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Pneumologie 2004; 58(12): 845-849
DOI: 10.1055/s-2004-830056
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Tirapazamine, Cisplatin und Gemcitabine beim fortgeschrittenen nichtkleinzelligen Bronchialkarzinom - eine Phase II-Studie

Phase II-Trial of Tirapazamine in Combination with Cisplatin and Gemcitabine in Patients with Advanced Non-Small-Cell-Lung-Cancer (NSCLC)M.  Reck1 , J.  von Pawel2 , C.  Nimmermann2 , G.  Groth1 , U.  Gatzemeier1
  • 1Onkologischer Schwerpunkt, Krankenhaus Großhansdorf, Großhansdorf (Leitung: Dr. U. Gatzemeier)
  • 2Onkologische Abteilung, Asklepios Kliniken Gauting, München (Leitung: Dr. von Pawel)
Diese Studie wurde unterstützt von der Firma Sanofi Synthelabo Deutschland.DanksagungFür die Erstellung des Manuskriptes danken wir Fr. Waltraud Krumm.
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Publication History

Eingang: 13. Juli 2004

Annahme: 4. August 2004

Publication Date:
14 December 2004 (online)

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Zusammenfassung

Trotz Fortschritte in der Chemotherapie des fortgeschrittenen und metastasierten nichtkleinzelligen Bronchialkarzinoms (NSCLC) ist die Prognose mit einer 5-Jahres-Überlebensrate von 2 - 5 % denkbar schlecht. Aufgrund des hohen Anteils von hypoxischen Zellen in soliden Tumoren bietet der Einsatz von Substanzen mit Wirksamkeit im hypoxischen Milieu wie dem Benzotriazinderivat Tirapazamine (SR 259 075) eine Möglichkeit, die Resultate zu verbessern. Wir behandelten 45 Patienten mit einem fortgeschrittenen oder metastasierten nichtkleinzelligen Bronchialkarzinom (Stadium IIIb: 20 Patienten), (Stadium IV: 25 Patienten) mit der Kombination Tirapazamine 330 mg/m2 (Tag 1), Cisplatin 75 mg/m2 (Tag 1), Gemcitabine 1250 mg/m2 (Tag 1 und 8) alle 3 Wochen. Bei einer Ansprechrate von 40 % beobachteten wir ein medianes progressionsfreies Überleben von 6,7 Monaten (4,8 - 8,1 Monate) und ein medianes Überleben von 8,1 Monaten (7,5 - 12,5 Monate) mit einer 1-Jahres-Überlebensrate von 35 %. Die hämatologische und nicht-hämatologische Toxizität war moderat (Neutropenie CTC Grad 3 und 4: 20 %, Thrombopenie CTC Grad 3 und 4: 16 %, Übelkeit und Erbrechen CTC Grad 3: 5 %). Die Kombination von Cisplatin/Gemcitabine mit Tirapazamine war gut durchführbar und zeigte vergleichbare Ergebnisse zur kombinierten Chemotherapie beim NSCLC. Die Ergebnisse einer anschließenden Phase III-Studie zur Bewertung des Stellenwertes des Tirapazamine stehen aus.

Abstract

Despite improvements in chemotherapy of advanced and metastatic Non-Small-Cell-Lung-Cancer (NSCLC) the prognosis of these patients still remains poor with a 5-year-survival of 2 to 5 %. Due to the high level of hypoxic cells in solid tumors agents with activity in hypoxic milieu as the Benzotriazine compound Tirapazamine (SR 259 075) might improve the therapeutic results. We treated 45 patients with advanced or metastatic Non-Small-Cell-Lung-Cancer (stage IIIb: 20 patients, stage IV: 25 patients) with the combination TPZ 330 mg/m2 (day 1), Cisplatin 75 mg/m2 (day 1) and Gemcitabine 1250 mg/m2 (day 1 and 8) every 3 weeks. With a response rate of 40 % median progression free survival was 6.7 months (4.8 - 8.1 months) and median survival was 8.1 months (7.5 - 12.5 months), (1-year-survival: 35 %). Hematologic and non-hematologic toxicity was moderate (neutropenia CTC grade 3 and 4: 20 %, thrombocytopenia CTC grade 3 and 4: 16 %, nausea and vomiting CTC 3: 5 %). Treatment of advanced and metastatic NSCLC with TPZ in combination with Gemcitabine/Cisplatin was well feasible and showed results recording to currently published data. The results of a following phase III-trial are awaited.

Literatur

  • 1 Globocan-2000. www-dep.iarc.fr/globocan/globocan.html. 
  • 2 Matthews M J, Gordon P R. Morphology of Pulmonary and Pleural Malignancies. In: Strauss MJ (Hrsg.). Lung Cancer: Clinical Diagnosis and Treatment. New York: Grune und Stratton 1977: 49-69
    Search in Google Scholar
  • 3 Ginsberg R J, Goldberg M, Waters P E. Surgery in Non-Small-Cell-Lung-Cancer. In: Roth JA, Ruckdeschel JC, Weisenburger TH (Hrsg.). Thoracic Oncology (Edition 2). Philadelphia: W.B. Thaunders Company 1995: 124-146
    Search in Google Scholar
  • 4 Non-Small-Cell-Lung-Cancer Collaborative Group . Chemotherapy in non-small-cell-lung cancer: Meta-Analysis using updated data on individual patients from 52 randomized clinical trials.  Br Med J. 1995;  311 899-909
    PubMedSearch in Google Scholar
  • 5 Stephens J, Fairlamb D, Gower N. et al . The Big Lung Trial (BLT): Determining the value of Cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the supportive care setting.  Proc Am Soc Clin Oncol. 2002;  21 Abstr. 1161-1161
    PubMedSearch in Google Scholar
  • 6 Schiller J H, Harrington D, Bellany C P. et al . Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.  N Engl J Med. 2002;  346 92-98
    CrossrefPubMedSearch in Google Scholar
  • 7 Kelly K, Crawley J, Bunn Jr P A. et al . Randomized phase III trial of Paclitaxel plus Carboplatin versus Vinorelbine plus Cisplatin in the treatment of patients with advanced non-small cell lung cancer: A Southwest Oncology Group Trial.  J Clin Oncol. 2001;  19 3210-3218
    PubMedSearch in Google Scholar
  • 8 Scagliotti G V, DeMarinis F, Rinaldi M. et al . Phase III randomized trial comparing three platinum-based doublets in advanced non-small cell lung cancer.  J Clin Oncol. 2002;  20 4285-4291
    CrossrefPubMedSearch in Google Scholar
  • 9 Denekamp J, Fowler J F, Dische S. The proportion of hypoxic cells in a human tumor.  Int J Radiat Oncol Biol Phys. 1977;  2 1227-1228
    PubMedSearch in Google Scholar
  • 10 Moulder J E, Rockwell S. Tumor Hypoxia: Its impact on cancer therapy.  Cancer Metast Rev. 1987;  5 313-341
    CrossrefPubMedSearch in Google Scholar
  • 11 Vaupel P W, Hockel M. Oxygenation status of human tumors: A reappraisal using computerized pO2 histography. In: Vaupel PW, Kelleher DK, Gunderoth M (Hrsg.). Tumor Oxygenation. New York: Gustav Fischer 1995: 220-232
    Search in Google Scholar
  • 12 Gatenby R A, Coia L A, Richter M P. et al . Oxygen tension in human tumors: In vivo mapping using CT-guided probes.  Radiology. 1985;  156 211-214
    PubMedSearch in Google Scholar
  • 13 Chaplin D J, Durand R E, Olive P L. Acute Hypoxia in Tumors: Implifications for modifiers of radiation effects.  Int J Radiat Oncol Biol Phys. 1986;  12 1279-1282
    PubMedSearch in Google Scholar
  • 14 Brown J M. Tumor Hypoxia, Drug Resistance and Metastases.  J Natl Cancer Inst. 1990;  82 338-339
    PubMedSearch in Google Scholar
  • 15 Zeman E M, Brown J M, Lemon M J. et al . SR-4233: A new bioreductive agent with high selective toxicity for hypoxic mammalian cells.  Int J Radiat Oncology Biol Phys. 1986;  12 1239-1242
    PubMedSearch in Google Scholar
  • 16 Baker M A, Zeman E M, Hirst V K. et al . Metabolism of SR-4233 by Chinese Hamster Ovary Cells: basis of selective hypoxic cells and toxicity.  Cancer Res. 1988;  48 5947-5952
    PubMedSearch in Google Scholar
  • 17 Cahill A, White I NH. Reductive Metabolism of 3-Amino-1,2,4-Benzotriacine-1,4-Dioxide (SR-4233) and the induction of unscheduled DNA-Synthesis in red and human derived cell lines.  Carcinogenesis. 1990;  11 1407-1411
    PubMedSearch in Google Scholar
  • 18 Keohane A, Godden J, Stratford I J. et al . The effects of three bioreductive drugs (Mitomycin C, RSU-1069 and SR-4233) on cell lines selected for their sensitivity to Mitomycin C or ionizing radiation.  Br J Cancer. 1990;  61 722-726
    PubMedSearch in Google Scholar
  • 19 Tocher J H, Virk N S, Edwards D E. DNA-Damaging effects and Voltametric Studies on the hypoxic cytotoxin 3-Amino-1,2,4-Benzotriacine-1,4-Dioxide, SR-4233, as a function of pH.  Biochem Pharmacol. 1990;  40 1405-1410
    CrossrefPubMedSearch in Google Scholar
  • 20 Herman T S, Teicher B A, Coleman C N. Interaction of SR-4233 with Hyperthermia and Radiation in the FSaIIC Murine Fibrosarcoma Tumor System in vitro and in vivo.  Cancer Res. 1990;  50 5055-5059
    PubMedSearch in Google Scholar
  • 21 Brown J M. SR-4233 (Tirapazamine): A new anticancer drug exploration hypoxia in solid tumor.  Br J Cancer. 1993;  67 1163-1170
    PubMedSearch in Google Scholar
  • 22 Holden S A, Teicher B A, Ara G. et al . Enhancement of alkylating agent activity by SR-4233 in the FSaIIC Murine Sarcoma.  J Natl Cancer Inst. 1992;  84 187-193
    PubMedSearch in Google Scholar
  • 23 Dorie M J, Brown J M. Potentiation of the anti-cancer effect of Cisplatin by the hypoxic Cytotoxin Tirapazamine. In: Vaupel PW, Kelleher DK, Gunderoth M (Hrsg.). Tumor Oxygenation. Stuttgart: Gustav Fischer Verlag 1995: 125-135
    Search in Google Scholar
  • 24 Siemann D W, Hinchman C A. Potentiation of Cisplatin activity by the bioreductive agent Tirapazamine.  Radiother Oncol. 1998;  47 215-220
    CrossrefPubMedSearch in Google Scholar
  • 25 Rodriguez G I, Cathcart D M, Devin J A. et al . A Phase I/II Dose Escalation Study of intravenously administered Tirapazamine in combination with Cisplatin, in subjects with non-small cell lung cancer.  Proc Am Soc Clin Oncol. 1996;  15 Abstract 1144-1144
    PubMedSearch in Google Scholar
  • 26 Treat J, Belani C, Johnson E. et al . A phase II multicentre study of intravenously administered Tirapazamine plus Cisplatin in subjects with non-small cell lung cancer: A phase I/II study amended for phase II investigational sites.  Proc Am Soc Clin Oncol. 1998;  17 Abstract 472a-472a
    PubMedSearch in Google Scholar
  • 27 Miller V A, Ng K K. et al . A phase II study of the combination of the novel bioreductive agent Tirapazamine with Cisplatin in patients with advanced non-small cell lung cancer.  Ann Oncol. 1997;  8 1269-1271
    CrossrefPubMedSearch in Google Scholar
  • 28 Treat J, Johnson E, Langer C. et al . Tirapazamine with Cisplatin in patients with advanced non-small cell lung cancer.  J Clin Oncol. 1998;  16 3524-3527
    PubMedSearch in Google Scholar
  • 29 Pawel J von, Römeling R von, Gatzemeier U. et al . Tirapazamine plus Cisplatin versus Cisplatin in advanced non-small cell lung cancer: A report of the international CATAPULT I study group.  J Clin Oncol. 2000;  18 1351-1359
    PubMedSearch in Google Scholar
  • 30 National Cancer Institute .Cancer Therapy Evaluation Programmes. Common Toxicity Criteria-Version 2.0. http://ctep.cancer.gov/reporting/ctc.html. 
  • 31 Nimmermann C, Pawel J von, Gatzemeier U. Phase I trial of Tirapazamine in combination with Cisplatin and Gemcitabine in patients with advanced non-small cell lung cancer.  Proc Am Soc Clin Oncol. 2002;  21 Abstract 1335-1335
    PubMedSearch in Google Scholar
  • 32 Shephard F, Koschel G, Pawel J von. et al . Comparison of Tirazone (Tirapazamine) and Cisplatin versus Etoposide and Cisplatin in advanced non-small cell lung cancer: Final results of the international Phase III CATAPULT II Trial.  Lung Cancer. 2000;  29 Suppl 1 28
    PubMedSearch in Google Scholar
  • 33 Williamsen S K, Crowly J J, Lara P N. et al . S0003: Paclitaxel/Carboplatin (PC) versus PC and Tirapazamine (PCT) in advanced non-small cell lung cancer. A phase III Southwest Oncology Group (SWOG) Trial.  Proc Am Soc Clin Oncol. 2003;  Abstract 2502-2502
    PubMedSearch in Google Scholar
  • 34 Rischin D, Peters L, Smith J. et al . Preliminary Results Of TROG 98.02-A randomized phase II study of 5-Fluoruracil, Cisplatin and radiation versus Tirapazamine, Cisplatin and Radiation for advanced Squamous Cell Carcinoma of the Head and Neck.  Proc Am Soc Clin Oncol. 2003;  Abstract 1992-1992
    PubMedSearch in Google Scholar

Dr. Martin Reck

Onkologischer Schwerpunkt, Krankenhaus Großhansdorf

Wöhrendamm 80

22927 Großhansdorf

Email: dr.martin.reck@web.de