Imaging, Diagnosis, Prognosis Interstitial Fluid Pressure as a Prognostic Factor in Cervical Cancer Following Radiation Therapy

Purpose: To investigate tumor interstitial fluid pressure as a prognostic factor for recurrence-free survival in patients with cervical cancer following radiation therapy. Experimental Design: Tumor interstitial fluid pressure was measured in 55 cervical cancer patients who received radiation therapy between August 1998 and September 2002. Interstitial fluid pressure measurements were made before radiation therapy (pre– radiation therapy interstitial fluid pressure) and after a median of 28.8 Gy in 16 fractions (range, 25.2-30.6 Gy in 14-17 fractions) of radiation therapy (mid–radiation therapy interstitial fluid pressure), using a modified wick-in-needle technique. Median follow-up was 74 months (range, 2-118 months). The Kaplan-Meier method with the log-rank test and Cox's proportional hazard model were used in univariate and multivariate analyses, respectively, of prognostic factors for recurrence-free survival. Results: Median pre–radiation therapy and mid–radiation therapy interstitial fluid pressure were 29.0 mm Hg (range, 4.0-93.9 mm Hg) and 20.0 mm Hg (range, -1.2 to 29.6 mm Hg), respectively (P = 0.001). Pre–radiation therapy interstitial fluid pressure was significantly higher in adenocarcinomas than squamous cell carcinomas (P = 0.028). Significant reductionof interstitial fluid pressurewasnotedonly in patientswith complete responses (P = 0.002), andmid–radiation therapy interstitial fluid pressurewas significantly lower in patients with complete responses (P = 0.036). In themultivariate analysis including interstitial fluid pressures and clinical variables, pre–radiation therapy interstitial fluid pressure was an independent prognostic factor for local and distant recurrence-free survival (P = 0.001 and 0.027, respectively). Conclusions:Mid–radiation therapy interstitial fluid pressure measurement may be useful in predicting radiation therapy responses, and pre–radiation therapy interstitial fluid pressure was a significant prognostic factor for local and distant relapse-free survival in patients with cervical cancer after radiation therapy. (Clin Cancer Res 2009;15(19):OF1–7) Interstitial fluid pressure in normal tissue is close to atmospherical pressure, whereas interstitial fluid pressure in solid tumors is increased by 10 to 100 mm Hg (1–5). This increased tumor interstitial fluid pressure is thought to be the result of unregulated angiogenesis, a lack of functional lymphatics, and abnormal extracellular matrix. The vessels produced in tumor angiogenesis are hyperpermeable, and the resultant net efflux of fluid into the interstitium, with impaired lymphatic drainage, increases interstitial fluid volume and distends the elastic extracellular matrix. In addition, tumor proliferates in confined space and tumor interstitium consists of dense collagen fibers and increased inflammatory components, such as fibroblasts and macrophages, contributing to the increased interstitial fluid pressure (6–10). Interstitial fluid pressure can be measured easily in accessible human tumors using a simple needle probe. Interstitial fluid pressure is thought to reflect the global physiology of a tumor, which is largely unrelated to perfusion or oxygen status (11, 12). Thus, tumor interstitial fluid pressure may be of prognostic use in the treatment of patients with cancer. To date, interstitial fluid pressure measurement and long-term follow-up after radiation therapy has only been reported at one institution; pretreatment interstitial fluid pressure was shown to be able to predict the radiation therapy response (13) and was an important prognostic factor for local and distant disease progression in patients with cervical cancer receiving radiation therapy (5, 14). However, to our knowledge, no reported study has investigated interstitial fluid pressures measured during treatment and pretreatment to assess their prognostic significance. We measured tumor interstitial fluid pressure before and during radiation therapy in patients with cervical cancer managed Authors'Affiliations: DepartmentofRadiationOncology, CollegeofMedicine; Cancer Research Institute, ChungnamNational University, Daejeon, Republic of Korea; Department of Radiation Oncology, Sanggye Paik Hospital, Inje University College of Medicine; and Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea Received 3/4/09; revised 6/14/09; accepted 6/26/09; published OnlineFirst 9/22/09. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Jun-Sang Kim, Department of Radiation Oncology, Chungnam National University Hospital, 33 Munhwa-ro, Jung-gu, Daejon 301-721, Republic of Korea. Phone: 82-42-280-8361; Fax: 82-42-280-7899; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0560 OF1 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Published Online First on September 22, 2009 as 10.1158/1078-0432.CCR-09-0560 Research. on May 29, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 22, 2009; DOI: 10.1158/1078-0432.CCR-09-0560