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Association between Tumor Hypoxia and Malignant Progression in Advanced Cancer of the Uterine Cervix¹

Department of Obstetrics and Gynecology [M. H., K. S., B. A., U. S.] and the Institutes of Pathology [M. M.] and Physiology and Pathophysiology [P. V.], University of Mainz Medical School, 55101 Mainz, Germany

Experimental tumors contain a significant fraction of microregions that are chronically or transiently hypoxic. Experimental evidence showing that hypoxia (and subsequent reoxyenation) may have a profound impact on malignant progression and on responsiveness to therapy is growing. The clinical relevance of tumor oxygenation in human solid malignancies is under investigation.

We have developed and validated a clinically applicable method for measurement of tumor oxygenation in locally advanced cancer of the uterine cervix using a computerized polarographic electrode system. Applying this procedure in patients with cervical cancers 3 cm in diameter, who gave informed consent, we have been studying the clinical relevance of tumor oxygenation prospectively since 1989.

As of June 1995, 103 patients with advanced cancers of the uterine cervix [Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stages Ib, bulky (n = 13), IIa and IIb (n = 51), IIIa and IIIb (n = 34), and IVa and IVb (n = 5)] had entered the study. Fifty % of the patients had carcinomas with median pO₂ readings <10 mm Hg, referred to as hypoxic tumors.

Tumor oxygenation was found to be independent of various patient demographics and also of pretreatment tumor characteristics, such as clinical tumor stage and size, histological type, and differentiation. However, histopathological examination of the surgical specimens following radical tumor resection in 47 patients showed that low-pO₂ tumors exhibited larger tumor extensions and more frequent (occult) parametrial spread, as well as lymph-vascular space involvement, compared to well-oxygenated tumors of similar clinical stage and size. Forty-two patients completing primary radiation therapy and 47 patients who underwent radical surgery were analyzed for treatment outcome after a median observation period of 28 months (range, 3–76 months). Patients with hypoxic tumors had significantly worse disease-free and overall survival probabilities compared to patients with nonhypoxic tumors. Cox regession analysis identified tumor oxygenation and FIGO stage as the most important independent prognostic factors. The poorer outcome of the patients with hypoxic tumors was mainly due to locoregional failures with and without distant metastases, irrespective of whether surgery or radiation was applied as primary treatment.

Tumor oxygenation as measured with a standardized polarographic method proved to be a powerful new pretherapeutic prognostic parameter providing important information on malignant progression in terms of extracervical tumor spread and radioresistance in advanced cervical cancers.

¹ Supported by Deutsche Krebshilfe Grant M 40/91/Va 1.

² To whom requests for reprints should be addressed, at Universitätsfrauenklinik. Langenbeckstrasse 1, D-55101 Mainz, Germany.

Received 4/ 5/96. Accepted 8/16/96.

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				L. Harrison and K. Blackwell Hypoxia and Anemia: Factors in Decreased Sensitivity to Radiation Therapy and Chemotherapy? Oncologist, November 1, 2004; 9(suppl_5): 31 - 40. [Abstract] [Full Text] [PDF]

				Y. Chen, G. Shi, W. Xia, C. Kong, S. Zhao, A. F. Gaw, E. Y. Chen, G. P. Yang, A. J. Giaccia, Q.-T. Le, et al. Identification of Hypoxia-Regulated Proteins in Head and Neck Cancer by Proteomic and Tissue Array Profiling Cancer Res., October 15, 2004; 64(20): 7302 - 7310. [Abstract] [Full Text] [PDF]

				T. Lofstedt, A. Jogi, M. Sigvardsson, K. Gradin, L. Poellinger, S. Pahlman, and H. Axelson Induction of ID2 Expression by Hypoxia-inducible Factor-1: A ROLE IN DEDIFFERENTIATION OF HYPOXIC NEUROBLASTOMA CELLS J. Biol. Chem., September 17, 2004; 279(38): 39223 - 39231. [Abstract] [Full Text] [PDF]

				T. Mikuni, G. He, S. Petryakov, M. M. Fallouh, Y. Deng, R. Ishihara, P. Kuppusamy, M. Tatsuta, and J. L. Zweier In vivo Detection of Gastric Cancer in Rats by Electron Paramagnetic Resonance Imaging Cancer Res., September 15, 2004; 64(18): 6495 - 6502. [Abstract] [Full Text] [PDF]

				E. M. Hammond, M. J. Dorie, and A. J. Giaccia Inhibition of ATR Leads to Increased Sensitivity to Hypoxia/Reoxygenation Cancer Res., September 15, 2004; 64(18): 6556 - 6562. [Abstract] [Full Text] [PDF]

				J. H. Connor, C. Naczki, C. Koumenis, and D. S. Lyles Replication and Cytopathic Effect of Oncolytic Vesicular Stomatitis Virus in Hypoxic Tumor Cells In Vitro and In Vivo J. Virol., September 1, 2004; 78(17): 8960 - 8970. [Abstract] [Full Text] [PDF]

				K. Maseide, R. A. Kandel, R. S. Bell, C. N. Catton, B. O'Sullivan, J. S. Wunder, M. Pintilie, D. Hedley, and R. P. Hill Carbonic Anhydrase IX as a Marker for Poor Prognosis in Soft Tissue Sarcoma Clin. Cancer Res., July 1, 2004; 10(13): 4464 - 4471. [Abstract] [Full Text] [PDF]

				M. Kim, S.-Y. Park, H.-S. Pai, T.-H. Kim, T. R. Billiar, and D.-W. Seol Hypoxia Inhibits Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Blocking Bax Translocation Cancer Res., June 15, 2004; 64(12): 4078 - 4081. [Abstract] [Full Text] [PDF]

				B. Clavo, J. L. Perez, L. Lopez, G. Suarez, M. Lloret, V. Rodriguez, D. Macias, M. Santana, M. A. Hernandez, R. Martin-Oliva, et al. Ozone Therapy for Tumor Oxygenation: a Pilot Study Evid. Based Complement. Altern. Med., June 1, 2004; 1(1): 93 - 98. [Abstract] [Full Text] [PDF]

				G. Hopfl, O. Ogunshola, and M. Gassmann HIFs and tumors--causes and consequences Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623. [Abstract] [Full Text] [PDF]

				R. A. Cairns and R. P. Hill Acute Hypoxia Enhances Spontaneous Lymph Node Metastasis in an Orthotopic Murine Model of Human Cervical Carcinoma Cancer Res., March 15, 2004; 64(6): 2054 - 2061. [Abstract] [Full Text] [PDF]

				S. M. Evans, K. D. Judy, I. Dunphy, W. T. Jenkins, P. T. Nelson, R. Collins, E. P. Wileyto, K. Jenkins, S. M. Hahn, C. W. Stevens, et al. Comparative Measurements of Hypoxia in Human Brain Tumors Using Needle Electrodes and EF5 Binding Cancer Res., March 1, 2004; 64(5): 1886 - 1892. [Abstract] [Full Text] [PDF]

				S. Welsh, R. Williams, L. Kirkpatrick, G. Paine-Murrieta, and G. Powis Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1{alpha} Mol. Cancer Ther., March 1, 2004; 3(3): 233 - 244. [Abstract] [Full Text]

				R. L. Cowen, K. J. Williams, E. C. Chinje, M. Jaffar, F. C. D. Sheppard, B. A. Telfer, N. S. Wind, and I. J. Stratford Hypoxia Targeted Gene Therapy to Increase the Efficacy of Tirapazamine as an Adjuvant to Radiotherapy: Reversing Tumor Radioresistance and Effecting Cure Cancer Res., February 15, 2004; 64(4): 1396 - 1402. [Abstract] [Full Text] [PDF]

				D. Hedley, M. Pintilie, J. Woo, T. Nicklee, A. Morrison, D. Birle, A. Fyles, M. Milosevic, and R. Hill Up-Regulation of the Redox Mediators Thioredoxin and Apurinic/Apyrimidinic Excision (APE)/Ref-1 in Hypoxic Microregions of Invasive Cervical Carcinomas, Mapped Using Multispectral, Wide-Field Fluorescence Image Analysis Am. J. Pathol., February 1, 2004; 164(2): 557 - 565. [Abstract] [Full Text] [PDF]

				L. B. Gardner, F. Li, X. Yang, and C. V. Dang Anoxic Fibroblasts Activate a Replication Checkpoint That Is Bypassed By E1a Mol. Cell. Biol., December 15, 2003; 23(24): 9032 - 9045. [Abstract] [Full Text] [PDF]

				K. L. Zakian, A. Shukla-Dave, P. Meyers, R. Gorlick, J. Healey, H. T. Thaler, A. G. Huvos, D. M. Panicek, and J. A. Koutcher Identification of Prognostic Markers in Bone Sarcomas Using Proton-Decoupled Phosphorus Magnetic Resonance Spectroscopy Cancer Res., December 15, 2003; 63(24): 9042 - 9047. [Abstract] [Full Text] [PDF]

				C. Bettegowda, L. H. Dang, R. Abrams, D. L. Huso, L. Dillehay, I. Cheong, N. Agrawal, S. Borzillary, J. M. McCaffery, E. L. Watson, et al. Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria PNAS, December 9, 2003; 100(25): 15083 - 15088. [Abstract] [Full Text] [PDF]

				N Raghunand, R A Gatenby, and R J Gillies Microenvironmental and cellular consequences of altered blood flow in tumours Br. J. Radiol., December 1, 2003; 76(suppl_1): S11 - S22. [Abstract] [Full Text] [PDF]

				B M Seddon and P Workman The role of functional and molecular imaging in cancer drug discovery and development Br. J. Radiol., December 1, 2003; 76(suppl_2): S128 - S138. [Abstract] [Full Text] [PDF]

				D. Hedley, M. Pintilie, J. Woo, A. Morrison, D. Birle, A. Fyles, M. Milosevic, and R. Hill Carbonic Anhydrase IX Expression, Hypoxia, and Prognosis in Patients with Uterine Cervical Carcinomas Clin. Cancer Res., November 15, 2003; 9(15): 5666 - 5674. [Abstract] [Full Text] [PDF]

				M. V. Papadopoulou and W. D. Bloomer NLCQ-1 (NSC 709257): Exploiting Hypoxia with a Weak DNA-Intercalating Bioreductive Drug Clin. Cancer Res., November 15, 2003; 9(15): 5714 - 5720. [Abstract] [Full Text] [PDF]

				J. G. Edwards, D. E. B. Swinson, J. L. Jones, S. Muller, D. A. Waller, and K. J. O'Byrne Tumor Necrosis Correlates With Angiogenesis and Is a Predictor of Poor Prognosis in Malignant Mesothelioma Chest, November 1, 2003; 124(5): 1916 - 1923. [Abstract] [Full Text] [PDF]

				Y. Azuma, S.-C. Chou, R. A. Lininger, B. J. Murphy, M. A. Varia, and J. A. Raleigh Hypoxia and Differentiation in Squamous Cell Carcinomas of the Uterine Cervix: Pimonidazole and Involucrin Clin. Cancer Res., October 15, 2003; 9(13): 4944 - 4952. [Abstract] [Full Text] [PDF]

				M. Demasi, L. G. Cleland, R. J. Cook-Johnson, G. E. Caughey, and M. J. James Effects of Hypoxia on Monocyte Inflammatory Mediator Production: DISSOCIATION BETWEEN CHANGES IN CYCLOOXYGENASE-2 EXPRESSION AND EICOSANOID SYNTHESIS J. Biol. Chem., October 3, 2003; 278(40): 38607 - 38616. [Abstract] [Full Text] [PDF]

				K. L. Blackwell, J. P. Kirkpatrick, S. A. Snyder, G. Broadwater, F. Farrell, L. Jolliffe, D. M. Brizel, and M. W. Dewhirst Human Recombinant Erythropoietin Significantly Improves Tumor Oxygenation Independent of Its Effects on Hemoglobin Cancer Res., October 1, 2003; 63(19): 6162 - 6165. [Abstract] [Full Text] [PDF]

				P. N. Lara Jr., P. Frankel, P. C. Mack, P. H. Gumerlock, I. Galvin, C. L. Martel, J. Longmate, J. H. Doroshow, H. J. Lenz, D. H. M. Lau, et al. Tirapazamine Plus Carboplatin and Paclitaxel in Advanced Malignant Solid Tumors: A California Cancer Consortium Phase I and Molecular Correlative Study Clin. Cancer Res., October 1, 2003; 9(12): 4356 - 4362. [Abstract] [Full Text] [PDF]