Topotecan After Standard Therapy Fails to Improve Overall Survival in Small-Cell Lung Cancer Patients

NEW ORLEANS—Topotecan (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 regimen—cisplatin 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 = .71).

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 than 22%.

“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 there’s 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 didn’t 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 survival—we 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.”