ARTICLE
Auteur(s) :, Olivier
Rixe1, Michel Gatineau2, Eric
Jauffret1, Jean-Philippe Spano1, Brigitte
Orcel2, Jean-Michel Vannetzel3, Jocelyne
Berille4, Jean-Philippe Derenne2, David
Khayat1
1Service d’oncologie, hôpital Pitié-Salpêtrière, 47
boulevard de l’Hôpital, 75013 Paris, France
2Service de pneumologie et réanimation respiratoire,
hôpital Pitié Salpêtrière, Paris, France
3Clinique Hartmann, Neuilly sur Seine, France
4Aventis Pharma, Antony Cedex, France
The prognosis of patients with metastatic and advanced non-small
cell lung cancer (NSCLC) is poor. The results of a recent
randomized phase III study investigating newer cytotoxic agents
including taxanes and gemcitabine, have demonstrated the limits of
conventional chemotherapy with a median survival of 7.9 months
[1].Among chemotherapeutic agents tested in NSCLC as monotherapy,
several give an objective response rate of at least 15 %, including
cisplatin, ifosfamide, mitomycin, vinblastine, vindesine,
vinorelbine, gemcitabine, irinotecan, paclitaxel, and docetaxel
[2]. Cisplatin is the backbone of chemotherapy combinations used
for treating NSCLC. The dose of cisplatin used is important for
achieving a response, and cisplatin-based regimens often use a dose
of 75-100 mg/m2. The response rates of regimens,
which include a platinum salt, range from 10%
(carboplatin–etoposide) to 60 % (mitomycin, vinblastine, or
vindesine, and cisplatin) [2].When this study was designed in 1995,
the synergistic combination of cisplatin and vindesine was
considered one of the standard treatments for NSCLC. Two trials
comparing cisplatin–vindesine with best supportive care (BSC)
showed a significant improvement in survival for the
chemotherapy-treated patients (27-32 weeks in the
cisplatin-vindesine arm versus 10-17 weeks in the BSC arm) [3, 4].
A further study comparing vindesine (3 mg/m2) combined
with either high- (120 mg/m2) or low- (60
mg/m2) dose cisplatin demonstrated that high-dose
cisplatin provided both response and survival benefits [5]. Median
duration of response (12 versus 5.5 months) and median survival
(21.7 versus 10 months) were significantly higher in the high-dose
arm compared with the low-dose arm. Complete and partial remission
rates were similar in both arms.Docetaxel (Taxotere®,
Aventis Pharma, Antony, France), a semi-synthetic taxoid, has
produced encouraging objective response rates of approximately 30 %
when administered as a single agent (100 mg/m2 every 3
weeks) in previously untreated patients with NSCLC [6]. The
principal dose-limiting toxicity was neutropenia; other toxicities
included fluid retention, asthenia, and neurotoxicity. The activity
exhibited by single-agent docetaxel suggested that studies
involving docetaxel combination chemotherapy regimens in first-line
NSCLC were warranted.Norton and day hypothesized that the
therapeutic effect of chemotherapy could be improved by
administering two active drugs or regimens in a sequential schedule
[7]. Sequential administration could also allow drug resistance to
be circumvented at the molecular level. Such a schedule typically
involves the administration of one specific treatment for a
previously defined number of cycles, immediately followed by a
second treatment for a specified number of cycles. Unlike the
switch from first-line to second-line therapy after documented
progression, the chemotherapy drugs are switched even if the
response to the first regimen is positive with no signs of
resistance.The choice of drug combination in a sequential
chemotherapy regimen is critical, both to reduce the risk of
cross-resistance and to maximize activity. In preclinical studies,
Minotti et al. [8] found that cell lines resistant to taxanes were
hypersensitive to vinca alkaloids and vice versa. This suggests a
taxane–vinca alkaloid sequential regimen may be effective in the
clinical setting.In order to test the efficacy of sequential
docetaxel and cisplatin–vindesine, we conducted a pilot phase II
study in chemotherapy-naïve patients with locally advanced or
metastatic NSCLC. A docetaxel dose of 100 mg/m2 was the
recommended dose for phase II studies at the time of the study
design [6]. The choice of this dose level for the study was based
on administering the highest possible dose intensity with
acceptable toxicity in a sequential setting. The primary aim was to
evaluate the objective response rate, duration of response, and
time to progression in these patients. Secondary objectives
included tolerability and overall survival.
Materials and methods
Patients
Chemotherapy-naïve patients with histologically proven unresectable
stage IIIB or stage IV progressive NSCLC were entered into this
study. Patients were aged between 18 and 70 years, with a Karnofsky
performance status ≥ 60 %, and adequate hematologic, renal, and
hepatic function. The inclusion criteria required at least one
bi-dimensionally measurable lesion. Patients were excluded if they
were exposed to radiotherapy greater than 25 % of their bone marrow
within 4weeks of entering the study. Other exclusion criteria
included previous chemotherapy or immunotherapy; presence or
history of central nervous system metastases; pre-existing motor or
sensory neurotoxicity ≥ grade 1 by National Cancer Institute Common
Toxicity criteria (NCI-CTC); other serious illness or medical
conditions; concurrent treatment with bisphosphonates if initiated
recently (< 3 months); and contraindications for the use of
corticosteroids as premedication. All patients gave written
informed consent before entering the study. Ethics Committee
approval was obtained at all three centers.
Treatment
Treatment comprised three different chemotherapy regimens given in
sequence as shown in ( figure 1 ). During sequence
A, docetaxel 100 mg/m2 IV was administered on day 1
every 3weeks. Patients received four cycles of docetaxel before
proceeding to sequence B (cisplatin-vindesine). Patients with
unacceptable toxicity who did not complete all four cycles of
sequence A, and patients with disease progression proceeded
directly to sequence B.
Sequence B was a 4-week cycle comprising cisplatin
120mg/m2 (Cisplatyl®, Rhône-Poulenc Rorer
Ltd) as a1-hour infusion on day 1 and vindesine 3 mg/m2
(Eldisine®, Lilly, France) as a bolus injection on days
1, 8, 15 and 22. Patients received 4 cycles of the sequence except
where disease progression or unacceptable toxicity occurred, in
which case patients were withdrawn from the study. The doses of
both cisplatin and vindesine were reduced in the case of
unacceptable toxicity to 100 and 2 mg/m2, respectively.
Patients who responded to sequence A and who had a complete or
partial response at the end of sequence B, had the option to
receive an additional three cycles of 100 mg/m2
docetaxel given every 3 weeks as consolidation treatment (sequence
C).
Dosing of docetaxel or cisplatin-vindesine was delayed for up to
two weeks in the event of neutrophil counts < 1.5 x
109/L or platelet counts < 100 x 109/L on
day 21 (docetaxel) or day 29 (cisplatin) of a cycle or grade 3
nonhematologic toxicity, with the exception of alopecia. Patients
were withdrawn if toxicities did not resolve within this period.
Immediate discontinuation of treatment occurred in the event of
grade 3 peripheral neuropathy or any grade 4 nonhematologic
toxicity, with the exception of alopecia and cutaneous toxicity.
Vindesine was withheld on days 8, 15, or 22 of a cycle in the event
of neutrophils < 1.0 x 109/L or platelets < 100 x
109/L. Depending on the nature and grade of toxicity
seen in a given cycle, the dose of docetaxel was reduced in
subsequent cycles, initially to 75 mg/m2 and then to 55
mg/m2 if a further reduction was needed.
Assessments
Tumor response was assessed after cycles 2, 4, 6, 8, and 11 (and/or
at the end of the study) and was classified according to World
Health Organization criteria. An external panel reviewed tumor
assessments. Safety was monitored by assessment of all adverse
events and by regular measurements of hematologic and biochemical
parameters. Clinical neurologic examinations were performed after
cycles 4 and 8.
Statistical analysis
All patients who received at least one dose of chemotherapy were
included in the safety analyses. Efficacy was assessed in those
patients who received a minimum of 2 cycles of treatment (6 weeks
on study) or less if a progression disease was noted and at least
one follow-up assessment of tumor response. Duration of response,
time to progression, and survival were calculated using the
Kaplan–Meier method. Safety data were analyzed using descriptive
statistics.
Results
Patients
A total of 32 patients from three French centers entered the trial
over a period of 18 months (table 1( Table
1 )). One proved ineligible because of diagnosis of ovarian
adenocarcinoma and lung metastases and thus was excluded from the
study analysis. Thirty-one patients were included in the safety and
survival analyses, while 30 patients were evaluable for response
(1patient for whom no assessments were available after baseline).
All the locally advanced patients were stage IIIB-N3 classified.
Treatment was discontinued because of disease progression in 14
patients.
Table 1 Baseline characteristics of patients and their
disease
|
Characteristic
|
Number of patients (%)
|
|
Registered
|
32a
|
|
Evaluable
|
|
- safety
|
31 (100)
|
|
- efficacy
|
30 (96.8)
|
|
Sex: male/female
|
24/7 (77.4/22.6)
|
|
Median age [range] in years
|
54.5 [40–70]
|
|
Performance status
|
|
|
- 0-1
|
25 (80.6)
|
|
- ≥2
|
6 (19.4)
|
|
Histology
|
|
- squamous cell carcinoma
|
13 (41.9)
|
|
- adenocarcinoma
|
11 (35.5)
|
|
- large cell carcinoma
|
7 (22.6)
|
|
Extent of disease
|
|
- locally advanced (IIIB)
|
12 (38.7)
|
|
- metastatic
|
19 (61.3)
|
|
Main organs involved
|
|
- lung
|
28 (90.3)
|
|
- lymph nodes
|
16 (51.6)
|
|
- bone
|
11 (35.5)
|
|
- pleura
|
6 (19.4)
|
|
- liver
|
3 (9.7)
|
|
- adrenal gland
|
3 (9.7)
|
|
Prior therapy
|
|
- no prior therapy
|
26 (83.8)
|
|
- radiotherapy only
|
2 (6.5)
|
|
- surgery only
|
1 (3.2)
|
|
- radiotherapy + surgery
|
2 (6.5)
|
aOne patient excluded from the analysis (see text).
Efficacy
Among the 30 patients evaluable for response, four achieved a
partial response, while one had a complete response, resulting in
an overall response rate of 16.7 % (95 % confidence interval [CI],
11.6-47.8 %) (table 2( Table 2 )).
Stable disease was observed in 17 patients (56.7 %), and
progressive disease in the remaining 8 patients (26.7 %). Of the
responders, one had large cell carcinoma, four had adenocarcinoma
and one had squamous cell carcinoma. One patient had locally
advanced disease (stage IIIB-N3) and four had metastatic
involvement.
The median progression-free survival was 17.6 weeks (95%CI,
11.9-28.6 weeks) in 29 evaluable patients (no data was available
for time to progression for two patients). Median overall survival
was 11 months (95%CI = 8.0–15.4 months), with a 1-year survival
rate of 47% calculated from the cohort of the 31 treated patients
(( figure 2
)).
Table 2 Response data
|
n (%)
|
Sequence A
|
Sequence B
|
Sequence C
|
|
docetaxel
|
cisplatin–vindesine
|
docetaxel
|
|
(n = 30)
|
(n = 21)
|
(n = 5)
|
|
CR
|
PR
|
CR
|
PR
|
CR
|
PR
|
|
Best response over sequence A
|
0
|
3 (10.0 %)
|
–
|
–
|
–
|
–
|
|
Best response over sequence B
|
–
|
–
|
0
|
2 (9.5 %)
|
–
|
–
|
|
Best response over sequence C
|
–
|
–
|
–
|
–
|
1
|
1
|
|
Total (best response)
|
–
|
–
|
–
|
–
|
1/30 (3.3 %)
|
4/30 (13.3 %)
|
Safety
One hundred and eighty-eight cycles were administered to 31
patients evaluable for toxicity: 122 cycles of docetaxel (including
10 cycles administered during the consolidation phase) and 66
cycles of cisplatin-vindesine (table 3( Table
3 )). The median number of cycles given was 6 (range 1-11).
Of the 188 cycles administered, 13 (6.9 %) were delayed for reasons
of toxicity (hematologic: 3 cycles and non-hematologic: 10cycles).
There were no delays during the docetaxel consolidation phase.
Forty-eight (25.5 %) of the 188 cycles were given at a modified
dose in 22 patients, primarily for vindesine. All cycles but one
had the dose modified during sequence B. Dose modification occurred
as a result of hematologic toxicity in 16cycles, nonhematologic
toxicity in an additional 15 cycles, and both hematologic and
nonhematologic toxicities in 3cycles. Dose modification in the
remaining 14 cycles was not drug-related.
Thirty-one, 21, and 5 patients were evaluated for toxicity after
sequences A, B, and C, respectively; details are presented in table
4( Table 4 ). The most frequent
hematologic toxicity was anemia, although the majority of cases
were grade 1 or 2. Twenty-nine patients experienced at least 1
episode of leukopenia and neutropenia, with grade 3 and 4
neutropenia reported in 11and 15 patients, respectively. Five
patients experiencedfebrile neutropenia. Thrombocytopenia was seen
in only 3patients, with no cases of grade 3 or 4 toxicity.
The most common nonhematologic toxicities were alopecia, sensory
neuropathy, nausea, and renal toxicity. Neuropathy was more common
during the third phase of treatment, suggesting a cumulative
toxicity. Two patients (6.5 %) experienced a hypersensitivity
reaction to docetaxel, including one case of bronchospasm.
Of the six patients who discontinued treatment following adverse
events, three were due to sensory neuropathy, one in combination
with elevated creatinine levels; two additional cases were due to
elevated creatinine levels, one of which required dialysis; and one
case was due to liver toxicity. The dose intensity of each drug
during cycle 1 and subsequent cycles for each sequence are shown in
table 5( Table 5 ).
Table 3 Number of cycles by treatment phase
|
Treatment phase
|
Number of patients
|
Number of cycles
|
|
Total
|
Median (range)
|
|
1st phase, sequence A:
|
31
|
112
|
4 (1–4)
|
|
docetaxel 100 mg/m2
|
|
|
|
|
2nd phase, sequence B:
|
21
|
66
|
2 (1–4)
|
|
cisplatin/vindesin 120/12 mg/m2
|
|
|
|
|
3rd phase, sequence C:
|
5
|
10
|
2 (1–3)
|
|
docetaxel 100 mg/m2
|
|
|
|
|
All
|
31
|
188
|
6 (1–11)
|
Table 4 Number of patients with hematologic and
nonhematologic toxicities
|
No. of patients (%)
|
Sequence A docetaxel
|
Sequence B cisplatin/vindesine
|
Sequence C docetaxel
|
|
(n = 31)
|
(n = 21)
|
(n = 5)
|
|
Hematologic
|
|
|
|
|
Grade 4 neutropenia
|
7 (21.9)
|
15 (71.4)
|
1 (20.0)
|
|
Febrile neutropenia
|
2 (6.3)
|
3 (14.3)
|
0
|
|
Grade 4 thrombocytopenia
|
0
|
0
|
0
|
|
|
|
|
|
Nonhematologic
|
|
|
|
|
Grade 2 neuropathy
|
3 (9.7)
|
3 (14.3)
|
2 (40.0)
|
|
Grade 3 neuropathy
|
0
|
5 (23.8)
|
2 (40.0)
|
|
Grade 4 neuropathy
|
0
|
0
|
0
|
|
Grade 1 renal toxicity
|
0
|
3 (14.3)
|
0
|
|
Grade 2 renal toxicity
|
0
|
1 (4.8)
|
1 (20.0)
|
|
Grade 3 renal toxicity
|
0
|
0
|
0
|
|
Grade 4 renal toxicity
|
0
|
1 (4.8)
|
0
|
Table 5 Patients receiving at least 95% of
startingdose
|
Sequence A
|
Sequence B
|
Sequence C
|
|
Docetaxel
|
Cisplatin
|
Vindesine
|
Docetaxel
|
|
Cycle 1
|
31/31
|
–
|
–
|
–
|
|
Other cycles
|
24/31
|
–
|
–
|
–
|
|
Cycle 5
|
–
|
21/21
|
12/21
|
–
|
|
Other cycles
|
–
|
14/18
|
0/18
|
–
|
|
Cycle 9
|
–
|
–
|
–
|
5/5
|
|
Other cycles
|
–
|
–
|
–
|
1/5
|
Discussion
Despite recent advances in the treatment of NSCLC, phase III
studies of platinum-based doublet regimens demonstrate a median
survival of only 8-9 months [1, 9]. Although triplet combinations
have shown promise in phase II studies [10], the use of these
regimens remains controversial [11]. The reasons for this
controversy include a potential increase in toxicity causing
suboptimal dosing and undemonstrated survival benefits compared
with doublet regimens to date. In an effort to improve
tolerability, alternating and sequential administration of
cytotoxics have been explored in several studies. A pilot phase II
study with docetaxel alternating with cisplatin improved
tolerability without compromising previously observed levels of
response and survival for docetaxel-cisplatin combinations [12].
The response rate of 16.7 % seen in our pilot phase II study
falls within the range observed for single-agent docetaxel [7] but
is lower than that seen with docetaxel-cisplatin doublets (34-36 %)
[13]. Almost 70 % of patients received sequence B as sequential
treatment and 15% received sequence C. The median number of cycles
given was six, while the usual median number of cycles received
with a doublet combination is only four [1, 9]. While the median
duration of response was not reached, the partial response ranged
from 23 to 29weeks. This suggests patients were sensitive to
cisplatin-vindesine after docetaxel treatment and supports the
notion that sequential treatment reduces the risk of developing
cross-resistance.
Although this sequential design succeeded in treating patients
longer than in previous studies, there was no impact on the median
time to progression (4 months). A median survival time of 11 months
is promising when compared with the median of 8-9 months usually
reported with platinum-based doublets. However, survival times may
vary according to the patient population. In our study, only 31
patients were treated and 38.7 % had locally advanced disease. The
population was relatively young, with a median age of 54.5 years.
Although one-third of our patients had bone metastases, this
population had a generally favorable prognosis that might have had
a positive impact on the overall survival observed.
Patient tolerance of this sequential regimen was also of
interest. No treatment-related deaths were reported and the grade
of toxicities seen was generally low despite the median number of
cycles received, excepted one severe renal toxicity directly
related to cisplatin (dialysis required). Most of the common severe
toxicities were observed during sequence B: neurosensory (23.8 %
grade 3, no grade 4), and neutropenia (71.4 % grade 4). Febrile
neutropenia occurred in 5 patients (2 during sequence A and 3
during sequence B), and no infections were documented. Mattson et
al. [12] reported a similar trend in tolerance in the pilot study
of docetaxel alternating with cisplatin. Additionally, the data
reported in table 5 illustrates a favorable toxicity profile as the
planned dose intensity was given in the majority of patients.
Sequential studies have been used in breast and ovarian cancer
to facilitate giving full doses of chemotherapy, and higher doses
have been given with support of hematologic growth factors in order
to significantly prolong survival [14, 15]. However, the role of
sequential chemotherapy in NSCLC remains to be defined. Our pilot
phase II sequential study allowed full doses of docetaxel and
cisplatin to be given and tolerated without the use of hematologic
growth factors. The median length of treatment was also longer than
commonly reported. For further studies, however, the use of
cisplatin-vindesine should be reconsidered. This doublet is no
longer considered optimal, since Le Chevalier et al. [16]
demonstrated superior survival for cisplatin-vinorelbine compared
with cisplatin-vindesine in a phase III setting [16]. To retain the
potential advantage of combining taxanes with vinca alkaloids
suggested by Minotti et al. [8], we recommend a new pilot study be
performed of docetaxel followed in sequence by vinorelbine-based
therapy. If this new sequential regimen proved feasible, it should
be considered in a phase III setting vs. the vinorelbine
doublet.
Acknowledgements
This study was supported by a grant from Aventis Pharma, 20 avenue
Raymond Aron, 92165 Antony Cedex, France. The authors acknowledge
J. Bloch, O. Ferment and R. Mouawad for their assistance with data
management. This work was supported by the Fondation
Betttencourt-Schueller and the Association pour la vie-Espoir
contre le cancer (AVEC). The order of the first two authors is to
be considered arbitrary.
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