Present status and future of Proton beam therapy Description At present, the types of proven treatment for cancer are surgery, radiotherapy, and chemotherapy. Depending on the characteristics of cancer such as such as nature, size, shape and position, and the personal circumstances such as age, sex, general health status and individual preferences for treatment of patient, an optimal therapy tailored to the patient can be chosen and performed in combination with other treatments. When cancer is localized without metastasis, surgery or radiotherapy, or the two in combination, is chosen, aiming at relieving symptom and controlling the cancer for as long as possible. The radiotherapies, in which proton beams of accelerated hydrogen nuclei or heavy particle beams of accelerated carbon nuclei are irradiated into cancer cells, are called particle beam therapies. In particle beam therapy, the radiation dose can be effectively focused on the cancer lesion exclusively and side effects of normal tissues can be minimized. In our hospital, proton beam therapy is performed and specialists in medical physics are engaged in a team approach of medical care to introduce state-of-the-art technologies into our proton beam therapy. This article introduces the advantage and current outcomes of our proton beam therapy. Contents 1. Leading-edge radiotherapies 2. Proton beam therapy facility 3. Features of the proton beam therapy system 4. Proton beam therapy for liver cancer 5. Proton beam therapy for lung cancer 6. Proton beam therapy for prostate cancer 7. Conclusions 8. Profile of the author Tetsuo AKIMOTO, M.D., Ph.D. Chief, Division of Radiation Oncology and Particle Therapy, Research Center for Innovative Oncology, National Cancer Center Hospital East
1. Leading-edge radiotherapies At present, the types of proven treatments for cancer are surgery, radiotherapy, and chemotherapy. Depending on the characteristics of cancer such as nature, size, shape and position relations, and personal circumstances such as age, sex, general health status and individual preferences for treatment of patient, an optimal therapy tailored to the patient can be chosen and performed in combination with other treatments. When a cancer is localized without metastasis, surgery or radiotherapy, or the two in combination, is chosen, aiming at relieving symptoms and controlling the cancer for as long as possible. The radiotherapy kills cancer cells in place of surgical operation with the power of radiation which destroys deoxyribonucleic acid (DNA). The radiotherapies, in which proton beams of accelerated hydrogen nuclei or heavy particle beams of accelerated carbon nuclei are irradiated into cancer cells, are called particle beam therapy. The particle beam therapy and the intensity modulated radiotherapy (IMRT) which is an improved technology of a conventional X-ray radiation, are the leading edge of radiotherapies. As for the nature of proton beam and heavy particle beam, the effect of radiation is small in the surface neighborhood because the energy is not released just after the beam line enters the body and a major dosage is given tissues by emitting energy just before it terminates. In radiotherapy of cancer, the radiation dose can be controlled to quickly increase depending on the depth and size of the cancer lesion. The X-ray used in a conventional radiotherapy is absorbed as it passes through the body and its radiation dose decreases gradually. Fig. 1 Comparison of Radiobiological effect Normal cells Cancer cells Normal cells Cancer cells 100 X-ray X-ray Bragg Peak (SOBP) Relative dose (%) 50 Neutron Proton Carbon 0 0 5 10 15 Depth (cm) Gamma ray Carbon Proton Bragg Peak formation 0 5 10 15 Depth (cm) Therefore, to irradiate a lesion with a sufficient dose, normal tissues in front of or behind the lesion are also irradiated similarly, leading to a side effect. However, in particle beam therapy, the radiation dose can be effectively focused onto the cancer lesion exclusively and side effects of normal tissues can be minimized. When the dose distribution of the proton beam is compared with those of X-rays for paranasal tumor, the proton beam can irradiate the tumor without affecting the optic nerve. 2
In conventional radiotherapies with X-rays, the intensity modulated radiotherapy (IMRT) in which a radiation can be focused onto a lesion by adjusting its intensity while irradiating from many directions can give the necessary dose for a lesion of cancer and minimize side effects to normal tissues. Fig. 2 Comparison of Dose distribution Tumor Tumor Dose Distribution (X-ray) Dose Distribution (Proton beam) Radiotherapy is a treatment applied to localized cancers without metastasis. It may be applied to elderly or people who are physically weak. It may potentially be applied to 60% of cancer patients in advanced countries, and 40% of cancer patients in Japan, where the number of cancer patients is increasing. The current radiotherapy is considered to be a more sophisticated therapy advanced from a conventional one. The applications for the proton therapy are brain tumor (primary chisel), skull base neoplasm (dorsal cord tumor, chondroma sarcomatosum), cervical part tumor, lung cancer, hepatoma, metastatic liver cancer (single onset and no metastasis), bone soft tissue sarcoma, prostate cancer. As for esophageal cancer, effective outcomes in combination with chemotherapy has been reported. Fig. 3 Clinical applications of radiotherapy Brain tumor Skull base Head & neck cancer Lung cancer Esophageal cancer Metastatic lung cancer Mediastinal tumors Bone & soft tissues Pediatric tumors Malignant lymphoma Hepatocellular cancer Pancreatic cancer Metastatic liver cancer Prostate cancer Rectal cancer Bladder cancer 3
Table 1 Comparison of leading-edge radiotherapies Intensity modulated radiotherapy (IMRT) X-ray, Photon beam Heavy particle beam therapy (Carbon ion - particle beam) Proton beam therapy (hydrogen nuclei - particle beam) Biological effectiveness ( 1) Insurance application Applicable from 2010 1 3 1 Advanced medical care Advanced medical care Number of institutions 80 3 7 Advantage Disadvantage Save medical cost on patients Reduce the burden of normal cells less than conventional X-ray Injure DNA of normal cells more than particle beam therapy May not become insurance application depend on institution ( 1: Power to destroy cells, X-ray is assumed 1.) Irradiate a strong radiation onto cancer cells only Stronger than other radiation Large medical cost Irradiate a strong radiation onto cancer cells only Versatility for various cancers Large medical cost The number of proton beam therapies in Japan is increasing every year, and the new therapy facilities are also being built. In comparison between Japan and the USA, there are more facilities and patients for proton beam therapy in Japan than the USA, although the population of the USA is 2.5 times larger than Japan s. Table 2 Comparison of status of particle beam therapy USA vs. Japan Number of particle beam therapy facilities (2008-2011) Number of new patients (2008-2011) Japan 6 8 9,057 USA 6 9 16,358 Table 3 Comparison of status of radiation therapy USA vs. Japan Number of radiation therapy facilities Number of new patients Japan (2005) 1 USA (2004) 2 735 162,000(estimated) 2,010 700,000(estimated) 1: Data from JASTRO, 2: Data from ASTRO 4
Table 4 Particle beam therapy in Japan Year Radiation therapy Number of institution Number of new patients Number of institution Particle beam therapy Number of new patients % of new patients per all patients 2003 700 149,793 6 657 0.44 2005 712 156,318 6 1,240 0.79 2007 721 170,229 6 1,643 0.97 2009 726 182,390 7 2,038 1.12 As well as proton beam therapy, the number of heavy particle beam therapy is also increasing. The heavy ion beam therapy uses carbon ion with mass 12 times as large as a proton and shows superior outcome of treatment for cancer in the deep part of the body due to higher focusability and biological effects. It can be applied for osteosarcoma and cancers in the bones and muscles, as well as the cancers that can be treated in proton beam therapy. Fig. 4 Changes in the Number of Patients treated with particle therapy - 1979 ~ 2012 - Next 5
2. Proton beam therapy facility Our hospital, National Cancer Center Hospital East, introduced the first proton beam therapy system in Japan, and started clinical use in 1998. It was the second such facility in the word. The proton beam therapy system was approved as a medical equipment, and this treatment was authorized the adaptation of (highly) advanced medical treatment in 2001. The proton beam therapy system is a large-scale system of approximately 35 meters by 55 meters in size that is composed of a proton accelerator (cyclotron) that is 220 tons in weight, two radiation units with a rotating gantry, and one unit for fixed field irradiation in a horizontal direction. The accelerator that generates proton beams, accelerates proton nuclei up to 60% of the speed of the light. An accelerated proton beam can reach to a depth of around 30 cm in the body. By using a rotating gantry (10 m in diameter, 120 tons in weight), proton beams can be irradiated a patient lying on a table from all direction. Fig. 5 Proton beam therapy facility in National Cancer Center Hospital East Proton beam therapy facility in National Cancer Center Hospital East Contracted with the Sumitomo heavy Industry in 1996 Clinical treatment was started in 1998 2nd hospital-based proton beam therapy facility in the world # The 1st hospital-based proton therapy facility was opened at Loma Linda Medical Center in 1990 Next 6
3. Features of the proton beam therapy system 1) A large-intensity proton beam can be irradiated from all directions A cyclotron accelerator is used as a proton beam generation equipment. Cyclotron accelerators are also used in other countries facilities for proton beam therapy, but our hospital is the only one in Japan. The characteristic of cyclotron accelerator is to irradiate a large intensity proton beam sequentially. This makes it possible to minimize the irradiation time, and reduce the burden on the patient. In addition, with a short irradiation time, patient s movement can be reduced and more accurate irradiation will be possible. Thus, tumors in organs that move with respiration, such as liver and lung, can also be irradiated with high accuracy. The proton beam is arranged in a form through a collimator and a compensation filter and its irradiation matching the size and shape of the tumor will be possible. The collimator limits a lateral range to irradiate only a lesion of cancer, and the compensation filter regulates the coverage of depth direction. Before treatment, collimator and compensation filter are produced individually based on the treatment plan for patient. In addition, physical aids are produced to enable patients to take same posture in multiple irradiations every time. 2) Research and development oriented advanced proton beam therapy system The specialists in medical physics are engaged in a team approach for medical care by utilizing their special knowledge for the treatment, our team maintains spirit of R&D and aims to provide advanced technology of proton beam therapy. As it progresses, the technology improvements are repeated to archive higher accuracy and continue to introduce state-of-the-art technologies into our proton beam therapy. 3) State-of-the-art technology of proton beam therapy Part 1: Observation of the tumor lesion where the proton beam irradiated When a proton beam is irradiated to the patient, a rare nuclear reaction (very difficult to observe), is induced between atomic nucleus in the body and the irradiated protons. By observing the positron releasing core created from the rare nuclear reaction with a detector, it is possible to visualize where proton beam is irradiated. We developed an observation system to measure the location and quantity of positron releasing core with high accuracy on the beam line of proton beam (Beam ON-LINE PET system mounted on a proton gantry port: BOLPs-RGp). With this system, we confirm whether proton beam radiation irradiates a tumor with precisely. The proton therapy using this device which is only provided in our hospital only, attracts high attention from all over the world and a few other counties facilities are considering to introduce this system. Fig. 6 Beam ON-LINE PET Beam ON-LINE PET PET image 7
4) State-of-the-art technology of proton beam therapy Part 2: Improvement of the focusability of a proton beam onto a tumor The proton beam therapy performed adopts the irradiation technique called the broad beam method to form three-dimensional dose distribution broadly in advance, and adjust it to the shape of the patient s tumor individually. In our hospital, we developed an irradiation system that enables a new method to scan a large intensity proton beam formed into a thin-sized pencil beam along the shape of a tumor at a high speed. With this method, higher focusability of a proton beam onto a tumor is achieved, and the proton beam therapy with higher accuracy can also be provided. The proton beam therapy with this scanning irradiation method will be applied to patients in the near future. Fig. 7 Line Scanning Scattering Method Line scanning Method Scattering Method Body Beam Tumor Line scanning Method Pencil beam scanning offers the best flexibility for shaping the dose distribution Improvement of dose distribution compared with scattering method Intensity modulation are possible Scattering Method Line scanning Method Dose distribution for prostate cancer 5) State-of-the-art technology of proton beam therapy Part 3: Measurement of the location of a tumor in the body accurately In proton beam therapy, the accurate measurement of the location of a tumor is important for drawing out the strong points to maximum the dose focusability on a tumor. Therefore, we installed a robot control table for arbitrary drive, a sliding gantry CT system and fluoroscope apparatus in our proton beam therapy room. This integrated system is the first of its kind in the world, and the positive outcomes are expected in future clinical practice. 8
6) State-of-the-art technology of proton beam therapy Part 4: Irradiation onto the tumor of the moving organ In proton beam therapy, a treatment planning is carried out by using CT (Computed Tomography) images. To make a treatment plan, it is necessary to evaluate size, shape, location in the body, neighboring structure and positional relations with healthy organs of a lesion as a three-dimensional structure. Also, since many organs in the body always are moving with respiration, it is also important to evaluate the moving three-dimensional structure with the temporal change. Therefore, CT examination for the treatment planning is performed before treatment. In the treatment of lung or liver, the 4DCT examination (Four-dimensional Computed Tomography) is performed. Fig. 8 Three-dimensional structure observation using CT images Fig. 9 Large-bore multislice CT for treatment planning Tumor When a lesion of cancer moves with respiration, the irradiation area can be set to the wider range to cover the moving area. However, a side effect may be induced in normal tissue around the lesion broadly. Therefore, respiration gating irradiation is used in our hospital. This is a dedicated technique of proton beam irradiation to irradiate a tumor only at the terminal expiratory phase in which the movement of tumor is stable in the respiratory cycle. The monitor system of the respiratory cycle using a laser beam is linked with the proton beam irradiation system in the treatment. Fig.10 Irradiation at the terminal expiratory phase and other phases Respiratory Gating Respiratory Gating Next 9
4. Proton beam therapy for liver cancer Cancer which occurred in liver newly is primary liver cancer. The incidence is 40,000 per year, and the mortality is 35,000 per year. In the number of deaths by cancer site, liver cancer is the third place in men, and the fifth place in women. When a cancer is localized in the liver, hepatectomy (liver transplantation), puncture therapy (radiofrequency ablation, percutaneous ethanol injection therapy), transcatheter arterial embolization, radiotherapy are selected treatments. Prognostic factor Good Liver function Blood vessel and capsular invasion Multiple occurrence Fig. 11 Classification of treatment for liver cancer Poor Puncture therapy Proton beam therapy Embolization Liver function decreases due to influence of cirrhosis, 3cm or less and 3 tumors or less. Exceed 4 cm and Invisible cancer cells spread to arteries widely in liver. Puncture therapy is not useful and 4 cm or less.. Tumor diameter Hepatectomy Liver function is good. A conventional radiation therapy has large effects on the liver, so that it may not be the majority of treatment for liver cancer. However, the proton therapy is a technique in which large intensity radiation can be safely irradiated on part of the liver only. Fig. 12 Comparison of dose distribution Conventional Proton beam from left and back The liver is a moving organ with respiration. Therefore, a liver cancer is treated with respiration-gated irradiation method, in which the respiration cycle is monitored with a measuring instrument using a special laser and the irradiation is performed only during breathing out. To confirm whether there is a cancer at the same position every time, the position of cancer is evaluated by using a fluoroscopy. At the time, one or two gold markers are embedded around a cancer by puncture in advance. The treatment is performed once a day, 5 times a week, in 10 to 20 times during 2 to 4 weeks in total. The outcomes of proton beam therapy is equivalent to that of surgery. Fig. 13 Progress of proton beam therapy Before treatment Dose distribution Follow-up after proton beam therapy 3 month later 6 month later 9 month later 1 year later 2 year later 10 Next
5. Proton beam therapy for lung cancer Lung cancer is the third place in incidence and the highest in mortality. It contributed to increase. Proton beam therapy is applied to non-small cell lung cancer. 1) Non-small cell lung cancer at early stages This is a case where there is isolated primary tumor in lung, no metastasis to lymph nodes or bones. The standard treatment is surgery (lobectomy, and hilar and mediastinal lymph node dissections), but it causes a large burden on the body and is sometimes difficult in elderly or a patient with poor respiratory function. In such cases, a limited surgical treatment to resect only primary tumor and neighborhood and radiotherapy onto only the primary lesion are performed. A proton beam therapy can reduce the radiation dose on normal tissues around a lesion and provides a concentrated dose onto a lesion only. In the case of non-small cell lung cancer at the early stage, a proton beam therapy is performed on a schedule of total dose 80GyE for 20 times. One month after the treatment, a remarkable shrinking of the tumor was observed, and 6 months later, a shadow indicating fibrosis was found. This is a normal change and the shadow of a tumor has disappeared two years later. Fig. 14 Dose distribution In summary of total 37 cases of early lung cancer, the treatment outcomes in which the 2-year locally event-free survival rate was 80% and overall survival ratio was 84%, were excellent. When it was subdivided to two groups with tumor sizes of 3 cm or less and larger than 3 cm, their 2-year locally event-free survival rates were 94% and 62%, respectively. It suggested that the recurrences increased when tumor size exceeded 3cm. The serious pneumonitis as side effect is not found and chest pain and rib fracture in radiation site are found as sequelae in around 10% and 5%, respectively. Fig. 15 Progress of proton beam therapy Follow-up before and after treatment Before 1 month later 6 months later 2 years later 2) Locally advanced lung cancer Locally advanced lung cancer is a lung cancer in which radical surgery is impossible because there is mediastinal lymph node metastasis. This accounts for around one-third of all non-small cell lung cancers. The standard treatment is the simultaneous therapy combining chemotherapy with anticancer drugs and radiotherapy, but it is an unfavorable cancer which median survival time is 16 to 20 months. A proton beam therapy may be able to raise radiation dose with increasing side effects. 11 Next
6. Proton beam therapy for prostate cancer Prostate cancer is the fourth place in incidence rate. The incidence rate is predicted to increase by the diffusion of PSA (tumor marker) examination in addition to the aging and westernization of dietary habits. Radical therapy includes surgery, radiotherapy, and internal brachytherapy. Radiotherapy includes three-dimensional conformation radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT). Proton beam therapy can reduce long-term side effects by decreasing radiation dose to normal tissues around rectum and Fig. 16 Dose distribution bladder, and may concentrate radiation dose onto a lesion only. And, the dose distribution focused on prostate is obtained by the irradiation from right and left directions. In locally advanced prostate cancer with extracapsular extension and seminal vesicle invasion, the effect on rectum and bladder is a concern because the irradiation range becomes wider. 1) Low-risk prostate cancer Since there is no potential risk of metastasis, a radical treatment is the local approach including surgery, internal brachytherapy, radiotherapy and proton beam therapy. Proton beam therapy is performed on the schedule, total dose of 74 GyE for 37 times. 2) Medium risk prostate cancer Risk group Low Medium High PSA 4-10 10-20 20< Gleason Score -6 7 8-10 from right and left Surgery, radiotherapy, and proton beam therapy are applicable. The treatment is usually initiated with hormone therapy provided in advance and proton beam therapy is simultaneously performed on the schedule, total dose of 74 GyE for 37 times. 3) High risk prostate cancer Since there is a high potential risk of metastasis, hormone therapy is provided in advance, and proton beam therapy is simultaneously performed on the schedule, total dose of 74 GyE for 37 times. In addition, hormone therapy is continued after proton beam therapy in principle for two years. In prostate cancer, the efficacy of treatment strategy to reduce total treatment period due to increasing the intensity per irradiation is suggested. Proton beam therapy is expected to reduce the treatment period. Table 5 Particle beam therapy for prostate cancer Locally advance Localize in a capsule Invade capsule outside and neighboring organ Next 12
7. Conclusions High precision technology overcoming current drawbacks of radiation therapy. World-leading innovative technologies and clinical experience in Japan Compact treatment system Improve cost effectiveness Establishment of effectiveness of proton beam therapy enables us to realize effective solutions for cancer treatment in an aging society. Continuous development of cutting-edge technologies of particle therapy would result in improving the role of Japan in the international particle radiotherapy community and encouraging Japanese radiotherapy equipment industries. Next 13
8. Profile of the author Tetsuo AKIMOTO, M.D., Ph.D. Chief, Division of Radiation Oncology and Particle Therapy, Research Center for Innovative Oncology, National Cancer Center Hospital East Chief, Department of Radiation Oncology, National Cancer Center Hospital East Career 1986 Graduate School of Medicine, Gunma University 1997 Deprt. of Experimental Radiation Oncology, MD Anderson Cancer Center 2001 Lecturer, Department of Radiology, School of Medicine, Gunma University 2006 Assistant Professor, Tokyo Women s Medical University 2010 Clinical Professor, Tokyo Women's Medical University 2011 Chief, Division of Radiation Oncology and Particle Therapy, Research Center for Innovative Oncology, NCC Hospital East Chief, Department of Radiation Oncology, NCC Hospital East 2014 Assistant Director, National Cancer Center Hospital East Visiting Professor, Cooperation graduate school, Juntendo University Academic activity Director, Japanese Society of Head and Neck Cencer American Society of Therapeutic Radiology and Oncology American Society of Clinical Oncology American Association for Cancer Research Japanese Cancer Association Japan Society of Clinical Oncology Japanese Society of Radiation Oncology 14