Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck – A systematic review and meta-analysis
ABSTRACT The importance of tumour hypoxia for the outcome of radiotherapy has been under investigation for decades. Numerous clinical trials modifying the hypoxic radioresistance in squamous cell carcinoma of the head and neck (HNSCC) have been conducted, but most have been inconclusive, partly due to a small number of patients in the individual trial. The present meta-analysis was, therefore, performed utilising the results from all clinical trials addressing the specific question of hypoxic modification in HNSCC undergoing curative intended primary radiotherapy alone.
A systematic review of published and unpublished data identified 4805 patients with HNSCC treated in 32 randomized clinical trials, applying, normobaric oxygen or carbogen breathing (5 trials); hyperbaric oxygen (HBO) (9 trials); hypoxic radiosensitizers (17 trials) and HBO and radiosensitizer (1 trial). The trials were analysed with regard to the following endpoints: loco-regional control (32 trials), disease specific survival (30 trials), overall survival (29 trials), distant metastases (12 trials) and complications to radiotherapy (23 trials).
Overall hypoxic modification of radiotherapy in head and neck cancer did result in a significant improved therapeutic benefit. This was most dominantly observed when using the direct endpoint of loco-regional control with an odds ratio (OR) of 0.71, 95% cf.l. 0.63-0.80; p<0.001), but this was almost mirrored in the disease specific survival (OR: 0.73, 95% cf.l. 0.64-0.82; p<0.001), and to a lesser extent in the overall survival (OR: 0.87, 95% cf.l. 0.77-0.98; p=0.03). The risk of distant metastases was not significantly influenced although it appears to be less in the tumours treated with hypoxic modification (OR: 0.87, 95% cf.l. 0.69-1.09; p=0.22), whereas the radiation related late complications were not influenced by the overall use of hypoxic modifications (OR: 1.00, 95% cf.l. 0.82-1.23; p=0.96). The improvement in loco-regional control was found to be independent of the type of hypoxic modification. The trials have used different fractionation schedules, including large doses per fraction, which may result in relatively more hypoxia and greater benefit. However, analysis of HNSCC trials using conventional fractionation only, showed that the significant effect of hypoxic modification was maintained.
The meta-analysis thus demonstrates that there is level 1a evidence in favour of adding hypoxic modification to radiotherapy of squamous cell carcinomas of the head and neck.
SourceAvailable from: Jasmina Hodzic[Show abstract] [Hide abstract]
ABSTRACT: Background Radiotherapy is one of the mainstays in the treatment for cancer, but its success can be limited due to inherent or acquired resistance. Mechanisms underlying radioresistance in various cancers are poorly understood and available radiosensitizers have shown only modest clinical benefit. There is thus a need to identify new targets and drugs for more effective sensitization of cancer cells to irradiation. Compound and RNA interference high-throughput screening technologies allow comprehensive enterprises to identify new agents and targets for radiosensitization. However, the gold standard assay to investigate radiosensitivity of cancer cells in vitro, the colony formation assay (CFA), is unsuitable for high-throughput screening. Methods We developed a new high-throughput screening method for determining radiation susceptibility. Fast and uniform irradiation of batches up to 30 microplates was achieved using a Perspex container and a clinically employed linear accelerator. The readout was done by automated counting of fluorescently stained nuclei using the Acumen eX3 laser scanning cytometer. Assay performance was compared to that of the CFA and the CellTiter-Blue homogeneous uniform-well cell viability assay. The assay was validated in a whole-genome siRNA library screening setting using PC-3 prostate cancer cells. Results On 4 different cancer cell lines, the automated cell counting assay produced radiation dose response curves that followed a linear-quadratic equation and that exhibited a better correlation to the results of the CFA than did the cell viability assay. Moreover, the cell counting assay could be used to detect radiosensitization by silencing DNA-PKcs or by adding caffeine. In a high-throughput screening setting, using 4 Gy irradiated and control PC-3 cells, the effects of DNA-PKcs siRNA and non-targeting control siRNA could be clearly discriminated. Conclusions We developed a simple assay for radiation susceptibility that can be used for high-throughput screening. This will aid the identification of molecular targets for radiosensitization, thereby contributing to improving the efficacy of radiotherapy.Radiation Oncology 02/2015; 10:55. DOI:10.1186/s13014-015-0355-2 · 2.36 Impact Factor
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ABSTRACT: Hypoxia is present to some extent in most solid malignant human cancers because of an imbalance between the limited oxygen delivery capacity of the abnormal vasculature and the high oxygen consumption of tumor cells. This drives a complex and dynamic compensatory response to enable continued cell survival, including genomic changes leading to selection of hypoxia-adapted cells with a propensity to invade locally, metastasize, and recur following surgery or radiotherapy. There is indisputable clinical evidence from numerous observational and therapeutic studies across a range of tumor types to implicate hypoxia as a key determinant of cancer behavior and treatment outcome. Despite this, hypoxia-targeted treatment has failed to influence clinical practice. This is explained, in part, by emerging findings to indicate that hypoxia is not equally important in all patients even when present to the same extent. The impact of hypoxia on patient outcome and the benefit of hypoxia-targeted treatments are greatest in situations where hypoxia is a primary biological driver of disease behavior-patients with tumors having a "hypoxic driver" phenotype. The challenge for the clinical and scientific communities moving forward is to develop robust precision cancer medicine strategies for identifying these patients in the setting of other etiologic, genomic, and host-tumor factors, considering not only the state of the tumor at diagnosis but also changing patient and tumor characteristics over time. Copyright © 2015 Elsevier Inc. All rights reserved.Seminars in Nuclear Medicine 03/2015; 45(2). DOI:10.1053/j.semnuclmed.2014.11.002 · 3.13 Impact Factor
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ABSTRACT: The mechanisms underlying cancer radioresistance remain unclear. Several studies have found that increased glucose transporter‑1 (GLUT‑1) expression is associated with radioresistance. Recently, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway was reported to be involved in the control of GLUT‑1 trafficking and activity. Activation of the PI3K/Akt pathway may itself be associated with cancer radioresistance. Thus, increasing attention has been devoted to the effects of modifying the expression of GLUT‑1 and the PI3K/Akt pathway on the increase in the radiosensitivity of cancer cells. This review discusses the importance of the association between elevated expression of GLUT‑1 and activation of the PI3K/Akt pathway in the development of radioresistance in cancer.Molecular Medicine Reports 11/2014; 11(3). DOI:10.3892/mmr.2014.2888 · 1.48 Impact Factor