Ernest Rutherford found a light particle in an alpha particle and nitrogen gas collision experiment in the early 1900s. He named it “proton,” coming from “protos,” meaning “first.” In 1929, Ernest Orlando Lawrence invented a cyclotron to accelerate protons and developed it further during the 1930s to accelerate protons for a high kinetic energy [5]. The idea to use proton beams for cancer treatment was proposed by Dr. Robert Rathburn Wilson in 1946. The preclinical research to understand the biological effects of the proton beam was done by Cornelius Anthony Tobias and John Hundale Lawrence, M.D., younger brother of Ernest O. Lawrence, using a 184-inch synchrocyclotron at the Lawrence Berkeley Laboratory in the 1940s to 1950s. The first PT patient in the world was a metastatic breast cancer case who received beam irradiation in the pituitary gland region. John H. Lawrence treated the patient at the University of California, Berkeley, in 1954. In 1957, Uppsala University in Sweden started providing PT. In 1961, the Massachusetts General Hospital in the United States started PT using a cyclotron from Harvard. Before the 1990s, more than 10 facilities had treated patients using proton beams at the laboratory level [6].

The first hospital-based PT facility was installed in Loma Linda University Hospital in 1990. Actually, it was the first facility designed for commercial purposes, and then the number of PT facilities in the world increased rapidly. From 1954 to 2018, over 190,000 patients got PT at 78 facilities worldwide (Fig. 1) [7].

The first PT facility project in Korea was suggested by the government in the early 2000s. The NCC carried it forward with a government budget in 2001 through a contract with Ion Beam Application (IBA). The facility consists of a cyclotron that can accelerate proton beams to 230 MeV, 2 gantry treatment rooms, and 1 fixed beam treatment room. IBA started the installation of the PT system at the beginning of 2005 and finished at the end of 2006. The passive beam irradiation modes were installed for patient treatment with a 2-dimensional (2D) based patient positioning system and a 6 degree of freedom couch system at the initial installation stage. The wobbling beam mode and pencil beam scanning (PBS) mode were upgraded in 2010 and 2015, respectively (Fig. 2). The first PT patient was a prostate cancer case who got treatment in March 2007 [8]. By the end of 2018, a total of 2,914 patients had received proton treatment at the NCC Korea (Fig. 3).

The SMC in Seoul opened the second PT facility in Korea in 2015. They introduced a PT system manufactured by Sumitomo Heavy Industry (Tokyo, Japan). The accelerator is a cyclotron with 230 MeV proton beam energy. It has 2 gantry treatment rooms with PBS dedicated nozzles and multipurpose nozzles. SMC PT started patient treatment at the end of 2015 and treated 1,250 patients by the end of 2018 (Fig. 4).

There are more than 10 PT solution providers, and each solution has been developed with its own design. So, there is a lack of user reference and guidelines for ATP. It is recommended that physicists use vendor guidelines for beam calibration and machine alignment in advance of the ATP. Actually, there are two groups of control values. One is machine parameter tolerance level values that were specified on the purchase contract. The other is machine parameter limitation values related to machine performance. Generally, the vendor engineers finish the calibration and alignment work within contractual conditions. The physicist can cooperate with them to tune the machine more precisely over the contractual values, which can reduce the ATP time.

Commercially available TPS models for PT are limited. Varian has their own PT solution and TPS. The other PT vendors need to collaborate with TPS providers for the development of a dedicated TPS solution. Sometimes, PT customers should be involved in the development of TPS for their preferred TPS solution; however, this requires more time and cost.

For the commissioning of TPS, the physicist has two main work items: CT Hounsfield unit (HU) calibration to proton beam stopping power ratio and beam modeling [23]. The proton beam stopping power ratio values of human organs are not linear to CT HU values. So, finding the best fitting curve of CT HU versus proton stopping power for the PT system is important. It is related to beam range uncertainty in proton planning. The proton beam data measurement for beam modeling [24] requires different dosimetry tools for the X-ray and the electron beam. The current main beam delivery technique is PBS in PT. The essential beam parameters are the beam profile and irradiation depth dose distributions of the pencil beam. To measure them, the scintillator and CCD combination system [25,26] and the multilayer ionization chamber types are used. As an indirect beam measurement, the Monte Carlo simulation modeling and calculation method is useful for TPS model commissioning [27 -29].

The American Association of Medical Physics (AAPM) task group 224 published a report titled “Comprehensive Proton Therapy Machine Quality Assurance” in August 2019 [22]. It describes the various beam delivery techniques in PT and is recommended as a good reference in PT QA. It categorizes 4 parts: dosimetry QA, mechanical (gantry, couch, snout, MLC, and alignment between beam and X-ray) QA, motion and radiation safety [30], and imaging QA. The medical physicist in a PT facility should determine their optimized machine QA period and check items, after considering machine specifications and clinical protocol.

The range uncertainty of the treatment proton beam is the most sensitive and critical parameter on proton treatment planning. Especially, the patient who has any implanted metallic material on the beam pathway should be considered carefully because this changes the beam range and perturbs dose distribution on treatment planning [31,32]. TPS has a limitation; it must calculate dose distribution accurately in the inhomogeneous tissue region with analytical beam modeling, and the Monte Carlo simulation method has recently been adapted to improve the dose calculation accuracy. The variable RBE [33] consideration is also a recent emerging issue in plan optimization. Currently, the recommendation for proton RBE values is 1.1 in clinic. However, it increases more than 1.1 in the distal falloff and could damage the OARs near the tumor. As a future feature of TPS, the proton RBE models based on LET and the α/β parameter of the linear quadratic model should be introduced for plan optimization. The physicist should carefully quantify the effects of patient setup variation, intra- and inter-fraction motion, and range uncertainty based on the specifications of beam delivery, patient imaging, and the alignment system in their PT facility. Especially, the range uncertainty of the treatment beam depends on the pathway and tissue type in the pathway. So, the field specific margin of target and beam angle dedicated planning target volume (PTV) are needed when planning. Generally, the uncertainty of HU versus relative stopping power (RSP) is 2.5% to 2.7% of range and setup error is 1.0–3.0 mm in PT. For the evaluation of target coverage and dose to the OARs in treatment, worst case scenarios need to be simulated and calculated with the internal margins and safety margins before the decision on a treatment plan. This is called “robustness evaluation.” To achieve a good robust treatment plan, close communication is necessary between the physicist and physician for potential target coverage limitations and possible OAR overdose. There are two proton beam delivery techniques: the passive beam mode using aperture and range compensator [34] and the PBS mode. The DQA of passive beam mode checks output factor, beam range, and width of SOBP [35]. The DQA of the PBS plan is similar to the X-ray IMRT DQA and evaluates the 2D dose distribution at several depths on the target volume.

The total number of PT patients at NCC in Korea was about 3,300 at the end of 2019, and the daily number of patients is about 40. Fig. 12 shows the PT indications at the NCC in Korea. The major indication was prostate cancer cases before 2015 because PT was not reimbursed by National Health Insurance expect for pediatric cancer. Since the National Health Insurance started reimbursing for almost all cancers except for breast and prostate, liver, lung, and brain cancer patients have increased at the NCC in Korea. The ratio of proton treatment patients to total new patients in the department of radiation oncology doubled from 7%–8% to 15%–16%.

The most compact PT is the Mevion system among the currently running PT systems. Its footprint is less than 180 m². Vendors are trying to develop PT solutions of more compact size with more user friendly operational systems. This will reduce the maintenance cost of PT systems and building construction costs. Another way to create a cost effective system is to increase patient throughput. Dynamic volumetric proton arc therapy can provide high patient throughput by reducing beam delivery time and patient setup time.

Proton beam range uncertainty mainly comes from converting the CT-HU value to proton stopping power ration. At present, proton planners apply about 3.5% beam range margin. There are several efforts, like proton CT, multi-energy X-ray CT, and Monte Carlo simulation method to reduce it.

Developing a technique for flash therapy is a hot topic for the big vendors of PT. There are many challenging issues before this can be a practical technique for clinical use, as I mentioned in the previous section. If it is successful, it will be a revolutionary technique to open a new era in PT. Because it will reduce total patient treatment time dramatically, with one day and less than 1 second beam irradiation time keeping clinical benefit. It can also enlarge the clinical indication, like a moving target. Still, there are unknown mechanisms and many technical barriers to overcome.