My 42-year Experience in Radiation Oncology

In the present review, I provide an overview of the development of radiation therapy and short history of the Department of Radiation Oncology, Juntendo University. I also emphasize the importance of radiation therapy as a major treatment modality for cancers. Radiation therapy is a standard treatment for malignant tumors. It aims to deliver a sufficient radiation dose to a target volume to eradicate tumor cells or relieve symptoms of disease. Therapy can achieve good results in many types of cancers. Although radiation therapy sometimes causes undesirable adverse events, it is generally less invasive than other treatment modalities and does not alter the shape and function of healthy organs. When the author joined this field in 1981, radiation therapy techniques were highly primitive; however, during the past 42 years, treatment has advanced rapidly with the development of computer science, mechanical techniques and instrumentation. Currently, patients can be treated with precise radiation techniques, including intensity-modulated radiation therapy, image-guided radiation therapy, stereotactic irradiation, and brachytherapy. We also introduced a new treatment planning system that uses not only anatomical but also metabolic imaging, which permits correct delineation of the target volume. Therefore, it is crucial to stay up to date with advances and developments in rapidly emerging technologies to maintain high-quality treatment. The Department of Radiation Oncology at Juntendo University (Tokyo, Japan) is still small; however, it is gradually expanding and conducting research in both clinical and basic fields. It is the author's hope that many young investigators will join this field in the future.


Introduction
Radiation therapy is a standard treatment for malignant diseases.It is a treatment modality that aims to deliver a sufficient radiation dose to a target volume to eradicate tumor cells or relieve symptoms of disease.
In the United States, approximately one-half of patients with cancers undergo radiation therapy; however, only one-quarter of such patients are irradiated in Japan 1) .There are several reasons for this low frequency of radiation therapy.For example, size the importance of radiation therapy as a major treatment modality for cancers.

Developments in radiation therapy since 1981
When I joined this field in 1981, radiation therapy techniques were highly primitive.Virtually all institutions in Japan were equipped only with low-energy photon sources, such as cobalt-60 machines or low-energy medical linear accelerators (Linacs).Treatment was usually performed using a simple technique, such as two opposing anterior-posterior and posterior-anterior ports.The field was trimmed using one or two monoblocs fabricated from thick heavy metals.The radiation treatment field was determined using an X-ray simulator, which is a type of X-ray fluoroscopy specifically designed for radiation therapy treatment planning, and it has the same geometric arrangement as the treatment device.The field was determined based on anatomical landmarks, such as bones, which are visualized using X-rays.For example, radiation fields for uterine cervical cancer were determined at the upper end, between the 4th and 5th lumbar vertebrae, the lateral margin at 1.5 cm lateral to the inner margin of the iliac bone, and the lower margin at the level of the caudal end of the obturate foramen.However, some institutions did not have an X-ray simulator; as such, they had to use fluo-roscopy dedicated to diagnostic use or simple X-ray photography.Low-energy photons cannot sufficiently penetrate to deep-seated areas of disease because they rapidly lose their energy along their track in the human body.Therefore, an extremely high dose was administered to the skin to treat deep-seated tumors, which sometimes caused severe side effects.The aforementioned factors, therefore, limited cure to only diseases located in superficial regions or easily approachable tumors, such as uterine cervical cancers in the early 1980s.As such, it was generally believed that radiation therapy was not a curative but a palliative method.
However, rapid advances in computer science and mechanical technologies have led to a revolution in the field of radiation oncology.Linacs with ultra-high-energy X-rays, which can easily reach deep-seated lesions, are now commercially available.In the final decade of the 20th century, many new techniques emerged.If sufficient radiation doses could be delivered to the target volume, desirable performance in treatment was achieved.Stereotactic radiosurgery uses three-dimensional images and focuses multidirectional beams on a small target.The treatment was first applied to intracranial lesions, then gradually extended to extracranial diseases (Figure 1) and has yielded a Figure 1 A male patient with prostate cancer underwent salvage radiation therapy for biochemical recurrence after surgical resection.However, his prostate-specific antigen levels gradually increased after five years.Computed tomography (CT) could not detect any recurrent lesions (A); however, 18 F-fluorodeoxyglucose positron emission tomography combined with CT clearly revealed suspected lymph node disease (B, indicated by white arrows).This lesion was treated using stereotactic radiation therapy using a total dose of 50 Gy in 10 fractions.Dose distributions of the treatments (C).Prostate-specific antigen levels dramatically decreased after treatment.
very high frequency of disease eradication.From Juntendo University, Naoi and colleagues were pioneers in this field in Japan and published highquality reports 2,3) .
Takahashi and colleagues proposed "conformation radiation therapy" in the 1960s 4,5) .This is a type of rotational radiation therapy, in which the tumor(s) is irradiated in a 360°direction, and the beams are trimmed to conform to the shape of the target volume during irradiation.However, the technique was not very popular until the 1990s because it was very complicated and there was no way to obtain trans-axial images of the body except by using Takahashi's rotation tomograms.In the 1990s, major instrument manufacturers equipped their Linacs with a multi-leaf collimator (Figure 2), which can easily shape the radiation field to conform to the target.Computed tomography (CT), which was introduced in the early 1970s, has also advanced to provide sufficient image quality for treatment planning.Since then, a new technique, known as "conformal radiation therapy", in which a target is irradiated by conformal beams from several fixed directions, has emerged and is widely used.At the turn of the new millennium, a more sophisticated treatment technique, known as intensity-modulated radiation therapy (IMRT), has been introduced in this field 6,7) , with developments in this technology advancing virtually every year.It can be used to treat patients using an acceptable dose distribution (Figure 3).
Another advance in treatment is the introduction of image-guided radiation therapy (IGRT) 8) .IMRT has a steep fall-off of the radiation dose at the edge of the target volume.If the position of the target volume differs in a radiation session from the planning CT, the volume receives a lower dose than the plan prescribes.To overcome this problem, the position of the target is monitored before or during each treatment session using imaging modalities such as CT, magnetic resonance imaging (MRI), and/or ultrasound.Furthermore, it is possible to detect the movement of the target during irradiation.At Juntendo University Hospital in Hongo, tumor movement was tracked during a treatment session using the SyncTrax system (Shimadzu, Kyoto, Japan) (Figure 4), a real tract radiation system 9) .It is combined with stereotactic radiation therapy to mainly treat lung or liver cancers.This technique, however, has drawbacks, including exposure to X-rays and the visualization of only the fiducial markers inserted near the target volume.A newly emerged MRI-guided treatment technique can detect the movement of  the target itself without any harmful effects 10) , and may be a future direction of research and therapeutics.
In 2000, Ling et al. proposed a concept known as "biological target volume" 11) .As mentioned above, multiple modalities can be used to precisely irradiate the target volume.However, defining the target volume, which is usually based on anatomical images, remains a problem.Ling et al. proposed the use of biological and mechanistic data to delineate target volumes.Biological images broadly include metabolic, biochemical, physiological, functional, molecular, genotypic, and phenotypic.Although positron emission tomography (PET) using 18 F-fluorodeoxyglucose (FDG) is available for this purpose at Juntendo (Figure 1), other imaging modalities, such as 18 F-misonidazole PET for hypoxic cells, have been tested at other institutions 12,13) .With advances in diagnostic and imaging modalities, functional imaging is anticipated to be introduced in this field in the future.
Lack of qualified personnel in this field is a major issue in Japan.There were only 899 certified radiation oncologists (ROs), 1213.9 full-time equivalent (FTE) ROs, and 295.7 FTE medical physicists, despite 846 institutions treating patients using radiotherapy in 2015 1) .Juntendo also contends with this problem, and will be addressed later.

Radiation therapy as a standard treatment for cancer
As shown in Table 1, radiation therapy can achieve good treatment results.Although it sometimes causes undesirable adverse events, it is generally less invasive than other modalities, and can preserve the shapes and functions of healthy organs.Therefore, it is regarded to be standard treatment for many types of malignant diseases and appears in domestic and international treatment guidelines for cancers.The therapy can be used not only as monotherapy, but can also be combined with other methods, including surgery, chemotherapy, and/or immunotherapy.

Radiation therapy at Juntendo University
When I was appointed to Juntendo University in 2000, the Radiation Oncology Division was a small part of the Department of Radiology.There was only one other RO with the exception of myself, although the individual was young and uncertified.Juntendo University had only two old-type Linacs (one at Juntendo University Hospital and another at Urayasu Hospital, Chiba, Japan).
The term "radiology" does not necessarily refer to radiation oncology (therapy) but refers to diagnostic radiology in the United States and major European countries.Because cancer is a leading cause of death, the Japanese government created the "Basic Plan to Promote Cancer Control Programs" based on the Cancer Control Act.One of the major policies is to promote radiation therapy, with the government encouraging each medical school to establish a radiation oncology department.In 2013, Juntendo University also established the Department of Radiation Oncology, and I was appointed to be the first Chair.Juntendo Hospital is now equipped with three cutting-edge Linacs and a remote after-loading brachytherapy system.These facilities permit the treatment of virtually all cancer types that are suitable candidates for radiation therapy.Table 1 summarizes the results of radiation therapy for major diseases in our department 14) .Generally, these values were better than expected.Other affiliated hospitals have also been equipped with new instruments, including Shizuoka Hospital (Shizuoka, Japan), with one; Urayasu Hospital, with two, and Nerima Hospital (Tokyo, Japan), with one (Table 2).Tables 2 and 3 summarize the changes in the radiation therapy facilities in the Juntendo University group and the number of patients treated at Juntendo Hospital, Hongo.
Although there are few members in the Department of Radiation Oncology, the number has gradually increased to 11 ROs and 3 physicists.

Research at the Department of Radiation Oncology
Research themes at the Department of Radiation Oncology include both the basic and clinical fields, which is very similar to themes in other departments.Basic research includes both medical physics and radiation biology.Although my majors were clinical and radiation biological research, the lack of personnel was limited to the clinical and medical physics themes at Juntendo.During these years, the department published only a few articles in English; however, this number is now increasing as the number of members in our department has increased.Among these publications, Akamatsu et al. reported a close relationship between the prognosis of patients with esophageal squamous cell carcinoma and the expression of c-erbB-2 in tumor tissue 15) .Kunogi et al. predicted the radiosensitivity of tumor cells by simultaneously detecting histone H2AX phosphorylation and apoptosis 16) .Recently, we reported that patients who underwent radiation therapy for cranial diseases experienced unusual visual and olfactory sensations 17,18) .Among them, one woman who underwent resection of the olfactory bulb and epithelium reported a pungent smell during the radiation session 19) .This phenomenon suggests that the central nervous system can detect X-rays, even in humans.

Figure 2 A
Figure 2 A medical linear accelerator (Linac) at the Juntendo University Hospital (Tokyo, Japan) (A) and multileaf collimator (B) placed at the aperture of the device, indicated by the white arrow.

Figure 3
Figure 3 Dose distributions in conventional conformal radiation therapy (A) and intensity modulation radiotherapy (B).

Figure 4 (
Figure 4 (A) The tracking system on a medical linear accelerator (Linac).The white arrows indicate X-ray detecting boards and the asterisk indicates one of four X-ray sources placed under the floor.(B) We usually use two sets of X-ray systems to tract a gold fiducial marker placed near the target volume.While the marker is out of position, the Linac beam is off.If the marker moves into the predefined position on images from both directions, the radiation beam is on.
Hospital, S: Shizuoka Hospital, U: Urayasu Hospital, N: Nerima Hospital, * numbers in parenthesis mean medical physicists at the faculty of health science

Table 1
Radiation therapy results for representative diseases at Juntendo University Hospital

Table 2
Changes of the radiation therapy facilities in Juntendo University from 2000 to 2021

Table 3
Changes of numbers of patients who received radiation therapy at Juntendo Hospital, Hongo, from 2000 to 2020 IMRT: intensity modulated radiation therapy including VMAT (volumetric-modulated arc therapy) SRT: stereotactic radiation therapy (including stereotactic radiosurgery)