SWOG 0004 - Pilot Study Of Tirapazamine (TPZ) Plus Cisplatin/Etoposide (PE) And Concurrent Thoracic Radiotherapy (RT) In Limited Small Cell Lung Cancer (LSCLC)

Reviewer: Heather Jones, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 22, 2002

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Presenter: Quynh-Thu Le
Presenter's Affiliation: SWOG
Type of Session: Scientific

Background

    Tirapazamine (TPZ)is a novel hypoxic cytotoxin that has been proven to increase cell killing in hypoxic cells. TPZ has also demonstrated synergistic increases in the effectiveness of chemotherapy and radiation therapy (RT) in both preclinical and clinical studies. The standard treatment for small cell lung cancer is the use of cisplatin and Etoposide with concurrent thoracic RT. This study evaluates the feasibility and toxicity of adding TPZ to the standard treatment.

Materials and Methods

  • The concurrent phase of therapy consisted of 2 cycles of P (50 mg/m2, d1, 8, 29, 36) and E (50 mg/m2 d1-5, 29-33) and once-daily thoracic RT (1.8-2 Gy/fx to 61 Gy)
  • TPZ was given at 260 mg/m2 1 hour prior to each cisplatin dose with planned dose escalation in the absence of protocol-defined dose-limiting toxicity (DLT), = 33% esophagitis
  • Consolidation consisted of 2 cycles of TPZ (330 mg/m2), P (60 mg/m2) and E (120 mg/m2, d1-3) on weeks 11 and 14. P
  • Patients with a complete response received prophylactic cranial irradiation

Results

  • 30 patients were enrolled at a TPZ dose of 260 mg/m2.
  • DLT was grade 3-4 esophagitis in 9 of 26 assessable patients (35%). Febrile neutropenia occurred in 15%
  • There were 2 treatment-related deaths, 1 from neutropenic fever during the concurrent phase and 1 from respiratory infection during consolidation
  • The toxicity profile of this study was comparable to that of SWOG S9713. The response rate was increase by 20% with the addition of TPZ

Author's Conclusions

    The dose limiting toxicity was observed at a TPZ dose of 260 mg/m2, consisting of esophagitis. TPZ may have increased vomiting and febrile neutropenia. Further study of this TPZ regimen is warranted

Clinical/Scientific Implications

    Although current therapy has a significant effect on the natural history of this disease, the number of patients cured remains frustratingly small. Clearly the procurement of new active agents for managing the disease as well as the identification of better ways of using presently available therapy is needed. This study demonstrates that Tirapazamine can be added to the standard therapy with comparable toxicity to standard therapy. One looks forward to the efficacy studies. One would also hope that more information on muscle cramping will be released as this is a known side effect of Tirapazamine therapy.

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