Progress of Carbon Ion Beam Radiotherapy for Cancer

Progress of Carbon Ion Beam Radiotherapy for Cancer

中国肿瘤 2019 年第 28 卷第 3 期  China Cancer,2019,Vol.28,No.3

CHEN Wei-zuo¹, TANG Jun-xia², ZHAO Da³, GUAN Quan-lin³, PAN Ting-ting²

（1. Gansu Heavy Ion Hospital, Wuwei tumor Hospital, Wuwei 733000, China; 2.The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China; 3.The First Hospital of Lanzhou University, Lanzhou 730000, China）

Abstract: Carbon ion beam radiotherapy (C-ion RT, CIRT) has the advantages of precise dose distribution, ideal biological effects, and dynamic beam monitoring, which can significantly decrease the damage to normal tissues while killing tumors strongly and reduce the treatment time. The treatment efficacy of CIRT for adenoid cystic carcinoma, osteosarcoma, hepatocellular carcinoma are well acknowledged. CIRT is thus quickly developed in German, Japan, and other countries, however, it is still in clinical trial stage in China. This article reviews the principle, advantages and clinical research status of CIRT for tumors.

Key words: Carbon ion beam; cancer; lung cancer; liver cancer; radiotherapy

Chinese Library Classification Number: R730.55  Document Code: A  Article ID: 1004-0242(2019)03-0208-06 doi: 10.11735/j.issn.1004-0242.2019.03.A009

For a long time, malignant tumors have been an important disease threatening the health of global human beings. Data from the Global Burden of Disease Study project in 2015 showed that tumors were the second leading cause of death globally ^[1]. The main treatment methods for malignant tumors include surgical therapy, chemotherapy, radiotherapy, etc. Among them, radiotherapy has always occupied an irreplaceable and important position in the comprehensive treatment of tumors. Conventional radiotherapy has currently developed into intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), volumetric-modulated arc therapy (VMAT) and other precise radiotherapies, which have significantly reduced to normal tissues and the side effects of radiotherapy compared with before, but still have not reached a satisfactory level. In recent years, heavy ion radiotherapy has become a cutting-edge technology in tumor radiotherapy, its potential advantages are constantly being explored, and the curative effect of treating tumors has been further affirmed.

1. Principle of Carbon Ion Therapy for Tumors

Heavy ions refer to particles heavier than helium, the second element in the periodic table, that have been ionized. An ion beam is used to bombard a gold target, and the scattered ion beam after elastic scattering is used as the radiation source. By utilizing the defocusing effect of the main quadrupole and multipole magnets of the Q3D magnetic spectrometer, the scattered ion beam is evenly spread in the vertical and horizontal directions. Through the methods of wave speed scattering and wave speed scanning, the ion beam is evenly and accurately irradiated on the tumor area ^[2].

As the most widely studied heavy ion at present, carbon ions have a high linear energy transfer (LET). Along the penetration path, carbon ions can produce strong local ionization. Compared with traditional photon radiation, they can induce more severe radiation damage. Ionizing radiation causes damage to the base sites of DNA molecules through direct and indirect effects, leading to single-strand breaks (SSBs) or double-strand breaks (DSBs) in DNA ^[3]. Evidence shows that high LET radiation can induce two or more damages in the local DNA of tumor cells ^[4]. The above damages are called DNA cluster damage. This type of damage hinders the repair of tumor cell DNA by affecting the binding of repair enzymes to DNA fragments, thereby causing cell death or misrepair. Carbon ion irradiation kills tumor cells through the above-mentioned cluster damage. Traditional low LET radiation, such as X-rays, mainly causes independent DNA single-strand or double-strand breaks in tumor cells, and tumor cells can repair this type of damage with high fidelity, for the more complex and diverse DNA cluster damage caused by heavy ions, it is less likely to be repaired. DNA cluster damage is an important mechanism by which carbon ions kill tumor cells ^[5].

2. Advantages of Carbon Ion Therapy for Malignant Tumors

As a current frontier and hot topic in medical research, carbon ion therapy for malignant tumors has incomparable advantages over traditional radiotherapy, including precise dose distribution, strong tumor cell-killing ability, and controllability of the carbon ion beam. Fully utilizing the above physical and biological advantages of carbon ions in the treatment of malignant tumors can produce a series of clinical advantages such as good treatment effects, mild adverse reactions, and accurate positioning.

2.1 Accurate Tumor Positioning and Reduced Damage to Surrounding Tissues

The inversed dose profile is an important characteristic of carbon ions. Carbon ion beams belong to high LET rays. That is, when penetrating a target, they continuously collide with the extranuclear electrons of target atoms, causing energy loss. Moreover, the lower the ion energy, the higher the collision probability. Therefore, a high-dose energy loss peak, called the Bragg peak, is formed at the end of the ion range. The area in front of the peak with low energy and a flat section is the plateau region, and the energy drops sharply after the peak. The LET in the plateau region is lower than that of X-rays, while that in the peak region is much higher than that of X-rays. Utilizing this characteristic and adjusting the width and initial energy of the Bragg peak, the Bragg peak of the carbon ion beam is accurately distributed on the tumor through an accelerator, thereby killing the tumor to the greatest extent with little impact on the normal tissues in the plateau region. Combined with the sharp drop characteristic of the Bragg peak, the damage to the normal tissues around the tumor during carbon ion beam irradiation is reduced compared with conventional radiotherapy ^[6].

2.2 Strong Tumor-Killing Ability and Low Oxygen Dependence

Radiotherapy mainly achieves therapeutic effects by damaging the DNA of tumor cells. In most cases, conventional radiation rays interact with water and oxygen inside cells outside the G0 phase through radiation, generating free radicals to indirectly damage DNA single strands. This type of damage is relatively simple and highly oxygen-dependent (fewer free radicals are generated in a hypoxic environment), and tumor tissues can initiate repair mechanisms to effectively repair this damage. However, due to its high LET characteristics, carbon ion beams can cause complex cluster damage to tumor cell DNA at any stage of the cell cycle. This type of damage is difficult to repair and has low oxygen dependence. Therefore, carbon ions have a strong killing effect on common malignant tumors and even hypoxic tumor cells that are resistant to radiation, reducing the recurrence rate of tumors ^{[7, 8]}.

2.3 Real-time Observation of Treatment

In the low-dose tail region formed by10C and 11C near the end of the fall of the carbon ion Bragg peak, a positron beam can be generated. This positron beam can be monitored by PET, thereby tracking the distribution of the carbon ion beam in the human body, enabling real-time observation and control of patient treatment to achieve the best treatment effect. This is a unique property of carbon ions ^[9].

3. Clinical Status of Carbon Ion Therapy for Malignant Tumors

In the 1970s, the Lawrence Berkeley National Laboratory (LBNL) in the United States was the first to apply heavy ion therapy to tumors in clinical trials and achieved remarkable therapeutic effects. Subsequently, Japan, Germany, and successively carried out clinical research on heavy ion therapy for tumors. To date, more than 24,000 patients with tumors have been treated with carbon ion beams ^[10]. The number and types of malignant tumors treated with carbon ion beams continue to expand.

3.1 Head, Neck and Skull Base Tumors

In the past 20 years, the National Institute of Radiation Medicine (NIRS) in Japan has intermittently conducted clinical research on carbon ion beam radiotherapy for head and neck tumors. This includes 175 cases of adenoid cystic carcinoma (ACC), 102 cases of mucosal malignant melanoma (MM), and 50 cases of adenocarcinoma, located in the paranasal sinuses, nasal cavity, major salivary glands, oral cavity, larynx, etc. Among them, nearly 74% of the tumors were inoperable. The 5-year local control rate (LCR) was 74%, 79%, and 81% respectively, and the 5-year overall survival rate (OSR) was 72%, 33%, and 57% respectively ^[9]. Another study included a total of 76 patients with skull base malignancies, including 44 cases of chordoma, 14 cases of chondrosarcoma, 9 cases of olfactory neuroblastoma, 7 cases of malignant meningioma, 1 case of giant cell tumor, and 1 case of neuroendocrine carcinoma. Carbon ion therapy was used at NIRS, with 5-year LCR and OSR of 88% and 82% respectively, and no serious adverse reactions occurred in any of the patients ^[11]. In a clinical trial of carbon ion therapy for parotid gland cancer, a total of 46 patients were included, including 16 cases of adenoid carcinoma, 8 cases of adenocarcinoma, 8 cases of mucosal epithelial carcinoma, and 14 cases of other types of carcinoma. The number of cases at T2, T3, T4a, and T4b stages were 3, 18, 8, and 17 respectively. One patient had residual tumor after surgery, 20 patients had local recurrence after surgery, and the rest were first-time treatments. The median follow-up time was 62 months. The 5-year LCR and OSR were 74.5% and 70.1% respectively. No facial nerve paralysis occurred in 30 patients before carbon ion irradiation, and 25 patients remained normal after treatment ^[12].

Currently, the main treatment for head, neck and skull base malignancies is surgical resection. However, for tumors with deep infiltration and special locations, complete resection is relatively difficult. Moreover, surgical treatment sometimes damages the patient's appearance, which seriously affects the patient's quality of life. Therefore, radiotherapy is needed to improve the local control rate (LCR). Some tumors are resistant to conventional radiation, such as chordoma and adenoid cystic carcinoma. A dose of 60 Gy or more is required to achieve the therapeutic effect of local control ^[13]. Conventional radiotherapy cannot safely deliver this dose level due to the influence of surrounding critical organs (spinal cord, brainstem, optic nerve pathway, etc.), while carbon ion beams can achieve the therapeutic effect of local control without damaging surrounding critical organs and changing the patient's appearance. Based on the above advantages, carbon ion beams alone or in combination with other treatment methods such as surgery will be an inevitable trend in the treatment of head, neck and skull base malignancies.

3.2 Thoracoabdominal Tumors

3.2.1 Lung Cancer

A clinical study in Japan on the sole use of carbon ion beams to treat stage I non-small cell lung cancer (NSCLC) included a total of 218 patients. The treatment dose ranged from 28 to 50 Gy, with an average age of 75 years. There were 123 patients in stage T1 and 95 patients in stage T2. The histological types included 146 cases of adenocarcinoma, 68 cases of squamous cell carcinoma, 3 cases of large cell carcinoma, and 1 case of mucosal epithelial carcinoma them, 61.5% of the patients were evaluated as inoperable. The average follow-up time was 57.8 months. The 5-year overall survival rate (OSR) was 49.4%, and the local control rate (LCR) was 72.7%. There was a significant statistical difference in LCR between patients with a treatment dose of ≥36 Gy and those with a dose of <36 Gy. Among 20 patients with a treatment dose between 48 and 50 Gy, the 5-year L 95.0%, the 5-year OSR was 69.2%, and the progression-free survival rate (PFSR) was 60.0% (with a median follow-up time of 58.6 months). As the treatment dose increased, the LCR also relatively increased, and all adverse reactions were acceptable ^[14]. Currently, a single-dose escalation study on lung cancer is underway.

Carbon ion beam radiotherapy causes relatively less damage to the normal lung tissue of NSCLC patients. The incidence of radiation-induced pulmonary fibrosis after radiotherapy is relatively lower than that of conventional radiotherapy, showing certain treatment advantages. However, the lung is an organ with large respiratory movements. The single-fraction dose of carbon ion beam radiotherapy is relatively large. How to more precisely track tumor tissues during the treatment process and how to determine the prophylactic irradiation area are currently new research directions.

3.2.2 Esophageal Cancer

From 2004 to 2008, the National Institute of Radiation Medicine (NIRS) conducted a phase I/II clinical trial of preoperative carbon ion radiotherapy for resectable esophageal cancer. A total of 31 patients were included. were staged according to the 9th edition of the Japanese Esophageal Cancer Staging System. Among them, 10 patients were in stage I, 14 in stage II, and 7 in stage III. The treatment dose was increased from 28.8 Gy to 36.8 Gy. Surgery was performed 4 - 8 weeks after the carbon ion therapy evaluation, followed by pathological assessment. Among the 31 patients, 12 achieved complete response (CR) and 13 achieved partial remission (PR). Among them, 12 achieved pathological CR. The 5-year overall survival rate (OSR) of patients in stages I, II, and III was 90%, 77%, and 33 % respectively, and the 5-year progression-free survival rate (PFSR) was 80%, 69%, and 17% respectively. Except for one patient who developed acute respiratory distress syndrome with an uncertain relationship to the treatment, no uncontrollable adverse reactions occurred in the remaining patients. During the subsequent follow-up observation, 11 of the  patients relapsed. The recurrence was considered to be related to lymph node metastasis ^[15]. Currently, a clinical trial on the synchronous treatment of esophageal cancer with chemotherapy and carbon ion beams is underway. However, the dosage of chemotherapy drugs and the reduction ratio of carbon ion beams during the treatment process need to be verified by a large number of clinical studies.

3.2.3 Hepatocellular Carcinoma (HCC)

The standard treatment methods for localized HCC include surgery, liver transplantation, radiofrequency ablation, hepatic artery embolization, etc. The specific treatment method is determined according to the patient and the specific tumor condition. When a patient does not meet the criteria or refuses the above treatment methods, radiotherapy can be used as an alternative. The National Institute of Radiation Medicine (NIRS) in Japan began researching and applying carbon ion therapy for HCC in 1995 ^[16]. The initial clinical research protocol was 15 Fr/5 W, which has now been shortened to 4 Fr/1 W. Between 2003 and 2012, 133 HCC patients were included in the study to receive carbon ion therapy. They were divided into a high-dose group (42.8 - 45.0 Gy) and a low-dose group (≤42.8 Gy), and a clinical treatment plan of 2 Fr was given. The total treatment dose ranged from 32.0 to 45.0 Gy. The treatment in both groups had no significant impact on liver function. The 1-year and 3-year local control rates (LCRs) in the high-dose group were 98% and 83% respectively, while those in the low-dose group were 90% and 76% respectively. There was no statistically significant difference between the two groups in terms of these data. However, the 3-year overall survival rates (OSRs) in the high-dose and low-dose groups were 71% and 59% respectively, and the difference was statistically significant. A subgroup analysis of the high-dose group showed that the LCR was not closely related to the size of the HCC volume ^[17]. A meta-analysis on the efficacy and safety of proton, heavy ion, and photon radiotherapy included a total of 73 cohort studies. The results showed that both the overall survival period and the LCR in the proton and heavy ion group were better than those in the conventional radiotherapy group ^[18]. The normal liver is a radiosensitive organ. When the whole liver is irradiated with a dose greater than 40 Gy, 75% of patients will experience liver dysfunction. The radiation lethal dose for liver tumors is approximately 60 Gy/6 W. Conventional radiotherapy causes relatively greater damage to normal liver tissue. Compared with photon radiotherapy, carbon ion beam therapy can deliver a higher prescription dose, and its safety is better than that of photon radiotherapy. However, the treatment cost is relatively high, and heavy ion therapy can only be implemented in a few countries.

3.2.4 Pancreatic Cancer

The conventional treatment for pancreatic cancer is surgery, and preoperative chemoradiotherapy can improve the tumor resection rate. However, due to the low tolerance dose of the organs around the pancreas (such as the duodenum), it poses certain difficulties for conventional radiotherapy. Carbon ions, with their dose steeply decreasing characteristics, can deliver a high dose to treat the tumor while reducing the dose to organs-at-risk (OARs).

In a study on preoperative short-course carbon ion therapy for pancreatic cancer, a total of 26 patients were included, including 15 cases in stage IIA and 11 cases in stage IIB. The treatment plan was 8 Fr/2 W, and the total dose ranged from 30 to 36.8 Gy. Surgery was performed 2 - 4 weeks after carbon ion therapy. Except for 5 patients who did not undergo surgical treatment due to distant metastasis or refusal, the 5-year local control rate (LCR) of the remaining 21 patients was 100%, and the 5-year overall survival rate (OSR) was 52% ^[19].

A clinical trial on the maximum tolerated dose of carbon ion combined with gemcitabine for pancreatic cancer was conducted. A total of 76 patients with locally advanced pancreatic cancer were included and the study was carried out in two phases. In the first phase, the carbon ion treatment dose was fixed at 43.2 Gy, and the gemcitabine dosage was increased from 400 mg/m² to 1000 mg/m² in increments of 300 mg/m². In the second phase, the gemcitabine dosage was fixed at 1000 mg/m², and the carbon ion beam irradiation dose was escalated from 45.6 to 55.2 Gy with an increment of 5%. The results showed that the safe treatment dose of the carbon ion beam when the full dose of gemcitabine (1000 mg/m²) was used was 55.2 Gy. The 2-year OSR for all patients and the high-dose group patients were 35% and 48% respectively. Only one patient developed a grade 3 gastric ulcer with bleeding 10 months after carbon ion therapy ^[20].

3.2.5 Cholangiocarcinoma

A clinical study on hypofractionated carbon ion radiotherapy for locally advanced, inoperable cholangiocarcinoma patients included a total of 7 patients. Among them, 2 were in stage I, 1 in stage II, 1 in stage III, and 3 in stage IVA. The treatment dose was 52.8 Gy or 60 Gy. For cases within the liver, 4 Fr was given, and for cases between the liver and stomach, 12 Fr was given. The median follow-up time was 16 months. Among the 7 patients, 5 achieved local control, and 6 of the 7 patients survived. No grade 3 or above adverse reactions were observed. This trial achieved a local control rate (LCR) similar to that of conventional radiotherapy, adverse reactions were significantly lower than those of conventional radiotherapy ^[21].

Cholangiocarcinoma is a relatively rare malignant tumor that originates from the biliary epithelium. It usually has a poor prognosis, and the disease progresses rapidly with inconspicuous symptoms. Most patients have lost the opportunity for surgery at the time of diagnosis. Carbon ion beam therapy can shorten the treatment time and significantly reduce adverse reactions compared with conventional radiotherapy. It can be explored as a new treatment direction for cholangiocarcinoma.

3.3 Bone and Soft Tissue Sarcomas

3.3.1 Osteosarcoma

Osteosarcoma is a malignant tumor that commonly occurs in children and adolescents. Although multi-drug chemotherapy and improved surgical treatment have increased the overall survival rate to 65% - 70% ^[22], surgical treatment is limited for some tumors due to their special anatomical locations. Chemoradiotherapy combined has become the preferred treatment for inoperable patients. Osteosarcoma is relatively insensitive to conventional radiation, so carbon ion irradiation can be used as a new treatment method. From June 1996 to July 2009, the National Institute of Radiation Medicine (NIRS) used carbon ion therapy to treat 78 inoperable osteosarcoma patients. Among them, 61 cases had tumors in the pelvic region, 15 cases had tumors in the spine or paravertebral area, and 2 cases had tumors in other areas. Pathologically, there were 36 cases of osteoblastic type, 16 cases of chondroblastic type, 14 cases of fibroblastic type, and 12 cases of other types. The carbon ion treatment dose was 52.8 - 73.6 Gy, 16 Fr. After treatment, the median survival time of the 78 patients reached 28 months (2 - 166 months). The 5-year overall survival rate (OSR), progression-free survival rate (PFSR), and local control rate (LCR) were 33%, 23%, and 62% respectively. Univariate and multivariate analyses showed that the clinical target volume (CTV) was an important factor affecting LCR and OSR. Among them, for 38 patients with CTV < 500 cm³, the 5-year OSR and LCR were 46% and 88% respectively, while for the other 40 patients with CTV ≥ 500 cm³, the 5-year OSR and LCR were 19% and 31% respectively ^[23].

3.3.2 Chondrosarcoma

Chondrosarcoma accounts for approximately 20% of bone sarcomas and is the second most common primary malignant tumor of the bone. In a Japanese clinical trial comparing surgery and carbon ion beam therapy for chondrosarcoma, a total of 31 patients were included. There were 24 patients in the surgical treatment group and 7 patients in the carbon ion beam treatment group (70.4 Gy/16 Fr, 4 weeks). The results showed that the treatment process (surgery or carbon ion therapy) did not affect the overall overall survival rate (OSR) (P = 0.347). However, compared with patients who underwent surgery, those treated with carbon ions had more severe functional impairment (P = 0.03) ^[24]. Another study analyzed the efficacy of carbon ion therapy for skull base chondrosarcoma. This study collected 79 patients with skull base chondrosarcoma who had not undergone surgery or had incomplete surgery, including 3 and 40 females. The median ages were 39 years (16 - 76 years) and 45 years (16 - 81 years) for males and females respectively. The average carbon ion beam treatment dose was 60 Gy (57 - 69 Gy), and the median follow-up time was 91 months (3 - 175 months). The 10-year local control rate (LCR) and OSR were 88% and 78.9% respectively. It was also observed that compared with the baseline (73.4%), cranial nerve deficits improved clinically from 7 to 10 years after carbon ion therapy (45.5% - 53.3%) ^[25].

3.3.3 Sacral Chordoma

Between 1996 and 2013, an independent research institute used carbon ion radiotherapy to treat 188 patients with sacral chordoma. The average age was 66 years. The treatment regimens were as follows: The median clinical target volume (CTV) was 345 cm³. Sixty-one patients received 67.2 Gy/16 Fr, 74 patients received 70.4 Gy/16 Fr, 7 patients received 73.6 Gy/16 Fr, and 1 patient received 64.0 Gy/16 Fr. The median follow-up time was 62 months (6.8 - 147.5 months). The results showed that the 5-year local control rate (LCR), overall survival rate (OSR), and progression-free survival rate (PFSR) were 77.2%, 81.1%, and 50.3% respectively. Local recurrence occurred in 41 patients. Gender, tumor volume, and radiation dose were not closely related to LCR. Six patients developed grade 3 peripheral nerve toxicity, and 2 patients developed grade 4 skin toxicity. After treatment, 97% of the 188 patients could walk normally ^[26].

Some bone malignancies have strong radioresistance and are insensitive to conventional photon radiotherapy. Compared with photon radiotherapy, carbon ion radiotherapy has a better tumor dose distribution. While achieving the same or even better therapeutic effects, it does not damage the patient's physical functions. Therefore, carbon ion beam radiotherapy will bring new hope to patients with bone malignancies after surgery or those who are inoperable. However, a large number of multi-center clinical studies are still needed to confirm these results.

3.4 Other Tumors

3.4.1 Prostate Cancer

The National Institute of Radiation Medicine (NIRS) in Japan has been conducting clinical research on carbon ion beam therapy for prostate cancer since 1995. To date, more than 1,700 prostate cancer patients have received carbon ion beam therapy, and it continues to be promoted due to its few adverse reactions and significant therapeutic effects ^[27]. A report from the Japanese Carbon Ion Radiation Oncology Study Group (J-CROS) conducted a multicenter, prospective analysis of carbon ion therapy for prostate cancer. This study included 1,210 patients with T1b-T2a (56.173 patients with T2b (3.4%), and 874 patients with T2c-T3b (40.5%), totaling 2,157 patients. Patients were classified into low-risk, intermediate-risk, and high-risk groups according to the D'Amico risk stratification criteria, with 1,215 patients (56.3%), 679 patients (31.5%), and 263 patients (12.2%) in each group, respectively. The study results showed that the 5-year biochemical recurrence-free survival (BRFS) rates for each group were 92%, 89%, and 92%, respectively; the 5-year local control rates (LCR) were8%, 96%, and 99%, respectively; and the 5-year overall survival rates (OSR) were 100%, 99%, and 96%, respectively. No uncontrollable adverse reactions occurred in any of the patients ^[28]. The efficacy of carbon ion therapy for prostate cancer is evident. Active scanning to protect the urethra and shorter treatment regimens will provide higher safety guarantees for carbon ion beam therapy in prostate cancer patients.

3.4.2 Cervical Cancer

Randomized clinical trials and meta-analyses related to cervical cancer have shown that, compared with radiotherapy alone, the combination with chemotherapy can change the local control rate (LCR) and overall survival rate (OSR) of cervical cancer patients. Intracavitary brachytherapy plays an important role in the treatment of cervical cancer patients. However, conventional intracavitary therapy cannot provide sufficient irradiation dose in cases of multiple or large tumors, thus requiring external irradiation support. The efficacy of carbon ion radiotherapy is significantly better than the best reported X-ray efficacy. From 1995 to 2013, the National Institute of Radiation Medicine (NIRS) used carbon ion radiotherapy to treat 197 patients with advanced cervical cancer. The treatment plan was 62.4 - 74.4 Gy/20 Fr, clearly demonstrating that carbon ion radiotherapy is a safe and effective short-course therapy for treating advanced cervical cancer ^[29]. A clinical study on the treatment of cervical cancer with carbon ion radiotherapy, completed in February 2010, included a total of 58 patients with advanced cervical adenocarcinoma. Among them, there were 20 cases in stage IIB, 35 cases in stage IIIB, and 3 cases in stage IVA. The median tumor size was 5.5 cm (3.0 - 11.8 cm). Pelvic lymph node metastasis was present in 27 patients. The median follow-up time was 38 months. The 5-year LCR and OSR were 54.5% and 38.1% respectively. Except for one case of grade 4 rectal complication requiring surgical treatment, no obvious adverse reactions were observed in the remaining patients ^[30]. Clinical trials on the treatment of cervical cancer with carbon ion irradiation combined with chemotherapy are also underway, and the optimal chemotherapy regimen is currently the mainstream research direction.

3.4.3 Ocular Melanoma of the Fundus

Although the incidence of ocular melanoma of the fundus is relatively low, it remains a relatively common tumor in the adult eye. The main treatment method is enucleation of the eyeball. Although this is a successful treatment strategy, the loss of the eyeball and vision is unacceptable to many patients. Radiotherapy may eradicate the tumor while protecting the eyeball and vision. As of February 2013, 127 patients with locally advanced or inoperable choroidal melanoma had received carbon ion beam therapy at the National Institute of Radiation Medicine (NIRS). The results showed that the 5-year overall survival rate (OSR) was 80.8%, and the eye preservation rate was as high as 93.1% ^[31]. Due to the lack of relevant clinical trials, further research is needed to determine whether carbon ion beam radiotherapy can replace surgery as the optimal treatment for ocular melanoma of the fundus.

3.4.4 Gynecological Melanoma

Carbon ion radiotherapy is an advanced treatment for malignant melanoma. Karasawa et al. ^[32] reported that between November 2004 and October 2012, a total of 23 patients with gynecological melanoma received carbon ion therapy. Among them, 14 cases were located in the vagina, 6 cases in the vulva, and 3 cases in the uterus. Among the 23 patients, 22 patients received an irradiation dose of 57.6 Gy, and 1 patient received 64 Gy. Eleven of these patients also received combination chemotherapy and interferon therapy. The median follow-up time was 17 months (ranging from 6 to 53 months). The 3-year local control rate (LCR) and overall survival rate (OSR) were 49.9% and 53.0%, respectively. Carbon ion radiotherapy may become a non-invasive treatment method for gynecological melanoma.

4. Prospects

The status and future development potential of carbon ion radiotherapy in medicine cannot be underestimated. It is an advanced treatment method that integrates multiple disciplines such as radiation biology, accelerator physics, and radiation oncology. Carbon ion radiotherapy has unique physical and biological advantages. While effectively killing tumor cells, it causes minimal damage to surrounding normal tissues. Moreover, due to hypofractionated treatment, it shortens the hospitalization time of tumor patients.

With the development of technologies like respiratory gating and active scanning, as well as the accumulation of experience, the types of tumors treated with carbon ion beams are continuously increasing. Besides common tumors, carbon ion radiotherapy has unique therapeutic effects on radioresistant tumors, tumors requiring re-irradiation, and tumors in complex anatomical locations.

In the process of leveraging the advantages of carbon ion radiotherapy, many issues are still in the exploratory stage. Firstly, there is a lack of clinical trial data for some tumors, and the treatment doses and regimens are not well-defined. Secondly, during the carbon ion radiotherapy for gastric tumors, it is necessary to figure out how to better protect normal hollow visceral organs. Thirdly, when combining carbon ion radiotherapy with chemotherapy, it is crucial to determine the chemotherapy regimens and drug doses.

Therefore, how to combine carbon ion therapy with advanced technologies such as imaging tracking more perfectly to ensure that carbon ions can fully exert their unique advantages during the tumor treatment process, as well as conducting large-sample, multi-center randomized controlled trials on the efficacy relationship between different tumors and treatment doses, are all new directions for our future research.

The Heavy Ion Hospital in Gansu Province, China, was officially completed in 2017. It is the first clinical hospital in China to treat tumors with carbon ion beams. At present, the equipment has been successfully debugged and is in the clinical trial stage. It is believed that carbon ion radiotherapy will be a new turning point in the treatment of malignant tumors.

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