BackgroundClinical parameters and proteins have recently been suggested as possible causes of radiotherapy (RT) resistance in cervical carcinoma (CC). The objective of the present study was to validate prognostic biomarkers of radiation resistance.MethodsThe present prospective study included patients undergoing RT with curative intent for histologically proven locally advanced squamous cell CC. Tissues and blood samples were systematically collected before RT initiation. Immuno-histochemistry was performed (IGF-IR α and β, GAPDH, HIF-1 alpha, Survivin, GLUT1, CAIX, hTERT and HKII). Response to radiation was assessed through tumour response 3 months after RT completion, through overall survival (OS) and through progression-free survival (PFS).ResultsOne hundred forty nine patients with a mean age of 46 years were included, with FIGO IIB (n = 53) and FIGO IIIB (n = 96) CCs. 61 patients were treated with exclusive RT + brachytherapy and 88 underwent chemo-radiotherapy + brachytherapy. Our findings suggest an association between hemoglobin level (Hb) (>11 g/dL) and 3 months complete response (p = 0.02). Hb level < 11 g/dL was associated with decreased PFS (p = 0.05) and OS (p = 0.08). Overexpression of IGF-1R β was correlated with a decreased OS (p = 0.007). Overexpression of GLUT1 was marginally correlated with reduced OS (p = 0.05). PFS and OS were significantly improved in patients undergoing chemoradiation versus exclusive radiotherapy (PFS: p = 0.04; OS: p = 0.01).ConclusionsIGF-1R β overexpression and Hb level (≤11 g/dl) were associated with poor prognosis, and thus appear to be possible interesting biomarkers of radiation resistance. Our results corroborate previous pre-clinical studies suggesting IGF-1R and hypoxia to be part of the biological pathways leading to radio-resistance.
In Colombia the cancer of uterine cervix is diagnosed in advanced stages and its treatment is based on the application of the radiotherapy or radiotherapy more chemotherapy. Most of studies show that the IGF-IR expression leads to the cellular increase of resistance to radiation, that the tumor like hypoxia induces the IGF-IR expression and selects cells that overexpressing IGF-IR. The aim of this study was to evaluate the effect of expression of IGF-IR, IGF-I, IGF-II, GAPDH, and hemoglobin concentration on tumoral response to ionizing radiation in patients with locally advanced cervical cancer. A series of 37 consecutive patients were recruited from 2002 to 2004. For each patient, a representative tumoral sample in fresh was taken at the time of diagnosis before the beginning of the treatment. In order to have a group control for the analysis of gene expression, 30 samples of normal tissue of uterine cervix from patients treated by exclusive hysterectomy were also analyzed. The mean age of the remaining 37 patients was 46 years (ranging from 33 to 70 years). All patients received exclusive pelvic external beam radiotherapy (EBRT). Treatment consisted of teletherapy using 6 to 18 MV photons with standard four field technique delivering a total dose of 45— 50,4 Gy in 28 fractions (1.8 Gy per fraction, 5 consecutive days per week, overall EBRT treatment time 5 weeks). Follow-up was scheduled at 6 weeks after completion of intracavitary brachytherapy, then every three months during the next 2 years. Complete remission was defined as no evidence of residual disease on clinical examination and radiological imaging, six weeks to three months after completion of the therapeutic sequence. Gene expression of IGF-IR, IGF-I, IGF-II and GAPDH was determined by Real Time PCR and IGF-IR protein was detected using Western Blot. Hemoglobin levels were also evaluated as a parameter of oxygenation before the beginning of ionizing radiation (Hgb≤11g/dl). Gene expression levels were compared between complete responders and non responders using Anova or Kruskal-allis Anova. A major increase was observed in gene expression IGF-IR (34%), followed by the expression of IGF-II (24%) in the cases of cancer in comparison with the control group (expression not detected). Gene expression of IGF-IR (p=0.04) and incomplete treatment (p=0.019) were associated with the lack of treatment response. Patients expressing IGF-IR had 4.6 times more risk of non treatment response; GAPDH expression was directly correlated with the IGF-IR expression, IGF-IR and IGF-II co-expression under anemic hypoxia conditions (Hgb≤11g/dl), demonstrated a possible activation of a glicolytic pathway as an answer to the high metabolic rate of tumoral cells. This is the first report in the clinical setting that relates the expression of IGF-IR as a strong marker of responsiveness. Therefore, the IGF-IR can be considered as a molecular target for optimizing the treatment of cervical cancer with radiotherapy.
Hypoxia involves neoplastic cells. Unlike normal tissue, solid tumors are composed of aberrant vasculature, leading to a hypoxic microenvironment. Hypoxia is also known to be involved in both metastasis initiation and therapy resistance. Radiotherapy is the appropriate treatment in about half of all cancers, but loco-regional control failure and a disease recurrence often occur due to clinical radioresistance. Hypoxia induces radioresistance through a number of molecular pathways, and numerous strategies have been developed to overcome this. Nevertheless, these strategies have resulted in disappointing results, including adverse effects and limited efficacy. Additional clinical studies are needed to achieve a better understanding of the complex hypoxia pathways. This review presents an update on the mechanisms of hypoxia in radioresistance in solid tumors and the potential therapeutic solutions.
Abstract. High hypoxic, glycolytic and acidosis metabolisms characterize cervical cancer tumors and have been described to be involved in chemoradioresistance mechanisms. Based on these observations, the present study assessed four selected novel biomarkers on the prognosis of locally advanced cervical carcinoma. A total of 66 patients with stage IIB/IIIB cervical cancer were retrospectively included. The protein expression levels of glucose transporter 1 (GLUT1), carbonic anhydrase 9 (CAIX) and hexokinase 1 (HKII) were investigated by immunohistochemistry on tumor biopsies, hemoglobin was measured and the disease outcome was monitored. A total of 53 patients (80.3%) presented a complete response. For these patients, the protein expression levels of GLUT1, CAIX and HKII were overexpressed. A significant difference was observed (P= 0.0127) for hemoglobin levels (≤11 g/dl) in responsive compared with non-responsive patients. The expression of GLUT1 is associated with a lower rate of both overall and disease-free survival, with a trend of decreased risk of 1.1x and 1.5x, respectively. Co-expression of GLUT1 and HKII is associated with a decreased trend risk of 1.6x for overall survival. Patients with hemoglobin levels ≤11 g/dl had a 4.3-fold risk (P=0.02) in decreasing both to the rate of overall and disease-free survival. The presence of anemic hypoxia (hemoglobin ≤11 g/dl) and the expression of GLUT1 and/or HKII influence treatment response and are associated with a lower overall and disease-free survival. The present results demonstrated that these biomarkers may be used as predictive markers and suggested that these metabolic pathways can be used as potential novel therapeutic targets.
BackgroundDespite screening campaigns, cervical cancers remain among the most prevalent malignancies and carry significant mortality, especially in developing countries. Most studies report outcomes of patients receiving the usual standard of care. It is possible that these selected patients may not correctly represent patients in a real-world setting, which may be a limitation in interpreting outcomes. This study was undertaken to identify prognostic factors, management strategies and outcomes of locally advanced cervical cancers (LACC) treated in daily clinical practice.MethodsMedical files of all consecutive patients treated with curative intent for LACC in a French Cancer Care Center between 2004 and 2014 were reviewed retrospectively.ResultsNinety-four patients were identified. Performance status was ≥ 2 in 10.6%. Median age at diagnosis was 63.0. Based on the International Federation of Gynecology and Obstetrics classification, tumours were classified as follows: 10.6% IB2, 22.3% IIA, 51.0% IIB, 4.3% IIIA and 11.7% IIIB. Pelvic lymph nodes were involved in 34.0% of cases. Radiotherapy was delivered for all patients. Radiotherapy technique was intensity modulated radiation therapy or volumetric modulated arc therapy in 39.4% of cases. A concurrent cisplatin chemotherapy was delivered in 68.1% of patients. Brachytherapy was performed in 77.7% of cases. The recommended standard care (concurrent chemoradiotherapy with at least five chemotherapy cycles during radiotherapy, followed by brachytherapy) was delivered in 43.6%. The median overall treatment time was 56 days. Complete tumour sterilisation was achieved in 55.2% of cases. Mean follow-up was 54.3 months. Local recurrence rate was 18.1%. Five-year overall survival was 61.9% (95% Confident Interval (CI) = 52.3–73.2) and five-year disease-specific survival was 68.5% (95% CI = 59.2–79.2). Poor performance status, lymph nodes metastasis and absence of concurrent chemotherapy were identified as poor prognostic factors in multivariate analysis.ConclusionsLess than 50% of patients received the standard care. Because LACC patients and disease are heterogeneous, treatment tailoring appears to be common in current clinical practice. However, guidelines for tailoring management are not currently available. More data about real-world settings are required in order to to optimise clinical trials’ aims and designs, and make them translatable in daily clinical practice.Trial registrationretrospectively registered.
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