The impact of hypoxia and its modification of the outcome of radiotherapy

Abstract

Since the initial observations made at the beginning of the last century, it has been established that solid tumors contain regions of low oxygenation (hypoxia). Tumor cells can survive in these hypoxic conditions and are a major factor in tumor radioresistance. This significance has resulted in hypoxia becoming the most cited biological topic in translational radiation oncology. Identifying hypoxic cells in human tumors has become paramount, and the ability to do this has been improved by the help of new imaging techniques and the use of predictive gene profiles. Substantial data confirm the presence of hypoxia in many types of human tumors, although with considerable heterogeneity among individual tumors. Various approaches have been investigated for eliminating the hypoxic population. These include increasing oxygen availability, directly radiosensitizing or killing the hypoxic cells, indirectly affecting them by targeting the tumor vascular supply, increasing the radiation dose to this resistant population, or by using radiation with a high linear energy transfer, for which hypoxia is believed to be less of an issue. Many of these approaches have undergone controlled clinical trials during the last 50 years, and the results have shown that hypoxic radiation resistance can indeed be overcome. Thus, ample data exists to support a high level of evidence for the benefit of hypoxic modification. However, such hypoxic modification still has no impact on general clinical practice. In this review we summarize the biological rationale, and the current activities and trials, related to identifying and overcoming hypoxia in modern radiotherapy.

Baseline hemoglobin and liver function predict tolerability and overall survival of patients receiving radioembolization for chemotherapy-refractory metastatic colorectal cancer

“…The more hypoxic environment of solid tumors is associated with decreased radiosensitivity thereby enabling malignant cells to remain viable, especially in patients with anemia (35). Clinically significant anemia is believed to be one cause of intratumoral hypoxia, which is a well-known negative factor in radioresistance of solid tumors (36). Oxygen is the most important agent enabling maximal tumor sensitivity to ionizing radiation, as demonstrated by numerous preclinical studies.…”

“…The magnitude of enhancement of radiation effect is a factor of between 2 and 3 times over hypoxic conditions receiving the same radiation treatment. Prospective clinical trials in a variety of tumor types have associated pre-radiotherapy hypoxia (2.5-10 mm Hg partial pressure of oxygen) with statistically significant reductions in local control, disease free survival and overall survival via multivariate analyses (35,36). A recent report analyzing anemia in cervical cancer patients suggested anemia during radiotherapy (external beam and brachytherapy) with our without concurrent chemotherapy was not an independent predictor of central recurrence (37).…”

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

“…Mild hyperthermia (HT), that is, raising the temperature of the tumour to approximately 40- 44 C, typically for one hour, acts as a sensitiser for radiotherapy and chemotherapy [25][26][27]. In this temperature range, improved drug delivery and dispersion in the tumour enhances the effect of chemotherapy [28][29][30].…”

Neutron Radiation Therapy for Treatment of Refractory Merkel Cell Carcinoma

“…Poor blood perfusion and hypoxia play a major role in such treatment resistance. in addition to other molecular mechanisms [11,13]. Neutron radiation is known for its lesser dependence on tissue oxygenation status compared with XRT [14] and can potentially overcome hypoxia-related treatment resistance to XRT, as demonstrated impressively in our patient with multiply recurrent MCC.…”

“…The response to reirradiation with XRT tends to be less successful, likely secondary to selection of radioresistant tumor and hypoxia [11]. Furthermore, delivering an adequate radiation dose may be limited by the tolerance of previously irradiated surrounding normal tissues.…”