A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients

Our plain-English summary of A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients, by C. Huisman, P.E. Postmus, G. Giaccone, et al (Annals of Oncology, 2001).

The study

• Authors: C. Huisman, P.E. Postmus, G. Giaccone, E.F. Smit
• Journal: Annals of Oncology
• Published: 2001;12(11):1567-73
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: The topoisomerase I inhibitor topotecan (T) and the topoisomerase II inhibitor etoposide (E) are active drugs in lung cancer. The complementary functions of their targets may suggest benefit from the combined use of these agents but drug scheduling has been shown to play a critical role in preclinical models. To establish the optimal schedule and assess the impact of sequential administration of the combination of T and E, we conducted a dose finding study of sequential intravenous T and E in a four-weekly-schedule in relapsed lung cancer patients.

Patients And Methods: The importance of drug sequence was assessed in consecutive patients throughout all dose levels; patients received in the first course either T followed by E (the TE group: T on days 1-3 and E on days 4-6) or E before T (the ET group: F on days 1-3 and Ton days 4-6). The sequence of Tand E was alternated in the successive courses. In this crossover design, each patient served as his own control for analysis of hematological toxicity in which TE sequence was compared to that of the ET sequence. Moreover, hematological toxicity after the first course was compared between the TE and the ET groups. The starting dose was T/E 0.75/75 mg/m2 at dose level 1and dose escalation was planned to T/E 1.00/75 mg/nm2 at dose level 2, T/E 1.00/100 mg/m2 at dose level 3, T/E 1.25/100 mg/m2 at dose level 4 and T/E 1.50/100 mg/m2 at dose level 5. Nineteen patients (small-cell lung cancer 7, non-small-cell lung cancer 11, mesothelioma 1 patient) were included.

Results: The principal toxicity was myelosuppression, primarily neutropenia and thrombocytopenia. At dose level 3 several grade 4 toxicities were observed. DLT (febrile neutropenia) occurred in two patients, one in the TE and one in the ET group and precluded further dose escalation. There was no significant difference in WBC and platelet nadirs during the first course between the TE and the ET group. The influence of the sequence of administration of topotecan and etoposide was calculated by comparing the nadir values of cycles I and II for each patient. For none of the dose levels, a significant sequence-dependent effect could be detected. The MTD was reached at the doses of 100 mg/m2 topotecan and 75 mg/m2 etoposide. No objective responses were seen.

Conclusion: Although the combined use of topoisomerase I and II inhibitors is attractive on theoretical grounds, excessive myelosuppression prevents substantial dose escalation.

In plain English

This was a phase I (dose-finding) study of two chemotherapy drugs, topotecan and etoposide, given into a vein one after the other in four-week cycles. At University Hospital Vrije Universiteit in Amsterdam, 19 patients whose cancer had progressed on or returned after earlier chemotherapy were enrolled between November 1998 and July 2000: 7 with small-cell lung cancer, 11 with non-small-cell lung cancer and 1 with mesothelioma. The order of the two drugs was meant to switch each cycle, but it was not switched for four patients. The study did not look at asbestos exposure. The main side effect was a fall in blood counts. Two patients at dose level 3 developed fever with low white cell counts, and the dose was not raised further. The authors set the maximum tolerated dose at 1.00 mg/m2 topotecan and 75 mg/m2 etoposide. Among 11 patients who could be compared, the drug order made no statistically significant difference to the lowest blood counts. No patient had an objective tumour response, and nine patients had stable disease. The authors concluded that severe suppression of blood counts prevents substantial dose increases with this combination.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I dose-finding study with a cross-over design (the order of the two drugs was planned to alternate between courses)
• Who was studied: 19 patients (10 male, 9 female) with lung cancer that had progressed on or relapsed after previous chemotherapy: 7 small-cell lung cancer, 11 non-small-cell lung cancer, 1 mesothelioma. Enrolled November 1998 to July 2000 at University Hospital Vrije Universiteit, Amsterdam
• Exposure: No asbestos exposure was studied. Patients received intravenous topotecan (30 minutes daily for three days) and intravenous etoposide (one hour daily for three days) in sequence, every four weeks. The order was planned to alternate between courses. Planned dose levels (topotecan/etoposide, mg/m2) were 0.75/75, 1.00/75, 1.00/100, 1.25/100 and 1.50/100. Escalation stopped at level 3 (1.00/100)
• Main results:
  • The planned alternation of drug order was not performed in four patients. Two patients received dose level 1 instead of their planned levels without alternation, and two more at dose levels 2 and 3 also did not have the sequence alternated. These patients were excluded from the sequence comparison
  • Dose-limiting toxicity (febrile neutropenia) occurred in two patients at dose level 3, one in each sequence group, and prevented further dose escalation
  • The authors set the maximum tolerated dose at topotecan 1.00 mg/m2 and etoposide 75 mg/m2, each given over three days
  • During the first course there was no significant difference in white blood cell and platelet nadirs (lowest counts) between patients given topotecan first and those given etoposide first
  • In the 11 patients who could serve as their own controls, drug order had no significant effect on nadirs (P-values 0.36 for white blood cells and 0.86 for platelets)
  • In all 11 of these patients, white blood cell nadirs were higher in the second course than in the first (P 0.006). Platelet nadirs were higher in the second course in 9 of 11 (P 0.068)
  • Grade 3-4 blood toxicity occurred in 50% of patients at dose level 1, 60% at dose level 2 and 83% at dose level 3. No treatment-related deaths occurred
  • No objective responses were seen. Nine patients had stable disease. Median time to progression was eight weeks, and median survival was 18 weeks (range 4 to 60 weeks)
• The authors' conclusion: The authors concluded that, although combining topoisomerase I and II inhibitors is attractive on theoretical grounds, excessive myelosuppression prevents substantial dose escalation. They could not establish relevant sequence-dependent toxic effects
• Limitations the authors state:
  • No pharmacokinetic analysis was performed
  • Too few patients received three alternating courses to analyse blood count nadirs after the third course
  • Patients were extensively pretreated, which the authors suggest may explain the lack of responses compared with studies in untreated small-cell lung cancer

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, Neutropenia.

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