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1029
Teniposide (VM-26) as a Single Drug Treatment for
Patients with Extensive Small Cell Lung Carcinoma
A Phase II Study of the Southwest Oncology Group
Petre N. Grozea, M.D.1
John J. Crowley, Ph.D.2
Vikki A. Canfield, M.D.1
Laura Kingsbury, M.R.T.2
S. William Ross, M.D.4
German S. Beltran, M.D.5
Leslie Rodgers Laufman, M.D.6
Geoffrey R. Weiss, M.D.7
Robert B. Livingston, M.D.3
BACKGROUND. Teniposide (VM-26) was reported to have activity in small cell lung
carcinoma (SCLC). The authors performed a Phase II study of teniposide as a
treatment for patients with previously untreated extensive SCLC.
METHODS. The study was open to patients with a histologic or cytologic diagnosis
1
University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
2
Southwest Oncology Group Statistical Center,
Seattle, Washington; Fred Hutchinson Cancer
Research Center, Seattle, Washington.
3
Puget Sound Oncology Consortium, Seattle,
Washington; Division of Oncology, University of
Washington, Seattle, Washington.
4
University of Arkansas for Medical Science, Little Rock, Arkansas.
5
Tulane University School of Medicine, New Orleans, Louisiana.
6
Columbus Community Clinical Oncology Program, Columbus, Ohio; Hematology/Oncology
Consultants, Inc., Worthington, Ohio.
7
Department of Medicine/Oncology, University
of Texas Health Sciences Center at San Antonio,
San Antonio, Texas.
of extensive SCLC who had not received prior radiation or chemotherapy. Patients
with hematologic values below normal were considered eligible if the impaired
bone marrow function was directly attributable to disease involvement. Treatment
consisted of teniposide 60 mg/m2 given intravenously (i.v.) on Days 1?5 every 3
weeks.
RESULTS. This study opened on September 15, 1988, closed permanently on November 15, 1990, and accrued 45 patients identified at 19 academic, military, and
Community Clinical Oncology Program institutions affiliated with the Southwest
Oncology Group. Of the 45 registered patients, 41 were eligible. Twenty eight (68%)
were males and 13 (32%) were females; the median age was 64 years (minimum,
46 years; maximum, 83 years). Twenty-four patients (59%) had a performance
status (PS) on the Zubrod scale of 0?1 and 17 cases (41%) had a PS of 2. Of the
41 eligible patients, 10 had confirmed partial responses (24%) (95% confidence
interval, 12?40%). The median survival was 7 months. The significant toxicities
noted were Grade 4 leukopenia and/or granulocytopenia, experienced by 15 patients; 1 of these patients also had Grade 4 hyponatremia. One patient died of a
respiratory infection.
CONCLUSIONS. When administered according to the dosage and schedule selected
for this study (60 mg/m2 i.v. on Days 1?5 every 3 weeks), teniposide as a single
agent had modest activity in extensive small cell lung carcinoma. The toxicities
observed in this study were acceptable. Cancer 1997;80:1029?33.
q1997 American Cancer Society.
KEYWORDS: extensive small cell lung carcinoma, teniposide, Phase II study, cooperative group.
T
Presented at the Seventh World Conference on
Lung Cancer, Colorado Springs, Colorado, July
1994.
Supported in part by the following Public Health
Service (PHS) Cooperative Agreement grant
numbers awarded by the National Cancer Institute: CA-35995, CA-38926, CA-20319, CA37981, CA-03389, CA-35261, CA-22433, CA04919, CA-32734, CA-35431, and CA-32102.
he anti-tumor activity of the podophyllotoxin derivatives VP-16213 (etoposide) and VM-26 (teniposide) is well known. The potential benefit of these compounds used singly or in combination with
other drugs in the treatment of small cell lung carcinoma (SCLC) had
been extensively reported for etoposide1,2 but had only recently been
documented for teniposide at the time this study was initiated.3,4 The
Address for reprints: Southwest Oncology
Group Operations Office, 14980 Omicron Drive,
San Antonio, TX 78245?3217.
q 1997 American Cancer Society
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W: Cancer
Received November 12, 1996; revisions received March 3, 1997, and May 23, 1997; accepted May 23, 1997.
1030
CANCER September 15, 1997 / Volume 80 / Number 6
methodology of the clinical testing of single agents for
their individual value in the management of small cell
lung carcinoma is still a matter of controversy.5 ? 12
Preliminary data supported the use of teniposide
as a single agent in the treatment of SCLC.13 ? 15 Most
data on its use in previously untreated cases has been
presented and published by the Danish investigators
Pedersen et al.16 and Bork et al.17 ? 19
Our interest in testing teniposide as a single agent
in SCLC was stimulated by a provocative communication from Bork et al representing the Danish investigators.19 They reported Phase II results for 33 evaluable
patients, 28 of whom were older than 70 years and 25
of whom had local disease. An overall response (partial
response [PR] / complete response [CR]) was observed in 30 of 33 patients (90%), with 7 CRs (21%). The
Danish group concluded that no other single agent has
shown comparable results in the treatment of SCLC,
including the closely related compound etoposide. To
confirm these results, the Southwest Oncology Group
(SWOG) undertook this trial using the same treatment
dose and schedule in previously untreated patients
with advanced stage SCLC.
PATIENTS AND METHODS
Patients with extensive SCLC with a performance status on the Zubrod scale of 0 ? 2 were eligible for this
study. Extensive disease was defined as dissemination
beyond the ipsilateral hemithorax and its regional
lymph node drainage. Staging evaluation included
computed tomography scans of the brain, chest, abdomen, and pelvis, as well as bone scans. Bone marrow
biopsies were performed on patients who otherwise
had clinically limited disease or an abnormal hemogram, to identify those with extensive disease based
on bone marrow involvement or to document bone
marrow involvement as a cause for the abnormal hemogram. Patients with ipsilateral pleural effusion and
no evidence of disease spread beyond the thorax and
regional lymph nodes were staged as limited and excluded from this trial, as were patients with contralateral hilar adenopathy, supraclavicular nodes, or superior vena caval syndrome (with no evidence of further
dissemination). Patients with brain metastases at the
time of prestudy staging were not eligible.
Patients were required to meet the following eligibility criteria: no prior malignancies (except nonmelanoma skin cancer); no prior therapy (chemotherapy
or irradiation) for malignancy; pretreatment hemoglobin of �5 grams, granulocytes �000/mL, and
platelet count �0,000/mL, except for patients with
biopsy-documented bone marrow involvement who
were permitted to have lower hematologic values; adequate renal function, with a serum creatinine level of
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08-27-97 07:30:56
�5 mg/dL; and adequate hepatic function, as evidenced by a bilirubin level of �5 mg % and serum
glutamic oxaloacetic transaminase (SGOT) within normal limits (unless the liver was involved with tumor, in
which case SGOT could be �times the upper limits of
normal).
There were no age restrictions. All patients were
informed of the investigational nature of the study
and gave written informed consent in accordance with
Food and Drug Administration, Southwest Oncology
Group, and institutional guidelines.
The study was planned for 30 eligible patients with
an interim analysis of the first 10 patients enrolled.
No response in the first 10 patients would have been
grounds for stopping the trial early. With 30 patients,
the response rate could be estimated to within plus or
minus 18% with a 95% confidence interval. A few more
patients were entered because accrual was rapid and
patients who were already evaluated for entry were
allowed on study before it was closed.
Patients were treated with VM-26 60 mg/m2 daily
1 5 every 3 weeks. Patients had a complete blood cell
count on Day 15 of the first treatment cycle and on
Day 1 of each cycle. Patients with an absolute neutrophil count (ANC) �00 and platelets �0,000 on the
day treatment was administered received full doses.
Patients with a Day 15 ANC �00 and a platelet count
�0,000 had a 10% increase in the daily dose of VM26. Patients with a Day 15 ANC of �0 or platelets
�,000 or a Day 1 ANC between 1500 and 2000 or
platelets between 75,000 and 100,000 had a 25% reduction in their daily dose of VM-26. Patients who had an
ANC �500 or platelets �,000 on Day 1 had therapy
postponed until recovery.
Patients with documented bone marrow involvement were required to receive full doses for the first
two cycles of therapy. Subsequent doses were modified according to the schedule just described. Patients
were assessed for response with chest X-rays before
each cycle of therapy and with all other pretherapy
scans after every two cycles.
CR was defined as complete disappearance of all
disease. PR was defined as a �% decrease in the
sum of the products of the perpendicular diameters
of all measurable disease or a �% decrease in the
estimated area of evaluable disease defined by 2 independent observers with no progression and no new
lesions. Progressive disease was defined as a 50% increase in the sum of the products of measurable lesions, an increase of 10 cm2, or the development of
new lesions. Stable disease included those with neither
progression nor PR. The best response was that seen
on two separate occasions at least 3 weeks apart.
Patients with no response after three cycles and
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VM-26 in Small Cell Lung Carcinoma/Grozea et al.
TABLE 1
Patient Characteristics
1031
TABLE 2
Response Assessment
Age (yrs)
Median
Range
Gender
Male
Female
Race
White
Black
Other
Performance status on the Zubrod scale
0?1
2
No. registered on study
Ineligible
Assessable for response
Complete response
Partial response
Unconfirmed response
Stable disease
Progressive disease
Early death
Inadequate assessment
64
46?83
28 (68%)
13 (32%)
37 (90%)
3 (7%)
1 (2%)
45
4
41
0 (0%)
10 (24%)
3 (7%)
6 (15%)
20 (49%)
1 (2%)
1 (2%)
24 (59%)
17 (41%)
those with progressive disease at any time had protocol therapy withdrawn. Otherwise, therapy was continued until disease progression or intolerable toxicity
developed. Use of other agents at the time of disease
progression was allowed but not mandated.
RESULTS
Forty-five patients were entered on the study and 41
patients were eligible. Reasons for ineligibility included wrong diagnosis (1 patient; the correct diagnosis was metastatic carcinoid tumor), chest CT performed � days prior to enrollment (1 patient), limited disease (1 patient), and prior chemotherapy (1
patient). All treated patients were adults ranging in
age from 46 to 83 years. Twenty-four patients (59%)
had a PS of 0 ? 1 and 17 patients (41%) had a PS of
2. All patients met the laboratory eligibility criteria.
Twenty-two patients had bone marrow biopsies performed, 1 for clinically limited disease and 21 for abnormal hemograms. Sixteen patients had a dose reduction and nine had an escalation of their doses,
according to the protocol guidelines outlined in ??Patients and Methods.?? Twelve of 17 patients with bone
marrow involvement received full doses for the first 2
cycles of therapy. Subsequent doses were modified
according to protocol guidelines. Patients received 1 ?
16 courses of teniposide (median, 10 courses).
Twenty-one patients had 3 or fewer courses and 5
patients had 10 or more courses. Patient characteristics are summarized in Table 1.
The results of the study are summarized in Table
2. There were 10 confirmed PRs, for a response rate of
24% (95% confidence interval, 12 ? 40%). The median
duration of response was 22 weeks (range, 10 ? 41
weeks). Three other patients had tumor shrinkage of
�% but no repeat assessment to confirm at least a
3-week duration. For all three patients, the time to
documented disease progression was �weeks. The
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FIGURE 1. This actuarial survival curve represents the overall survival
of all eligible patients with extensive small cell lung carcinoma treated
with teniposide (VM-26) as a single agent.
current SWOG policy is to require consecutive documentation of response on at least two occasions to
classify responses as ??confirmed.?? When ??unconfirmed?? responses were included based on measurement on one occasion, the response rate rose to 32%
(95% confidence interval, 18 ? 40%).
Patients had response rates based on disease
course at the following organ sites: colon, lung, liver,
bone marrow, bone, adrenals, and lymph nodes. The
median survival was 7 months (Fig. 1).
Toxicity was graded using NCI common toxicity
criteria. Significant toxicity is summarized in Table 3.
Toxicity in the study was primarily hematologic.
Twenty-two patients had neutropenia, either Grade 3
(8 patients) or Grade 4 (15 patients). There were six
documented infections. Five were Grade 1 ? 2, and
there was one episode of fatal pneumonia. Two patients had fever without documented infection. Three
patients had Grade 3 thrombocytopenia and 8 patients
had Grade 1 ? 2. There was one patient with Grade 4
hyponatremia and one patient each with Grade 3 nau-
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1032
CANCER September 15, 1997 / Volume 80 / Number 6
TABLE 3
Toxicity
NCI Grade
Toxicity
1?2
3
4
Neutropenia
Anemia
Thrombocytopenia
Infection
Fever without infection
Nausea
Vomiting
Hyponatremia
6
20
8
1
2
19
8
8
4
3
4
15
5 (fatal)
1
1
1
1
NCI: National Cancer Institute.
sea and Grade 3 vomiting. All other toxicities were
mild (Grade 1 ? 2) and included nausea (in 19 patients),
vomiting (8), alopecia (4), diarrhea (4), elevated liver
enzymes (3), hypotension (3), skin rash (2), weight loss
(2), hypertension (2), rise in creatinine (2), anorexia
(2), and weakness (2). Edema, erythema, malaise, myalgia, somnolence, and stomatitis were reported for
one patient each.
DISCUSSION
In this multi-institutional, cooperative group trial, we
observed a confirmed response rate of 24%, with no
CRs, to teniposide as a single agent. This is discrepant
with the response rate of 90% and the CR rate of 30%
initially reported by Bork et al.17 Part of the reason
for this discrepancy is the current SWOG policy that
requires consecutive documentation of response on at
least two occasions to be classified as ??confirmed.??
However, even when ??unconfirmed?? responses based
on one measurement were included, the response rate
only rose to 32% (95% confidence interval, 18 ? 40%),
which is still in marked contrast. Another reason for
the different results observed is the proportion of patients with limited disease (21 of 33) in Bork?s original
report, whereas our study excluded patients with limited disease. In the second report by Bork et al., 46
patients were randomized to etoposide and 48 to teniposide, with 13 in each group staged as extensive.18
Among the patients with extensive disease, one CR
was observed in the teniposide group, as compared
with three in the etoposide group. The overall response rates were 65% for etoposide and 71% for teniposide, with a median duration of response of 6
months for patients in both groups who had extensive
disease. This is comparable to the median response
duration of 22 weeks observed in our study. Bork et
al. observed a median survival of 11.3 months for all
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08-27-97 07:30:56
patients, but 73% had limited disease.18 Our median
survival of 7 months for a patient population with exclusively extensive disease is comparable to their observations, and it can be concluded that the activity
of teniposide is similar to that of etoposide.
Three other studies have reported results of administering teniposide as a single agent in the treatment of SCLC. Holoye et al.,20 using a schedule like
ours and that of Bork et al.,17,18 reported 12 PRs
and no CRs for 24 evaluable patients (among 38
entered), for a 50% response rate. Cerny et al.21 used
a different schedule: 100 mg/day on Days 1 ? 5 every
3 to 4 weeks in the treatment of 32 ??elderly or poor
prognosis?? patients, half of whom had extensive
disease. The PR rate was 33%, with no CRs. Median
survival was 5.6 months. Nine of 30 eligible patients
had early deaths, including 5 who had fatal septicemia while they were neutropenic; the authors concluded that single agent teniposide produced unacceptable toxicity in this group of patients. Finally,
Tummarello et al.22 followed a schedule of 60 mg/
m 2/day on Days 1 ? 5 every 3 weeks (identical to ours
and that of Bork et al.17,18) in the treatment of 26
??elderly or poor performance status?? patients, of
whom 24 were evaluable for response and 11 had
extensive disease. The latter group demonstrated
five PRs (45%), and the median survival of the entire
group was 7 months.
None of the confirmatory studies, including the
SWOG trial reported herein, have been able to confirm the promising response rates reported by the
Danish investigators. We conclude that teniposide
probably offers no advantage over etoposide in the
management of SCLC.
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