Results of a european randomized trial of Etanidazole combined with radiotherapy in head and neck carcinomas

Eschwège, F.; Sancho‐Garnier, H.; Chassagne, D.; Brisgand, D.; Guerra, Marta; Malaise, E.P.; Bey, P.; Busutti, L.; Cionini, L.; Nguyen, Tan Dat; Romanini, A; Chavaudra, J.; Hill, Catherine

doi:10.1016/s0360-3016(97)00327-1

Cited by 70 publications

(19 citation statements)

References 10 publications

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“…The first of these was a European trial with pimonidazole in uterine cervical cancer, but the preliminary results were disappointing [ 42 ]. Etanidazole was then tested in two other multicenter trials in head and neck cancer, but the results showed no benefit [ 43 , 44 ]. Additional studies with nimorazole, a less efficient sensitizer but less toxic drug, in head and neck cancer patients (DAHANCA 5) showed a highly significant benefit in terms of improved locoregional tumor control and disease-free survival [ 31 ].…”

Section: Approaches For Dealing With Hypoxiamentioning

confidence: 99%

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

2016

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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.

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Section: Approaches For Dealing With Hypoxiamentioning

confidence: 99%

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

2016

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“…Although pimonidazole showed no significant benefit in combination with conventional radiation therapy for the treatment of cervical carcinoma, it is widely used for hypoxic cell imaging using immunohistochemistry (38). Etanidazole progressed to phase 2 and phase 3 clinical trials, but it too showed no positive improvement to treatment of squamous cell carcinoma of the head and neck (HNSCC) or small cell lung cancer (SCLC) in combination with radiation therapy (39,40).…”

Section: Combining Haps With Ionizing Radiation Nitro-based Hapsmentioning

confidence: 99%

Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy

Mistry

Thomas

Calder

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

112

117

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With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level.

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“…Unfortunately, the results from numerous major clinical trials were largely discouraging [19–21]. Second-generation agents did not fare much better with the European etanidazole (ETA) trial demonstrating no advantage of adding the drug to RT [22], and the Radiation Therapy Oncology Group ETA trial failing to show advantage of using the drug on the trial population as a whole [23]. …”

Section: Need For Novel Radiosensitizers: Past Present and Future Attementioning

confidence: 99%

Towards Novel Radiosensitizing Agents: The Role of Cytosolic PLA2α in Combined Modality Cancer Therapy

Craft

Hallahan

2011

Future Med. Chem.

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The radioresistant nature of some tumors serves as an obstacle to curative therapy for several poor-prognosis malignancies. The radiosensitivity of a cancer is dependent not only on the intrinsic ability of tumor cells to recover from radiation-induced damage, but also the ability of stromal elements (e.g., vasculature) in the tumor microenvironment to survive and continue proliferating in the face of ionizing radiation. In this regard, it is important to understand the initial events activating radiation-induced signal transduction pathways. Among these events is the activation of cytosolic phospholipase A2α and the subsequent production of the lipid second messengers. These events occur within minutes following exposure to ionizing radiation, and have been shown to enhance cell viability through a number of prosurvival signaling pathways. Furthermore, inhibition of cytosolic phospholipase A2α has now been shown to reduce the viability of endothelial cells in culture after exposure to ionizing radiation, as well as slowing the growth of tumors in animal models of cancer.

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Results of a european randomized trial of Etanidazole combined with radiotherapy in head and neck carcinomas

Cited by 70 publications

References 10 publications

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

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

Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy

Towards Novel Radiosensitizing Agents: The Role of Cytosolic PLA2α in Combined Modality Cancer Therapy

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