Correspondence to: Filippo Alongi, MD, Researcher, Radiotherapy, Scientific In- stitute H San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Tel +39-02- 26435458; fax +39-02-26435451; e-mail filippo.alongi@hsr.it Received May 22, 2009; accepted June 11, 2009. LETTERS TO THE EDITOR Radiobiology and molecular oncology: how are they changing radiotherapy in clinical practice? Filippo Alongi 1,2,3 and Nadia Di Muzio 2 1 Institute of Molecular Bioimaging and Physiology, National Rese- arch Council (IBFM-CNR); 2 Radiotherapy, Scientific institute San Raffaele, Milan, 3 Intraoperative Radiotherapy, Breast Unit, San Raf- faele-G.Giglio Foundation, Cefalù, Italy To the Editor: At the 4 th International Conference on Translational Research and Preclinical Strategies in Ra- diation Oncology (ICTR) held in Geneva, Switzerland, on March 11-13, 2009, more than 270 experiences from many parts of the world regarding innovation in radio- therapy approaches to cancer and radiation biology re- search were presented 1 . This confirmed the growing in- terest of radiation researchers in conducting preclinical studies at their centers and translating the results as soon as possible to clinical radiotherapy practice. Recent papers have greatly enriched the current knowledge of radiation oncology, especially radiobiolo- gy and molecular oncology, and this has radically changed the oncology practice in radiation therapy in just a few years 1-17 . Radiotherapy is currently in the midst of new devel- opments both in technology and radiobiology. High- tech improvements are refining the “ballistic” approach to delivering radiation to target volumes and the sur- rounding organ tissues by means of intensity-modulat- ed radiation therapy or high-LET ionizing radiation as represented by protons and other hadrons 2,3 . The quali- ty of images utilized in the control and monitoring of setup and tumor variations during treatment with im- age-guided radiation therapy devices is now at the same level as fine diagnostic radiology, and permits greater precision than was possible in the past 3 . However, the real revolution in radiotherapy derives from the stronger correlations between new radiobiological data and experimental results that are increasingly available and ready to be translated to clinical practice 4 . The long-term objective of the translational research program in radiation oncology is to improve the thera- peutic window, minimizing the damage to normal tis- sue and increasing the efficacy of radiation in eradicat- ing cancer. The selective inactivation of tumor cells in a solid mass is the most important finding related to the eradication of tumors by means of radiation without se- verely damaging healthy surrounding tissue. Recent ex- perimental research has reported that tumors can be expected to recur after ionizing radiation treatment even if only one cancer stem cell survives 5 . Cancer stem cells are a specific subpopulation of cancer cells with high tumorigenic potential. In terms of clinical applica- tion, it should be investigated how cancer stem cells can be selectively destroyed, and whether they may respond differently to more selective radiotherapy and a more selective combined radio-pharmacological modality 6 . Radiation therapy can be customized to the individ- ual patient and the effectiveness of radiation can be en- chanced by targeted vector delivery and transcriptional regulation if a pathway in the tumor microenvironment is expressed, which will lead to selective eradication of the tumor. Studies are currently investigating, for exam- ple, the role of enzyme-inducible nitric oxide synthase (iNOS), which plays an important role in the proapop- totic and radiosensitizing effect on tumor cells. Gene therapy can thus permit, directly or indirectly, various degrees of radiosensitivity, with the endpoint of improv- ing the effectiveness of radiation 7 . Biological heterogeneity of neoplastic cells is an im- portant factor in the variable radiosensitivity within a tumor mass. Selective dose escalation to the more ra- dioresistant parts of the lesion is considered feasible af- ter the use of dose painting based on the increased availability of molecular imaging technologies such as PET, SPECT and MR imaging/spectroscopy 8 . High me- tabolism, high proliferation, and increased hypoxia now represent the targets for higher doses of radiation. New biological molecules fundamental in the tumor profile are being studied to reveal these and other fea- tures in detail. Hypoxia, for example, is known to be in- volved in the radioresistance of cancer. Hypoxia can be measured using 18FDG, 18F-labeled nitroimidazoles, and Cu ATSM, and has been demonstrated as a prog- nostic factor in many clinical studies 9 . “Theragnostic imaging” in radiotherapy is a new term used to de- scribe the introduction of molecular images to define and more selectively treat each voxel of tumor volume with dose painting based on biological and functional characterization 10 . This type of approach is currently being routinely applied in many radiotherapy centers for various solid cancers, such as tumors of the head and neck area. The correct determination of the single patient pro- file as well as single tumor behavior is the next challenge in radiation oncology. The routine personalization of treatment schedules will increasingly involve radiation oncology patients, as is currently the case with chemotherapy, by means of an individualized pharma- cological approach where all predictive and prognostic factors are taken into account. Tumori, 96: 175-181, 2010