998

Evaluation of Cisplatin, Carboplatin, and Etoposide in

Metastatic Nonsmall Cell Lung Carcinoma
A Phase I1 Study of the Southwest Oncology Group

Robert A. Figlin, M.o.' BACKGROUND.The combined use of cisplatin and carboplatin chemotherapy offers
John J. CrOWley, Ph.D.* a unique means of platinum dose intensification. Response rates using either of
Edwin L. Jacobs, M.O? these agents in combination with etoposide are comparable. In a Phase II trial,
Michael Muirhead, M . o . ~ the authors investigated the combination of cisplatin and carhoplatin with etopo-
John Wendall Goodwin, M . D . ~ side for the treatment of patients with advanced nonsmall cell lung carcinoma.
John J. Rinehart, M . O ~ METHODS. Eligible patients were chemotherapy naive and had histologically con-
Robert B. Livingston, M.o.' firmed. evaluable, or measurable selected Stage IIIB and Stage IV nonsmall cell
lung carcinoma. Based upon the results of an earlier Phase I and I1 pilot study,
' Department of Medicine, University of Califor- patients received carboplatin, 225 mg/m2,on Day 1; cisplatin, 50 mglm', on Days
nia at Los Angeles, Los Angeles, California. 2 and 3 ; and etoposide, 75 mg/m', on Days 1, 2, and 3 every-4-weeks.
RESULTS. Eighty-three patients (75 eligible patients) received chemotherapy with
SWOG Statistical Center, Fred Hutchinson
cisplatin, carboplatin, and etoposide. Two patients refused therapy after registra-
Cancer Research Center, !;eattie, Washington.
tion and were n'ot analyzable. Thirty-six of the remaining 75 patients had Grade
East Valley Hematology and Oncology Medical 4 toxicities, mostly hematologic, and 6 patients died of toxicity. The confirmed
Group, Inc., Burbank. California. response rate was 24% (95% confidence interval, 1 5 3 5 % ) . Median progression-
Department of Medicine, John L. McElellan free survival was 4 months and the median survival was 8 months.
Memorial Veterans Administration Center, Little CONCLUSIONS. Combination cisplatin, carboplatin. and etopvside chemotherapy
Rock, Arkansas. appears to be no better than cisplatinletoposide or carboplatinletoposide for the
Department of Medicine, Smith-Glynn-Gal- treatment of patiients with nonsmall cell lung carcinoma. The toxicity of this regi-
laway Clinic, Springfield, Missouri. men may be higher, and therefore it cannot be recommended For general use.
Cancer 1996; 78:998-1003. 0 1996 Aiizericnn Cnricer Society.
Department of Medicina, Scott and White
Clinic, Temple, Texas.
KEYWORDS lung carcinoma, cisplatin, carboplatin, etoposide, chemotherapy.
Department of Medicine, University of Wash-
ington Medical Center, Seattle, Washington.

P atients with metastatic nonsmall cell lung carcinoma have median

survivals that range from 15 to 25 weeks in most modern series,
with 1-year suirvival in the range of 10-20%.' A variety of combination
chemotherapy regimens have been shown to be active in nonsmall
Supported in part by the following PHS Co- cell lung ~ a r c i n o m a . " ~Cisplatin is one of the most active single
operative Agreement grarit numbers awarded agents, with a response rate of 15-20%, with conflicting data regard-
by the National Cancer Institute, DHHS: ing higher response rates observed with increasing doses of cisplatin."
CA58348, CA37981, CA45560, CA28862, Carboplatin has also been evaluated in nonsmall cell lung cancer with
CA27057, CA35431, CA35200, CA58686,
CAI 3612, CAI 2644, 0135281, CA52654, response rates of 9-16% as a single agent in previously untreated
CA58861, CA45377, CH46441, CA52772, patients with advanced disease.',"." A randomized study comparing
CA46113, CA46282, CA38926, and CA32102. either carboplatin or cisplatin in combination with etoposide resulted
in objective response rates of 16% and 27%, respectively, in previously
Address for reprints: Southwest Oncology untreated patients6
Group (SWOG-9127), Operations Office, 14980
Omicron Drive, San Antonio, TX 78245-3217.
Recently, there has been an interest in therapy combining cis-
platin and carboplatin as a means of escalating the effective dose of
Received January 18, 1996; revision received platinum-based chemotherapy. Cisplatin and carboplatin have differ-
May 14, 1996; accepted June 3, 1996. ent pharmacokinetics and dose-limiting toxicities. The combination

0 1996 American Cancer Society

 Phase 11: Cisplatin, Carboplatin, Etoposide/Figlin et al. 999

of cisplatin and carboplatin may therefore have a su- cer. The qualitative and quantitative toxicities of this
perior therapeutic index.'," Cisplatin is considerably combination were also evaluated.
more likely to lead to nephrotoxicity, neurotoxicity,
nausea, and vomiting, whereas myelosuppression is PATIENTS AND METHODS
dose-limiting for carboplatin. The pharmacology of Patient Selection
cisplatin and carboplatin also differ. Cisplatin is highly Criteria for study entry was comprised of histologically
protein bound and its active moiety is cleared by non- confirmed advanced (1'4 by the presence of a malig-
renal mechanisms.'' Conversely, carboplatin is protein nant pleural effusion) Stage IIIB or metastatic ( M l )
bound to a substantially lesser extent and is highly Stage IV nonsmall cell lung cancer. All patients had
dependent on renal mechanisms for clearance.'" The bidimensionally measurable or evaluable disease out-
molecular species formed when either cisplatin or car- side of any prior radiation field. Evaluable disease in-
boplatin react with DNA is a similar bidentate, N-7- cluded unidimensionally measurable lesions, masses
deoxy (GPG) guanine-guanine intrastrand adduct. with margins not clearly defined, palpable lesions with
However. the rate at which cisplatin and carboplatin either diameter less than 2 cm, any lesion with both
react with DN,4 is different, suggesting differences in diameters less than 0.5 cm. and bone disease. 1Malig-
intracellular pharmacodynamics.''~'* nant pleural effusions did not constitute measurable
A limited number of cell lines and murine tumors or evaluable disease. Patients with a history of brain
have been described in which cisplatin and car- metastases were ineligible. Patients must not have re-
boplatin are not completely cross-resistant.'.'-" Fur- ceived prior chemotherapy or biologic therapy. Pa-
thermore, a prospectively randomized trial comparing tients were permitted to have received prior radiation
cisplatin and carboplatin as primary therapy for ovar- therapy that must have been completed at least 4
ian carcinoma showed a 15-20% crossover response weeks prior to initiation of chemotherapy. All patients
had adequate renal (creatinine 5 1.2 mg% or creatine
rate to carboplatin after disease progression on cis-
platin."' Further rationale for combining cisplatin and clearance 2 65 mL/min) and hepatic function and a
Southwest Oncology Group (SWOG) performance sta-
carboplatin may be derived from the evidence sup-
tus of 0-2 by history. These criteria are standard for
porting ii steep dose-response curve for both cisplatin
advanced nonsmall cell lung cancer trials in SWOG
and carboplatin,'i,'Mand the advantage that using
using cisplatin. All patients had absolute granulocyte
moderate doses may avoid the chronic toxicities pro-
counts of 21500/pL and platelet counts of 2 150,000/
hibiting further treatment that have been associated
p L . Patients were classified by disease status (measur-
with high dose cisplatin, including renal, auditive, and
able vs. evaluable) and by performance status (0-1
neurologic toxicities.
vs. 2). Signed informed consent was obtained for all
Several Phase 1/11 studies have evaluated the com- patients. The protocol was approved by SWOG and
bination of cisplatin and carboplatin. Trump et al. by the institutional review boards of all participating
studied sequential infusions of carboplatin and then institutions.
cisplatin, showing thrombocytopenia and leukopenia
to be the dose-limiting toxicities of the combination. Treatment Schedule
Nausea and vomiting were similar to that observed The dose and schedule of chemotherapy was based
with cisplatin alone and there was no clinically sig- upon a pilot Phase 1/11 study"! initiated in 1989 and
nificant nephrotoxicity, ototoxicity, peripheral neu- included; carboplatin, 225 mg/m', administered by in-
ropathy, nor other limiting or unusual toxicities ob- travenous piggyback (IVPH) in 100 ml. NS over 30 min-
served with this combination," utes on the first day of each 4-week cycle: etoposide,
A Phase 1/11 study was initiated at the 1Jniversity 75 mg/m,* administered by IVPR in 500 mI. NS over
of California at LaosAngeles to assess the efficacy and 2 hours on Days 1 , 2, and 3 of each 4-week cycle; and
toxicity of cisplatin and carboplatin combination che- cisplatin, 50 mglm' administered by IVRP infusion on
motherapy with etoposide in previously untreated pa- Days 2 and 3 of each 4-week cycle. Cisplatin was ad-
tients with advanced, measurable nonsmall cell lung ministered on an outpatient basis. Standard intrave-
carcinoma." This trial established the maximum toler- nous hydration and antiemetics were used. Chemo-
ated doses and the dose-limiting toxicities of the com- therapy was repeated every 4 weeks for up to 6 cycles.
bination as leukopenia and thrombocytopenia. The Nonresponding patients received a minimum of two
objectives of the current trial were to assess the sur- cycles or until progression of disease. Responding pa-
vival and response rates of cisplatin/carhoplatin/eto- tients received a maximum of six cycles. Patients were
poside combination chemotherapy in patients with se- removed from the protocol for progression of disease
lected Stage IllB and Stage 1V nonsmall cell lung can- at any time, unacceptable toxicity, or patient refusal
loo0 CANCER September 1, 1996 / Volume 78 / Number 5

to continue therapy. Standard dose reductions were TABLE 1

incorporated for hematologic and nonheniatologic Patient Characteristics
toxicities. Dose reductions for hematologic toxicity
No (Yo)
was based on nadir counts after the preceding course.
If the leukocyte count was < 3500 or the platelet count .Age [yrs]
was < 125,000 on Day 1 of cycle, treatment was de- Median GO
layed until recovery and then reduced to carboplatin, Range 3a - 77
Sex
165 mg/m' for a leukocyte count between 1000-1499
Male
or platelet count between 25,000-49,000, or car- I:eniale
boplatin, 110 rng/ni', for a leukocyte count of < 1,000 Perfurinalice Sratus
or platelet count of < 25,000 for nonhematologic toxic- 0- I
ities. A 50% dose reduction of cisplatin was incorpo- L
Ilisease
rated for Grade 3 gastrointestinal toxicity, renal toxicity
Veasurable
with creatinine > 1.3, and Grade 2 neurologiclcentral Evdlua blr
nervous system toxicity .

Response and Toxicity Criteria

Response and toxicity were graded according to stan- Median
dard SWOG criteria." Complete response was defined _
At R_
sk -Fo.lures in Montnr
CDDPICBDCAIVP-Ib 73 70 4
as complete resolution of all measurable and evaluable
disease and the appearance of no new lesions for a
period of at least 4 weeks. Partial response was defined
as a >SO% decrease under baseline in the sum of the
products and perpendicular diameters of all measur-
able lesions with no progression of evaluable lesions
for at least 4 weeks. Progressive disease was defined
as a 25% increase in the sum of the products of the
measurable lesions over the smallest sum observed,
or the appearance CJf new lesions. Stable disease was
defined as disease riot qualifying for classification as 3 b 12 18 id 33
complete response, partial response, or progression. Mon:hs Aft91 tniiiat Registration

FIGURE 1. Progression free survival of patients in study.

Statistical Methods
This study was designed for a single stage of accrual.
Progression free survival was defined as the time of tion and were not analyzable. Table 1 describes the
registration to the time of progression or last contact, patient ch.aracteristics.
and survival was defined as the time from registration Sevenly-five patients were analyzed for treatment
to last contact. Both were estimated using the product- efficacy and toxicity. Eleven patients completed 6
limit method," with patients who were alive at last courses of therapy as planned. Twenty-nine patients
contact treated as censored. The confidence interval discontinued therapy due to progression or relapse,
(CI) for the response rate was calculated by the exact 20 patient:; due to toxicity or side effects, and 8 due
method. to death. Seven patients were taken off treatment for
reasons not protocol-specified. There were no major
RESULTS protocol violations.
Patient Characteristics Response assessnient was determined in 75 pa-
Between August 1991 and March 1992, 83 patients tients. There were 18 responses 3 complete, l l partial,
from SWOG institutions were registered. Six patients and 4 partial nonmeasurable disease) for a confirmed
(7%) were ineligible and excluded from the analyses. response rate of 24% (95% CI, 15-35'76). Sixteen re-
]:our patients did not have the correct stage of disease sponses (29%) and 2 responses (10%) were observed
(three did not have metastatic disease, and one had in Eastern Cooperative Oncology Group (ECOG) 0,1
brain metastasis), and two had baseline laboratory versus 2 p,3tients, respectively. 'I'wenty-four patients
measurements taken outside the required time con- had stable disease (32%), 15 had progressive disease
straints. Two patients refused treatment after registra- (20%), and 4 died before response could be assessed
 Phase II: Cisplatin, Carboplatin, Etoposide/Figlin et al. 1001

in 40 patients (53%). Febrile neutropenia was noted

Median
-
At Risk Deaths in Months
in IS patients (42%) with Grade 4 granulocytopenia.
i\ CDDP/CBDCA/VP-I6 73 65 8 Seven patients (9%) experienced nephrotoxicity (one
patient with Grade 4).

DISCUSSION
Chemotherapy dose intensification is a potentially im-
portant strategy in cancer treatment."' For cisplatin,
experimental studies have demonstrated a steep dose-
response relationship in vitro in a variety of tumor
types. 17. I&Xi,27 A variety of strategies have been used to
attempt dose escalation clinically using either cisplatin
or carboplatin alone."^'".'" Recently, there has been an
0 6 12 18 24 33
M o n t h s After initial Registration
interest in therapy combining cisplatin and car-
boplatin as a means of escalating the effective dose
FIGURE 2. Overall survival of patients in study. of platinum-based chemotherapy.'".'I Several groups
have investigated the administration of cisplatin and
carboplatin, showing thrombocytopenia and leukope-
TABLE 2 nia to be the dose-limiting toxicity. Nausea and vom-
Maximum Toxicities (73 patients) iting were similar to cisplatin administration and there
were no unusual toxicities with this combination.'"
Grade (9'0) The activity of both cisplatin and carboplatin are
3 4 Total enhanced when combined with noncross-resistant
chemotherapy."."' A pilot Phase 1/11 study of the com-
bination of cisplatin, carboplatin, and etoposide was
performed." Seventeen patients (100%) were eligible
with a median performance status of 90% (ECOG 0,l
patient eligible only),with only 3 patients (19%)having
had prior weight loss of greater than or equal to 10%.
In contrast, in the current study, 27% of patients had
a performance status of ECOG 2, a status not permit-
(.5%). Five patients had responses that could not be ted in the pilot, 49% had a weight loss greater than
confirmed with appropriate and timely follow-up test- or equal to S Kg, and 54% had an elevated lactate
ing (7%))and in 9 patients response assessment was dehydrogenase (LDII) whereas 47% had some degree
inadequate (12%). The median progression free sur- of bone involvement, all of which are poor prognostic
vival tinif! was 4 months and the median survival time signs. Nine patients had Stage IIIB and 8 patients had
was 8 months. Median survival time was 10 months Stage IV disease in contrast to the current study, which
for E(:OG performance status 0,1 patients and 4 had predominantly Stage IV patients (91%).Maximum
months for ECOG performance status 2 patients. Pro- tolerated dose was established at a carboplatin dose
gression free survival and overall survival are shown of 22s mg/m' on Day 1 followed by 50 mglm' of cis-
in Figures 1 and 2 respectively. platin on Days 2 and 3 . Etoposide was found to be
Table 2 summarizes the Grade 3 and 4 toxicities. dose-limiting at 75 mglnY' on Days 1, 2, and 3 . Sixteen
'Toxicity was moderately severe. The number of pa- patients were evaluable for response with therapy
tients with a maximum graded toxicity l and 2 was 10 demonstrating a partial response in 9 patients of S6%
( 13%); 23 patients had maximum Grade 3 toxicity (95% CI, 30-80%). This study demonstrated that cis-
(31%);36 patients had a maximum Grade 4 toxicity platin, carboplatin, and etoposide combination che-
(48%),and 6 patients died (8%):3 patients due to respi- motherapy had activity in patients with advanced
ratory infection, 2 due to pulmonary edema (1 associ- nonsmall cell lung carcinoma with dose-limiting he-
ated with renal failure), and 1 due to bowel obstruc- matologic toxicity. Granulocytopenia and thrombocy-
tion. All deaths but one (postobstructive pneumonia) topenia were Grade 3 and 4 in 76% and 11%, respec-
were felt to be treatment-related. Grade 3 or 4 hemato- tively.
logic toxicity was most common: leukopenia in 39 pa- The current study was initiated to evaluate this
tients (52%), granulocytopenia in 48 patients (64%), regimen in a cooperative group setting. The confirmed
anemia in 16 patients (21 %), and thrombocytopenia response rate of2496 is not markedly superior to that of
1002 CANCER September 1, 1996 / Volume 78 / Number 5

other comparable cisplatin- or carboplatin-containing C arms (57%, 38%, and 34%, respectively; P < 0.05).
combination regimen^.^',^' The median progression However, there were no significant differences in me-
free and median survival times of 4 months and 8 dian survival time between the three treatment arms,
months, respectively, were also not substantially bet- although the delivered dose intensity for cisplatin was
ter than comparable studies using either agent alone significantly greater in the high dose arms. The high
or in similar combinations.""."' However, toxicity was dose arms resulted in an increased incidence of oto-
moderately severe, with only eight patients suffering toxicity, emesis, and myelosuppression, but with simi-
Grade 2 or lower toxicity as maximal toxicity and these lar degrees of renal toxicity and neuropathy compared
toxicities were mainly hematopoietic. The Calvert dos- with standard dose cisplatin.
ing system"' was not used in either the pilot or the These studies would indicate that the current level
current trial, which may account in part for the fre- of platinum dose intensification that is achievable with
quency of hematopoietic toxicity. These trials were be- cisplatin, carboplatin, or their combination is unlikely
ing performed just as the Calvert dosing system was to have any clinical impact in the treatment of ad-
being published. Granulocytopenia and thrombocyto- vanced nonsmall cell lung carcinoma. Although higher
penia were Grade 4 in 47% and 27% of patients, respec- response rates may be observed in isolated studies,
tively. There were six deaths due to a variety of causes, there appears to be no survival benefit for escalation
including ileus, pulmonary edema, renal failure, and of cisplatin or carboplatin alone or in combination.
respiratory infection. We concluded that there is no The current study indicates that although the
clear evidence of improved response rate, progression combination of cisplatin with carboplatin and etopo-
free survival, or overall survival using this regimen, but side is feasible, toxicity is high and response rates,
that toxicity is higher than that described for other progression free survival, and median survival are not
trials using cisplatin and etoposide or carboplatin and appreciably improved. At the time this study was
etoposide combination therapy. The higher response planned, a number of agents subsequently identified
rate in the pilot study may be related in part to patient as being active in nonsmall cell lung cancer had not
selection factors, including a better overall perfor- been adequately studied in clinical trials. Currently,
mance status, more Stage IIIB patients, and fewer pa- the platinums are being explored in combination with
tients with weight loss, bone involvement, and an ele- taxanes and other new drugs such as Gemcitabine,
vated LDH. and the promising response rates and survival data
A Phase 111 trial that compared low dose cisplatin with these combinations may make etoposide a less
(60 mg/m2)with high dose cisplatin (120 mglm') both attractive agent to study in nonsmall cell lung cancer.
combined with vindesine suggested that although the A current three-arm ECOG trial in patients with non-
response rates for the 2 treatment groups were compa- small cell lung carcinoma comparing cisplatin and
rable (46%vs. 40%), the high dose regimen was supe- etoposide with cisplatin and paclitaxel at one of two
rior to the low dose regimen in median duration of doses has been completed and the results of this trial
response (12 months vs. 5.5 months) and in median may impact the use of etoposide and cisplatin as a
survival (21.7 months vs. 10 months) for responding reference regimen in patients with nonsmall cell lung
patienk3"However, this finding was not confirmed in carcinoma.
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