(CANCER RHSl-AKCH 56. 45(»-45l5. Octnbcr I. 1996] Association between Tumor Hypoxia and Malignant Progression in Advanced Cancer of the Uterine Cervix1 Michael Höckel,2Karlheinz Schienger, Billur Aral, Margarete Milze, Uwe Schäffer, and Peter Vaupel Department iif Ohsieirics anil üyneciiltiuy /M. H., K. S.. B. A.. U. S.] unti lile Institutes ¡ifPiilholiifty ¡M.M./ und Ph\\inli>K\ ami Paihuiihysii>li>Ky¡P-V.]. University <ifMainz Metileni Schnei. 55/W Mitin:. Genniin\ ABSTRACT ture is evident ( I ). As a consequence, tissue hypoxia results from either insufficient O-, diffusion (chronic hypoxia) or insufficient Experimental tumors contain a significant fraction of microregions that perfusion (acute hypoxia. transient hypoxia. or ischemie hypoxia). are chronically or transiently hvpoxic. Experimental evidence showing Moreover, in vitro and experimental tumor studies showed that that hypoxia (und suhsequent reoxygenation) muy huve a profound impact hypoxia (and subsequent reoxygenation) may have a dramatic on malignant progression and on responsiveness to therapy is growing. I lie clinical relevance of tumor oxygénationin Immun solid malignancies impact on malignant progression in terms of tumor spread and is under ¡mesticatimi. resistance to therapy (2-13). Despite these striking observations in \\ e huve developed and validuted a clinically applicable method for tumor models, the clinical relevance of tumor oxygénation is still measurement of tumor oxygénation in locully udvunced cancer of the unclear. After Thomlinson and Gray (14) presented evidence for uterine cervix using a computerized polarographic electrode system. Ap hypoxic microregions within human tumors from a detailed his- plying this procedure in patients with cervical cancers S3 cm in diameter, topathological study of lung cancers. Urbach (15) was the first to who gave informed consent. \ve have been studying the clinicul relevance measure low oxygen tensions in malignant skin tumors directly of tumor oxygénationprospective!)' since 1989. with pO2 polarography. Gatenby et al. (16) reported in 1988 the As of June 1995, 103 patients with advanced cancers of the uterine results from polarographic oxygen tension measurements in lymph cervix [Federation Internationale des Gynaecologistes et Obstetristes (FICO) stages Ih. bulky di = 13). Ha and Uh (H = 51), IIIu and IHh node métastasesof head and neck cancers showing a significant (n = 34). and IVa und I\ h (n = 5)| hud entered the study. Fifty "i of the relationship between low mean intratumoral pO-, values and failure patients had carcinomas with median pO, readings <10 mm Hg. referred to respond to fractionated radiotherapy thus supporting older stud to as hypoxic tumors. ies, such as that of Kolstad (17). with cancer of the uterine cervix. Tumor oxygénation was found to be independent of various patient These investigations, however, did not receive widespread atten demographics and also of pretreutment tumor churucteristics, such as tion because of the low number of patients involved, methodolog clinical tumor stage and size, histológica! type, and differentiation. How ical limitations of pO, determinations, and both short and/or in ever, histopatbological examination of the surgical specimens following complete patient follow-up. radical tumor resection in 47 patients showed that lm\-p<>, tumors ex In 1989. a computerized histography system was introduced, al hibited larger tumor extensions and more frequent (occult) parumetrial spread, as well as lymph-vusculur space involvement, compared to well- lowing quick and reliable polarographic tissue pO, readings in the clinical setting (18-21 ). Applying this device in patients with locally oxygenated tumors of similar clinicul stuge und size. Forty-two putients completing primary radiatimi therapy and 47 patients who underwent advanced cancer of the uterine cervix, we initiated a controlled pro radical surgery were analyzed for treatment outcome after u median spective trial to evaluate the clinical relevance of tumor oxygénation. observation period of 28 months (range. 3-76 months). Patients with The measurements were performed according to the principles of hypoxic tumors had significantly worse disease-free und overall survival systematic random sampling (22, 23) to take into account intratumorul probabilities compared to patients with nonhypoxic tumors. Cox regres heterogeneity. After having presented preliminary data from the first sion analysis identified tumor oxygénationand FICO stage as the most analysis in 1992 demonstrating the powerful predictive value of tumor important independent prognostic factors. The poorer outcome of the oxygénation on recurrence-free and overall survival for patients patients with hypoxic tumors was mainly due to locoregionul failures with treated with radiation (24. 25). we now report the results from a larger and without distunt metustuses. irrespective of whether surgery or radi patient cohort and longer follow-up, including a subgroup of patients ation was applied as primary treatment. Tumor oxygénation as measured with a standardized polarographic who underwent primary surgery. We show that the adverse out method proved to be a powerful new pretherapeutic prognostic parameter come of patients with hypoxic cervical tumors is independent of the providing important information on malignant progression in terms of standard treatment and apparently represents a tumor biological extracervical tumor spread and rudioresistunce in advanced cervical phenomenon. cancers. MATERIALS AND METHODS INTRODUCTION Study Protocol. All patients with cervical cancers of at least 3 cm in largest In normal tissue, oxygénation is a spatially and temporally diameter as estimated by clinical investigation who had been admitted to the heterogenous homeostatic flow equilibrium determined by micro- Department of Obstetrics and Gynecology at the University of Mainz Medical School for treatment were eligible for the open prospective trial initiated in regional oxygen delivery and oxygen consumption. In fast-growing June 1989. The study was approved by a medical ethics committee. All experimental tumors, a Multhusian principle characteri/ed by a patients needed to give informed consent to be enrolled in the study. Clinical more rapid increase of oxygen-consuming tumor cell populations staging according to FIGO1 and si/ing were performed by experienced than expansion of the oxygen-supplying functional microvascula- gynecological oncologists. Histopathology. Histológica! type and grade according to the modified Broders' system were obtained from routine H&E-stained sections of defined Rcccivcd 4/5/96; accepted X/I6M6. The costs ot publication of this article were defrayed in part by the payment of page tumor biopsies. The specimens from radical surgery were processed in giant charges. This article must therefore he hereby marked aihvriisement in accordance wilh sections for histológica! examination to verify tumor extension, depth of 18 U.S.C. Section 1734 solely to indicate this laci. 1Supported by Deulsehe Krehshille Grani M4(V9]/Va I. To whom requests tor reprints should be addressed, at Universitätsfrauenklinik. 1The abbreviation used is: FIGO. Federation Internationale des (¡ynaecologisles et Langcnhcckstrassc I. D-55IOI Main/. Cicrmany. Ohslclrisles. 4509 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1996 American Association for Cancer Research. IIYPOXIA IS O-:RVICAI CANCI-.K cervical invasion, and bladder or rectal involvement. Paramctriul tumor infil Follow-Up. Regular follow-up investigations were performed either in the tration was investigated in the axial sections of the lateral parts of the surgical Department of Obstetrics and Gynecology at the University of Main/ Medical specimens. The presence of tumor cell clusters within an endothelial-lined School or in other clinical institutions at 3-month intervals during the first 2 space was regarded as lymph-vascular space involvement. This feature was years following treatment and twice yearly thereafter. The patients were classified as pronounced if it could he detected in nearly all of the high-power interviewed and examined clinically. In case of symptoms or suspicious or fields at the invading tumor front. The demonstration of a tumor cell embolus pathological clinical findings, further diagnostic procedures were ordered, within a blood vessel identified by the tunica media was interpreted as including interventional biopsies for definitive diagnosis. Further information evidence of vascular invasion. Four sections from each removed lymph node regarding the posttreatment disease course of the patients was obtained by were scrutinized for tumor métastases. telephone interviews or correspondence with the patients, their relatives, or Treatments. Primary treatments with curative intent were performed uni their primary care physicians. formly during the study period by either surgery or radiation. Treatment Statistical Analysis. Statistical analyses were performed with the SAS decisions for the individual patients were made at a tumor conference with Sottware. Version 6.04. For comparison, the determination of correlation coefficients. Fisher's exact test, and the Mann-Whitney-Wilcoxon test (U test) participation of the radiation oncologists and gynecological oncologists based on the clinical judgment of tumor rescctability and on the age and nutritional were applied. Survival and recurrence-free survival probabilities were calcu and performance