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Background: The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA )., Material and Methods: Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk., Results: Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD)., Conclusion: PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance.

The study aimed to determine whether post-radiation vaginal side effects in cervical cancer patients can be correlated with DVH parameter D(2cc). The result was negative in that no correlation could be demonstrated between D(2cc) and the presence and grade of side effects in this patients' subset treated with high brachytherapy doses., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To explore intratumor heterogeneity in gene expression profiles from patients with cervical cancer., Experimental Design: A total of 33 biopsies were obtained from 11 patients, sampling between two and five different areas for each tumor. The extracted RNA was hybridized onto the Affymetrix U133 Plus 2.0 oligonucleotide chip. The variance of expression within a patient (W), between patients (B) and the total variance (T = W + B) were calculated for each ProbeSet, and the ratio W/T was used as a measure of intratumor heterogeneity. Gene Ontology functional analysis was done to assess the function of genes that had high W/T (top 10%) and low W/T (bottom 10%) values., Results: In total, 448 ProbeSets (2.2% of the total) had W/T < 0.10, indicating low intratumor heterogeneity, and 537 ProbeSets (2.7% of the total) had W/T > 0.90, indicating high intratumor heterogeneity. In total 14,473 ProbeSets (72.4%) had higher intertumor than intratumor heterogeneity (W/T < 0.5). Genes with low intratumor heterogeneity were characterized by a statistically significant enrichment of immune-related functions (P < 0.0001). Genes with high intratumor heterogeneity were characterized by a significant tendency towards nuclear localization and nucleic acid binding (both P < 0.0001). For genes with W/T > 0.5, more than six biopsies would be required to minimize the intratumoral heterogeneity to <0.15; if W/T is 0.3 to 0.4, four biopsies are required; and for low W/T of 0.16 to 0.3, only two to three biopsies would be needed., Conclusion: Although the intratumor heterogeneity was low for the majority of the tested ProbeSets, for many genes, multiple biopsies are required to obtain a reliable estimate of gene expression.

Background and Purpose: To assess feasibility, safety and effectiveness of CT-based 3D conformal external beam radiotherapy (EBRT) plus concurrent cisplatin and MRI-based 3D conformal HDR-brachytherapy (HDR-BT) in the treatment of advanced cervical cancer., Patients and Methods: A total of 48 patients with advanced cervical cancer, treated with CT-based EBRT plus simultaneous cisplatin chemotherapy (40mg/m(2) of body surface per week for 5 weeks) and MRI-based HDR-BT, were included for analysis., Results: All patients completed radiotherapy as planned and 90% received at least four cycles chemotherapy. Frequencies of CTC grade 3 anaemia, grade 3-4 leucopenia and grade 3 thrombocytopenia were 4, 23 and 10%, respectively. Two patients developed deep vein thrombosis and one non-fatal pulmonary embolism. Grade 4 genitourinary late side effects (bladder) occurred in 2 patients. No grade 3-4 gastrointestinal side effects were observed. Complete response (CR) was obtained in 45 patients (94%). After a median follow-up of 33 months, 27 patients were disease free. Actuarial overall survival at 3 years was 61%, progression free survival 51% and continuous complete remission for true pelvis 85%., Conclusions: MRI-based 3D HDR-BT and 3D EBRT plus cisplatin appears to be safe and effective, although acute haematological toxicity is increased. Gastrointestinal morbidity is minimal when prospectively applying 3D dose volume constraints and MRI-based 3D dose volume adaptation.

Purpose: To compare survival and severe late radiation toxicity between patients who received continuous low-dose-rate (LDR) brachytherapy (BT) and pulsed-dose-rate (PDR) BT for cervical cancer., Methods and Materials: A retrospective review of cervical cancer patients who underwent primary radiotherapy with or without concurrent cisplatin was performed. Late Grade 3 or worse toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. The study endpoints were overall and disease-free survival and the probability of severe late toxicity., Results: A total of 109 patients (65.7%) received LDR BT and 57 (34.3%) received PDR BT. Seventy patients received concurrent chemotherapy with cisplatin. The 3-year overall survival and disease-free survival rate was 70% and 57% for the LDR group and 82% and 70% for the PDR group, respectively (p = 0.25 and p = 0.19). The 3-year probability rate for late Grade 3 or worse toxicity was 7.4% for LDR BT patients and 7.6% for PDR BT patients, respectively (p = 0.69) and 6.9% and 7.6%, respectively, for concurrent chemotherapy vs. none (p = 0.69)., Conclusion: No difference was found in severe late toxicity, overall survival, or disease-free survival between the LDR and PDR groups.

Background: The impact of radiotherapy alone (RT-alone) and radiotherapy plus concurrent chemotherapy with cisplatin (RT-CHT) was determined for lymphocyte subpopulations in cervical cancer patients., Materials and Methods: Thirty-four women were treated either with RT-alone (n=14) or RT-CHT (n=20). Peripheral lymphocytes were collected before, immediately after and 6, 12 and 24 weeks after completion of treatment. Flow cytometric analysis included total T-cells, T-helper-cells, T-suppressor-cells, T-cytotoxic-cells, NK-cells, B-cells and the CD4+/CD8+ratio., Results: Twenty-four weeks after treatment, B-cells had recovered to pretreatment levels whereas total lymphocyte counts, T-helper and T-cytotoxic-cells were still significantly reduced in both groups. In contrast, T-suppressor-cells and NK-cells had recovered to pretreatment levels only in patients who received RT-alone and were still significantly reduced in patients who received RT-CHT., Conclusion: RT-alone and RT-CHT induce a significant and prolonged suppression of all lymphocyte subpopulations. RT-CHT, but not RT-alone, causes a prolonged suppression of NK-cells and T-suppressor cells.

Purpose: The purpose is to investigate the impact of hypoxia-inducible factor (HIF)-1alpha expression on response to radiotherapy and prognosis of patients with primary irradiated cervical cancer. Because human papillomavirus (HPV) oncoprotein E6 might interact with HIF-1alpha in various pathways, we also investigated the relation of HIF-1alpha and HPV status., Experimental Design: Expression of HIF-1alpha was investigated by immunohistochemistry in 67 specimens of patients who had received radical radiotherapy for cervical cancer stages IB-IIIB. HPV analysis was performed using type-specific PCR, cloning, and sequencing. Survival analysis was performed using univariate and multivariate analysis., Results: Immunohistochemistry revealed expression of HIF-1alpha in 72.1% of the tumor samples. In 16 (23.9%) cases, there was a weak expression, in 25 (37.3%) a moderate expression, and in 7 cases (10.4%) a strong expression of HIF-1alpha. Nineteen samples (28.4%) were considered negative for HIF-1alpha expression. Strong/moderate expression of HIF-1alpha was associated with only partial response to radiotherapy (P = 0.037, chi(2) test). Strong/moderate expression of HIF-1alpha was also an independent prognostic factor for shorter progression-free survival (P = 0.036, Cox regression) and cervical cancer-specific survival (P = 0.04, Cox regression). No association between HIF-1alpha expression and infection with different HPV types could be found., Conclusions: Overexpression of HIF-1alpha has predictive and prognostic significance in cervical cancer patients receiving curative radiation therapy. Possibly, expression of HIF-1alpha could serve as intrinsic marker of hypoxia in cervical cancer.

To obtain information on the incidence and the clinical significance of infection with various types of the human papillomavirus (HPV) in cancer of the uterine cervix, we retrospectively examined the HPV status of 106 patients who had received radical radiotherapy for cervical cancer stages IB to IIIB. DNA was extracted from formalin-fixed, paraffin-embedded biopsies and PCR was carried out to identify HPV types 16, 18, 31, 35, 33 and 45. To detect additional HPV types, consensus PCR products were cloned and sequenced. A catalyzed signal-amplified colorimetric in situ hybridization was carried out in 84 of 106 specimens as a positive control. Response to therapy, progression-free survival (PFS) and cervical cancer-specific survival (CCSS) were the statistical endpoints. Survival analysis was carried out using univariate and multivariate analysis (Cox regression). Ninety-six patients (90.6%) were HPV-positive and 42/96 (43.7%) were positive for multiple HPV types. Eight patients had persistent disease after radiotherapy. From these 8 patients, 7 were infected with multiple HPV types and only 1 patient had an infection with a single HPV type. After a median follow up period of 50 months, patients with multiple HPV infection had a significantly shorter PFS and CCSS compared to those with single HPV infection (24.8% and 34.9% vs. 64% and 60.8%, Log rank, p < 0.01 and 0.04). In multivariate analysis, the presence of multiple HPV types (RR 1.9), node status (RR 2.3), tumor size (RR 3.2) and histologic type (RR 4.8) were independent prognostic factors of CCSS. Our results demonstrate that the presence of multiple HPV types is associated with poor response and with reduced survival in cervical cancer patients who receive radiotherapy as the primary treatment., (Copyright 2002 Wiley-Liss, Inc.)

Vascular endothelial growth factor (VEGF) plays an important role in the regulation of tumour growth and metastasis. It was the aim of this study to examine the impact of serum VEGF levels on the likelihood of response to radiotherapy and on the disease-free survival in patients with cervical cancer. Blood was taken before commencing treatment and serum VEGF was assessed by quantitative ELISA in 23 patients with cervical cancer stage IB-IVA undergoing primary radiotherapy. Serum VEGF levels were correlated with clinical and histopathologic factors as well as with response to radiotherapy and time to progression. Nineteen of the 23 patients had a complete response and four patients had persistent disease at 3 months. The median follow-up was 25 months (95% confidence interval: 23.5-26.5 months). At the time of analysis, eight patients were tumour-free and 15 patients had tumour progression; 12 of these 15 patients died of disease. Overall, the median serum VEGF level was 244 pg/ml (range 31.9-817.6 pg/ml). All four patients with local failure had VEGF levels >244 pg/ml, whereas 11 of the 19 patients with complete response had serum VEGF of < or =244 pg/ml (P=0.035). The median time to progression was 5 months in patients with VEGF of >244 pg/ml compared to 19 months in patients with VEGF of < or = 244 pg/ml (log rank, P=0.003). In multivariate analysis, serum VEGF, tumour size and histological type, but not the patient's age, stage and grade of histological differentiation influenced the progression-free survival. Elevated pre-therapeutic serum VEGF levels are associated with poor response and a shorter time to progression in patients with cervical cancer undergoing primary radiotherapy.