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 pO2values below 5mmHg (HSV (pO2< 5mmHg) as the only significant, independent prognostic factor for locoregional control, disease-free survival and overall survival. The probabillities 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. © 2000 Cancer Research Campaign
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References
Brizel DM, Rosner GL, Prosnitz LR and Dewhirst MW (1995) Patterns and variability of tumour oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases. Int J Radiat Oncol Biol Phys 32: 1121–1125
Brown JM and Giaccia AJ (1998) The unique physiology of solid tumours: opportunities (and problems) for cancer therapy. Cancer Res 58: 1408–1416
Bush RS (1986) The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys 12: 2047–2050
Coleman CN (1988) Hypoxia in tumours: a paradigm for the approach to biochemical and physiologic heterogeneity. J Natl Cancer Inst 80: 310–317
Cooper RA, West CML, Logue JP, Davidson SE, Miller A, Roberts S, Stratford IJ, Honess DJ and Hunter RD (1999) Changes in oxygenation during radiotherapy in carcinoma of the cervix. Int J Radiat Oncol Biol Phys 45: 119–126
Dunst J, Hänsgen G, Lautenschläger C, Füchsel G and Becker A (1999) Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis -retinoic acid/interferon. Int J Radiat Oncol Biol Phys 43: 367–373
Fagundes H, Perez CA, Grigsby PW and Lockett MA (1992) Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 24: 197–204
Fyles AW, Milosevic M, Pintile M and Hill RP (1998 a) Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys 42: 751–753
Fyles AW, Milosevic M, Wong R, Kavanagh M-C, Pintile M, Sun A, Chapman W, Levin W, Manchul L, Keane TJ and Hill RP (1998 b) Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 48: 149–156
Hill RP (1990) Tumour progression: potential role of unstable genomic changes. Cancer Metastasis Rev 9: 137–147
Höckel M, Schlenger K, Knoop C and Vaupel P (1991) Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2tension measurements. Cancer Res 51: 6098–6102
Höckel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG and Vaupel P (1993) Intratumoural p O2predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26: 45–50
Höckel M, Schlenger K, Aral B, Mitze M, Schäffer U and Vaupel P (1996) Association between tumour hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515
Horsman MR (1995) Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. Acta Oncol 34: 571–587
Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA and Ruijs SJH (1996) Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional T1-weighted magnetization-prepared-rapid gradient-echo sequence. Am J Roentgenol 167: 1503–1507
Leibel SA and Fuks Z (1992) Is local failure a cause of or a marker for metastatic dissemination in carcinoma of the uterine cervix?. Int J Radiat Oncol Biol Phys 24: 377–380
Overgaard J, Bentzen SM, Kolstad P, Kjørstad K, Davy M, Bertelsen K, Mäntylä M, Frankendal B, Skryten A, Lövquist I, Pedersen M, Sell A and Jensen RH (1989) Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 16: 1069–1072
Overgaard J (1994) Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumours. Oncol Res 6: 509–518
Rofstad EK (2000) Microenvironment-induced cancer metastasis. Int J Radiat Biol 76: 589–605
Rofstad EK and Danielsen T (1999) Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer 80: 1697–1707
Schwickert G, Walenta S, Sundfør K, Rofstad EK and Mueller-Klieser W (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res 55: 4757–4759
Stadler P, Becker A, Feldmann HJ, Hänsgen G, Dunst J, Würschmidt F and Molls M (1999) Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys 44: 749–754
Stone HB, Brown JM, Phillips TL and Sutherland RM (1993) Oxygen in human tumours: correlations between methods of measurement and response to therapy. Radiat Res 136: 422–434
Sundfør K, Lyng H, Kongsgård U, Tropé C and Rofstad EK (1997) Polarographic measurement of p O2in cervix carcinoma. Gynecol Oncol 64: 230–236
Sundfør K, Lyng H and Rofstad EK (1998) Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Br J Cancer 78: 822–827
Sundfør K, Lyng H, Tropé CG and Rofstad EK (2000) Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumour oxygenation and vascularization. Radiother Oncol 54: 101–107
Vaupel P (1990) Oxygenation of human tumours. Strahlenther Onkol 166: 377–386
Wong RKW, Fyles A, Milosevic M, Pintile M and Hill RP (1997) Heterogeneity of polarographic oxygen tension measurements in cervix cancer: an evaluation of within and between tumour variability, probe position, and track depth. Int J Radiat Oncol Biol Phys 39: 405–412
Young SD, Marshall RS and Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumour cells. Proc Natl Acad Sci USA 85: 9533–9537
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Rofstad, E., Sundfør, K., Lyng, H. et al. 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. Br J Cancer 83, 354–359 (2000). https://doi.org/10.1054/bjoc.2000.1266
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DOI: https://doi.org/10.1054/bjoc.2000.1266
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