Ion therapy guideline (Version 2020)

Charged particle radiotherapy can be traced back to 1954 when Lawrence Berkeley National Laboratory launched proton therapy. After experimentation with different kinds of particles, including neutrons, mesons, helium ions, and neon ions, the National Institute of Radiological Sciences in Japan started using carbon ions for cancer treatment. Proton therapy has the physical advantage of the Bragg peak, which can well realize the high-dose distribution in the tumor target volume and the low-dose distribution in surrounding normal tissue, so proton therapy has found wide applications in the field of ion radiotherapy. Nevertheless, the physical dose distribution and biological characteristics of carbon ions are significantly superior to those of other particles. Compared with the conventional photon radiotherapy, carbon ion radiotherapy stands outwith its favorable radiophysical and biological advantages.1 In the current clinical practice, heavy ion radiotherapymainly refers to the carbon ion radiotherapy. So far, although some textbooks and publications have provided references for standardized applications of ion radiotherapy, there has not yet been any consensus to guide clinical practices. With the rapid development of ion radiotherapy in China, and the increase of proton and heavy ion therapy centers, ion radiotherapy, which serves as a promising radiotherapy technology, has been applicable to more and more indications. Nevertheless, there has not yet been a guideline to guide ion therapy clinical practices based on national circumstances

linear energy transfer difference between proton and carbon ions, they have their own physical characteristics.
The physical characteristics of protons are as follows: (i) nearly three-dimensional dose distribution can be formed in longitudinal and transverse directions; (ii) the penumbra edge is very sharp due to the proton energy deposition track being an approximate straight line; and (iii) the proton beam hardly deposits any dose outside the far edge of the Bragg peak by limiting the range. 3 The physical characteristics of carbon ions are as follows: (i) com-

Biological characteristics
Protons belong to the low linear energy transfer beam that maintains a low relative biological effect (RBE) in radiobiology, although they have physical properties of the Bragg peak. The RBE of protons is 1.1-fold compared with photon rays.
Carbon ion therapy is a kind of high linear energy transfer beam, which can cause high ionization density and a severe DNA damage rate by radiation damage, mainly DNA double strand damage, resulting in high cell mortality. Carbon ions have the following biological effects: (i) higher RBE, which is generally 2-5-fold compared with photon rays; (ii) lower oxygen enhancement ratio, which can effectively treat hypoxic tumors that are resistant to photon rays; and (iii) less dependence on the cell cycle, as it has a higher radiosensitivity to Sphase cells resistant to photon rays. Therefore, the modes of cell death caused by carbon ion radiation are more diverse, including apoptosis, necrosis, autophagy, premature senility, accelerated differentiation, delayed proliferation, and death of offspring cells and bystander cell death, and so on. In view of the aforementioned physical and biological characteristics, carbon ion therapy can use fewer fractions and shorter time to treat cancer. 5

INDICATIONS OF ION THERAPY
Proton therapy has a wide range of indications, covering almost all types cancers using photon radiotherapy, which has certain advantages in reducing the toxicity and side-effects of normal tissue, and is more suitable for children with cancer. Because of its special physical and biological advantages, carbon ion therapy has prominent superiorities in insensitive tumors with photon radiotherapy, hypoxic tumors, reradiotherapy of recurrent tumors, and some tumors in special sites.
With reference to the existing research results, the indications of carbon ion therapy are summarized as follows.

4.3
History of radiotherapy 1. The same site has received radiotherapy during a short time, or the site has received two or more treatments of radiotherapy; 2. Serious radiation injury, such as unhealed skin ulcer, pulmonary fibrosis, tissue necrosis, or severe luminal narrowing caused by radiation, has occurred at the radiotherapy site.

IMPLEMENTATION OF ION RADIOTHERAPY
The physical characteristics, biological advantages, and beam delivery system of the ion beam should be fully utilized to successfully implement ion radiotherapy.
According to different beam delivery systems, there are two main ion therapy techniques, one is passive scattering and another is the pencil beam scanning technique, the latter has better conformability.
Many ion treatment planning systems are currently available in clinical research or practice, such as Raystation, HIPAN, Xio-N, CiPlan, and Syngo. In the design of treatment planning, single-field optimization or intensity-modulated (multi-field simultaneous optimization) method can be selected for plan optimization. The former has better robustness, and the latter has better conformability. Repeated scanning (rescanning) techniques can further increase the accuracy of dose delivery to moving targets. 40 The clinical dose is defined as the RBE weighted dose, expressed in Gy (RBE). 41 Dose-volume histograms are also suitable for the assessment of ion radiotherapy plans, and the criteria for dose distribution are generally 95% of the prescribed dose line covering 99% of the clinical target volume (CTV) and 90% of the prescribed dose line covering 90% of the planning target volume volume. 42

Positioning
Computed tomography (CT) images of the patients are the basis for treatment planning design. Given that the dose distribution of ionizing rays is greatly affected by tissue densities, it is important to accurately fix patients according to the treatment requirements. According to the characteristics of the beam delivery system at each treatment unit, the angle of the treatment port and the tumor site determine the incident angle of the ion beam, and then design simulation positioning using individualized fixtures. 43 The supine or prone position is usually used for trunk tumors (depending on the location of the tumors), with both hands placed above the top of the head or on both sides of the body, and the lateral or oblique position is avoided as much as possible; Ocular tumors usually require a special beam and treatment room, and a special treatment chair has been designed to use the sitting position for treatment. 44 The design of the therapeutic bed should fully consider the characteristics of ion radiotherapy equipment beam delivery system, allowing the

Definition and delineation of target volume
The target definition of ion therapy is carried out according to the prin- Ion therapy differs from photon radiotherapy in that planning target volume needs to consider the influence of beam range uncertainty.
Depending on the depth of the tumor, a boundary of 0.3-0.5 cm is generally added to the lateral side of the radiation field, and a boundary of 0.7-1.0 cm is added along the incident direction. 47 If using a pattern of carbon ion combined with photon or proton to treat cancer, the target volume is delineated the same as photon radiotherapy. In general, photon or proton is used to radiate CTV, and carbon ion radiates GTV for a boost.

Dose constraints for organs at risk
There is no uniform standard for the limit of organs at risk (OARs) in ion therapy. At present, it mainly refers to the data of photon radiotherapy.
For hypofractionated radiotherapy, the early and late toxicity of each OAR should be fully considered, and the dose should be strictly limited with reference to stereotactic body radiation therapy. Referring to the OARs dose limitation of proton and carbon ion therapy in Japan and Shanghai, China, the recommended dose of OARs is shown in Table 1.

Position verification
All kinds of ion therapy devices should be equipped with an imageguided treatment system. Cone beam CT or digital radiography imag-ing is usually used for position verification, and it is associated with the treatment control system to realize online position correction. It is required to correct the position of the treatment bed until the position difference between the verified image and reference image in all directions is <3 mm before ion treatment. 42 In addition, radioactive isotopes are produced when proton or carbon ions collides with the nucleus of the target substance, and positron is emitted in a short period of time. PET can be used to monitor the position of the positron, so as to verify the actual dose distribution of ions.
It is suggested that the ion therapy center can carry out the relevant research to verify the actual dose distribution using PET in ion therapy.

RECOMMENDED DOSE OF ION THERAPY FOR VARIOUS CANCERS
The indications for proton therapy are basically the same as those for photon therapy. The treatment plan basically references the dose fractionation patterns of photon therapy. The proton therapy for pediatric tumors mainly refers to the treatment recommendations in the International Consensus on Proton Therapy for Pediatric Tumors. 55 There is no standard guideline for carbon ion therapy, and a vari-  (Table 2) and Shanghai Proton and Heavy Ion Hospital in China (Table 3).

COMPLICATIONS OF ION RADIOTHERAPY
Complications of ion therapy are basically consistent with the conventional photon radiotherapy. In general, the incidence of serious adverse events caused by ion therapy is lower than that of photon radiotherapy because of the physical advantages of ion therapy. As the normal tissue dose limit of carbon ion therapy has not been clarified, it is Organs at risk (OARs) dose constraints are equal to intensity-modulated radiation therapy for proton therapy, but for carbon ion therapy, they mainly refer to the clinical experiences from the National Institute of Radiological Science in Japan recommended to monitor and record the adverse events in detail during ion therapy in a timely manner, so as to establish the dose-effect relationship of OARs and collect original data. The long-term toxicity of OARs after high-dose irradiation should be closely observed.

Common complications of ion therapy for head and neck cancer
Compared with photon radiotherapy, ion therapy can reduce the dose to the retina, optic nerve, optic chiasm, cochlea, parotid gland, and brainstem, and reduce the incidence of acute oral mucositis, prolonged xerostomia, and other toxicity and side-effects, significantly reducing the incidence of late radiation-induced brain injury (for example, the incidence of radiation-induced brain injury of skull base malignant tumors is <3%), and significantly improving the treatment tolerance and quality of life of patients. Prospective studies indicate that the grade 3 mucosal reaction of proton therapy for nasopharyngeal cancer is 11%, which is much lower than the 30-40% of intensity-modulated radiation therapy, and no grade ≥4 toxicity. 56,57 According to reports of many carbon ion therapy centers, carbon ion therapy has more advantages in reducing adverse events, as the incidence of late adverse events is approximately 1-7%, and most adverse events were mild to moderate. The late severe toxicity of carbon ion therapy in re-irradiation was significantly reduced compared with re-irradiation of photon (the incidence of grade ≥3 toxicity was ∼7%). 58

Common complications of ion therapy for thoracic tumors
Ion therapy has a lower incidence of grade ≥3 radiation pneumonitis than stereotactic body radiation therapy to early-stage lung cancer. For patients combined with interstitial pneumonitis, the incidence of radiation pneumonitis will increase after ion therapy.
For locally advanced lung cancer, the most common complications of ion therapy are radiation pneumonitis and radiation esophagitis.
Prospective studies have found that the incidence of grade 2 radiation pneumonitis with carbon ion therapy is approximately 6%, grade 3 radiation pneumonitis is approximately 2%, and the incidence of grade 3 tracheo-esophageal fistula is approximately 2%. 59 After carbon ion reirradiation for locally recurrent NSCLC, only approximately 2.1% of patients experience grade 3 radiation pneumonitis. 60 Concurrent chemotherapy has the potential to increase the toxicity of ion therapy. What is worth paying great attention to is that the tumor shrinkage during concurrent chemoradiotherapy will lead to a higher than planned therapeutic dose to the esophagus or spinal cord behind the target volume. Therefore, adaptive radiotherapy techniques are especially warranted.

Common complications of ion therapy for abdominal and pelvic tumors
The most common complication of ion radiotherapy for liver cancer is hepatotoxicity. The incidence is higher in patients who have poor basic liver function, poor liver reserve before treatment or received previous radiotherapy. Therefore, it is essential to assess the liver function of patients before treatment. The injury of the biliary system is secondary, including inflammation of the hepatic duct or biliary stricture (14-28%), but also gastrointestinal toxicity, which may present with hemorrhagic duodenitis, hemorrhagic ulcers in the colon, and   The most common complications of ion therapy for pelvic tumors, such as rectal cancer and cervical cancer, are radiation enteritis and cystitis. 64 Overall, ion therapy has certain advantages in decreasing toxicity compared with traditional radiotherapy, but further study is still required.

Complications of ion therapy for bone and soft tissue tumors
Ion therapy, like photon radiotherapy, also has the following radiotherapy complications: delayed postoperative incision healing; abnormal growth, and development of bone and soft tissue; limb length inequality (those with a gap of 2-6 cm use modified shoes, otherwise surgical correction is required); osteoporosis of the affected bone; increased risk of fracture; dysfunction caused by joint fibrosis; soft tissue edema; radiotherapy recall reaction caused by chemotherapeutic drugs; skin discoloration and/or telangiectasia; secondary second malignant tumors, and TA B L E 3 Dose fractionation patterns of many common cancers using proton and carbon ion (LEM model)  The above dose fractionation patterns refer to clinical practice in Shanghai Proton and Heavy Ion Hospital, China. ACC, adenoid cystic carcinoma; C, carbon ion therapy; HCC, hepatocellular carcinoma; MMM, mucosal malignant melanoma; NPC, nasopharyngeal cancer; P, proton therapy; X, X-ray radiotherapy. so on; and there is still a lack of data for direct comparison with photon radiotherapy. 65

EFFICACY EVALUATION AND FOLLOW UP AFTER TREATMENT
The efficacy evaluation method after ion therapy is basically the same as that of photon radiotherapy. For all cases, baseline and efficacy eval-