Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

Abstract

Poor outcome of treatment in advanced cervix carcinoma has been shown to be associated with poor oxygenation of the primary tumour. Hypoxia may cause radiation resistance and promote lymph-node metastasis. The purpose of the study reported here was to investigate whether hypoxia-induced treatment failure in advanced cervix carcinoma is primarily a result of hypoxia-induced radiation resistance or the presence of hypoxia-induced lymph-node metastases at the start of treatment. Thirty-two patients with squamous cell carcinoma of the uterine cervix were included in the study. Radiation therapy was given with curative intent as combined external irradiation and endocavitary brachytherapy. The oxygenation status of the primary tumour was measured prior to treatment using the Eppendorf PO2 Histograph. Pelvic and para-aortal lymph-node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. The primary tumours of the patients with metastases (n = 18) were significantly more poorly oxygenated than those of the patients without metastases (n = 14). Multivariate Cox regression analyses involving biological and clinical parameters identified the tumour subvolume having PO2 values below 5 mmHg (HSV (pO2 < 5 mmHg) as the only significant, independent prognostic factor for locoregional control, disease-free survival and overall survival. The probabilities of locoregional control, disease-free survival and overall survival were significantly lower for the patients with HSV (PO2 < 5 mmHg) above the median value than for those with HSV (PO2 < 5 mmHg) below the median value. On the other hand, the outcome of treatment was not significantly different for the patients with metastases and the patients without metastases at the start of treatment, irrespective of clinical end-point. Consequently, treatment failure was primarily a result of hypoxia-induced radiation resistance rather than hypoxia-induced lymph-node metastasis, suggesting that novel treatment strategies aiming at improving tumour oxygenation or enhancing the radiation sensitivity of hypoxic tumour cells may prove beneficial in attempts to improve the radiation therapy of advanced cervix carcinoma.

References 29

1. 1.

   Brizel D. M., Rosner G. L., Prosnitz L. R., Dewhirst M. W. Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases. Int J Radiat Oncol Biol Phys. 1995;32(4):1121-1125.

   Not in our library10.1016/0360-3016(95)00106-9

2. 2.

   Brown J. M., Giaccia A. J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 1998;58(7):1408-1416.

   Not in our library

3. 3.

   Bush R. S. The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys. 1986;12(11):2047-2050.

   Not in our library10.1016/0360-3016(86)90146-x

4. 4.

   Coleman C. N. Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity. J Natl Cancer Inst. 1988;80(5):310-317.

   Not in our library10.1093/jnci/80.5.310

5. 5.

   Cooper R. A., West C. M., Logue J. P., Davidson S. E., Miller A., Roberts S., Statford I. J., Honess D. J., Hunter R. D. Changes in oxygenation during radiotherapy in carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 1999;45(1):119-126.

   Not in our library10.1016/s0360-3016(99)00093-0

6. 6.

   Dunst J., Hänsgen G., Lautenschläger C., Füchsel G., Becker A. Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon. Int J Radiat Oncol Biol Phys. 1999;43(2):367-373.

   Not in our library10.1016/s0360-3016(98)00361-7

7. 7.

   Fagundes H., Perez C. A., Grigsby P. W., Lockett M. A. Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1992;24(2):197-204.

   Not in our library10.1016/0360-3016(92)90671-4

8. 8.

   Fyles A. W., Milosevic M., Pintilie M., Hill R. P. Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys. 1998;42(4):751-753.

   Not in our library10.1016/s0360-3016(98)00307-1

9. 9.

   Fyles A. W., Milosevic M., Wong R., Kavanagh M. C., Pintilie M., Sun A., Chapman W., Levin W., Manchul L., Keane T. J. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998;48(2):149-156.

   Not in our library10.1016/s0167-8140(98)00044-9

10. 10.

    Hill R. P. Tumor progression: potential role of unstable genomic changes. Cancer Metastasis Rev. 1990;9(2):137-147.

    Not in our library10.1007/bf00046340

11. 11.

    Hockel M., Schlenger K., Aral B., Mitze M., Schaffer U., Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56(19):4509-4515.

    Not in our library

12. 12.

    Horsman M. R. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. A review. Acta Oncol. 1995;34(5):571-587.

    Not in our library10.3109/02841869509094031

13. 13.

    Höckel M., Knoop C., Schlenger K., Vorndran B., Baussmann E., Mitze M., Knapstein P. G., Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26(1):45-50.

    Not in our library10.1016/0167-8140(93)90025-4

14. 14.

    Höckel M., Schlenger K., Knoop C., Vaupel P. Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res. 1991;51(22):6098-6102.

    Not in our library

15. 15.

    Jager G. J., Barentsz J. O., Oosterhof G. O., Witjes J. A., Ruijs S. J. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared-rapid gradient-echo sequence. AJR Am J Roentgenol. 1996;167(6):1503-1507.

    Not in our library10.2214/ajr.167.6.8956585

16. 16.

    Leibel S. A., Fuks Z. Is local failure a cause of or a marker for metastatic dissemination in carcinoma of the uterine cervix? Int J Radiat Oncol Biol Phys. 1992;24(2):377-387.

    Not in our library10.1016/0360-3016(92)90694-d

17. 17.

    Overgaard J., Bentzen S. M., Kolstad P., Kjoerstad K., Davy M., Bertelsen K., Mäntyla M., Frankendal B., Skryten A., Löftquist I. Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1989;16(4):1069-1072.

    Not in our library10.1016/0360-3016(89)90918-8

18. 18.

    Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res. 1994;6(10-11):509-518.

    Not in our library

19. 19.

    Rofstad E. K., Danielsen T. Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer. 1999;80(11):1697-1707.

    Not in our library10.1038/sj.bjc.6690586

20. 20.

    Rofstad E. K. Microenvironment-induced cancer metastasis. Int J Radiat Biol. 2000;76(5):589-605.

    Not in our library10.1080/095530000138259

21. 21.

    Schwickert G., Walenta S., Sundfør K., Rofstad E. K., Mueller-Klieser W. Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res. 1995;55(21):4757-4759.

    Not in our library

22. 22.

    Stadler P., Becker A., Feldmann H. J., Hänsgen G., Dunst J., Würschmidt F., Molls M. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 1999;44(4):749-754.

    Not in our library10.1016/s0360-3016(99)00115-7

23. 23.

    Stone H. B., Brown J. M., Phillips T. L., Sutherland R. M. Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held November 19-20, 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res. 1993;136(3):422-434.

    Not in our library

24. 24.

    Sundfør K., Lyng H., Kongsgård U. L., Tropé C., Rofstad E. K. Polarographic measurement of pO2 in cervix carcinoma. Gynecol Oncol. 1997;64(2):230-236.

    Not in our library10.1006/gyno.1996.4571

25. 25.
    Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix · 1998

    No notice
26. 26.

    Sundfør K., Lyng H., Tropé C. G., Rofstad E. K. Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization. Radiother Oncol. 2000;54(2):101-107.

    Not in our library10.1016/s0167-8140(99)00175-9

27. 27.

    Vaupel P. Oxygenation of human tumors. Strahlenther Onkol. 1990;166(6):377-386.

    Not in our library

28. 28.

    Wong R. K., Fyles A., Milosevic M., Pintilie M., Hill R. P. Heterogeneity of polarographic oxygen tension measurements in cervix cancer: an evaluation of within and between tumor variability, probe position, and track depth. Int J Radiat Oncol Biol Phys. 1997;39(2):405-412.

    Not in our library10.1016/s0360-3016(97)00328-3

29. 29.

    Young S. D., Marshall R. S., Hill R. P. Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci U S A. 1988;85(24):9533-9537.

    Not in our library10.1073/pnas.85.24.9533

Cited by papers we hold 1

• The lncRNA PVT1 Contributes to the Cervical Cancer Phenotype and Associates with Poor Patient Prognosis · 2016
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.