A 2-week pretreatment with 13-cis-retinoic acid + interferon-α-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers (original) (raw)

Abstract

Background

We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-α-2a prior to and during radiotherapy.

Patients and Methods

From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-α-2a (IFN-α-2a) as part of a phase-II protocol. cRA/IFN-α-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 × 106 IU IFN-α-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy. cRA/IFN-α-2a-treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph.

Results

In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 ± 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3±21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7±16.3 mm Hg to 27.6±19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3±2.7 mm Hg to 27.0±5.6 mm Hg (p=0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values <5 mm Hg) decreased from 44.7±17.1% to 2.0±2.5% (p=0.012, t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-α-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission.

Conclusions

Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended.

Zusammenfassung

Hintergrund

Wir haben Patientinnen mit Zervixkarzinomen vor und während einer Radiotherapie mit 13-cis-Retinsäure (cRA, Isotretinoin) und Interferon-α-2a (IFN) behandelt und den Einfluß dieser medikamentösen Zusatztherapie auf den Oxygenierungsstatus untersucht.

Patienten und Methodik

Von Juni 1995 bis April 1997 wurden 22 Patientinnen mit lokal fortgeschrittenem Plattenepithelkarzinom der Zervix (FIGO-Stadien IIB/III) im Rahmen eines Phase-II-Protokolls zusätzlich zur kurativen Radiotherapie mit cRA/IFN behandelt. Die medikamentöse Therapie begann 14 Tage vor der Bestrahlung. Die täglichen Dosen betrugen 1 mg/kg Körpergewicht cRA oral und 6 × 106 IU IFN-α-2a s. c. Nach zweiwöchiger Vorbehandlung begann die Radiotherapie (5mal wöchentlich 1.8 Gy am Referenzpunkt bis 50,4 Gy, zusätzlich 5 HDR-Fraktionen mit 7 Gy am Punkt A in wöchentlichen Abständen). Während der Radiotherapie wurden cRA und IFN in verringerter Dosis weitergegeben (täglich 0,5 mg/kg cRA oral plus 3mal wöchentlich 3×106 IU IFN-α-2a s. c.). Vor und nach der zweiwöchigen cRA/IFN-Phase sowie bei 20 Gy wurde die Tumoroxygenierung mittels pO2-Histographie gemessen.

Ergebnisse

Der mediane pO2 vor Behandlung (n=11) betrug 17,7±16,3 mm Hg. Nach zweiwöchiger cRA/IFN-Therapie war er auf 27,6±19,1 mm Hg gestiegen (nicht signifikant). Fünf Patientinnen hatten hypoxische Tumoren mit einem medianen pO2⪯10 mm Hg vor Behandlung. Bei diesen Patientinnen stieg der mediane pO2 durch die cRA/IFN-Therapie von 6,3±2,7 auf 27,0±5,6 mm Hg (p=0,004, t-Test für verbundene Stichproben). Der Anteil hypoxischer Meßwerte mit einem pO2<5 mm Hg field durch die cRA/IFN-Vorbehandlung von 44,7±17,1 auf 2,0±2,5% (p=0,012, t-Test für verbundene Stichproben). Eine komplette Remission erreichten 19/22 Patientinnen der Gesamtgruppe und 4/5 Patientinnen mit initial hypoxischen Tumoren.

Schlußfolgerungen

Eine Behandlung mit Isotretinoin und Interferon-α-2a verbessert die Oxygenierung primär hypoxischer Zervixkarzinome. Der genaue Mechanismus ist noch unklar und bedarf weiterer Klärung.

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Authors and Affiliations

  1. Department of Radiotherapy, Martin-Luther-University Halle-Wittenberg, Halle-Wittenberg, Deutschland
    Jürgen Dunst, Gabriele Hänsgen & Axel Becker
  2. Department of Pathology, Martin-Luther-University Halle-Wittenberg, Halle-Wittenberg, Deutschland
    Ulf Krause
  3. Department of Gynecology, Martin-Luther-University Halle-Wittenberg, Halle-Wittenberg, Deutschland
    Glenn Füchsel
  4. Department of Gynecology, University of Leipzig, Leipzig, Deutschland
    Uwe Köhler

Authors

  1. Jürgen Dunst
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  2. Gabriele Hänsgen
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  3. Ulf Krause
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  4. Glenn Füchsel
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  5. Uwe Köhler
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  6. Axel Becker
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Dunst, J., Hänsgen, G., Krause, U. et al. A 2-week pretreatment with 13-cis-retinoic acid + interferon-α-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers.Strahlenther Onkol 174, 571–574 (1998). https://doi.org/10.1007/BF03038294

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