Oral Topotecan Plus Supportive Care Offers Survival Benefit Compared To Supportive Care Alone

Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 6, 2005

Presenter: Mary O'Brien, MD
Presenter's Affiliation: Royal Marsden Hospital, UK
Type of Session: Scientific


  • Controlled, randomized trials are considered the gold standard of evidence-based medicine.
  • For patients (pts) with small cell lung cancer (SCLC) that has relapsed after initial chemotherapy, second-line chemotherapy has not previously been tested against best supportive care (BSC) in a controlled, randomized setting.
  • Topoisomerase I-inhibiting agents such as irinotecan and topotecan have shown activity in SCLC.
  • Oral and intravenous topotecan appear to have equivalent activity in delaying time-to-progression (TTP) after first chemotherapy in patients with SCLC.
  •  A multi-institutional trial was designed to evaluate the use of oral topotecan as second-line treatment for pts with relapsed, resistant SCLC.

Materials and Methods

  • Open-label, multicenter, randomized phase III trial
  • Eligible pts had limited stage or extensive stage SCLC that relapsed between 45-90 days after response to initial chemotherapy.
  • Pts had to have adequate hematologic and organ function, and a life expectancy of at least 3 months.
  • Pts were randomized to either : Arm 1) oral topotecan 2.3 mg/m2/day x 5 days, repeated every 21 days + BSC  or Arm 2) BSC alone                        
  • Pts were stratified based on gender, performance status, presence of liver mets, and TTP from end of prior chemo
  • Primary endpoint was overall survival (OS)
  • Secondary endpoints included response rates, TTP, quality of life, symptom control, and toxicities
  • 141 pts were enrolled over 3.5 years, from 40 centers in 11 countries
  •  Arm 1 = 71 pts and Arm 2 = 70 pts
  • Pt demographics and tumor characteristics were well-balanced between the two arms       
  • About 75% of pts in both arms had platinum-based first-line chemo                           



  • Median OS was 25.9 weeks in the topotecan + BSC arm vs. 13.9 weeks in the BSC alone arm
    • Hazard ratio was 0.64 (p=0.0104)
  • Six-month survival was 48.8% vs. 25.7%, respectively
  • Median TTP was 16.3 weeks in the topotecan + BSC group
  • Overall response rate (complete and partial) was 7%, and stable disease was achieved in 44%
  • Pts with absence of liver metastases had greater benefit from the addition of oral topotecan to BSC than did pts with liver metastases.
  • The major grade 3/4 toxicities were hematologic, specifically neutropenia, thrombocytopenia, and anemia.
  • Non-hematologic toxicities were grade 3/4 nausea, vomiting, and diarrhea.
  • There was statistically significant improvement in shortness of breath, disturbed sleep, and fatigue for pts in the topotecan + BSC group compared to the BSC alone arm.

Author's Conclusions

  • This is the first randomized trial showing a statistically significant survival benefit over BSC in relapsed SCLC.
  • Oral topotecan and BSC reduced the risk of dying from disease by almost 40%, giving a hazard ratio of 0.64.
  • This agent is well tolerated in the majority of pts.
  • It helps to reduce symptoms of disease and thereby improves quality of life over BSC alone. 

Clinical/Scientific Implications
This study shows great clinical promise for the use of the topoisomerase I inhibitor topotecan in patients with relapsed, refractory small cell lung cancer (SCLC). This is a patient population that traditionally has suffered from very poor survival outcomes, with few effective options following initial treatment and disease progression. While platinum-based therapies represent the most popular first-line approach, there is no clear consensus on second-line chemotherapy regimens. Unfortunately, anti-cancer agents have shown very little promise in successfully and durably fighting this aggressive disease. For these reasons, many relapsed SCLC patients are often considered "beyond therapy", and instead are offered best supportive care (BSC), with the goal of providing them comfort as their inevitably fatal disease progresses onward. This trial demonstrates a statistically significant survival benefit over BSC alone, as well as a clinically meaningful improvement in patients' quality of life. Most importantly, it demonstrates that there is an options for patients with relapsed SCLC, and gives some hope that perhaps there are more options out there, awaiting further study. Until then, oral topotecan should be strongly considered in the management of these patients.