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

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 x 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.