P, Massacesi C, Rocchi MB, Mattioli R, Lippe P,
Trivisonne R, Buzzi F, De Signoribus G, Tuveri G, Rossi G, Di
Lullo L, Sturba F, Morale D, Catanzani S, Pilone A, Bonsignori M, Battelli T: Randomized, multicenter, phase II
study of gemcitabine plus cisplatin versus gemcitabine
plus carboplatin in patients with advanced non small cell
lung cancer. Lung Cancer, 41: 81-89, 2003.
22. Iaffaioli RV, Tortoriello A, Facchini G, Caponigro F, Gentile
M, Marzano N, Gravina A, Dimitri P, Costagliola G, Ferraro
A, Ferrante G, De Marino V, Illiano A: Phase I-II study of
gemcitabine and carboplatin in stage IIIB-IV non smallcell lung cancer. J Clin Oncol, 17: 921-926, 1999.
23. Yoshimura M, Imamura F, Ueno K, Ichida J: Gemcitabine/carboplatin in a modified 21-day administration
schedule for advanced-stage non small-cell lung cancer.
Clin Lung Cancer, 8: 208-213, 2006.
24. Abratt RP, Bezwoda WR, Goedhals L, Hacking DJ: Weekly
gemcitabine with monthly cisplatin: effective chemotherapy for advanced non small-cell lung cancer. J Clin Oncol,
15: 744-749, 1997.
25. Song SY, Kim WS, Kim K, Jung CW, Im YH, Kim HJ, Kang
WK, Lee HG, Kwon OJ, Rhee CH, Park CH, Park K: Vinorelbine, ifosfamide, and cisplatin combination as salvage
chemotherapy in advanced non-small cell lung cancer. Jpn
J Clin Oncol, 33: 509-513, 2003.
26. Hamada H, Irifune K, Ito R, Sakai K, Kadowaki T, Katayama
H, Abe M, Shiode M, Nishimura K, Higaki J. Docetaxel and
cisplatin as second-line chemotherapy for advanced nonsmall cell lung cancer. Gan To Kagaku Ryoho, 34: 12351239, 2007.
27. Crino L, Scagliotti G, Marangolo M, Figoli F, Clerici M, De
Marinis F, Salvati F, Cruciani G, Dogliotti L, Pucci F,
Paccagnella A, Adamo V, Altavilla G, Incoronato P, Trippetti
M, Mosconi AM, Santucci A, Sorbolini S, Oliva C, Tonato M:
Cisplatin-gemcitabine combination in advanced nonsmall-cell lung cancer: a phase II study. J Clin Oncol, 15:
297-303, 1997.
28. van Moorsel CJ, Kroep JR, Pinedo HM, Veerman G, Voorn
DA, Postmus PE, Vermorken JB, van Groeningen CJ, van
der Vijgh WJ, Peters GJ: Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann Oncol, 10: 441448, 1999.