Abstract

Stereotactic body radiation therapy is a new treatment modality where narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. This technique basically derived from that of radiosurgery for intracranial lesions allows us to deliver high dose to the target leading to high control of the tumor without causing significant cytotoxicities associated with the treatment. Early-stage non-small cell lung cancers are regarded as most appropriate malignancies for this modality and accordingly have most intensively been investigated. With many encouraging outcomes in retrospective studies, several prospective clinical trials have been started world-wide. Japan Clinical Oncology Group protocol 0403 is a phase II trial of stereotactic body radiation therapy for T1N0M0 non-small cell lung cancer including both inoperable and operable patients. The results for operable patients are to be disclosed this year after 3 years of follow-up. It is highly probable that stereotactic body radiation therapy can be a standard treatment modality for inoperable patients for early-stage non-small cell lung cancer. The role of stereotactic body radiation therapy for operable patients is expected to be clarified by the outcomes of coming clinical trials. Tremendous advance in stereotactic body radiation therapy is expected when four-dimensional radiation therapy coping with tumor movement is realized. Among several approaches, tumor tracking appears most ideal. The new image-guided radiotherapy system which has the capability of tumor tracking has been developed in Japan.

INTRODUCTION

Radiation therapy (RT) is recognized as one of three major treatment modalities in the management of cancer. The ratio of newly diagnosed cancer patients treated by RT is around 60% in developed countries. The only exception is Japan where only 25% of patients receive RT as of 2004. The ratio has increased by 10% in the last decade, and it is estimated that it will be up to 40% in 2015 (1). The rapid increase in elderly patients, who are not amenable to surgical treatment, and innovations of RT in both physical and biological aspects to meet the demands of patients explain this increased use of RT.

The goal of RT is to accomplish the improvement of survival and also the improvement of quality of life in cancer patients. There are two limiting factors to achieve this goal in current RT. One is insufficient biological effects of radiotherapy, and the other is unsatisfactory dose localization techniques. To overcome these problems, several strategies have been investigated, which are divided into two approaches, one is a biological approach and the other is a physical one. The biological approach includes combination of anti-cancer drugs with RT (chemoradiotherapy), modification of fractionation regimen, use of radiosensitizers or radioprotectors, use of hyperthermia and heavy particle therapy. As regards the physical approach, which allows us to irradiate the target as most physically localized as possible, there are intraoperative RT, brachytherapy, conformal radiotherapy, three-dimensional conformal RT (3DCRT), stereotactic irradiation (STI), intensity-modulated RT (IMRT) and proton or heavy particle therapy.

Among those approaches, chemoradiotherapy, STI, IMRT and proton or heavy particle therapy have been applied intensively in clinics as advanced RT modalities.

STI started with intracranial lesions in 1960s. The great success of this innovative treatment, in terms of the technologies used, quality assurance and quality control and clinical outcomes indicating high local control rate with minimal toxicities has induced much interest in the application of this treatment for extracranial regions (2,3). The technologies and methods have been improved greatly in the last decade, and now it is used in clinics as an effective treatment for tumors including early-stage non-small cell lung cancer (NSCLC), liver tumor and so on. STI for extracranial lesions is usually named as stereotactic body RT (SBRT). Radiation oncologists in Japan have contributed greatly to the development of this innovative treatment modality, and furthermore are leading the next generation of SBRT, that is four-dimensional SBRT.

In this 40th anniversary issue of Japanese Journal of Clinical Oncology, achievements and future perspectives of SBRT will be reviewed focusing on studies in Japan.

CONCEPT AND HISTORY

STI was originally developed by Leksell (4) for intracranial lesions. The concept of this new treatment technology is that narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. This technique allows us to deliver high dose to the target leading to high control of the tumor without causing significant cytotoxicities associated with the treatment. The Gamma Knife had been invented for this purpose and installed at Karolinska Hospital in 1968. Following the great success of the Gamma Knife, linear accelerator (LINAC)-based STI has been developed. It is advantageous over the Gamma Knife in that fractionated irradiation is feasible. With the use of fractionated STI, function preservation rate (like hearing capability) is improved and relatively larger tumors can be treated (5).

SBRT is an applied form of STI. It has taken a few decades for STI to be applied for extracranial lesions since the Gamma Knife had been invented. There were several issues to be resolved before it could be utilized for extracranial organs: computed tomography (CT) which can visualize and localize lesions precisely, a treatment planning system for 3D dose calculation and a fixation device for the body. Lax et al. (6) developed the first stereotactic body frame with vacuum pillow stabilization for SBRT in 1994. Blomgren et al. (2) published the first report on SBRT using the stereotactic body frame in 1995. Forty-two tumors in the lung and liver of 31 patients were treated with SBRT. The local control rate was 80%. In Japan, Uematsu et al. (3) developed a frameless system (FOCAL unit) that consisted of a LINAC, an X-ray simulator, CT and a table. They treated 66 lung tumors in 45 patients using this system. Local progression was observed only in 2 of the 66 tumors (3%). Several researchers studied SBRT for lung tumors after these reports, and their results were also promising. These promising results encouraged multi-institutional oncology groups to conduct trials of SBRT for the lung. The Radiation Therapy Oncology Group (RTOG) and Japan Clinical Oncology Group (JCOG) started the RTOG 0236 protocol and JCOG 0403 protocol, respectively.

Since SBRT was covered by the governmental health insurance in Japan in 2004, the number of patients treated with SBRT is increasing. SBRT was performed in 2104 cases with lung cancer at 53 institutions in Japan as of November 2004 (7).

RATIONALES AND INDICATIONS

The use of a high dose per fraction with small fraction number (hypofractionation) for a small tumor is the basis of SBRT. This approach is a double-edged sword. This scheme provides much higher effects on the tumor compared with conventionally fractionated RT, while much worse influence on normal tissues. This is because irradiation with high dose per fraction has been shown to produce more toxicities in a late phase. Prerequisites for SBRT are (i) the lesion is clearly visualized; (ii) the target is precisely localized; (iii) no serial organs are adjacent to the lesion and (iv) tumor size is relatively small. Considering these conditions, the lung and the liver are most suitable for SBRT. Recently, SBRT has been investigated clinically for cancers in the pancreas (8), the prostate (9), paraspinal areas (10) and so on.

Lung cancer is the leading cause of cancer-related death in Japan (11). Approximately 65 000 patients died of lung cancer in 2007 in Japan. For the management of stage I NSCLC, surgical resection is the standard treatment, and lobectomy is generally accepted as the optimal surgical procedure. Survival outcomes of surgical treatment have recently been reported by the Japanese Joint Committee of Lung Cancer Registry (12). According to these data, the overall survival of patients in clinical stage IA is 77.3% at 5 years, and that of patients in clinical stage IB is 59.8% at 5 years.

What about RT alone for stage I NSCLC? As is known, RT has been used primarily for those patients who are not considered to be surgical candidates; that is, those who refuse surgical intervention, and those who are medically inoperable. The reported 5-year survival rate is around 6–32%, and is not satisfactory (13). SBRT is expected to improve the outcomes for these patients.

TECHNIQUES

Details on SBRT procedures for lung cancer in Kyoto University were described in the previous paper (14). The criteria for SBRT for lung tumors were one or two tumors in the lung with size <5 cm in diameter. Two kinds of body frame, Stereotactic Body Frame (Elekta, Stockholm, Sweden) and BodyFIX (Medical Intelligence, Schwabmünchen, Germany), are used to attain accurate and precise patient positioning and immobilization. The former has built-in reference indicators which provide accurate determination of target coordinates. In our experience, daily setup errors with Stereotactic Body Frame were within 5 mm in 90, 100 and 93% of all verifications in the mediolateral, anteroposterior and craniocaudal directions, respectively (15). BodyFIX is composed of radiolucent materials that allow image guidance with X-ray.

X-ray fluoroscopy is performed to measure tumor movement before CT scan. When the tumor moves more than 8 mm in the craniocaudal direction, we use a small plate called a ‘diaphragm control’ which suppresses the movement of the diaphragm and reduces respiratory motion of the tumor. After fluoroscopy, the patient is transferred to a CT room. CT scan is performed under free-breathing with a slow scan technique which can visualize a major part of the trajectory of the tumor by scanning each slice for a time longer than the respiratory cycle, or a 4D-CT technique.

The internal target volume (ITV), which encompasses the whole trajectory of the tumor motion, is delineated on the scanned CT images. After contouring on CT, we compare the ITV on CT with the tumor motion, which was evaluated on fluoroscopy. If the delineated ITV is found to be insufficient to encompass respiratory motion, we extend the ITV. The planning target volume (PTV) is defined by adding a 5-mm margin of setup error to the ITV. The planning organ-at-risk volumes (PRVs) are defined for lung, spinal cord, esophagus, stomach, intestine, trachea, bronchus, pulmonary artery and other organs at risk (OARs). The margin between PRV and OAR is 5 mm, except for the spinal cord and lung. The PRV for the spinal cord is defined as a 3-mm margin with the spinal canal delineated on CT images. The PRV for the lung is the bilateral pulmonary parenchyma outside the PTV. Non-coplanar static beams (5–8 ports) with 6-megavolt (MV) X-rays are used. The margin between the PTV and the field edge is 5 mm, as a rule.

We prescribe a total dose of 48 Gy in four fractions at the isocenter for primary lung cancer with a diameter of 3 cm or less, and 56 Gy in 14-Gy fractions for primary tumor larger than 3 cm and metastatic lung cancer, respectively. Calculated biological effective doses (BEDs) are 105.6 and 134.4 Gy at the isocenter (under α/β = 10 Gy), respectively.

CLINICAL OUTCOMES

Primary NSCLC

Table 1 summarizes reports on outcomes of SBRT for NSCLC. There are some variations in dose-fractionation and patient characteristics including operability. It is obvious that SBRT outcomes are much better than those of conventional radiotherapy persistently.

Table 1.

A summary of outcomes after SBRT for primary lung cancer

Author Year No. of cases T-stage (T1:T2) Dose 3y LC 3y OS MST (mo) 
Nyman et al. (392006 45 18:27 45 Gy/3 fr. 80% 55% 39 
Hoyer et al. (402006 40 22:18 45 Gy/3 fr. 85% (2y) 48% (2y) NA 
Koto et al. (412007 31 19:12 45 Gy/3 fr. or 60 Gy/8 fr. 77.9% (T1) 71.7% NA 
Fakiris et al. (422009 70 34:36 60 or 66 Gy/3 fr. 88.1% 42.7% 32.4 
Ricardi et al. (432009 62 43:19 45 Gy/3 fr. 87.8% 57.1% NA 
Kopek et al. (442009 88 51:36 45 or 67.5 Gy/3 fr. 89% 36% 21.8 
Matsuo et al. (162010 101 73:28 48 Gy/4 fr. 86.8% 58.6% 48.8 
Author Year No. of cases T-stage (T1:T2) Dose 3y LC 3y OS MST (mo) 
Nyman et al. (392006 45 18:27 45 Gy/3 fr. 80% 55% 39 
Hoyer et al. (402006 40 22:18 45 Gy/3 fr. 85% (2y) 48% (2y) NA 
Koto et al. (412007 31 19:12 45 Gy/3 fr. or 60 Gy/8 fr. 77.9% (T1) 71.7% NA 
Fakiris et al. (422009 70 34:36 60 or 66 Gy/3 fr. 88.1% 42.7% 32.4 
Ricardi et al. (432009 62 43:19 45 Gy/3 fr. 87.8% 57.1% NA 
Kopek et al. (442009 88 51:36 45 or 67.5 Gy/3 fr. 89% 36% 21.8 
Matsuo et al. (162010 101 73:28 48 Gy/4 fr. 86.8% 58.6% 48.8 

SBRT, stereotactic body radiation therapy; LC, local control; OS, overall survival; MST, median survival time.

We recently reviewed 10-year experiences at Kyoto University to investigate the factors that influence clinical outcomes following SBRT for lung cancer (16). A total of 101 patients with histologically confirmed stage I NSCLC who underwent SBRT with 48 Gy in four fractions from September 1998 to December 2007 were examined. Multivariate analysis using the Cox proportional hazards model was used to find potential factors that affected clinical outcomes after SBRT. The factors evaluated were age, maximal diameter of tumor, overall treatment time, sex, performance status, operability and histology. The analysis has revealed that tumor diameter and sex were the most significant factors. Recursive partitioning analysis indicated a condition for good prognosis (class I) as follows: female or T1a (tumor diameter ≤20 mm). When the remaining male patients with T1b–2a (>20 mm) were defined as class II, 3-year rates of local progression, disease progression and overall survival were 6.8, 23.6 and 69.9% in class I, respectively, whereas these values were 19.9, 58.3 and 47.1% in class II. The differences between the classes were statistically significant.

There are two large series of multi-institutional studies that retrospectively surveyed clinical outcomes of SBRT for NSCLC. Onishi et al. (17) reviewed 257 patients who underwent SBRT for stage I NSCLC during 1995–2004 at 14 institutions in Japan. Local progression was observed in 14.0% of patients. The overall 3- and 5-year survival rates were 56.8 and 47.2%, respectively. The local recurrence rates were 8.4% in patients who received a BED of 100 Gy or more at the isocenter, and 42.9% in patients receiving a BED <100 Gy. This difference was statistically highly significant (P < 0.001). Baumann et al. (18) retrospectively reviewed results of SBRT for 138 patients with medically inoperable stage I NSCLC treated during 1996–2003 at five centers in Sweden and Denmark. Local failure was observed in 12% of patients. The overall 3- and 5-year survival rates were 52 and 26%, respectively. Local failure was associated with tumor size, target definition and central or pleura proximity. There was a significant advantage in survival for the group receiving a dose above 55.6 Gy in equivalent dose in 2 Gy fractions (EQD2). This report indicates that 55.6 Gy in EQD2 at the PTV periphery corresponds to BED of 100 Gy at the isocenter as is shown in the Onishi's study.

Two multi-institutional prospective trials of SBRT for primary lung cancer have been reported so far. One is a phase II trial for inoperable stage I NSCLC which was undertaken at seven centers in Sweden, Norway and Denmark (19). The prescription dose was 15 Gy with a total dose of 45 Gy at the 67% isodose of the PTV. The 3-year local control rate and overall the survival rate were 92 and 60%, respectively, at a median follow-up of 35 months. Another trial is RTOG protocol 0236 (20). A total dose of 60 Gy was delivered in three fractions to cover 95% of the PTV. Three-year estimates of disease-free and overall survival were 48.3 and 55.8%, respectively.

JCOG protocol 0403 is a phase II trial of SBRT for T1N0M0 lung cancer including both inoperable and operable patients. Patient accrual for operable cases and their 3-year follow-up has already finished in February 2010, and the outcomes are to be disclosed in 2010. This is the first prospective trial for operable T1N0M0 lung cancer (21).

Metastatic Lung Cancer

There are several reports on SBRT for metastatic lung cancer (Table 2). Up to two lesions were simultaneously treated in most of these reports, except for that by Okunieff (up to five lesions). The local control rate was around 80% and the overall survival rate was more than 30% at 2 years. These outcomes seem comparable to those by surgical metastatectomy (22).

Table 2.

A summary of outcomes after SBRT for metastatic lung tumor

Author Year No. of cases/lesions Dose LC (%) OS (%) 
Onimaru et al. (262003 20/32 48–60 Gy/8 fr. 93.8 48.8 
Wulf et al. (452004 41/51 26 Gy/1 fr. or 30–37.5 Gy/3 fr. 80 33 
Okunieff et al. (462006 50/125 50–55 Gy/10–11 fr. 83 38 
Hof et al. (472007 61/71 12–30 Gy/1 fr. 73.7 65.1 
Norihisa et al. (482008 34/43 48–60 Gy/4–5 fr. 90.0 84.3 
Kim et al. (492009 13/18 39–51 Gy/3 fr. 52.7 75.5 
Author Year No. of cases/lesions Dose LC (%) OS (%) 
Onimaru et al. (262003 20/32 48–60 Gy/8 fr. 93.8 48.8 
Wulf et al. (452004 41/51 26 Gy/1 fr. or 30–37.5 Gy/3 fr. 80 33 
Okunieff et al. (462006 50/125 50–55 Gy/10–11 fr. 83 38 
Hof et al. (472007 61/71 12–30 Gy/1 fr. 73.7 65.1 
Norihisa et al. (482008 34/43 48–60 Gy/4–5 fr. 90.0 84.3 
Kim et al. (492009 13/18 39–51 Gy/3 fr. 52.7 75.5 

Rusthoven et al. (23) reported a multi-institutional phase I/II trial of SBRT for metastatic lung tumor. Actuarial local control rate at 1 and 2 years after SBRT was 100 and 96%, respectively, at a median follow-up of 15.4 months. Median survival was 19 months, and overall survival rate at 2 years was 39%.

Complications

Onishi et al. (17) reported that pulmonary complications above grade 2 were observed in 5.4%, grade 3 esophagitis in 0.8% and grade 3–4 dermatitis in 1.2% in the retrospective study of 257 SBRT patients. In Baumann's retrospective study, grade 3–4 toxicity was observed in 10.1% (18).

One of the most informative reports on toxicities associated with SBRT for the lung cancer is the article published in 2006 by Timmerman et al. (24). They reported that grade 5 toxicity was observed in 6 patients (8.6%), and grade 3–4 was in the 8 patients (11.4%) of 70 patients who underwent SBRT for NSCLC with a prescription dose of 60–66 Gy in three fractions. Such severe toxicities were related with tumor location. Patients treated for tumors in the peripheral lung demonstrated a 2-year freedom from severe toxicity in 83% compared with 54% for patients with central tumors. On the basis of this study, central tumor was excluded from the RTOG trial 0236. Protocol-related grade 3 and 4 adverse events in the RTOG 0236 were reported in 12.7 and 3.6%, respectively (20).

PERSPECTIVES OF CLINICAL ISSUES

SBRT for Centrally Located Tumors

Relatively, few data have been available for centrally located tumors. Timmerman et al. (24) demonstrated that a total dose of 60–66 Gy in three fractions caused severe toxicities in 40% for centrally located tumors in the lung. The dose to the organs in the mediastinum should be low enough in those tumors. One possible approach to a central tumor is the use of a mild hypofractionation regimen with a smaller fractional dose. Lagerwaard et al. (25) used three fractionation schemes depending on T-stage and normal tissue toxicity; three fractions of 20 Gy (for T1 tumors), five fractions of 12 Gy (for T1 tumors showing broad contact with the thoracic wall, or T2 tumors) or eight fractions of 7.5 Gy (for tumors adjacent to the heart, hilus or mediastinum). They reported that this risk-adapted SBRT was well tolerated and severe late toxicity was observed in <3% of patients. Eight fractions of 7.5 Gy may be a reasonable approach for most central tumors. There is a case report that a lower dose of 48 Gy in eight fractions caused a grade 5 esophageal ulcer (26). Further studies are needed to determine an optimal dose and fractionation for centrally located tumors.

SBRT for Operable Patients

One of the biggest questions to be answered is whether SBRT can be an alternative to surgical treatment. Several results suggest the potential use of SBRT for those patients. JCOG0403 to be open this year will answer this question since it is the first prospective trial dealing with operable patients. If the results appear almost equivalent to those of surgery, a phase III trial which randomizes lobectomy with SBRT is obviously warranted.

In conclusion, technologies of SBRT have been almost established in the last decade. Clinical efficacy and safety of SBRT for lung cancers are being evaluated favorably by clinical studies. SBRT is less invasive than surgery, and it can play an important role for operable patients with early-stage NSCLC who refuse surgery due to the invasiveness, especially for elderly patients. For inoperable patients, SBRT is considered as a standard treatment with curative intent.

PERSPECTIVES OF INNOVATIONS FROM 3DRT TO 4DRT

Three-dimensional conformal irradiation techniques have improved the dose distributions greatly. It enabled the delivery of high-dose irradiation to the target while minimizing the dose to the surrounding normal tissues. The most advanced treatment of this 3DCRT is STI and IMRT, and many patients with cancer enjoy the benefits of this innovative treatment.

Tremendous advance in sophisticated RT is expected when 3DRT is moved up to 4DRT (four-dimensional RT). Almost all tumors in the body are never static. A tumor in the intra-thoracic and upper-abdominal regions may move 1–3 cm with respiration (27,28). If sufficiently large safety margins are setup to encompass large tumor motions, a large amount of normal tissues have to be irradiated, which obviously increases the risk of radiation-induced cytotoxicities. Several approaches to compete with tumor motions have been clinically attempted, including respiratory inhibition with abdominal compression (15), breath-holding (29,30), respiratory gating (31–33) and tumor tracking. The 4DRT is generally defined in that information on the target position is tracked directly or indirectly in real-time during the treatment session, and the treatment beams are adaptively delivered in accordance with the motion information. Realization of this 4DRT obviously will open a new era of external RT. It will dramatically improve the tumor conformality, and accordingly SBRT and IMRT will be applied to larger tumors and malignancies in various sites for which 3DRT has contributed little.

HISTORY OF THE 4DRT

Japan has contributed much to the development of the 4DRT. In the late 1980s and early 1990s, respiratory gating in RT was first studied by Ohara et al. (31) to apply proton therapy mostly for liver tumors. They used a pressure sensor for the abdominal wall as a respiratory signal. This method was followed by Minohara et al. (32) in gated heavy-ion beam treatment. In the USA, in the mid 1990s, Kubo and Hill (33) investigated different external respiratory signals to monitor respiratory motion. Currently, gated radiotherapy using an external respiratory signal has being clinically implemented using commercially available systems. One of the problems of this method is low duty cycle (typically 30–50%). Since the beam is not continuously delivered, gating procedures take longer treatment time than non-gating procedures. Another problem is that the time-dependant target position might not match the respiration monitoring, and position accuracy is not always guaranteed.

To solve the latter problem, Hokkaido University and Mitsubishi Electronics Co. Ltd developed a new approach in the late 1990s, named ‘real-time tumor-tracking radiotherapy (RTRT) system.’ It consists of four diagnostic X-ray fluoroscopy units located in a radiation treatment room. Two units of the four are used to track 2-mm gold fiducial markers inserted in or near the tumor using image-guided implantation, and the 3D position of the each fiducial can be calculated every 0.03 s in real-time. The LINAC is gated to irradiate the tumor when each fiducial is within an acceptable range of the desired position (34,35). This system realized real-time tracking radiotherapy, and enabled us to know the details of tumor motion by respiration, which have not been evaluated. However, since the beam delivery method is categorized as gated radiotherapy, the problem of treatment time prolongation has still remained. In addition, this system requires implantation of gold fiducial markers. Unfortunately, the system has not been distributed in the world market, and finally discontinued from production.

An attractive and ideal approach to compete with tumor movement is dynamic-tracking irradiation in which the beam is continuously delivered focusing on the tumor. It is advantageous in that beam delivery is highly efficient and the procedure is totally non-invasive. Figure 1 summarized differences between a conventional method with wide margin, respiratory gating and dynamic-tracking irradiation.

Figure 1.

From 3DRT to 4DRT. (A) Conventional method: Wide margin is needed to include respiratory motion. It causes excess irradiation to the normal tissue. (B) Respiratory gating: Beam delivery is gated. Treatment time is prolonged. (C) Dynamic tracking: Beam tracks the target. It allows continuously irradiation with a small field.

Figure 1.

From 3DRT to 4DRT. (A) Conventional method: Wide margin is needed to include respiratory motion. It causes excess irradiation to the normal tissue. (B) Respiratory gating: Beam delivery is gated. Treatment time is prolonged. (C) Dynamic tracking: Beam tracks the target. It allows continuously irradiation with a small field.

Kyoto University, Institute of Biomedical Research and Innovation (IBRI) and Mitsubishi Heavy Industries, Ltd have started collaboration in 2000 to develop an innovative image-guided radiotherapy (IGRT) system which has the capability of dynamic tumor tracking using a novel gimbaled X-ray head and a dual real-time X-ray monitoring system (36–38). The first clinical version of the IGRT system has been approved in FDA in August 2007 and PMDA in January 2008 as ‘MHI-TM2000.’ Its clinical application started in May 2008 at IBRI, and five machines are working or are under construction in Japan and in Belgium as of March 2010.

DYNAMIC TUMOR-TRACKING IRRADIATION BY MHI-TM2000

The configuration of MHI-TM2000 is shown in Fig. 2. The system is designed to efficiently implement genuine high-precision radiotherapy. A rigid ring gantry supports both the beam delivery system and on-board imaging system. An on-board dual kilovoltage X-ray imaging system provides orthogonal radiographs or cone-beam CT (CBCT) for an image-guided setup. The setup error is automatically calculated by the image registration software shown in Fig. 3, and a patient support couch can automatically correct the error not only in translational shift but also rotational movement. The beam delivery system consists of an originally developed C-band compact LINAC which produces 6-MV photon beam, and a multi-leaf collimator (MLC) which produces conformal beams for 3DCRT or intensity-modified beams for IMRT. These components above are highly integrated to implement a fast and accurate image-guided setup and precise beam delivery. Those capabilities are being investigated clinically for 150 patients treated at IBRI.

Figure 2.

An innovative image-guided radiotherapy (IGRT) system ‘MHI-TM2000’. (A) Overview of the machine. (B) Configuration of the system. Abbreviations: FPD, flat panel detector; EPID, electronic portal imaging device.

Figure 2.

An innovative image-guided radiotherapy (IGRT) system ‘MHI-TM2000’. (A) Overview of the machine. (B) Configuration of the system. Abbreviations: FPD, flat panel detector; EPID, electronic portal imaging device.

Figure 3.

Image-guided setup using simultaneously obtained orthogonal radiographs. (A) Dual kilovoltage (kV) X-ray imaging subsystem consisting of two sets of a kV X-ray tube and an FPD provides simultaneous orthogonal radiographs. (B) The obtained radiographs are automatically registered to the digitally reconstructed radiographs (DRR) for image-guided setup based on bone structures.

Figure 3.

Image-guided setup using simultaneously obtained orthogonal radiographs. (A) Dual kilovoltage (kV) X-ray imaging subsystem consisting of two sets of a kV X-ray tube and an FPD provides simultaneous orthogonal radiographs. (B) The obtained radiographs are automatically registered to the digitally reconstructed radiographs (DRR) for image-guided setup based on bone structures.

The X-ray head with the LINAC and the MLC is mounted on a gimbals mechanism. As illustrated in Fig. 4, the gimbals mechanism has two rotational axes, and an active control of rotations along these axes allows the treatment beam to swing toward a designated position around the isocenter. Each rotation (pan and tilt motion) ranges up to +/−2.4°, which means that the MV beam can swing in the range of up to +/−4.2 cm from the isocenter. This beam swing function can be used to achieve high accuracy of the beam delivery to the mechanical isocenter by active compensation for any mechanical distortion in the static mode. A star-shot irradiation test demonstrated its high-beam positioning accuracy <0.1 mm. In the dynamic mode, this function enables the MV beams to track a target in real-time while continuously being delivered. This dynamic-tracking irradiation method named ‘gimbaled tracking’ has three advantages. First, one-degree-ordered small-angle rotations of the gimbals provide quick and accurate beam adaptation to designated positions of a mobile target. Secondly, the mechanism is relatively simple and thus minimizes mechanical load. Finally, the treatment system is safer than systems involving a robotic arm because the moving unit is covered so as not to touch a patient.

Figure 4.

Gimbaled X-ray head. X-ray head with a LINAC and an MLC is mounted on a gimbals mechanism. Rotations along the two orthogonal gimbals (pan and tilt rotations) up to +/−2.4° allow the therapeutic beam swing toward a designated position in the range of up to +/−4.2 cm from the isocenter. Abbreviations: LINAC, linear accelerator; MLC, multi-leaf collimator.

Figure 4.

Gimbaled X-ray head. X-ray head with a LINAC and an MLC is mounted on a gimbals mechanism. Rotations along the two orthogonal gimbals (pan and tilt rotations) up to +/−2.4° allow the therapeutic beam swing toward a designated position in the range of up to +/−4.2 cm from the isocenter. Abbreviations: LINAC, linear accelerator; MLC, multi-leaf collimator.

In terms of real-time imaging, the system can use orthogonal serial radiographs scanned with the gantry-mounted kilovoltage X-ray imaging system. This technique is capable of directly tracking tumors based on the density difference between the tumor and normal lung tissue, provided that the tumor is well defined with a high-contrast edge. Several variations for real-time tracking would be possible in a clinical setting, such as direct tracking, external surrogates and internal surrogates including fiducial markers, diaphragms and so on.

The validation tests using a computer-controlled three-dimensionally movable phantom have shown that the gimbals tracking system significantly reduced motion blurring effects in the dose distribution compared with the non-tracking state, and produced a dose profile slope similar to the profile that is obtained when the phantom was stationary (<1 mm) (37,38). Currently, the gimbals tracking irradiation function is not installed in a commercially available version. Mitsubishi Heavy Industries is developing a clinically applicable system in collaboration with Kyoto University and IBRI.

CONCLUSIONS

SBRT is an innovative treatment modality for early-stage NSCLC. It is considered to be a standard treatment option for inoperable patients. The role of SBRT for early-stage NSCLC should be clarified by the coming clinical trials.

Realization of four-dimensional RT coping with tumor movement obviously causes dramatic advancement of SBRT. The new IGRT system which has the capability of tumor tracking has been developed in Japan, and is expected to be applied in clinics.

Funding

This work was partially supported by a Grant-in-Aid for Scientific Research (S) from Japan Society for the Promotion of Science (No. 20229009); and a grant for Practical Application of Next-generation Strategic Technology Commissioned by New Energy and Industrial Technology Development Organization of Japan (No. 0901002-2006).

Conflict of interest statement

Masahiro Hiraoka and Kenji Takayama have a consultancy agreement with Mitsubishi Heavy Industries.

References

1
Teshima
T
Numasaki
H
Shibuya
H
Nishio
M
Ikeda
H
Ito
H
, et al.  . 
Japanese structure survey of radiation oncology in 2005 based on institutional stratification of patterns of care study
Int J Radiat Oncol Biol Phys
 , 
2008
, vol. 
72
 (pg. 
144
-
52
)
[PubMed]
2
Blomgren
H
Lax
I
Näslund
I
Svanström
R
Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients
Acta Oncol
 , 
1995
, vol. 
34
 (pg. 
861
-
70
)
3
Uematsu
M
Shioda
A
Tahara
K
Fukui
T
Yamamoto
F
Tsumatori
G
, et al.  . 
Focal, high dose, and fractionated modified stereotactic radiation therapy for lung carcinoma patients: a preliminary experience
Cancer
 , 
1998
, vol. 
82
 (pg. 
1062
-
70
)
4
Leksell
L
Stereotactic radiosurgery
J Neurol Neurosurg Psychiatry
 , 
1983
, vol. 
46
 (pg. 
797
-
803
)
5
Andrews
DW
Suarez
O
Goldman
HW
Downes
MB
Bednarz
G
Corn
BW
, et al.  . 
Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution
Int J Radiat Oncol Biol Phys
 , 
2001
, vol. 
50
 (pg. 
1265
-
78
)
[PubMed]
6
Lax
I
Blomgren
H
Näslund
I
Svanström
R
Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects
Acta Oncol
 , 
1994
, vol. 
33
 (pg. 
677
-
83
)
7
Nagata
Y
Hiraoka
M
Mizowaki
T
Narita
Y
Matsuo
Y
Norihisa
Y
, et al.  . 
Survey of stereotactic body radiation therapy in Japan by the Japan 3-D conformal external beam radiotherapy group
Int J Radiat Oncol Biol Phys
 , 
2009
, vol. 
75
 (pg. 
343
-
7
)
[PubMed]
8
Chang
DT
Schellenberg
D
Shen
J
Kim
J
Goodman
KA
Fisher
GA
, et al.  . 
Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas
Cancer
 , 
2009
, vol. 
115
 (pg. 
665
-
72
)
9
King
CR
Brooks
JD
Gill
H
Pawlicki
T
Cotrutz
C
Presti
JC
Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial
Int J Radiat Oncol Biol Phys
 , 
2009
, vol. 
73
 (pg. 
1043
-
8
)
[PubMed]
10
Chang
EL
Shiu
AS
Mendel
E
Mathews
LA
Mahajan
A
Allen
PK
, et al.  . 
Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure
J Neurosurg Spine
 , 
2007
, vol. 
7
 (pg. 
151
-
60
)
11
Foundation for Promotion of Cancer Research
Cancer Statistics in Japan
2009
 
12
Asamura
H
Goya
T
Koshiishi
Y
Sohara
Y
Eguchi
K
Mori
M
, et al.  . 
A Japanese Lung Cancer Registry study: prognosis of 13,010 resected lung cancers
J Thorac Oncol
 , 
2008
, vol. 
3
 (pg. 
46
-
52
)
13
Sibley
GS
Radiotherapy for patients with medically inoperable Stage I nonsmall cell lung carcinoma: smaller volumes and higher doses—a review
Cancer
 , 
1998
, vol. 
82
 (pg. 
433
-
8
)
14
Takayama
K
Nagata
Y
Negoro
Y
Mizowaki
T
Sakamoto
T
Sakamoto
M
, et al.  . 
Treatment planning of stereotactic radiotherapy for solitary lung tumor
Int J Radiat Oncol Biol Phys
 , 
2005
, vol. 
61
 (pg. 
1565
-
71
)
15
Negoro
Y
Nagata
Y
Aoki
T
Mizowaki
T
Araki
N
Takayama
K
, et al.  . 
The effectiveness of an immobilization device in conformal radiotherapy for lung tumor: reduction of respiratory tumor movement and evaluation of the daily setup accuracy
Int J Radiat Oncol Biol Phys
 , 
2001
, vol. 
50
 (pg. 
889
-
98
)
16
Matsuo
Y
Shibuya
K
Nagata
Y
Takayama
K
Norihisa
Y
Takashi
M
, et al.  . 
Prognostic factors in stereotactic body radiation therapy for non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
 , 
2010
17
Onishi
H
Shirato
H
Nagata
Y
Hiraoka
M
Fujino
M
Gomi
K
, et al.  . 
Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study
J Thorac Oncol
 , 
2007
, vol. 
2
 
7 Suppl 3
(pg. 
S94
-
S100
)
[PubMed]
18
Baumann
P
Nyman
J
Lax
I
Friesland
S
Hoyer
M
Ericsson
SR
, et al.  . 
Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries
Acta Oncol
 , 
2006
, vol. 
45
 (pg. 
787
-
95
)
19
Baumann
P
Nyman
J
Hoyer
M
Wennberg
B
Gagliardi
G
Lax
I
, et al.  . 
Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
3290
-
6
)
20
Timmerman
R
Paulus
R
Galvin
J
Michalski
J
Straube
W
Bradley
J
, et al.  . 
Stereotactic body radiation therapy for inoperable early stage lung cancer
JAMA
 , 
2010
, vol. 
303
 (pg. 
1070
-
6
)
21
Hiraoka
M
Ishikura
S
A Japan clinical oncology group trial for stereotactic body radiation therapy of non-small cell lung cancer
J Thorac Oncol
 , 
2007
, vol. 
2
 
7 Suppl 3
(pg. 
S115
-
7
)
[PubMed]
22
The International Registry of Lung Metastases Writing Committee
Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases
J Thorac Cardiovasc Surg
 , 
1997
, vol. 
113
 (pg. 
37
-
49
)
23
Rusthoven
KE
Kavanagh
BD
Burri
SH
Chen
C
Cardenes
H
Chidel
MA
, et al.  . 
Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
1579
-
84
)
24
Timmerman
R
McGarry
R
Yiannoutsos
C
Papiez
L
Tudor
K
DeLuca
J
, et al.  . 
Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
4833
-
9
)
25
Lagerwaard
FJ
Haasbeek
CJ
Smit
EF
Slotman
BJ
Senan
S
Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
 , 
2008
, vol. 
70
 (pg. 
685
-
92
)
[PubMed]
26
Onimaru
R
Shirato
H
Shimizu
S
Kitamura
K
Xu
B
Fukumoto
SI
, et al.  . 
Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers
Int J Radiat Oncol Biol Phys
 , 
2003
, vol. 
56
 (pg. 
126
-
35
)
[PubMed]
27
Keall
PJ
Mageras
GS
Balter
JM
Emery
RS
Forster
KM
Jiang
SB
, et al.  . 
The management of respiratory motion in radiation oncology report of AAPM Task Group 76
Med Phys
 , 
2006
, vol. 
33
 (pg. 
3874
-
900
)
28
Shirato
H
Suzuki
K
Sharp
GC
Fujita
K
Onimaru
R
Fujino
M
, et al.  . 
Speed and amplitude of lung tumor motion precisely detected in four-dimensional setup and in real-time tumor-tracking radiotherapy
Int J Radiat Oncol Biol Phys
 , 
2006
, vol. 
64
 (pg. 
1229
-
36
)
[PubMed]
29
Onishi
H
Kuriyama
K
Komiyama
T
Tanaka
S
Sano
N
Aikawa
Y
, et al.  . 
A new irradiation system for lung cancer combining linear accelerator, computed tomography, patient self-breath-holding, and patient-directed beam-control without respiratory monitoring devices
Int J Radiat Oncol Biol Phys
 , 
2003
, vol. 
56
 (pg. 
14
-
20
)
[PubMed]
30
Wong
JW
Sharpe
MB
Jaffray
DA
Kini
VR
Robertson
JM
Stromberg
JS
, et al.  . 
The use of active breathing control (ABC) to reduce margin for breathing motion
Int J Radiat Oncol Biol Phys
 , 
1999
, vol. 
44
 (pg. 
911
-
9
)
[PubMed]
31
Ohara
K
Okumura
T
Akisada
M
Inada
T
Mori
T
Yokota
H
, et al.  . 
Irradiation synchronized with respiration gate
Int J Radiat Oncol Biol Phys
 , 
1989
, vol. 
17
 (pg. 
853
-
7
)
[PubMed]
32
Minohara
S
Kanai
T
Endo
M
Noda
K
Kanazawa
M
Respiratory gated irradiation system for heavy-ion radiotherapy
Int J Radiat Oncol Biol Phys
 , 
2000
, vol. 
47
 (pg. 
1097
-
103
)
[PubMed]
33
Kubo
HD
Hill
BC
Respiration gated radiotherapy treatment: a technical study
Phys Med Biol
 , 
1996
, vol. 
41
 (pg. 
83
-
91
)
34
Shirato
H
Shimizu
S
Shimizu
T
Nishioka
T
Miyasaka
K
Real-time tumour-tracking radiotherapy
Lancet
 , 
1999
, vol. 
353
 (pg. 
1331
-
2
)
35
Shirato
H
Shimizu
S
Kitamura
K
Nishioka
T
Kagei
K
Hashimoto
S
, et al.  . 
Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor
Int J Radiat Oncol Biol Phys
 , 
2000
, vol. 
48
 (pg. 
435
-
42
)
[PubMed]
36
Kamino
Y
Takayama
K
Kokubo
M
Narita
Y
Hirai
E
Kawawda
N
, et al.  . 
Development of a four-dimensional image-guided radiotherapy system with a gimbaled X-ray head
Int J Radiat Oncol Biol Phys
 , 
2006
, vol. 
66
 (pg. 
271
-
8
)
[PubMed]
37
Nakayama
H
Mizowaki
T
Narita
Y
Kawada
N
Takahashi
K
Mihara
K
, et al.  . 
Development of a three-dimensionally movable phantom system for dosimetric verifications
Med Phys
 , 
2008
, vol. 
35
 (pg. 
1643
-
50
)
38
Takayama
K
Mizowaki
T
Kokubo
M
Kawada
N
Nakayama
H
Narita
Y
, et al.  . 
Initial validations for pursuing irradiation using a gimbals tracking system
Radiother Oncol
 , 
2009
, vol. 
93
 (pg. 
45
-
9
)
39
Nyman
J
Johansson
KA
Hultén
U
Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer—mature results for medically inoperable patients
Lung Cancer
 , 
2006
, vol. 
51
 (pg. 
97
-
103
)
40
Hoyer
M
Roed
H
Hansen
AT
Ohlhuis
L
Petersen
J
Nellemann
H
, et al.  . 
Prospective study on stereotactic radiotherapy of limited-stage non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
 , 
2006
, vol. 
66
 
4 Suppl 1
(pg. 
S128
-
35
)
41
Koto
M
Takai
Y
Ogawa
Y
Matsushita
H
Takeda
K
Takahashi
C
, et al.  . 
A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer
Radiother Oncol
 , 
2007
, vol. 
85
 (pg. 
429
-
34
)
42
Fakiris
AJ
McGarry
RC
Yiannoutsos
CT
Papiez
L
Williams
M
Henderson
MA
, et al.  . 
Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study
Int J Radiat Oncol Biol Phys
 , 
2009
, vol. 
75
 (pg. 
677
-
82
)
[PubMed]
43
Ricardi
U
Filippi
AR
Guarneri
A
Giglioli
FR
Ciammella
P
Franco
P
, et al.  . 
Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial
Lung Cancer
 , 
2010
, vol. 
68
 (pg. 
72
-
7
)
[PubMed]
44
Kopek
N
Paludan
M
Petersen
J
Hansen
AT
Grau
C
Høyer
M
Co-morbidity index predicts for mortality after stereotactic body radiotherapy for medically inoperable early-stage non-small cell lung cancer
Radiother Oncol
 , 
2009
, vol. 
93
 (pg. 
402
-
7
)
45
Wulf
J
Haedinger
U
Oppitz
U
Thiele
W
Mueller
G
Flentje
M
Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients
Int J Radiat Oncol Biol Phys
 , 
2004
, vol. 
60
 (pg. 
186
-
96
)
46
Okunieff
P
Petersen
AL
Philip
A
Milano
MT
Katz
AW
Boros
L
, et al.  . 
Stereotactic body radiation therapy (SBRT) for lung metastases
Acta Oncol
 , 
2006
, vol. 
45
 (pg. 
808
-
17
)
47
Hof
H
Hoess
A
Oetzel
D
Debus
J
Herfarth
K
Stereotactic single-dose radiotherapy of lung metastases
Strahlenther Onkol
 , 
2007
, vol. 
183
 (pg. 
673
-
8
)
[PubMed]
48
Norihisa
Y
Nagata
Y
Takayama
K
Matsuo
Y
Sakamoto
T
Sakamoto
M
, et al.  . 
Stereotactic body radiotherapy for oligometastatic lung tumors
Int J Radiat Oncol Biol Phys
 , 
2008
, vol. 
72
 (pg. 
398
-
403
)
[PubMed]
49
Kim
MS
Yoo
SY
Cho
CK
Yoo
HJ
Choi
CW
Seo
YS
, et al.  . 
Stereotactic body radiation therapy using three fractions for isolated lung recurrence from colorectal cancer
Oncology
 , 
2009
, vol. 
76
 (pg. 
212
-
9
)