High interstitial fluid pressure (IFP) and hypoxia as biomarkers of cisplatin chemoradiation response in advanced cervix cancer

Abstract

5584 Background: Chemoradiotherapy (CRT) has been shown to improve survival compared to RT alone for locally advanced cervix cancer. The tumour microenvironment in cervix cancer is also known to influence disease progression and response to treatment. In this prospective study, pre-treatment tumour hypoxia and interstitial fluid pressure (IFP) were examined as potential biomarkers of improved treatment effectiveness in a cohort of patients treated with definitive radiation alone, or with the addition of concurrent cisplatin CRT. Methods: Between April 1994 and January 2006, 309 eligible patients with cervix cancer were entered into a prospective study of hypoxia and IFP prior to definitive treatment. Patients accrued between 1994 and 1999 (n = 115) were treated with RT alone, and those accrued between 2000 and 2006 (n = 194) received RT and concurrent weekly cisplatin CRT. Clinical characteristics were similar between the two cohorts except pelvic lymph node metastases were more frequent in the CRT cohort (42% vs. 19%, p = 0.0005), likely due to changes in definition of positive nodes on CT or MR imaging. The median follow-up was 3.6 years (2.9 years for CRT and 7.8 years for RT). Results: The use of CRT improved outcome in hypoxic tumors compared to RT (57% 3-yr DFS vs. 42%, p = 0.045) with a trend to improved DFS in patients with high IFP tumors (57% 3-yr DFS vs. 44% for RT alone, p = 0.056). A strong interaction was identified between IFP and treatment (CRT vs. RT, p = 0.007). After correcting for the effects of clinical prognostic factors, cisplatin significantly improved DFS in the high IFP group (p = 0.02), and showed a trend towards improved DFS in those with hypoxia (p = 0.1). In patients with both high IFP and hypoxia a similar benefit of cisplatin was seen. Conclusions: Patients with high IFP and hypoxic tumours may selectively benefit from the addition of concurrent cisplatin CRT to their treatment regimen. This observation is contrary to an effect of high IFP on impaired drug delivery, but may reflect reduced DNA repair under hypoxic conditions, which could facilitate cell killing with both radiation and cisplatin chemotherapy. No significant financial relationships to disclose.