Current Drug Therapy, 2007, 2, 105-109 105 1574-8855/07 $50.00+.00 ©2007 Bentham Science Publishers Ltd. A Review of the Current Role of Proton Therapy in Modern Oncology Maurizio Amichetti 1,* , Augusto Lombardi 2 , Carlo Algranati 1 , Marco Schwarz 1 , Marco Cianchetti 1 and Lamberto Widesott 1 1 ATreP, Provincial Agency for Proton Therapy, Trento, Italy; 2 INFN Laboratori Nazionali di Legnaro, Legnaro, Padova, Italy Abstract: Proton therapy (PT) is a high-precision form of radiotherapy. The interest in clinical application in oncology of PT is related to its ballistic selectivity capable to adequately cover the tumor target with high homogeneity, high confor- mality and sparing the surrounding organ at risk (OAR), mainly in the middle-low dose area, with a potential significant reduction of toxicity and development of radio-induced second tumors. PT has gained a renewed interest in very recent years after its first pioneering beginning in Berkeley in 1954 due to the advancement in treatment planning, delivery sys- tems (gantry), radiobiological knowledge and clinical imaging. This fact has permitted the transit of PT from laboratory research structures to modern clinically-oriented treatment facilities. The results of PT in some specific sites such as ocu- lar tumors and base of the skull tumors are well known approaching local control rates at five years of 100% and 90%, re- spectively. Indications are now evolving towards the treatment of other very common tumors such as lung, head and neck, liver: all of them show very attractive response rates. A particular interest is now growing for pediatric tumors considering the possibility of reducing not only the dose to OAR but also the integral dose. Integration with chemotherapy represents another challenge thanks to the possibility of increasing dose intensity of chemotherapy or total radiation dose and/or re- ducing the toxicity of the combined treatment. Key Words: Proton therapy, radiotherapy, chemotherapy, cancer. INTRODUCTION The use of Proton beams has been proposed in 1947 by R. Wilson. The first proton therapy was carried out in 1954 with the Bevatron accelerator at Berkeley, and to date, ac- cording to data from PTCOG [1], as of July, 2005, more than 42.000 patients had been treated using protons around the world. Protons and other light ions have been experimentally evaluated over the past four decades at a number of centers throughout the world but mainly in laboratories for nuclear physics research, on a limited time basis with extremely re- stricted beam access, using machines designed and opti- mized for fundamental research. Only recently thanks to positive and suggestive clinical results and improvement in systems of image-guided treatment planning, accelerator control, beam delivery, and patient positioning, a number of hospital-based proton medical facilities perform the medical treatments allowing therapy to be offered more widely and with the characteristics of a modern radiation treatment [2,3] passing from the treatment of rare tumors to more common sites. PHYSICAL PROPERTIES AND NORMAL TISSUE SPARING Proton treatment is a precise form of external radiation treatment that uses electrically charged particles, the protons, to target a given tumor volume sparing as much as possible the surrounding tissues. The proton beam radiation therapy (RT) uses special machines, the particle accelerators, called cyclotron or synchrotron to energize protons. The protons are extracted from the accelerator and directed to the patient *Address correspondence to this author at the ATreP, Provincial Agency for Proton Therapy, Via Perini, 181, 38100 Trento, Italy; Tel: +39-0461.390409; Fax: +39-0461.391648; E-mail: amichett@ect.it using magnetic field channels and special focussing elements to have the proper spot dimensions. The main advantage of the use of protons over photons, used in conventional radiotherapy, has to do with the way their energy is released. X-rays are highly penetrating elec- tromagnetic waves and when used in radiotherapy, they de- liver dose throughout the entire volume of the irradiated tis- sue, almost regardless of its thickness. For tumors located deep in the body, a substantial dose is inevitably delivered to the normal tissues anterior and posterior to the tumor. By using photon beams from multiple directions centered on the tumor (multiportal treatment), the maximum dose is concen- trated within the tumor volume. However, many tissues along the directions of beam arrival are irradiated, even though with smaller doses. Unlike X-rays, the delivered dose of a proton beam increases very gradually with increasing depth and then suddenly rises to a peak at the end of its track where the particles are very close to rest; this is the so-called Bragg Peak (Fig. 1). The location of this peak depends on the proton energy selected to precisely direct the Bragg Peak at the depth of the tumor volume. The range may be modulated, either by changing the initial beam energy or by placing custom de- signed absorbing filters in the primary beam for producing spread-out Bragg peaks (SOBP) that cover larger targets treatable with pristine Bragg peaks. Consequently the dose released around the tumor volume is much less than the dose delivered in the tumor itself, thus sparing normal tissues. This delivering mechanism results in a much lower dose to normal tissues surrounding the lesion. It also enables deliv- ery of higher treatment doses to the tumor, allowing for the sparing of all normal tissues beyond the tumor volume. The feasibility of delivering higher doses to the tumor can lead to