Download Phase II Study of Paclitaxel in Patients With

Phase II Study of Paclitaxel in Patients With
Extensive-Disease Small-Cell Lung Cancer:
An Eastern Cooperative Oncology Group Study
By David S. Ettinger, Dianne M. Finkelstein, Ravi P. Sarma, and David H. Johnson
Purpose: To evaluate the efficacy and safety of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ), a
novel diterpene plant product in the treatment of previously untreated patients with extensive-disease smallcell lung cancer (SCLC).
Patients and Methods: Patients with extensive-disease SCLC received paclitaxel 250 mg/m2 intravenously
over 24 hours every 3 weeks. Nonresponders or partial
responders, who received the maximum number of cycles (n = 4) of paclitaxel received salvage chemotherapy
that consisted of etoposide (VP-16) 120 mg/m2 intravenously over 45 minutes on days 1, 2, and 3, and cisplatin
60 mg/m 2 intravenously as a short infusion on day 1.
Cycles were repeated every 3 weeks.
Results: Of 36 patients entered onto the study, 34 and
32 patients were assessable for toxicity and response,
respectively. No complete responses (CRs) were observed. Eleven patients (34%) had a partial response (PR)
and six (19%) had stable disease (SD). In three of six
patients categorized as having SD, there was greater
than 50%tumor shrinkage. However, no 4-week followup measurements were made, so these could not be considered PRs, in part because patients received salvage
chemotherapy by study design. In this trial, induction
and salvage chemotherapy resulted in a response (two
CRs and 15 PRs) (53%) in 17 patients. The estimated median survival duration was 43 weeks. Dose-limiting toxicity was leukopenia, with 19 patients (56%) having
grade 4 leukopenia. The numbers of patients who experienced other grade 4 toxicities were as follows: pulmonary, three (9%); liver, two (6%); cardiac, one (3%);
thrombocytopenia, one (3%); metabolic, one (3%); stomatitis, one (3%); and allergic reaction, one (3%). Four
additional patients had grade 3 leukopenia and one patient (3%) died of sepsis (grade 5 toxicity).
Conclusion: Paclitaxel is an active new agent in the
treatment of SCLC. Further investigation of this agent in
combination with other active agents is appropriate.
J Clin Oncol 13:1430-1435. © 1995 by American Society of Clinical Oncology.
T
Taxus brevifolia,3 paclitaxel exerts its cytotoxic effect by
interfering with microtubule structure and function.4' 5 In
phase I studies, the dose-limiting toxicity of paclitaxel
when administered as 1- or 6-hour infusion was either
leukopenia or peripheral neuropathy (mainly sensory). 67
Frequent allergic reactions necessitated prolongation of the
infusion period to 24 hours continuously. 8 In addition, patients who received the drug were premedicated with corticosteroids and antihistamines (H 1 and H 2 blockers).
Based on these preclinical data and preliminary reports
that indicated paclitaxel may be active against lung cancer, the Eastern Cooperative Oncology Group (ECOG)
undertook an evaluation of this agent in SCLC. The
ECOG conducts its phase II trials in SCLC in previously
untreated extensive-stage patients, as this is believed to
be the ideal setting to assess the activity of new agents.9 "'
Here we report the results of an ECOG phase II study that
evaluated paclitaxel followed by salvage chemotherapy
(etoposide [VP-16] plus cisplatin) in patients with extensive-disease SCLC.
HERE ARE a number of active agents for the treatment
of small-cell lung cancer (SCLC).' Moreover, many
combination chemotherapeutic regimens have built on these
single-agent activities to develop more effective treatments
for SCLC. Still, despite these combination therapies, most
patients with SCLC will eventually die of the disease. Accordingly, the identification of new drugs with significant
activity against lung cancer clearly is needed.
One new agent that has generated considerable enthusiasm based on its broad-spectrum activity is paclitaxel
(Taxol; Bristol-Myers Squibb Co, Princeton, NJ). 2 A novel
diterpene plant product isolated from the western yew
From The Johns Hopkins Oncology Center, Baltimore, MD;
Dana-FarberCancer Institute, Boston, MA; Emory University, Atlanta, GA; and Vanderbilt University, Nashville, TN.
Submitted December 22, 1994; accepted February 2, 1995.
This study was conducted by the Eastern Cooperative Oncology
Group (Douglass C. Tormey, MD, PhD, Chairman) and supported
in part by Public Health Service grants no. CA16116, CA49957,
CA66636, CA21115, and CA23318 from the National Cancer Institute, National Institutes ofHealth, Department ofHealth and Human
Services, Bethesda, MD.
Presented in part at the 29th Annual Meeting of the American
Society of Clinical Oncology, Orlando, FL, May 16-18, 1993.
Address reprint requests to David S. Ettinger, MD, The Johns
Hopkins Oncology Center, 600 N Wolfe St, Baltimore, MD 212878936.
© 1995 by American Society of Clinical Oncology.
0732-183X/95/1306-0021$3.00/0
1430
PATIENTS AND METHODS
Patient Selection and Eligibility
Criteria for study entry were as follows: (1) SCLC confirmed
histologically or with an unequivocally positive cytologic diagnosis
(-> two sputum samples or aspiration biopsy); (2) extensive-stage
disease, defined as disease extending beyond one hemithorax or
involving contralateral mediastinal, hilar lymph nodes or ipsilateral
supraclavicular lymph nodes, and/or pleural effusion with positive
cytology; (3) ECOG performance status of 0, 1, or 2; (4) adequate
Journal of Clinical Oncology, Vol 13, No 6 (June), 1995: pp 1430-1435
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Copyright © 1995 by the American Society of Clinical Oncology. All rights reserved.
1431
PACLITAXEL AS TREATMENT FOR ED-SCLC
bone marrow (WBC count ;- 4,000/IL and platelet count >
100,000/pL), liver (bilirubin level -- 2.0 mg/dL), and kidney (creatinine concentration c 1.5 mg/dL and blood urea nitrogen level !
25 mg/dL) function; (5) measurable disease; (6) absence of active
infection; (7) no prior chemotherapy; (8) no history of myocardial
infarction in the last 6 months; (9) no congestive heart failure or
significant arrhythmia; (10) no prior second primary cancer, except
skin cancer, and no brain metastases; and (11) the ability of the
patient to give written, informed consent.
Patients were ineligible for the study if they had prior irradiation
to any sites of disease.
PretreatmentStudies
Before study entry, all patients underwent a staging evaluation that
consisted of a complete history and physical examination; hemogram;
blood urea nitrogen, creatinine, and liver function studies; determination
of calcium and phosphorus serum levels; chest roentgenogram; computer tomographic (CT) scan of the chest and abdomen; bone scan and
bone survey if the bone scan was positive; CT scan of the brain; ECG;
bone marrow aspiration and biopsy; and fiberoptic bronchoscopy. A
bronchoscopy was not necessary initially if the diagnosis of SCLC was
established by another procedure. A radionuclide cardiac scan was
required before the start of therapy if there was a history of heart
disease; otherwise, it was performed after four cycles of therapy and
then was repeated with every other drug cycle.
Follow-Up Studies
During cycle 1, patients were evaluated weekly, and a complete
blood cell (CBC) count was performed routinely. At 3-week intervals, just before each cycle of drug administration, response was
assessed by obtaining serum chemistries, a chest roentgenogram,
and tumor measurements, in addition to the CBC count. Additional
CBC counts were performed as clinically indicated. All positive tests
were to be repeated before the fifth chemotherapy cycle and at the
time clinical complete response (CR) was diagnosed. If the bronchoscopy was initially positive, it had to be repeated when clinical
and radiologic CR was achieved. Complete responders were monitored every 3 months with a CBC count, serum chemistries, CT scan
of the chest and abdomen, and bone scan.
Treatment
The treatment schema is shown in Fig 1. Patients with extensivedisease SCLC received paclitaxel 250 mg/m 2 administered intrave-
nously over 24 hours every 3 weeks. Because of a limited drug
supply at the time this study was activated, patients received a maximum of four doses of paclitaxel as induction therapy. Those patient
with disease progression after one cycle of therapy or stable disease
(SD) after two cycles or who achieved a partial response (PR) only
after four cycles of paclitaxel received salvage chemotherapy that
consisted of VP-16 120 mg/m2 intravenously over 45 minutes on
days 1, 2, and 3, and cisplatin 60 mg/m 2 intravenously as a short
infusion on day 1. Cycles were repeated every 3 weeks. Patients
who attained a CR were to receive a minimum of four cycles of
chemotherapy. Prophylactic whole-brain irradiation (25 Gy in 10
fractions over 2 weeks) was to be given to patients who achieved a
CR, beginning 1 week after completion of induction therapy.
If progression occurred after induction therapy had been completed in patients who attained a CR, the patients were to receive
salvage chemotherapy. Patients with disease progression after one
cycle of salvage chemotherapy or with SD after two cycles were
removed from study. Those who achieved only a PR after salvage
chemotherapy continued therapy until progression of disease, and
were then removed from study. Patients who achieved a CR on
salvage chemotherapy, received six to eight cycles of therapy and
then no maintenance chemotherapy. If a CR was obtained on salvage
chemotherapy, prophylactic whole-brain irradiation was to be given
if the patient had not already received it.
Drug doses were modified for hematologic toxicity as follows:
patients received 50% or 75% of the original dose for an absolute
neutrophil nadir count less than 750/pL or between 750 and 999/
MpL,respectively. Doses were reduced by 75%, 50%, or 25% for a
platelet nadir count less than 25,000/gL, between 25,000 and 49,999/
ML, or between 50,000 and 99,999/gL, respectively. Dose modifications were also made for renal or hepatic dysfunction, mucositis,
and auditory, neurologic, or cardiac toxicity.
Response Criteria
Standard ECOG criteria for solid tumor response were used."
A CR was defined as the complete disappearance of all clinically
detectable disease for at least 4 weeks. A PR of measurable disease
was defined as a - 50% decrease in the sum of the products of the
two longest perpendicular diameters, lasting for at least 4 weeks, in
the absence of progressive disease elsewhere and no new areas of
malignant disease. Disease progression was defined as a greater than
25% increase in the size of any single malignant lesion if the lesion
was greater than 2 cm2 or new malignant lesions appeared.
VBI-
Fig 1. Treatment schema.
WBI, whole-brain irradiation;
Prog, disease progression.
Observation
PCTXL
Etoposide +
Cislalin
Prog
Etposide +
Cisplatin
Etoposide +
Cisplalin
SD or Prog
SD or Prog
Off
-OMy
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Off
Study
1432
ETTINGER ET AL
Table 1. Patient and Disease Characteristics
Statistical Analyses
Response rates were calculated as the proportion of assessable
cases. Estimated survival distributions were calculated by the method
of Kaplan and Meier.12 Variance of the survival estimates calculated
using Greenwood's formula." For mortality, estimates, patients lost
for follow-up evaluation are treated as censored.
RESULTS
This study was activated by the ECOG in October 1990
and registered 36 patients before its closure in October
1991. Two patients were cancelled before the initiation
of therapy because they were determined to be ineligible:
one was receiving radiation therapy as treatment for spinal cord compression, while the other had a platelet count
of 52,000//L on the day therapy was to be started. The
remaining 34 patients were included in the analysis, however, two patients were deemed nonassessable for response because there was inadequate response documentation.
The 34 assessable patients received 88 cycles of paclitaxel. The median number of cycles patients received was
two (range, one to four). For cycle 1, all patients but one
received the full dose of the drug. The latter patient had
paclitaxel discontinued after 57% of the drug was administered due to anaphylaxis. For cycles 2, 3, and 4, patients
received 78% (n = 25), 66% (n = 16), and 74% (n =
13), respectively, of the prescribed dose of the drug.
Of 34 patients analyzed for induction chemotherapy
(paclitaxel), 24 received salvage chemotherapy (VP-16
plus cisplatin). Of 10 patients who did not receive salvage
therapy, four died within 6 weeks of completing induction
therapy, three experienced excessive toxicity, two refused
treatment, and one patient withdrew at the physician's
discretion.
Table 1 lists patient and disease characteristics of the
34 assessable SCLC patients. The median age was 63
years, with a range of 40 to 78. Sixty-two percent of
patients were male, 82% were ambulatory (ECOG performance status of 0 or 1), and 67% had less than a 5%
prior weight loss. The majority of patients had metastases
to the liver, mediastinum, and ipsilateral lung. Eightyone percent had more than one metastatic site.
Toxicity
Treatment complications were reported according to
ECOG standard criteria 9 by degree (none, mild, moderate,
severe, life-threatening, or lethal), by type (gastrointestinal vomiting, etc), and by cause. Table 2 lists the incidence of severe and life-threatening complications from
both induction and salvage therapy. ECOG grade 4 hematologic toxicity occurred in 19 patients (56%) with leukopenia and one patient (3%) with thrombocytopenia while
Characteristic
Patients
Assessable for toxicity
Assessable for response
Sex
Male
Female
Race (white)
Age, years
Median
Range
Initial performance status
0
2
Prior weight loss (%)
None
<5
5-10
> 10
Sites of distant metastases
Ipsilateral lung
Contralateral lung
Mediastinum
Pleura
Scalene lymph node
Liver
Bone marrow
Bone
Subcutaneous
Other
No. of distant metastases
1
2
3
4
5
>6
Response (paclitaxel only, n =32)
CR
PR
SD
Progression
Grade 4 and 5 toxicity (paclitaxel only, n = 34)
Leukopenia
Pulmonary
Hepatic
Cardiac
Thrombocytopenia
Stomatitis
Allergic reaction
Sepsis (lethal)
No. of Patients
%
36
34
32
21
13
33
62
38
97
63
40-78
9
19
6
26
56
18
13
10
6
5
38
29
18
15
22
3
24
7
7
22
9
7
1
10
65
9
71
21
21
65
26
21
3
29
3
6
10
10
3
2
9
18
29
29
9
6
0
11
6
15
0
34
19
47
19
3
2
1
1
1
1
1
56
9
6
3
3
3
3
3
receiving paclitaxel. Nonhematologic life-threatening
toxicities that occurred during induction therapy, due to
paclitaxel, consisted of the following: (1) pulmonary,
three patients (9%). Specifically, one patient experienced
pulmonary edema during day 2 of cycle 1; another patient
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Copyright © 1995 by the American Society of Clinical Oncology. All rights reserved.
1433
PACLITAXEL AS TREATMENT FOR ED-SCLC
Table 2. Incidence of Severe and Life-Threatening Complications
Poclitaxel
Complication
Severe
Life-Threatening
Severe
Life-Threatening
Leukopenia
Thrombocytopenia
Anemia
Infection
Nausea
Vomiting
Diarrhea
Stomatitis
Hepatic
Pulmonary
Cardiac
Hypertension
Neuroclinical
Neuromotor
Metabolic
Allergy
Dysphagia
4
19
1
-1
1
2
3
1
-
10
1
1
1
9
1
1
1
2
-
-
-
4
1
1
1
5
1
2
1
1
1
1
1
associated with salvage therapy. However, there were no
lethal complications.
Salvage
1
1
-
1
1
1
1
1
Response
Among 34 patients who could be analyzed while on
induction, two were deemed nonassessable because of
inadequate response documentation. All available patients
had at least one two-dimensional measurable lesion. On
induction therapy, there were no CRs; however, there
were 11 PRs (34%). Six patients had SD. In three of
these six, there was a greater than 50% tumor shrinkage;
however, there were no 4-week follow-up measurements,
partly because the patients received salvage chemotherapy 3 weeks after their last dose of paclitaxel. Therefore,
three patients were not considered as having had a PR
since, by definition, such a response must last at least 4
weeks.
Response duration was measured from the time a
response was documented to the time of relapse or
patient last known to be in response (censored). For
the 11 patients who responded to paclitaxel, the median
response duration was 12 weeks, with a range of 5 to
33 weeks. The response duration may be falsely low
because responding patients who received four cycles
of paclitaxel, by study design, had to be crossed over
to salvage therapy when, in fact, they might have been
still responding to paclitaxel.
Considering the best response achieved by patients,
whether or not they went on to salvage therapy, two
patients (6%) achieved a CR, 15 (47%) a PR, and five
(16%) SD, while 10 (31%) had progressive disease.
Twenty-four patients proceeded to the salvage regimen.
Among patients who received both induction and salvage
chemotherapy, the overall rate for best response achieved
was 8% CRs (both induction PRs) and 58% PRs (six
induction PRs, two SD, and six progressive disease).
1
-
2
-
-
-
developed respiratory failure on day 11 of cycle 2 and
was placed on a ventilator and then home oxygen; and a
third patient experienced wheezing and shortness of
breath during day 2 of cycle 1. (2) Hepatic, two patients
(6%) with known liver metastases developed elevated
liver function tests; (3) cardiac, one patient (3%) developed an acute myocardial infarction during day 16 of
cycle 3; (4) metabolic, one patient (3%) developed hypocalcemia during day 3 of cycle 1; (5) stomatitis, one
patient (3%) experienced reddening and swelling in the
mouth during day 9 of cycle 1; and (6) allergy, one patient
(3%) developed anaphylaxis during day 2 of cycle 1. On
salvage chemotherapy, nine patients (37.5%) experienced
grade 4 leukopenia.
Table 3 lists the worst degree of treatment complications experienced by patients. The worst degree of treatment complication on induction therapy (paclitaxel) was
of grade 4 in 20 patients (59%). Twelve (35%) of these
patients had grade 4 leukopenia only. One patient who
received paclitaxel died of sepsis. In regard to this patient,
6 days after receiving the first dose of paclitaxel, the
patient was hospitalized with leukopenia (400/pL),
thrombocytopenia (19,000/L), and elevated liver function tests. Despite supportive measures, the patient died
on the third day after the admission.
There were 12 (50%) life-threatening complications
Survival
Overall survival was measured from the date of registration to date of death due to any cause or date last
known to be alive (censored). Of 34 assessable patients,
one was censored for this analysis, because the patient
moved and was lost for follow-up evaluation. The estimated median survival time was 43 weeks. Figure 2 gives
the Kaplan-Meier estimate of survival distribution for the
Table 3. Worst Degree of Treatment Complication
Agent(s)
Paclitaxel
VP-16 + cisplatin
N No
1
1
Lethal
Life-Threatening
Severe
Moderate
None/Mild
.
No.
%
No.
%
No.
%
No.
%
Total
3
4
3
2
9
8
9
9
26
38
20
12
59
50
1
3
34
24
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-
1434
ETTINGER ET AL
I-
0.9
asas-
G70R
26
P
030
N
Fig 2. Kaplan-Meier survival
estimates.
a4 -
52 -
0
10
2
0
40
so
60
70
a
90
0
10
110
13
WEEKS
overall survival time. Survival times ranged from 1 to
111 weeks. Based on the Kaplan-Meier estimate, the 1year survival rate was 37% ± 8% (SE). Twelve patients
survived longer than 1 year. One patient survived longer
than 2 years (780 days). She had an initial performance
status of 0 and less than 5% weight loss in the previous
6 months. Her disease progressed on induction, but she
achieved a PR on salvage therapy.
DISCUSSION
The results of this phase II study demonstrate that
paclitaxel is an active anticancer agent against SCLC. The
overall response rate was only 34%, which we believe to
be the minimal level of activity of paclitaxel in SCLC.
Indeed, if the three SCLC patients who had 50% shrinkage of tumor, but were considered as having SD, were
included as responding, the overall response rate for
paclitaxel would be 44%. The high frequency of grade
4 toxicity during induction therapy, mainly leukopenia
(56%), is due primarily to the high dose of paclitaxel
administered, with possibly a small percentage due to the
24-hour infusion duration.
Following this study, the North Central Cancer
Treatment Group (NCCTG) conducted a trial similar
to the ECOG study to confirm the activity of paclitaxel
in patients with extensive-disease SCLC.14 The dose of
paclitaxel administered was 250 mg/m 2 as a continuous
intravenous infusion over 24 hours every 3 weeks.
Granulocyte colony-stimulating factor 5 ug/kg was
also given on days 2 to 15. In their study, the number
of cycles of paclitaxel was not limited to four as it was
in the ECOG study. Patients who experienced disease
progression were crossed over to a regimen that contained VP-16 plus cisplatin. At the time of their initial
report, 37 of 43 patients were assessable.14 There were
no CRs and 15 PRs (40.5%). Ten additional patients
(27%) with assessable disease had a major response. If
both the assessable and measurable-disease patients are
considered as responders, then the overall response rate
was 67.5%. The median survival duration was 29
weeks. Of 12 patients who received salvage chemotherapy in their study, there was one CR, three PRs, and
two major responses among assessable patients. This
study corroborates the activity of paclitaxel in the treatment of SCLC.
There are a number of potential combination chemotherapeutic regimens that contain paclitaxel to be studied
in patients with SCLC. These include, in part, paclitaxel
combined with the following: (1) VP-16, (2) cisplatin, (3)
topotecan, (4) ifosfamide, and (5) VP-16 plus cisplatin.
In addition, since paclitaxel has been shown to cause
radiosensitization,"5 studies are needed to evaluate the
drug with concurrent radiation therapy in the treatment
of SCLC.
ACKNOWLEDGMENT
We thank Carol Crouse Fitzpatrick, ECOG Statistical Center, for
assistance with data collection.
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1435
PACUTAXEL AS TREATMENT FOR ED-SCLC
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