Data from 125 studies describing the pretreatment oxygenation status as measured in the clinical setting using the computerized Eppendorf pO2 histography system have been compiled in this article. Tumor oxygenation is heterogeneous and severely compromised as compared to normal tissue. Hypoxia results from inadequate perfusion and diffusion within tumors and from a reduced O2 transport capacity in anemic patients. The development of tumor hypoxia is independent of a series of relevant tumor characteristics (e.g., clinical size, stage, histology, and grade) and various patient demographics. Overall median pO2 in cancers of the uterine cervix, head and neck, and breast is 10 mm Hg with the overall hypoxic fraction (pO2 <or= 2.5 mm Hg) being approx. 25%. Metastatic lesions do not substantially deviate from the oxygenation status of (their) primary tumors. Whereas normal tissue oxygenation is independent of the hemoglobin level over the range of 8-15 g/dL, hypoxia is more pronounced in anemic patients and above this range in some cancers. Identification of tumor hypoxia may allow an assessment of a tumor's potential to develop an aggressive phenotype or acquired treatment resistance, both of which lead to poor prognosis. Detection of hypoxia in the clinical setting may therefore be helpful in selecting high-risk patients for individual and/or more intensive treatment schedules.

Detection and characterization of tumor hypoxia using pO2 histography.

We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.

https://bioone.org/journals/radiation-research/volume-177/issue-3/RR2773.1/Radiation-Induced-Vascular-Damage-in-Tumors--Implications-of-Vascular/10.1667/RR2773.1.pdf

Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO(2) levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO(2) thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.

Impact of Tumor Hypoxia and Anemia on Radiation Therapy Outcomes

Purpose : To present and evaluate clinical data suggesting that cancer metastasis may be induced by the microenvironment of the primary tumour and to discuss possible mechanisms of microenvironment-induced metastasis, based on a critical review of relevant data from studies of experimental tumours and cells in culture. Conclusions : Low oxygen tension in the primary tumour is associated with metastasis in soft tissue sarcoma, cervix carcinoma and carcinoma of the head and neck. Multiple mechanisms may be involved in hypoxia-induced metastasis. Thus, hypoxia followed by reoxygenation may induce point mutations and DNA strand breakage leading to deletions, amplifications and genomic instability. Hypoxia may also provide a physiological pressure in tumours selecting for metastatic cell phenotypes. Moreover, hypoxia may induce a temporary increase in the expression of gene products involved in the metastatic cascade, either through gene amplifications or through normal physiological processes by activating ox...

Carolin Creighton

Papers

Changes in tumor oxygenation during combined treatment with split-course radiotherapy and chemotherapy in patients with head and neck cancer