Purpose: Although hypoxia is considered a major cause of failure of radiotherapy, the mechanisms of tumor hypoxia are unclear, and effective ways for its correction or targeting are missing. Tumoral vasculature is the vehicle for the hemoglobin to reach the tumoral stroma. Although anemia has long been focused on as an important parameter related to tumor hypoxia, differences in vascular density may also affect the intratumoral access of hemoglobin.
Methods and materials: In the present study, we examined the vascular density in 1459 human carcinomas. The distribution of the vascular density within tumors was studied in 436 non-small-cell lung carcinomas and 298 breast carcinomas.
Results: The vascular density was found to vary up to 22-fold even among tumors of the same histology. Overall, the vascular density was significantly higher in the tumor periphery as compared to inner areas. Three different patterns of vascularization were identified in both lung and breast cancer specimens; (1) tumors with low or (2) tumors with high vessel density throughout the tissue section, and (3) tumors with high vessel density in the tumor periphery and low in inner areas. The death rate following surgery showed a direct association with the vascular density in lung, breast, colon, and endometrial cancer. In inoperable gastric cancer patients treated with chemotherapy, and in head and neck cancer patients treated with radical chemoradiotherapy there was a 'U-like' association of the death rate with the vascular density suggesting that very low (poor oxygen and drug availability) and very high (intensified angiogenic pathways) vascularization are both linked to poor outcome.
Conclusion: The present study stresses the importance of the vascular density as a putative variable that may have affected the results of large clinical trials that investigated the role of anemia, hyperbaric oxygen, hypoxic sensitizers, or even of combined chemoradiotherapy in the outcome of radiation treatment.