Proton therapy has emerged in radiotherapy for cases where tumors are located near anatomically sensitive areas [5]. Examples include tumors at the base of the skull, spine or its vicinity close to the brainstem, cranial nerves, and/or optic structures, as well as other tumors such as hepatocellular carcinoma to maximize the preservation of non-cancerous liver parenchyma or mediastinal lymphomas, which occupy a large area, and many more [6]. Maximizing the therapeutic ratio is the primary goal of radiotherapy, involving delivering lethal doses of ionizing radiation to the tumor while minimizing the dose to normal tissues [6]. In proton therapy, the beam energy can be directed to a precise depth, resulting in reduced toxicity compared to conventional photon radiation, as outlined in Table 1. This is achievable because proton beams deposit most of their energy at the end of their path as their velocity decreases, ultimately releasing all their energy, thus lacking an exit dose [7]. Consequently, the radiation dose increases to a certain peak, then sharply decreases and is not delivered beyond a certain range [7]. The position of the maximum dose deposition is termed the Bragg peak, illustrated in Fig. 1. In clinical proton therapy, a spread-out Bragg peak (SOBP) is commonly used to achieve tumor volume coverage [8]. The SOBP is a sum of several Bragg peaks with different ranges. In contrast, X-rays utilize photons, which enter and pass through tissues, depositing energy and exiting the body on the other side, constituting an exit dose that affects nearby tissues [7].

Comparison of depth dose curves for a 10 MV photon beam and a 10 MeV proton beam (shown with and without a SOBP). This figure shows the decreased entrance dose and absence of exit dose for the proton beam in comparison to the photon beam. [15] –with the author's permission Torunn I. Yock

In proton therapy, a significant group of patients comprises young individuals, especially children, adolescents, and young adults, due to the lower likelihood of complications to normal tissues with this therapy [6]. In the UK, a foreign proton therapy program was launched in 2008, with 1144 patients approved for therapy [9]. Pediatric patients represent 65% of all enrolled patients, while adolescents and young adults account for 12%. Proton therapy is likely to reduce the risk of growth and development disorders, endocrinological dysfunction, reduced fertility, and secondary tumors in children, adolescents, and young adults [10]. Another significant group comprises pregnant patients with brain tumors or tumors within the head and neck region. Study results show that the average measured equivalent dose to the fetus, considering photons and neutrons, for brain plans was 0.4 mSv for pencil beam scanning proton therapy (PBS-PRT) and 7 mSv for conventional radiotherapy (XRT) [11]. For head and neck plans, the values were 6 mSv and 90 mSv for PBS-PRT and XRT, respectively [11]. This represents a 15-fold reduction in fetal dose for head and neck tumors and a 17.5-fold reduction for brain tumor locations.

To maximize the benefits of proton therapy in preventing late radiation side effects compared to photon therapy, appropriate patient selection is necessary [12]. Various tools are used for this purpose, including Normal Tissue Complication Probability (NTCP) models, cost-effectiveness modeling, or radiation dose comparisons [13]. The most commonly reported clinical indication for patient selection for proton therapy was head and neck cancer (48% of studies), where dose comparison methods were most frequently employed [13]. In patient groups with head and neck tumors, the changing anatomy of the patient during proton therapy is of great importance. Patient anatomical changes concerning changes in tumor volume and the volume of surrounding normal tissues translate into a significant difference between the planned and actually delivered dose range. Protons are highly sensitive to tissue inhomogeneities along the beam path, and therefore, patient configuration errors, in some cases, can seriously jeopardize the proper delivery of the intended radiation dose, thus complicating locoregional control [14].

Since the advent of proton therapy, the number of patients receiving such treatment has been gradually increasing worldwide [16]. The intensive advancement of science provides increasing evidence of the effectiveness of proton therapy, leading to continuous expansion of indications for the use of this therapy. Regarding pediatric patients, proton therapy is indicated for the majority of benign and malignant tumors in children: chordomas and chondrosarcomas within the skull base or spine, nasopharyngeal carcinomas, meningiomas, Ewing's sarcomas, intracranial embryonal tumors, rhabdomyosarcomas, optic nerve tumors, and other low-grade gliomas [13]. Due to the physical properties of protons and well-documented results of proton therapy, there is consistency among various foreign centers regarding this matter [17]. However, in the case of adult patients, their selection for proton therapy is variable. Indications for proton therapy in the UK, United States, Canada, the Netherlands, Australia, and New Zealand were consistent only for chordomas and chondrosarcomas within the skull base or spine [13]. This difference arises from insufficient scientific evidence confirming greater benefits of proton therapy compared to conventional photon radiation in the adult patient group.

Nevertheless, the utilization of proton therapy for extracranial tumors is increasing worldwide with the emergence of new studies in this area. In prostate cancer, proton therapy and intensity-modulated photon therapy have shown very good and comparable long-term disease control outcomes [18]. Data on reduced rates of secondary malignant tumors in the proton therapy-treated group have also been obtained, although they are purely hypothetical and require further investigation [18]. Results comparing both methods in the treatment of uterine cancer indicate that proton therapy may reduce the frequency of diarrhea at the end of radiotherapy and lower the risk of fecal incontinence after 12 months compared to intensity-modulated photon therapy [19]. In a meta-analysis evaluating the effectiveness and safety of proton and photon therapy in esophageal cancer patients, proton therapy was associated with reduced doses to at-risk organs, lower toxicity, and improved prognosis compared to photon therapy [4]. These presented results are very promising but should be further confirmed in future randomized clinical trials. Selected research outcomes of proton therapy application in liver, esophageal, lung, bladder, kidney, biliary tract, and rectal cancers are presented in Table 2 [20,21,22,23,24,25,26,27,28,29].