An estimated 164,100 new cases of lung cancer will be diagnosed in
2000, and approximately 25% or 41,000 of these cases will be
small-cell lung cancer (SCLC). Nearly one-third of the patients with
SCLC present with limited-stage disease. This is defined as disease
that is confined to one hemithorax without pericardial or pleural
effusion and thus, encompassable by a single radiotherapy port.
Limited-stage SCLC is potentially more curable than extensive
disease. Prior to the use of chemotherapy, patients diagnosed with
limited-stage SCLC survived an average of 3 months. With the advent
of polychemotherapy, median survival is approximately 10 to 14
months, with 5-year survival ranging between 2% and 8%.
Of the currently available chemotherapeutic agents, several have been
associated with response rates of 30% or more. These agents include
cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), methotrexate
(Folex, Mexate), etoposide (VePesid, VP-16), vincristine (Oncovin),
and carboplatin (Paraplatin). Despite the known chemosensitivity
of SCLC (with response rates of approximately 70% to 80% in all
patients, and up to 50% complete responses with combination
chemotherapy in patients with limited disease), the majority of
patients diagnosed with limited-stage SCLC will die from recurrent
disease. Over the past several years, investigators have attempted to
improve upon this high relapse rate with different approaches.
Goldie and Coldman Hypothesis
The mathematical model described by Goldie and Coldman suggests that
rapid alternation of noncross-resistant regimens might improve
tumor-cell kill. The combination of cisplatin (Platinol) and
etoposide (PE) has been shown to be effective salvage therapy in SCLC
patients treated with CAV (cyclophosphamide, doxorubicin,
vincristine), with response rates approaching 50%. Additionally, a
phase III study by the Southeastern Cancer Study Group randomized
limited-disease SCLC patients to receive six cycles of CAV
administered with or without two cycles of PE as consolidation
therapy. Survival was significantly longer in the PE arm, 97.7 weeks
vs 68 weeks, P = .0094. Because of these results, it is
believed that CAV and PE may be noncross-resistant regimens.
Three randomized phase III trials in SCLC have attempted to prove
this theory.[8-10] The first trial was conducted in Canada in 289
patients with extensive-disease SCLC.[8 ] Patients were randomized to
receive either standard therapy consisting of CAV administered every
3 weeks for six courses or CAV alternating with PE every 3 weeks for
six treatment cycles. The overall response rate (80% vs 63%, P
< .002), and overall survival (9.6 vs 8.0 months, P = .03)
favored the alternating regimen. Fukuoka et al conducted a randomized
trial comparing CAV with PE and CAV alternating with PE. This
trial included 288 eligible patients with both limited and extensive
diseae. Patients with limited disease received thoracic radiation
after completing chemotherapy.
Overall response rates were superior in the PE and CAV/PE arms
compared to CAV alone, 78%, 76%, 55%, respectively (P <
.005). Overall survival favored the alternating regimen, CAV/PE, as
compared to either PE or CAV alone, 11.8 months, 9.9 months, and 9.9
months, respectively (P = .056). When the data were analyzed
by stage, there was no difference in survival among patients with
extensive disease (8 to 9 months). There was, however, a significant
survival advantage for the alternating regimen in patients with
limited disease when compared to either PB or CAV alone, 16.8 months,
11.7 months (P = .023), or 12.4 months (P = .14), respectively.
The Southeastern Cancer Study Group (SECSG) conducted a trial in
patients with previously untreated extensive-disease SCLC. The
437 enrolled patients were randomized to receive either six cycles of
CAV, four cycles of PE, or CAV alternating with PE (three cycles
each). There was no difference in overall response rate, 51%, 61%,
and 59%, respectively, or median survival, 8.3, 8.6, and 8.1 months, respectively.
Two phase II trials have established the activity of the VIP
(cisplatin, ifosfamide, and etoposide) regimen.[11,12] Subsequently,
the Hoosier Oncology Group conducted a randomized trial comparing
VP-16 and cisplatin (VP) with or without ifosfamide (VIP) in patients
with previously untreated extensive-disease SCLC. Between May
1989 and March 1993, 171 patients with chemotherapy-naive,
extensive-disease SCLC were entered into the trial and 163 were
evaluable for response. Responses were seen in 67% of patients
treated with VP and 73% of patients treated with VIP (P = NS).
Overall survival favored the VIP arm, 9.1 vs 7.3 months, and was
statistically significant (P = .044). Myelosuppression was the
most frequent toxicity, with grade 4 granulocytopenia occurring in
24% of patients treated with VP and 43% of patients treated with VIP.
Miyamoto et al reported on a similar randomized trial comparing
cisplatin and etoposide with or without ifosfamide in patients with
both limited and extensive disease. This trial demonstrated no
differences in response rate or overall survival, but the outcome may
be equivocal because the study was small (N = 92) and included
a mixed patient population.
The results of these studies suggest that for patients with extensive
disease, there is no obvious survival advantage associated with any
particular chemotherapy combination.
Short Intensive Weekly Therapy
Another treatment approach is the rapid sequencing of a regimen
incorporating several active agents over a short period. One such
regimen, CODE, consists of weekly treatments of cisplatin,
vincristine (Oncovin), doxorubicin, and intravenous etoposide, with
the myelosuppressive and nonmyelosuppressive agents alternated. The
CODE regimen was designed to double the dose intensity of these
agents in comparison with the more traditional regimen of CAV
alternating with etoposide and cisplatin.
In a promising Canadian pilot study, Murray et al reported a 94%
overall response rate (40% CR) in 48 patients (all less than 66 years
old) with extensive-disease SCLC. Median survival was 61 weeks.
The principal toxicities were grade 4 granulocytopenia in 56% of
patients and anemia requiring blood transfusions in 58% of patients.
There were four incidents of neutropenic fever. Nonhematologic
toxicities included grade 2/3 mucositis in 12% of patients and grade
2 or greater neurologic complications in 16% of patients. There were
two treatment-related deaths, one from neutropenic fever and the
second from pneumonia in a non-neutropenic patient.
However, a larger phase III trial conducted in Japan failed to
confirm a survival advantage with the CODE regimen. In this
study, 228 patients with extensive-disease SCLC were randomized
either to the CODE plus granulocyte colony-stimulating factor (G-CSF,
filgrastim, [Neupogen]) arm or the standard arm of CAV alternating
with PE. Overall response rates (85.3% and 76.7%, respectively) and
survival (11.9 months and 10.6 months, respectively) were not
statistically different between the two treatment arms. A
confirmatory Canadian/United States trial included 220 patients
randomized between CODE and CAV/PE. The study closed prematurely due
to an excess number of toxic deaths in the CODE arm (8.2% vs 0.9%).
There was no statistical difference in overall survival between the
two arms, 0.98 years vs 0.91 years, P = NS.
In order to improve the resistance of SCLC to chemotherapy
administered after the first four to six cycles, investigators have
designed trials to test the hypothesis that higher doses of
chemotherapy, particularly in the first one to four cycles, may
This approach was investigated in seven randomized trials (Table
1).[18-24] In the late 1970s and 1980s, five studies evaluated
either doxorubicin-based or alkylating agent-based
chemotherapy,[18-22] and only one of these studies demonstrated a
survival advantage in favor of the dose-intensive arm. That
study, conducted by the Eastern Cooperative Oncology Group (ECOG),
randomized 349 patients with limited- or extensive-disease SCLC to
receive either standard therapy with cyclophosphamide 700 mg/m²
on days 1 and 22, Lomustine (CCNU) 70 mg/m² on day 1, and
methotrexate 15 mg/m² twice weekly during weeks 2, 3, and 5, 6
or to receive the same regimen with an increased dose of
cyclophosphamide (1,500 mg/m²). All responding patients on the
standard arm received maintenance therapy with doxorubicin,
vincristine, and procarbazine (Matulane) alternating with a low-dose
version of the induction regimen.
In a second randomization designed to test the role of maintenance
therapy, only half the patients in the dose-intensive arm received
maintenance therapy. Survival was improved in the dose-intensive arm,
41 weeks vs 36 weeks (P = .04). This difference was most
pronounced in the group of patients with limited disease, where
survival was 56 vs 42 weeks (P = .02). Toxicity, particularly
hematologic toxicity, was more pronounced in the dose-intensive arm,
with life-threatening and lethal toxicities reported as 53% vs 7% and
4% vs 1%, respectively (P < .0001).
Two randomized trials of cisplatin-based chemotherapy in
limited-disease SCLC have been published with conflicting
results.[23,24] A French study randomized 105 patients to receive a
chemotherapy regimen consisting of cisplatin, cyclophosphamide,
doxorubicin, and etoposide. All patients received doxorubicin 40
mg/m² and etoposide 75 mg/m² on days 1 to 3. The standard
regimen consisted of cisplatin 80 mg/m² and cyclophosphamide 900
mg/m² divided over 4 days in addition to the doxorubicin and
etoposide combination. The dose-intensive arm consisted of cisplatin
100 mg/m² and cyclophosphamide 1,200 mg/m² divided over 4
days plus doxorubicin and etoposide. Chemotherapy doses differed for
the first cycle of treatment only. All patients received the
identical standard arm dose for cycles 2 through 6 as well as
identical chest radiotherapy. With a median follow-up of 33 months,
the 2-year survival rate for patients in the higher-dose chemotherapy
arm was 43% vs 26% for those in the standard arm. There was no
difference in the patterns of toxicity between the two arms.
Another study, conducted at the National Cancer Institute (NCI),
randomized 90 patients with extensive-disease SCLC to receive
standard-dose or high-dose cisplatin and etoposide for cycles 1 and
2. The standard-dose arm consisted of cisplatin (P) 80 mg/m²
on day 1 and etoposide (E) 80 mg/m² on days 1 to 3 every 3
weeks. The high-dose arm consisted of cisplatin 135 mg/m²
divided over 5 days and etoposide 80 mg/m² on days 1 to 5.
Cycles were repeated every 3 weeks. All patients received
standard-dose PE in cycles 3 and 4. Patients in complete remission
continued to receive PE in cycles 5 through 8. All other patients
received CAV or a drug program based on in vitro drug sensitivity
testing from tumor cell lines established for individual patients.
The authors reported no difference in overall median survival between
the two arms, 10.7 months for the standard arm and 11.4 months for
the high-dose arm, P = .68. Toxicities including leukopenia (P
< .0001), febrile neutropenia (P = .01), thrombocytopenia (P
< .000l), and weight loss (P = .02) were seen more commonly
in the high-dose arm.
Currently, there are no data demonstrating the superiority of
higher-dose over standard-dose chemotherapy. However, several studies
may have detected a survival advantage associated with high-dose
chemotherapy in patients with limited disease. Future studies aimed
at testing this hypothesis should be conducted in this patient population.
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