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REVIEW

Special Focus Issue: Future Oncology: a 10-year anniversary issue

The development of stereotactic body radiotherapy in the past decade: a global perspective Simon S Lo*,1, Ben J Slotman2, Michael Lock3, Yasushi Nagata4, Matthias Guckenberger5, Shankar Siva6, Matthew Foote7, Daniel Tan8, Bin S Teh9, Nina A Mayr10, Eric L Chang11, Robert D Timmerman12 & Arjun Sahgal13

In the past 10 years, there has been an exponential increase in the incorporation of stereotactic body radiotherapy, also known as stereotactic ablative radiotherapy, into the armamentarium against various types of cancer in different settings worldwide. In this article in the 10th year anniversary issue of Future Oncology, representatives from the USA, Canada, Japan, Germany, The Netherlands, Australia and Singapore will provide individual perspectives of the development of stereotactic body radiotherapy in their respective countries. Stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), entails the delivery of individual ablative doses of radiation to extracranial tumors using advanced technology and treatment planning techniques [1] . It can be delivered using a linear accelerator with image guidance or a robotic system (CyberKnife®, Accuray, CA, USA). Since its inception in the 1990s in Sweden and Japan, there has been exponential interest in the development of SBRT for various disease sites [2] . In the early years, the use of SBRT was limited to lung, liver and spinal tumors. Early investigators from Europe, North America and Asia have contributed significantly in the literature on the use of SBRT for early-stage lung cancer, lung oligometastases, liver metastases and spinal metastases [1] . In the past decade, a large number of investigators globally have conducted prospective clinical trials of SBRT for more established indications such as medically inoperable stage 1 non-small-cell lung cancer (NSCLC), lung oligometastases, liver oligometastases and spinal metastases, and have explored the use of SBRT for emerging applications such as pancreatic cancer, primary liver cancer, prostate cancer, renal cell cancer, head and neck cancer, gynecologic cancer and nonspine bone metastases [2–22] . In this article in the 10th year anniversary issue of Future Oncology, colleagues from the USA, Canada, Japan, Germany, The Netherlands, Australia and Singapore will give individual accounts

KEYWORDS

• global • stereotactic body

radiotherapy

Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Cleveland, OH, USA 2 Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands 3 Department of Radiation Oncology, London Regional Cancer Program, University of Western Ontario, London, ON, Canada 4 Department of Radiation Oncology, Hiroshima University, Hiroshima, Japan 5 Department of Radiation Oncology, University of Zurich, Zurich, Switzerland 6 Division of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 7 Department of Radiation Oncology, Princess Alexandra Hospital, School of Medicine, University of Queensland, Queensland, Australia 8 Asian American Radiation Oncology, Singapore 9 Department of Radiation Oncology, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA 10 Department of Radiation Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 11 Department of Radiation Oncology, Keck School of Medicine & Norris Cancer Center at the University of Southern California, Los Angeles, CA, USA 12 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA 13 Department of Radiation Oncology, Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada *Author for correspondence: Tel.: +1 216 286 6740; [email protected] 1

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Review Lo, Slotman, Lock et al. of the development of SBRT in their respective countries. USA In the USA, before mid-2000s, SBRT was performed in limited number of treatment centers which enrolled a majority of their patients in clinical trials and the disease treated were largely limited to medically inoperable stage 1 NSCLC, lung and liver oligometastases and spinal metastases [1] . In the past decade, with the increased availability of advanced technology and rising interest in the utilization of SBRT for various neoplastic conditions, nearly all major academic centers, some veteran affairs hospitals and a large number of community centers have been equipped with treatment machines that are SBRT-capable. This has resulted in wide availability of SBRT to most US citizens and residents in most metropolitan areas. Patients residing in more rural areas frequently need to travel a long distance to a bigger city to receive SBRT treatments. As a result of the wide adoption of SBRT, the American Society for Radiation Oncology (ASTRO) and American College of Radiology have jointly compiled practice guidelines for SBRT in 2004 and 2010 [23,24] . The American Association of Physics in Medicine (AAPM) Task Group 101 also published best practice guidelines for SBRT in 2010 [25] . Going a step further, ASTRO also published the white paper on quality and safety consideration for SBRT in 2012 [26] . These official guidelines have established the technical standards of SBRT in the USA. The application of SBRT has been expanded to include other body sites including the pancreas [8–12] , the prostate [14–16] , the head and neck region [19,20] , the pelvis [2] , the adrenals [2,27] , nonspine bone [2,28–29] and the kidneys [2] . Numerous centers in the USA have gained and published their experience on SBRT for those disease indications, and early promising results have been observed. Since 2005, several Phase I or II studies of SBRT for lung cancer [3] , primary liver cancer [13] , liver oligometastases [4] , lung oligometastases [5] , oligometastases from specific or unspecified histologies [30–34] , recurrent or metastatic gynecologic cancer [21,22] , prostate cancer [14–16] , pancreatic cancer [8–12] , renal cell carcinoma (RCC) [35,36] and recurrent head and neck cancer [19,20] have been completed and most of them have been published. Indiana University completed a

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Phase II trial of SBRT for early-stage medically inoperable NSCLC showing prohibitive toxicities with the three-fraction regimen in patients with centrally located tumors [37] . Based on these findings, subsequent trials in the USA are separating patients with peripherally and centrally located tumors. The first SBRT trial in a national setting was Radiation Therapy Oncology Group (RTOG) 0236, a Phase II trial of SBRT for peripherally earlystage medically inoperable NSCLC. The local control and overall survival rivaled surgical resection and SBRT has been established as one of the standard therapies for this group of patients in the USA [3] . Since the completion of this trial, RTOG has conducted trials of SBRT for centrally located early-stage NSCLC (RTOG 0813), SBRT for peripherally located early-stage NSCLC using one versus four fractions (RTOG 0915), and SBRT for operable early-stage NSCLC (RTOG 0618) [38] . The final results are pending for these trials. For hepatocellular carcinoma (HCC), Indiana University conducted a Phase I SBRT trial, showing that it was safe to treat Child-Pugh A patients to 48 Gy in three fractions but unsafe to use a three-fraction regimen for Child-Pugh B patients [13] . Current RTOG Phase III trial (RTOG 1112) is comparing sorefenib alone and SBRT followed by sorenfenib for HCC in Child-Pugh A patients [38] . The two Phase I/II trials led by University of Colorado, one on lung and one on liver oligometastases, have demonstrated safety and efficacy of SBRT using a three-fraction regimen with local control rates of >90% [4,5] . Two Phase I trials of SBRT for liver metastases led by University of Texas Southwestern Medical Center have shown minimal toxicities and good to excellent local control with the use of regimens 50–60 Gy in five fractions or 35–40 Gy in one fraction [39,40] . There have also been several US Phase I trials of SBRT for oligometastases with or without systemic therapy for oligometastases of unspecified or specific histologies showing promising local control and acceptable toxicities [30–34] . Regarding recurrent metastatic or recurrent gynecologic cancer, there have been two Phase I or II trials on the utilization of SBRT ± systemic therapy for recurrent or metastatic gynecologic cancer from Case Western Reserve University yielding acceptable rates of toxicities and excellent local control although the rates of distant relapse were high [21,22] .

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Global perspective of stereotactic body radiotherapy There have been several Phase I/II trials of SBRT for prostate cancer conducted in the USA showing its efficacy and relatively low toxicities [14] . RTOG 0938 is a Phase II randomized trial comparing SBRT and hypofractionated radiotherapy for favorable prostate cancer and its accrual of patients has been completed with results pending [41] . Stanford University is the pioneer of SBRT for pancreatic cancer and they have completed prospective trials of single fraction SBRT for pancreatic cancer either as the sole treatment, as a boost or with gemcitabine with good local control but with significant toxicities [9–12] . The overall survival rates were similar to conventional chemoradiotherapy. A subsequent multiinstitutional Phase II trial of SBRT for pancreatic cancer utilizing 33 Gy in five fractions and sandwiched between cycles of gemcitabine showed similar overall survival compared with conventional chemoradiotherapy and the gastrointestinal toxicities were much lower compared with the Stanford regimen [8] . With regard to RCC, both Beth-Israel Deaconess Hospital and University Hospitals Seidman Cancer Center have individually completed their Phase I trials and the preliminary analysis showed favorable toxicity profile [35,36] . Prospective data on SBRT for recurrent head and neck are emerging. University of Pittsburgh Medical Center has completed a Phase I dose-escalation SBRT trial and a Phase II trial of combined cetuximab and SBRT trial, both for recurrent head and neck cancer [19,20] . Both trials showed acceptable toxicities and the Phase II trial showed reasonable progression-free survival. Most recently, University of Texas Southwestern Medical Center completed a Phase II trial of SBRT combined with erlotinib for oligoprogressive metastatic NSCLC and reported high progression-free and overall survival [42] . This novel approach to delay relapse is expected to be an area of intense interest for further clinical trials in the USA. Currently, there are multiple ongoing institutional and national SBRT trials using different strategies in the USA. The results of these trials are crucial in guiding appropriate practice of SBRT. Interested readers are advised to obtain more details at the RTOG, NRG Oncology [43] , and ClinicalTrials.gov [44] websites. Canada The Canadian healthcare system is organized by province, and each province has their own


Review

programmatic approach to cancer care. At this time there is no private radiation oncology practice and each Canadian is entitled to cancer care according to the provincial guideline. The availability of complex radiation treatments, including SBRT, in Canada is variable [45] . It is estimated that a maximum of 10% of patients are treated with SBRT and less than 50% of centers across the country are offering SBRT. Utilization is improving with the increased acquisition of modern linear accelerators equipped with imageguidance and multileaf collimators, and we expect the availability of SBRT to become more uniform. The first SBRT case treated in Canada may have been a liver tumor treated in Toronto in September 2003, and the earliest Canadian SBRT publications described localization of lung tumors for SBRT [46] and radiobiologically based SBRT dosing for liver tumors [47] . There are now over 400 Canadian SBRT papers identified on a PubMed search: (canada[ad] OR canada[mh]) AND (sbrt[tw] OR sabr[tw] OR stereotactic[tw]). Research in all areas of SBRT is emerging across the country, especially in liver tumors [48,49] , oligometastatic disease [50] , RCC [51] , spinal metastases [52–55] and prostate cancer [17,18] . The Canadian Association of Radiation Oncology (CARO) recognized the need for standardization and guidelines, and in 2010 formed the Stereotactic Body Radiotherapy Task Force. This group established guidelines reported in 2012 [56] for SBRT for lung, liver and spine and represents a significant Canadian landmark. Canadian research in SBRT has had global impact in several areas. For lung SBRT, there has been a considerable focus on the technical aspects of planning and delivery [57] , and both patient selection and follow-up [58] . The Canadian contribution to co-operative groups is also significant in both accrual and leadership [59–62] , such as the practice-defining Canadian-led NRG Oncology (previously called RTOG) SBRT study for central lung cancer. Lung SBRT is likely the most widely practiced indication across the country at this time, and is considered nationally as a standard of care for medically inoperable early-stage disease. Canada has also made a major contribution to the development and adoption of SBRT for liver tumors. In particular, pioneering work has addressed critical aspects of liver cancer radiation including technology options [63,64] ,

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radiobiological [65] – and respiratory-guided treatment [66] , and safety [48,49] . This research has led to global impact with international guidelines and co-operative group trials [67] . In comparison to liver SBRT, the adoption of SBRT for prostate has been a latter development. However, it is increasing in practice with most patients treated on clinical trials [17,18] . We expect in the coming years considerable contributions with respect to optimal dose fractionation for both the prostate and nodal volumes [68] . There is considerable interest in SBRT for metastatic disease. For example, the Canadian contribution to the development of SBRT specific to spinal metastases has been significant. Contributions include guidance for delivery [69,70] , treatment planning [71] , outcomes [72] and safety practices especially for fracture and myelopathy [53–55,73] . Canada is now at the point where randomized trials can be conducted to clarify the role of SBRT for oligometastases. Two notable Canadian-led trials include the active international multicenter trial randomizing patients between standard palliative radiation and SBRT in oligometastatic patients [74] , and a national randomized trial comparing conventional radiation to SBRT for spine metastases due to open next year. Several other trials evaluating the role of SBRT in patients with oligometastases and oligoprogression are underway. Based on this history and several upcoming Canadian trials, it is predicted that Canadian research will have global impact with respect to defining optimal current practice and potentially new indications for SBRT.

summarized at International Atomic Energy Agency (IAEA) [78] . Onishi et al. examined cases from 13 medical facilities throughout Japan and reported treatment outcomes. The overall local control rate was 86%. The 5-year survival rate for medically operable patients was excellent at 90% for stage 1A patients and 84% for the IB patients when SBRT delivered a BED of >100 Gy [79] . JCOG 0403 is a multicenter collaborative Phase II clinical trial of SBRT for T1N0M0 NSCLC with participation of 15 treatment centers throughout Japan. The goals of the trial are to evaluate the efficacy and safety of SBRT for both operable and inoperable T1N0M0 NSCLC cases. The 3-year survival rate is the primary endpoint. The dose regimen used is 48 Gy in four fractions, three or four-times per week, with the total treatment period of 4–8 days. The results of the operable cohort with a mean age of 79 years were reported in 2010 [80] , showing 3-year survival and local control rates of 76 and 86%, respectively. Grade 3 or higher adverse events were observed in 6% of the patients. The results of the inoperable cohort with a mean age of 78 years were reported in 2012 [81] , showing 3-year survival and local control rates of was 60 and 88%, respectively. There were no grade 5 adverse events. On the other hand, JCOG 0702 trial [82] demonstrated the ideal dose for T2N0M0 lung cancer could be 60 Gy in 4 fractions and JROSG 0701 trial [Kimura et al., Pers. Comm.] suggested that 60 Gy in eight fractions could be applicable for central lung cancer. A prospective randomized trial comparing two different doses for early lung cancer is underway through JCOG.

Japan In Japan, the universal health insurance system provides coverage for the citizens. Japan is one of the pioneers of SBRT and SBRT was first implemented by Uematsu et al. [75] and Arimoto et al. [76] in 1994. A Japanese study group of SBRT was subsequently formed in 1999, and the group held semiannual meetings. It then transformed into the Japan 3D conformal external beam radiotherapy group (J-CERG) in 2002. Because of the significant impact of this SBRT procedure, the Japanese government approved SBRT to be covered by the health insurance in 2004. SBRT is now in clinical use at more than 200 institutions in Japan [77] . The consensus of this treatment method was

Germany Based on a long tradition and experience in cranial stereotactic radiotherapy and radiosurgery, German University centers were among the early adopters of SBRT with the first patients treated in 1997. The University Hospital Heidelberg evaluated mostly single fraction radiosurgery for lung and liver tumors in both prospective and retrospective studies. The University Hospital Wuerzburg evaluated mostly fractionated SBRT and treated the majority of the patients for primary and secondary lung tumors. Studies from these institutions pioneered and further developed important clinical and technical aspects of SBRT, for example, targeting accuracy of stereotactic patient set-up demonstrating the need for



Global perspective of stereotactic body radiotherapy image-guidance [83,84] , integration of breathing induced target motion into treatment planning and delivery [85,86] , normal tissue response to high-dose-per-fraction SBRT [87,88] , relevance of accurate dose calculation algorithms [86] , doseresponse for local tumor control [89–91] as well as for SBRT related toxicity [92] and applicability of radiobiological models in SBRT [93] . Early prospective and retrospective studies in these two centers were started in the late 1990s and demonstrated safety and efficacy of SBRT for primary and secondary liver tumors [91,94] , primary and secondary lung tumors [94,95] , vertebral metastases [96,97] and other abdominal and pelvic targets like recurrent gynecological tumors [94,98] . Despite limited clinical experience in this field and technology vastly inferior to current standards (e.g., treatment planning software, 4D imaging, linac characteristics, motion compensation and in-room image guidance) local tumor control has been consistently in the range of 80–90% with low rates of severe toxicity. Based on these promising data and supported by an early establishment of a working group for extracranial stereotactic radiotherapy within the German Society for Radiation Oncology, SBRT was quickly adopted in the Germany. Further adoption of SBRT started in 2000 such that in 2011, >13 mostly academic centers had >1 year experience in SBRT for stage 1 NSCLC; >50% of these centers started SBRT before the year 2004 [99] . Rapid adoption was associated with rapid development of the SBRT practice, for example, systematic implementation of FDG-PET staging, use of in-room volumetric image-guidance and use of advanced dose calculation algorithms. Despite large interinstitutional variability and time-trends in SBRT practice, no systematic change of SBRT outcome has been observed in a national pattern of care analysis for stage 1 NSCLC. Additionally, a learning curve for lung SBRT was not evident. Only radiotherapy dose was associated with outcome. Today, SBRT is practiced in the vast majority of all academic centers and in many nonacademic public centers as well as in private practice. This rapid adoption is observed despite there is no national reimbursement code for SBRT; only few centers do have bilateral arrangements with healthcare insurers. In contrast to the dynamic development of SBRT technology and methodology in


Review

Germany, the characteristics of patients referred to lung SBRT remained stable. Relatively small [99,100] numbers of patients were referred to SBRT for stage 1 NSCLC – 95 patients were treated in these 13 centers in 2010 – and these patients were almost exclusively medically inoperable due to severe comorbidities. In contrast, German centers were unique in a recent European survey (England, The Netherlands, Austria, Belgium, Denmark and Germany) such that the SBRT practice was larger in secondary compared with primary lung cancer [101] . The recent publication of national practice recommendations for lung and liver SBRT [102,103] will hopefully support homogenising SBRT practice within Germany and together with a growing level of evidence and integration of SBRT into international guidelines further improve acceptance of SBRT in multidisciplinary discussions. The Netherlands In The Netherlands, SBRT was started in 2003 at VU University Medical Center. As in most centers, initially mainly small peripheral lung tumors treated. Radiotherapy in The Netherlands, with a population of about 17 million people, is delivered in 20 departments. These departments at that time were at an average size of 4.5 linear accelerators (LINACs) per department. This increased to 6.5 LINACs in 2013 [104] . The minimum size of a department is nowadays four LINACs, and departments can start a satellite center with at least two LINACs, provided that it is an integral part of the main institute and all treatment planning is also done at the main center. This size allows for sufficiently high number of (subspecialized) radiation oncologists and clinical physicists, as well as the opportunity for frequent installation of the latest equipment. These are ideal prerequisites for the early implementation of new technologies, not only at larger university centers, but throughout the country [104] . A few years after 2003, three other centers also started SBRT and in 2014, more than 90% of the centers performed SBRT for lung tumors. VU University Medical Center has remained one of the main centers for SBRT with occasional referrals from the majority of the Dutch hospitals. In more recent years, these referrals were predominantly more challenging larger and/or central tumors, for reirradiation, and for treatment of other indications. SBRT for spine, liver and


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Review Lo, Slotman, Lock et al. oligometastases is now performed on a regular basis in an increasing number of Dutch centers. At VU University Medical Center, there was already a lot of experience on hypofractionation for lung tumors [105] . Since 2003, all patients were prospectively treated according to a risk-adapted fractionation protocol [106] and the largest experience on lung SBRT has been published [106–109] . The low incidence of granulamatous diseases in the country, combined with the results from studies performed with the introduction of PET scanning in the 1990s, has resulted in a policy were patients with new or growing PET-positive lung lesions are accepted for SBRT, after discussion in a multidisciplinary tumor board [110] . No difference in outcome between patients with or without pathologic diagnosis were seen [110] . Populationbased studies in The Netherlands showed that the introduction of SBRT for lung cancer led to an increased use of radiotherapy and a significant increase in survival in the elderly Dutch population [108,111] . The excellent results of SBRT are not only observed in medically inoperable patients, with a high rate of comorbidity, but also in longer surviving medically operable patients who were treated with SBRT because they refused surgery [112] . This has led to a randomized controlled trial comparing surgery and SBRT for early-stage lung cancer patients (ROSEL study). Unfortunately, the ROSEL trial was closed prematurely due to poor accrual. However, the guidelines for SBRT described in this trial have been very helpful for the introduction of SBRT in the country [113] . The radiotherapy departments who had implemented SBRT, each treated between 25 and more than 1000 lung cancer cases in 2013. Similarly, the number of nonlung cancer cases treated with SBRT varied from 0 to more than 250 per department. Australia Australia is a vast continent with a modest population of 23 million inhabitants and a population density of 3.0 per square kilometer [114] . The majority of the populace is distributed in coastal regions across the eastern, southern and southwestern seaboards. Due to the geographical isolation of a significant proportion of the populace from metropolitan capitals, many smaller regional radiotherapy centers provide services for large geographic catchments. There

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are a total of 71 radiotherapy centers with an equal distribution of public and private service providers. Given the resource intensive nature of SBRT coupled with the decentralized distribution of access to radiation facilities, the implementation of these techniques have largely been limited at present to major metropolitan centers. The uptake of SBRT in the region has been slow with the first treatments delivered in 2010. There are several plausible explanations for the modest adoption of this technology. Early experiences with hypofractionation with conventional radiotherapy techniques at the Peter MacCallum Cancer Centre throughout the 1960s to 1980s in combination with hyperbaric oxygen were unfavorable, with excessive toxicities recorded in the head and neck [115,116] , spinal cord [117] and brachial plexus [118] . These historical toxicities translated into cautious uptake of hypofractionation with SBRT [119] . Additionally, the governing body for medical reimbursement has been traditionally reluctant to reimburse advancements in technology. Although SBRT is efficient from a patient throughput perspective, it may be financially disadvantageous for the treatment facility [120] . Consequently, the initial SBRT programs in Australia were limited to public metropolitan centers where often resource allocation restrictions applied. Despite these challenges, the number of centers performing SBRT is rising rapidly in Australia. In response to this, a committee was established with representation from the Faculty of Radiation Oncology (FRO) of the Royal Australian and New Zealand College of Radiologists (RANZCR), Australian Institute of Radiography (AIR), and the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) to establish guidelines to ensure appropriate care of patients receiving SBRT. Although similar to other international guidelines [23,56,121] the guideline accounts for the complex geography and provision of radiation therapy services in Australia and New Zealand. With the increasing availability of SBRT there has been growing trial activity utilizing these techniques. The TROG 09.02 (CHISEL) trial is a randomized Phase III study of SBRT versus conventional radiotherapy in inoperable early stage 1 NSCLC that has completed accrual in 2015. The TROG 13.01/ ALTG 13.001 (SAFRON II) trial is a randomized, Phase II


Global perspective of stereotactic body radiotherapy study comparing single versus multifraction SBRT for patients with lung metastases which opened in 2015. Additionally, the TROG 15.01 SPARK study investigates kilovoltage intrafractional monitoring in the setting of primary prostate SBRT. In conjunction with the IAEA, assistance has been provided to strengthen the application of SBRT to improve cancer treatment in southeast Asia. Sydney, Australia will host the regional training course in July 2015. Notwithstanding the initial measured adoption of SBRT in Australia the application of this technique has expanded rapidly in recent years. There is a history of conducting and completing well-designed trials with the supporting co-operative research infrastructure and rigorous centralized quality assurance mechanisms to ensure high-standard outcomes. Given the relatively recent uptake of SBRT, there still exists the necessary clinical equipoise in Australia required to complete randomized controlled trials in the field. A considered approach to this technique and consequent focus on standardization through clinical trials is likely to ensure that this region is well represented in the wider SBRT community leading into the future. Singapore Singapore is equipped with modern radiotherapy equipment capable of various SBRT. As of April 2015, there are 18 linear accelerators serving the population of 5.39 million spread over a land area of 716.1 square kilometers [122] . All machines are equipped with at least multileaf collimators, including two Tomotherapy machines, one Novalis classic, two Varian trilogies and three Elekta IGRT capable machines. Thirteen of these are located within the public sector and all patients are within 1.5 h from a facility by public transport [Tan D, Pers. Comm.] . The first SBRT treatments commenced in 2010 were led by neurologic and thoracic radiation oncologists within the public sector, focusing on spinal metastases and early-stage medically inoperable NSCLC, respectively. Subsequently, a prostate SBRT program was established through a Phase II prospective clinical trial for the treatment of low and intermediate risk prostate cancer. Lung and liver oligometastases in good performance status patients were added to the list of SBRT indications as the teams gained experience. SBRT has also been used for retreatment of well-defined recurrences.


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As of April 2015, approximately 90 lung lesions (20% metastases), 19 prostate cases, 12 spine SRS lesions, ten retreatments of various sites (bone, pelvic soft tissue, three liver metastases) have been treated with no grade 3 or above toxicity [Tan D, Pers. Comm.] . As median follow-up approaches meaningful length for evaluation, clinical audits have been carried out and will be presented at major international conferences. Preliminary findings show comparable local control rates [Tan D, Pers. Comm.] . An oligometastases Phase II study and a study on SBRT for HCCs in cooperation with IAEA are underway. Lung SBRT are mostly treated with 12 Gy × four to five fractions depending on size and proximity to critical structures, prostates are treated with 7.25 Gy × five fractions every other day, spine lesions are treated with 24 Gy/two fractions, retreatments to various sites are treated with a range of 24–40 Gy in three to five fractions and liver metastases are treated with 10 Gy × five fractions [Tan D, Pers. Comm.] . The conservative number of patients treated is a reflection of the traditional mindsets of practicing oncologists who hold to the paradigm that metastatic disease should be treated with systemic therapy or with palliative intent thus precluding advanced radiation techniques. Patients generally assume a passive role and thus will accept treatment that is recommended to them. Nevertheless, there is a pool of practitioners who have trained overseas who are taking leadership in raising the awareness of SBRT in Singapore and southeast Asia. Singapore hosted the first IAEA regional training course in 2012 and have held symposiums locally and overseas (e.g., the Philippines Radiation Oncology Society Annual Convention in 2014 was focused on SBRT with speakers from Singapore) to educate oncologists of its applications. Recognizing its limitations as a small country, Singapore has positioned itself as the training hub for its neighbors so as to contribute to the field of SBRT. There is a growing recognition of SBRT and acceptance of the increasing body of literature among oncologists. However, availability of Phase III randomized controlled trials supporting the use of SBRT will greatly accelerate its acceptance and in turn referral patterns. Conclusion In the past decade, there has been tremendous advancement of SBRT globally. Variations exist with regard to different aspects of SBRT among


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Review Lo, Slotman, Lock et al. EXECUTIVE SUMMARY USA ●●

I n the past 10 years, multiple important stereotactic body radiotherapy (SBRT) Phase I and II trials for medically inoperable stage 1 non-small-cell lung cancer (NSCLC), primary liver cancer, lung oligometastases, liver oligometastases, oligometastases from specific or unspecified histologies, recurrent or metastatic gynecologic cancer, prostate cancer, pancreatic cancer, renal cell carcinoma, head and neck cancer have been completed.

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Multiple clinical trials of SBRT for various disease sites are ongoing in the USA.

Canada ●●

The development of SBRT has been very rapid in Canada in the past 10 years.

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S eminal Phase I/II trials of risk-adapted SBRT for hepatocellular carcinoma and liver metastases have been completed and reported and a Canadian-led international Phase III trial addressing the value of SBRT in addition to sorafenib is underway.

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Phase I/II trials of SBRT for low- and high-risk prostate cancer have been completed and reported.

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esearch on SBRT for spinal tumors, oligometastasis, lung cancer, primary liver cancer and prostate cancer has R contributed tremendously to the literature.

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ne Canadian-led randomized Phase II trial of SBRT versus conventional treatment for oligometastases (SABR-COMET) O is accruing patients and another Canadian-led randomized Phase III trial comparing conventional radiotherapy and SBRT for spinal metastasis will be opened for patient accrual soon.

Japan ●●

The Japanese are one of the pioneers of SBRT for lung cancer.

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esearch on SBRT, especially in the area of NSCLC, has contributed immensely to the literature and provided practice R guidelines in terms of dose response.

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J apan Clinical Oncology Group (JCOG) has conducted Phase I/II trials for early-stage NSCLC with preliminary results reported on operable and medically inoperable patients with T1N0M0 disease and patients with T2N0M0 disease.

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A prospective randomized trial comparing two different doses for early-stage lung cancer is underway through JCOG.

Germany ●●

Germany is among one of the early adopters of SBRT.

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Early prospective trials for lung and liver tumors have contributed to the literature.

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There is rapid development of SBRT across Germany in the past 10 years.

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erman investigators have contributed significantly in the research on the technical aspects of SBRT, especially in lung G and liver tumors.

The Netherlands ●●

I n the past 10 years, the number of centers providing SBRT has increased rapidly such that more than 90% of the centers are currently offering the procedure.

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Dutch investigators have reported the largest body of experience in SBRT for lung cancer.

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opulation-based studies in The Netherlands showed that the introduction of SBRT for lung cancer led to an increased P use of radiotherapy and a significant increase in survival in the elderly Dutch population.

Australia ●●

The first SBRT treatments were delivered in 2010.

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iven the resource-intensive nature of SBRT and the decentralized distribution of access to radiation facilities, the G implementation of these techniques have largely been limited at present to major metropolitan centers. However, the number of centers performing SBRT is rising rapidly in Australia.

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committee with representatives from various professional organizations in Australia has been established to develop A guidelines to ensure appropriate care of patients receiving SBRT.

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EXECUTIVE SUMMARY (CONT.) Australia (cont.) ●●

A randomized, Phase III study of SBRT in inoperable early stage 1 NSCLC is being conducted and is close to completion.

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Other SBRT trials are in development in Australia.

Singapore ●●

The first SBRT treatments for lung cancer and spinal metastases were commenced in a public hospital in 2010.

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The utilization of SBRT is gradually increasing.

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A Phase II prospective clinical trial for the treatment of low- and intermediate-risk prostate cancer is being conducted.

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Prospective trials of SBRT for oligometastases and hepatocellular carcinoma are currently under development.

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Singapore has positioned itself as the training hub for its neighbors so as to contribute to the field of SBRT.

different centers across the globe. Collaborative research is necessary to help develop consensus guidelines for safe and effective practice of SBRT. Future perspective With the rapid development of advanced technology, SBRT has been very actively incorporated into the armamentarium against various types of cancer in different setting in North America, Europe, Asia, Australia and other parts of the world. Numerous retrospective studies and single arm prospective trials have been performed. However, comparative effectiveness studies and randomized Phase III trials comparing SBRT and conventional therapy are lacking. Without randomized comparison, all results are subject to bias. Most recently, American and Dutch investigators have collaborated by combining the data of two underaccrued randomized Phase III trials comparing SBRT and lobectomy for operable stage 1 NSCLC and have successfully generated meaningful data, establishing SBRT as an alternative to lobectomy [41] . Interested readers are advised to go to the original publications for details. There are several ongoing or planned randomized Phase II or III trials comparing SBRT and standard treatment for various disease conditions, with some of them open to international treatment centers. The randomized Phase III portion of RTOG 0631 trial comparing SBRT and conventional radiotherapy for one to three spinal metastases is still accruing patients [38] . Other ongoing RTOG or NRG Oncology randomized Phase III trials comparing SBRT and standard therapy including RTOG 1112 (sorefenib vs SBRT + sorefenib for Child-Pugh A patients with HCC), and NRG-BR002 (standard therapy vs standard therapy + SBRT for oligometastatic


breast cancer). In Canada, the SABR-COMET randomized Phase II trial comparing standard treatment and SBRT for oligometastases are currently accruing patients and a randomized Phase III trial comparing conventional radiotherapy and SBRT for spinal metastases is due to open in 2016. In Australasia, TROG 09.02 (CHISEL) is a randomized Phase III trial comparing SBRT and conventional radiotherapy for medically inoperable stage 1 NSCLC and is expected to be completed in 2015. Hopefully, the results of these randomized Phase II or III trials can better define the role of SBRT in the management of cancer. There are some variations in indications, treatment techniques, radiation dose regimens and dose constraints for SBRT among different treatment centers across the globe. Collaborative research, whether retrospective or prospective, will be needed for the development of international consensus guidelines for SBRT for various organ sites. Financial & competing interests disclosure SS Lo has received honorarium and travel support for a previous educational symposium from Varian Medical Systems and has also received research support from Elekta AB. Ben Slotman has received speaker honorarium and travel support from Varian Medical Systems. RD Timmerman has received research funding from Varian Medical Systems. A Sahgal has received honorarium for previous educational seminars for Medtronic Kyphoplasty division, Elekta AB and Varian Medical Systems and has also received research grants from Elekta AB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.


2729

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