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Background and purpose: To evaluate longitudinal patient-reported distress in cervical cancer patients treated with definitive chemoradiation (CRT). Materials and methods: Between 2011 and 2016, consenting cervical cancer patients treated with definitive CRT who completed ≥ 2 revised Edmonton Symptom Assessment System (ESAS-r) questionnaires at clinical visits, including baseline, were included. A linear mixed model was used to assess the longitudinal trend in ESAS-r. A minimal clinically important difference (MCID) for total ESAS-r score was defined as a change of 3-points for improvement and 4-points for deterioration. The proportion of patients with an MCID over time was described using moving averages. To test for changes, mixed effects logistic models were fitted, each of which included patient-specific random intercepts and random slopes. Results: 67 patients were eligible for analysis (736 ESAS-r assessments). Median (range) follow-up was 24 months (range: 15–45) and compliance at 12 months was 60% (40/67). There was a significant decrease in ESAS-r scores over time. Baseline ESAS-r was strongly predictive of ESAS-r at follow-up (p

Background and Purpose: Gene expression signatures are often used to identify hypoxic tumors. However, intratumoral heterogeneity raises concern that multiple biopsies may be necessary to assess global hypoxia status. The objective of this study was to compare the impact of heterogeneity on the discriminative capacity of several previously described hypoxia gene signatures and determine if a single biopsy is sufficient to obtain a reliable estimate of hypoxia in cervical cancer. Materials and Methods: Multiple biopsies (33) were obtained from 11 locally advanced (FIGO IB to IVB) cervical cancers prior to treatment. Ten hypoxia gene signatures were analyzed. Variance component analysis was used to determine the ratio of within-tumor variability to total-tumor variability when one to five biopsies are available for analysis (W/T1–5). The mean standardized error in the signature scores was estimated by comparing the score using one biopsy randomly selected from each tumor to the ‘global’ score using all available biopsies. Results: The ten hypoxia signatures were comprised of 6–99 genes each. The W/T1 ratios for individual genes commonly found in the signatures ranged from 0.17 to 0.73. W/T1 ratios for the signatures were generally lower (0.21–0.45), implying greater capacity to discriminate among tumors. With additional biopsies, the signature W/T ratios (ie W/T2-5) decreased further. The mean error in the signature scores varied from 0.27 to 0.40 of one standard deviation, suggesting high capacity to discriminate among tumors with different global hypoxia scores. Conclusions: Compared with individual probes, hypoxia gene expression signatures are generally more consistent across multiple biopsies from different regions of a tumor and more tolerant of intratumoral heterogeneity. Keywords: Hypoxia, Gene signature, Heterogeneity, Cervical cancer

Background and purpose: Hypoxia, high interstitial fluid pressure (IFP) and immune effects have individually been shown to modulate radiotherapy (RT) response in cervical cancer. The aim of this study was to investigate the interplay between hypoxia or IFP and circulating neutrophil levels, and their combined effect on survival following RT. Material and methods: A total of 287 FIGO stage IB to IIIB cervical cancer patients treated with RT or RT and cisplatin (RTCT) were included. Tumor hypoxia and IFP were measured at baseline prior to treatment. Absolute neutrophil count (ANC) was measured at baseline and weekly during treatment. Median follow up was 7.1 years. Results: High nadir ANC at the point of maximal myelosuppression was a stronger predictor of inferior survival than high baseline ANC after adjusting for clinical prognostic factors and treatment (RT vs. RTCT). The predictive effect of nadir ANC was most evident in patients with well-oxygenated tumors or tumors with high IFP at diagnosis. Conclusions: This study provides new information about the combined influence of the tumor microenvironment and myeloid cells on the survival of cervical cancer patients treated with RT/RTCT to motivate the development of new treatments based on molecular targeting of immune–based radioresistance pathways.