HighlightsHypoxia-activated prodrugs have yielded promising results up to phase II trials.Implementation of hypoxia-activated prodrugs in the clinic has not been successful.Phase III clinical trials lack patient stratification based on tumor hypoxia status.Stratification will decrease the number of patients needed and increase success.Improvements in hypoxia-activated prodrug design can also increase success rates.

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Tumour hypoxia and its molecular responses have been shown to be associated with poor prognosis. Detection of hypoxia, preferably in a non-invasive manner, could therefore predict treatment outcome and serve as a tool to individualize treatment. This review gives an overview of recent literature on hypoxia imaging markers currently used in clinical trials. Furthermore, recent progress made in targeting hypoxia (hypoxia-activated prodrugs) or hypoxia response (carbonic anhydrase IX inhibitors) is summarized. Last, window-of-opportunity trials implementing non-invasive imaging are proposed as an important tool to prove anti-tumour efficacy of experimental drugs early during drug development.

Evaluation of tumor micro-environmental conditions, such as intratumoral hypoxia, is important to predict treatment outcome and efficacy. Promising non-invasive imaging-techniques have been suggested to assess tumor hypoxia and hypoxia-associated molecular responses. However, extensive validation in EC is lacking. Hypoxia-associated markers that are independent prognostic factors could potentially provide targets for novel treatment strategies to improve treatment outcome. For personalized hypoxia-guided treatment, safe and reliable makers for tumor hypoxia are needed to select suitable patients.

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HighlightsTH-302 combined with RT enhances tumor growth delay in esophageal cancer models.This combination does not increase normal tissue toxicity on the short and long term.The increased therapeutic index (1.38) paves the way for future clinical trials.

The survival of tissue-engineered mucosa (TEM) after implantation is mostly dependent on the presence of blood vessels for continuous oxygen supply. Therefore the stimulation of vascularization of TEM is essential to improve survival in vivo. Hyperbaric oxygen (HBO) treatment, used to improve wound healing, stimulates the secretion of angiogenic factors. In this study we evaluated the effect of daily HBO treatments on TEM for 1, 3, or 5 consecutive days. Overall histology with hematoxylin-eosin staining showed no apparent changes after one treatment. After three and five HBO treatments, the basal layer became irregular and pyknotic cells were observed. Measurements of the viable epithelium showed significant thinning after one and five treatments, however, proliferation was not affected. The angiogenic factors keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (FGFbasic), and placental growth factor (PlGF) were significantly increased after one HBO treatment, whereas after three treatments a significant decrease of FGFbasic and PlGF was seen. After five treatments KGF, PlGF, and vascular endothelial growth factor (VEGF) were significantly increased. One HBO treatment of TEM enhances the secretion of important angiogenic factors, hereby potentially improving the survival rate after in vivo implantation.

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