NEW ORLEANSTopotecan (Hycamtin) after standard therapy with
etoposide/cisplatin (Platinol) improved progression-free survival but
failed to improve overall survival in extensive-disease small-cell
lung cancer (SCLC) when compared to observation, according to a
randomized phase III trial presented at the 36th Annual Meeting of
the American Society of Clinical Oncology (ASCO).
Patients randomized to the topotecan arm after standard therapy also
experienced added toxicity and no improvement in quality of life,
compared with the observation arm, reported David H. Johnson, MD, of
Vanderbilt University Medical School. The study was conducted by the
Eastern Cooperative Oncology Group.
If one looks at any grade 3 or 4 toxicity, 10% of the patients
in the observation arm experienced such vs 90% of patients in the
topotecan arm, Dr. Johnson said.
Disease-free survival in the topotecan arm was 3.6 months vs 2.3
months in the observation arm (P = .0001). While this is
highly statistically significant, you might question the clinical
relevance of this difference, Dr. Johnson said.
The disappointing study results prompted a query to Dr. Johnson
during the question-and-answer period about the proper order in which
to administer topoisom-erase-I and topoisomerase-II inhibitors.
Reports at future ASCO meetings, Dr. Johnson speculated, may
demonstrate that the sequencing of the topoisomerase-I/II inhibitors
might be more effective. Topotecan is a topoisomerase-I inhibitor.
Etoposide is a topoisomerase-II inhibitor.
The 405 eligible enrollees in the study were previously untreated
patients with measurable or evaluable disease. Patients with stable
brain metastases were allowed.
All patients received the etoposide/cisplatin standard
regimencisplatin 60 mg/m² IV on day 1 and etoposide 120
mg/m² IV on days 1, 2, and 3 every 3 weeks for four cycles.
In step 2 of the study, patients with stable or responding disease
were then randomized to observation or to the topotecan arm: 1.5
mg/m²/d for 5 days every 3 weeks for four cycles. The
researchers enrolled 223 patients into step 2 of the study, 112 to
the topotecan arm, and 111 to the observation arm.
The primary endpoint was survival. The secondary endpoint was a
quality of life assessment using FACT-L.
The complete and partial response rates to etoposide/cisplatin
induction were 3% and 30%, respectively. There were seven
patients who experienced a response after switching to topotecan: two
patients achieved a complete response and five a partial response.
There were slightly more patients on the topotecan arm who appeared
to have stable disease, Dr. Johnson said.
The overall disease-free survival for the group as a whole from the
start of registration was 8 months. The median survival was 9.6
months, and 1-year survival was 35%, he said.
When analyzing subsets of patients for various prognostic factors,
the topotecan arm was favored in every instance. However, survival
from step 2 was not significantly different between the two arms: 9.3
months in the topotecan arm vs 8.9 months in the observation arm (P
This was true too of 1-year survival. There was no difference
in the 1-year survival rate from step 2, Dr. Johnson said.
The trial outcome index of the quality-of-life tool also showed
absolutely no difference in the two arms, Dr. Johnson said.
He noted that toxicity was pretty much as anticipated and
commensurate with previous trials done by ECOG.
After etoposide/cisplatin induction, the incidence of grade 3-4
hematologic toxicity was as follows: leukopenia occurred in
approximately 40% of patients, neutropenia was seen in close to 70%,
the incidence of thrombocytopenia was only 8.5%, and anemia occurred
in less than 10% of patients.
In step 2, grade 3-4 hematologic toxicity seen in the topotecan arm
included leukopenia in nearly 60%, neutropenia in 80%,
thrombocytopenia in about a third of patients, and anemia in less
GI toxicities were relatively rare in both groups, Dr.
Johnson said. Hepatic, pulmonary, and cardiac toxicities were
likewise quite rare.
The study also looked at the incidence of the central nervous system
(CNS) as the initial sites of recurrence largely because
theres been some speculation that topotecan has some perhaps
magical impact on CNS disease, Dr. Johnson said. There
were actually more CNS sites of recurrence in the topotecan arm in
comparison to the observation arm.
Corey Langer, MD, of the Fox Chase Cancer Center, and co-chair of the
ASCO session, told ONI that the study was a major
disappointment, a test of consolidation with a putative
non-cross-resistant regimen that didnt really show any true benefit.
The true arbiter of benefit in extensive disease remains survival,
Dr. Langer said. We look at response, we look at time to
progression, but ultimately we want survivalwe want to break
this 12-month survival bar, he commented.
Like Dr. Johnson, Dr. Langer speculated that it may be better to give
the topoisomerase-I inhibitor prior to the topoisomerase-II
inhibitor, yet he acknowledged that the safety of this sequencing
needs to be established.
The other possibility is that a lot of these patients, although
they ostensibly had responded or had stable disease, in fact really
had less resistant clones at the time they started topotecan,
Dr. Langer said.
Alan Sandler, MD, of Vanderbilt University, expressed his
disappointment with another aspect of the study in an ONI interview.
The other thing that was disconcerting was that the overall
response rate to the induction was very low. People would expect 50%
or 60% response rates to the two-drug combination.