Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China

Stereotactic radiation therapy in the era of precision medicine for cancer

Yang CONG, Shi-kai WU

Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China

doi 10.13459/j.cnki.cjap.2015.06.002

Unlike conventional radiation therapy, stereotactic radiation therapy (SRT) is an emerging tumor-ablave radiaon technology with a high-dose delivery to targets while dramacally sparing adjacent normalssues. The strengths of SRT involve noninvasive and short-course treatment, high rates of tumor local control with a low risk of side ef f ects. Although the scienf i c concepts of radiobiology fail to be totally understood currently, SRT has shown its potenal and advantages against various tumors, especially for those adjacent to less tolerable normal organs (spinal cord, opc nerve, bowels, etc.). Nowadays, the clinical efficacy of SRT has been widely conf i rmed in certain paents, especially for those medically inoperable, unwilling to undergo surgery, medicine inef f ecve with tumor progression. Moreover, SRT could be properly used as palliave treatment aiming at relieving local symptoms and pain, and eventually achieving a potenal survival benef i t of several months. However, the weaknesses of SRT relate to inevitable radiaon-induced toxicies as well as the inaccessibility of prophylacc irradiaon. In general, one fl aw cannot obscure the splendor of the jade. The emergence and development of SRT has opened the new era of precision radiaon therapy, and SRT will probably step gloriously onto the remarkable stage for precision medicine.

stereotactic radiation therapy; precision medicine; cancer

Introduction

During the past decades, the study of clinical oncology has made great achievements. According to the latest World Cancer Report, cancer remains to be the leading cause that threatens human life with 14 million new cases per year. However, with the diversity of treatment options, the individualization of treatment planning, the popularity of multidisciplinary treatment, the survivals of cancer patients have markedly been extended. Long-term survival with tumor brings a new blessing to cancer patients. Surgical oncology is developing rapidly with the new-born medical devices like ultrasound knife, laparoscope, and da Vinci Surgical System, with which treatmentcould be more precise and less invasive. Medical oncology currently has come into the promising era of precision therapy driven by gene, following the paradigm shifrom the period of cytotoxic drugs-dominated to the period of the rise of individualized molecular targeted therapy. Radiation oncology has experienced a paradigm shift from 2-dimensional (2D) radiotherapy to 3-dimensional (3D) radiotherapy, and fortunately the emergence of SRT has opened the new era of precision radiation therapy.

With the rapid development of the techniques of radiation therapy in recent 10 years, conventional dose fractionation has been challenged to some extent. Hypofractionation for SRT by Gamma Knife and Cyberknife has come into a new trend, including stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT), and stereotactic ablative radiotherapy (SABR). SRS, first defined in 1951 by Lars Leksell, is used for treating intracranial tumor to prevent possible bleeding or infection by surgery [1]. SBRT is the terminology used when treatment is in the body, while SABR has come into common use more recently [2-3]. SRT involves extremely high-dose delivery to target volumes and has the ad-vantages of precision irradiation, highly conformal dose distribution, sharply steep dose gradients, fewer treatment visits and greater convenience [4]. As such, SRT could achieve better local control of tumor with well-accepted toxicities, which usually means a better clinical prognosis. SRT also provides a new treatment option for those medically inoperable or unwilling to undergo surgery [5]. Moreover, SRT could be properly used as palliative care for those medically inoperable, medicine-inef f ective, or with tumor progression, which aims at relieving local symptoms and pain, and eventually achieving a potential survival benefit of several months [6-8]. In this article, we will describe the scientif i c concepts and techniques, together with clinical experiences and future expectations of SRT.

Concepts and techniques

The emergence of SRT is changing the landscape of radiation oncology treatments, radiobiologically and clinically. Normal healthy organs are usually divided into the serial ones and the parallel ones.e maximum dose delivered should be considered for serial organs such as the spinal cord, optic nerve, and esophagus, while the mean dose delivered should be considered for parallel organs such as the lung, heart, and liver. Precisely and accurately, high-dose irradiation with SRT largely spares the innocent normal tissues, and could create a fi ne and elegant “art” by “sculpturing” the target surrounded by critical normal tissues in some specif i c tumors, like spinal cord metastasis. Currently, there are two dif f erent ways to account for SRT. One is calculating Biologically Ef f ective Dose (BED) with the Linearquadratic (LQ) model whereby the laws of repair, redistribution, repopulation, and reoxygenation (4-Rs) apply. The other is new radiobiology rationales of hypofraction such as bystander/abscopal factors, immune activation and tumor endothelium cell death [9]. Biologically, SRT proves to have a variety of advantages over conventional radiotherapy. As is known, conventional fractionation radiotherapy usually suppresses the immune system [10], while SRT does the opposite. Fuks first reported that hypofractionated radiation was superior to that of the conventional due to more endothelial apoptosis and microvascular dysfunction [11]. Peters discussed the potential use of the interesting “abscopal ef f ect”in cancer treatment, that is, SRT produces a clinical ef f ect on the distant targets without being irradiated [12], which may be explained by the CD8+T-cellmediated immune response [13-15]. In conclusion, the real radiobiological mechanism is still a mystery, and the classic 4-Rs theory without indirect damage fails to fully account for the ef f ective tumor control by SRT.

SRT could not have been achieved without the rapid development of physical techniques in radiation therapy. Nowadays, an increasing number of radiation oncology treatment centers own the SRT devices such as Gamma Knife, linac accelerator, Cyberknife, charged particle radiation device. Gamma Knife was fi rst applied to clinical work with an ideal photon radiation source, namely cobalt-60, in 1967 by the Swedish neurosurgeon Lars Leksell. Then it has evolved from the fi rst models A to the following models B, C, 4C, and the latest PERFEXION. Gamma Knife SRT involves multiple isocenters of radiation delivery which means a high dose in the middle of target.e PERFEXION is the state-of-the-art Gamma Knife unit using 192 60Co sources arranged in a cylindrical conf i guration in fi ve concentric rings, and the bigger radiation cavity offers expanded indications of SRT by a greater treatment range [16]. Linear accelerators which are commonly used in conventional radiotherapy like 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) have been widely modif i ed for SRT.is SRT technique, also called X-knife, is now easily accessible in major radiation oncology departments. Edge Radiosurgery, first used in 2014 in the world, is a dedicated system for of f ering high-intensity radiation to tumors while reducing the risk of irradiation to surrounding healthy tissues. With accuracy and speed, Edge represents one of the most advanced SRT technologies with linear accelerators. X-knife, as one of the SRT techniques, has such advantages like hypofractionation and precise irradiation. However, the radiation dose curve of X-knife is not so steep as that of Gamma Knife, and both of them are framebased stereotactic techniques. Afterwards, here comes the frameless Cyberknife. Cyberknife could be used for both isocentric and non-isocentric treatment plans. Most importantly, it has an advanced image-guided real-time tracking system to ensure the accuracy of treatment, including skull tracking, XSight Spine tracking, XSight Lung tracking, and Fiducial tracking. Currently, Cyberknife has become one of the most advanced SRT technologies worldwide. Charged particle radiation device is capable of releasing the energy until a certain depth is reached by delivering proton or carbon ion beams with Bragg Peak, and largely protects normal non-irradiated tissues, whereas socioeconomic factors restrict its development and popularization.

Given the characteristics of SRT, precise treatment to spare the normal tissue is an utmost concern. The precise SRT requires strict treatment process involving patient evaluation, immobilization and simulation, target delineation, treatment planning, treatment delivery and image guidance. Comprehensively analyzing patients’ past medical histories and current status by laboratory tests and image examinations is essential to a best therapeutic regime [17]. Immobilization limits the external motion of tumor during treatment, which usually uses thermoplastic membrane and vacuum cushion to keep patients in the same position throughout the course. After immobilization, simulation with CT or CT /MRI is performed to provide imaging data for further treatment planning. With the development of tracking systems like respiratory gating, 4D-CT, and fi ducial insertion, respiratory motion can be monitored in real-time, which drastically improves the accuracy of SRT in various tumors. Then, the involved physician carefully delineates tumor tissues and adjacent normal organs on image set, with a principle of considering heterogeneity of tumor growth and avoiding primary physiological barriers. Gross tumor volume (GTV) is the target area visible on image set. Clinical target volume (CTV) includes subclinical microscopic disease which is not visible on imaging. Although CTV is not contoured in most SRT, there is still the possibility of treating subclinical targets for tumors in the body [18]. Planning target volume (PTV) is the actual radiation area during treatment delivery, requiring a careful consideration of virtually safe dose. Considering respiratory motion in 4D CT simulation, internal target volume (ITV) is used to include the full excursion of tumor with respiratory cycle. Aer carefully contouring targets and critical organs, medical physicists make a plan according to the prescribed dose by physicians. The treatment plan must be critically reassessed and fi nally determined by both physicians and physicists in charge to ensure safety, accuracy, and ef fi cacy. During treatment delivery, using image guidance for quality assurance (QA) and quality control (QC) is critical, and physicians must check regularly to assess tumor conditions and should redesign the plan when necessary.

Clinical experences

Despite the limited understanding of radiobiological mechanisms currently, SRT has been evolving since its initial treatment for cancer. SRT has been widely accepted for providing a noninvasive precise alternative treatment in most cancers with a satisfying outcome.

SRT has a variety of clinical experiences for brain tumors in view of its strengths in less neurotoxicity. Brain metastases, which are gradually developed from primary tumors of the lung, breast, kidney, and melanoma, continue to be a signif i cant lethal factor that severely affects the survival and quality of life of cancer patients. Whole brain radiation therapy (WBRT) alone in treating brain metastases was fi rst reported in 1950s [19], and remains to be one of the main treatment modalities for brain metastases today, especially among patients with multiple lesions. Many clinical trials have been conducted to find the most appropriate dose fractionation scheme for WBRT. The latest National Comprehensive Cancer Network (NCCN) guidelines recommend 30 Gy/10 f or 40 Gy/20 f for WBRT standard fractionation scheme. However, due to impossibility to deliver a lethal dose of tumor in the brain by this modality, WBRT fails in radical treatment while ironically producing potential neurocognitive dysfunction to long-term survivors.us, the question whether SRT could be used in initial treatment for brain metastases with the avoidance or delay of WBRT has become a heated issue [20-22]. SRT, usually 15-30 Gy/1-5 f, shows efficacy and safety in delivering a tumor-ablative dose of radiation to treat limited brain tumor sites.is new scheme of SRT with few fractions and higher doses is called hypofractionation which shows promising outcomes even for radioresistant tumors. RTOG 9005 determined the dose delivery to brain metastases by measuring the maximum tumor diameter. In a single irradiation, prescription doses are 24 Gy for a tumor less than 20 mm in diameter, 18 Gy for 21-30 mm, and 15 Gy for 31-40 mm [23]. Despite such advantages SRT over WBRT, there is no denying that patients receiving SRT alone possibly are at a higher risk of distant brain recurrence than those with WBRT. Previous research reported SRT+WBRT shows a significant decline in neurocognitive function at 4 months, and it is likely to develop central nerve system (CNS) relapses in the group receiving SRT alone [20]. However, some studies indicate that comparing the SRT alone group with the WBRT plus SRT group, it is surprising to see the similar median survivals and local tumor control rates in patients with few brain metastases. Currently, radiation oncology circles have reached a consensus that for patients with 1 to 3 brain metastases, SRT alone is preferred [24-25]. Meanwhile, there has been a popular trend to treat patients with more than 3 lesions by SRT. More clinical research has demonstrated thefeasibility of SRT to multiple lesions [26-28]. Considering the advantages of SRT, how to select the optimal treatment modality undoubtedly requires further study and discussion. Besides, the technique of SRT has proved to be effective among primary brain tumors, benign and malignant alike.

Despite tumor heterogeneity, various extracranial tumors have also been explored in treating with SRT, such as lung cancer, gastrointestinal cancer, prostate cancer, and sarcoma.

As air pollution aggravates, lung cancer shows increasing morbidity and mortality worldwide [29]. Historical retrospective studies [30-31] indicated generally poor outcomes in patients with stage I nonsmall-cell lung cancer (NSCLC) treated by conventional radiation to a dose of 60 or more, while SBRT is well tolerated and has better local control. As is reported, reaching a high BED is correlated with the improvement of overall survival and local tumor control rates in various tumors [32]. Using the L-Q equation to derive a BED, a conventionally fractionated radiation therapy plan of 60-66 Gy delivers a BED of 70-80 Gy to the tumor, while the SBRT dose-fractionation scheme of 48-60 Gy in 1-5 fractions delivers a BED of greater than 100 Gy. To our best knowledge, SBRT has emerged as the standard of care for medically inoperable patients with early stage lung cancer [33-36]. RTOG 0236 initially recommended 60 Gy/3 f or 54 Gy/3 f as the standard-of-care. However, alternative regimens of 48-50 Gy/4-5 f, which have been proposed to be safer and equally ef f ective, are being used with increasing frequency [37]. Recently, SBRT has shown promising outcome and less invasiveness for operable stage I NSCLC patients. Although surgical excision by lobectomy remains the gold standard treatment, SBRT is an emerging alternative treatment [38]. Despite poor clinical outcomes in treatment of locally advanced NSCLC with traditional concurrent chemoradiotherapy, SBRT boost could be safe for salvage treatment [39-40]. Moreover, based on previous published reports, SBRT could be used for treating relapses in lung cancer [41-45]. The emergence of SBRT has also played a key role in primary or metastatic liver cancer. More research has indicated that SBRT could of f er good local control with acceptable radiation toxicity for liver cancer and other gastrointestinal tumors [44-46]. Van De Voorde L reported the same result that SABR provided a safe and ef f ective option for medically inoperable patients with liver cancer [47]. Another study shows the promising outcome of SBRT in unresectable intrahepatic or hilar cholangiocarcinoma which has limited success by systemic chemotherapy, conventional external beam radiation and brachytherapy [48]. Although pancreatic cancer is usually medically incurable due to the advanced stage when initial diagnosed, SBRT proves to be feasible combined with other treatments [49].e Stanford group reported on the fi rst study to demonstrate the feasibility of a single- fraction of 25 Gy in SBRT regimen for locally advanced pancreatic cancer (LAPC) [50]. The subsequent studies showed SBRT delivered in 3-5 fractions had similar local control rates and a lower incidence of highgrade toxicity, as compared to that of single-fraction [51-52]. Recently, a retrospective research has shown that pancreatic cancer patients receiving SBRT to 25-33 Gy in 5 fractions following gemcitabine or FOLFIRINOX-based chemotherapy has the median overall survival of 18.4 months and 20% patients underwent successful surgical resection following SBRT [53]. For patients with curable localized prostate cancer, radiation therapy has indeed become one of the main treatments for malignant tumors, and conventional radiotherapy already shows a non-inferior outcome to radical prostatectomy or brachytherapy [54]. However, conventional radiotherapy which usually takes 7-8 weeks is time-consuming, while SBRT could signif i cantly reduce the duration of treatment to 5 days or less and maintain curative ef f ects [55].

Childhood cancer referring to tumors generated among children aged 0-19 years needs to be specially treated.e common tumors are CNS tumors composed of astrocytoma, medulloblastoma, primitive neuroectodermal tumor, pineoblastoma, craiopharyngioma, germ cell tumors. SRT is oen considered as an alternative radiotherapy option for primary pediatric CNS tumors for less neurotoxicity. However, SRT is worth discussing for lack of long-term follow-up outcomes. Encouragingly, in recent years, proton SRT has been more acceptable for children with medulloblastoma in treatment of craniospinal irradiation, which could in turn reduce side effects and achieve better clinical outcomes [56].

In short, SRT is an emerging radiotherapy technology which is able to be used in most tumors for curative treatment, palliative care, or as a bridge procedure to downsize a lesion for coming surgical opportunity.

Future expectations

Although previous data suggest SRT can achieve a safe dose delivery with high local control rates and well-accepted side effects for most tumors, more multi-institutional clinical trials should be performedto illuminate the exact mechanism of radiobiology by SRT, develop a nomogram to predict distant metastases following SRT for various tumors, and establish the perfect clinical guidelines. Late side effects and long-term morbidity of this technique require more follow-up data to make it well known. However, SRT has shown its promising prospect with many advantages over conventional ones, and become a new trend in the era of precise radiation therapy. SBRT has an effect on radioresistant tumors probably for the reason that large dose radiation can impact on the immune system [57]. Recently, SABR combined with immunotherapy has aroused extensive concern. It is reported that a single dose of SABR (20 Gy) activated the CD8+T cell-dependent immunity leading to primary and metastatic tumor shrinkage [58].SABR as a trigger before administrating immunotherapy perhaps enhance the immune response inside irradiation fi eld and at metastatic sites [59]. In view of the idea of multi-discipline treatment, SRT combined with immunotherapy or other therapeutic modalities is becoming a popular trend.

Conclusion

In summary, SRT is an emerging tumor-ablative radiation technology with a high-dose delivery to targets while dramatically sparing adjacent normal tissues for various tumors with a purpose of curative treatment, palliative care, or as a bridge procedure to downsize a lesion for coming surgical opportunity. The techniques of SRT include Gamma Knife, linac accelerator, Cyberknife, charged particles radiotherapy. To achieve precision and ef f ectiveness, SRT procedures involve patient evaluation, immobilization and simulation, target delineation, treatment planning, treatment delivery and image guidance. Currently, the clinical efficacy of SRT has been widely confi rmed in certain patients with various tumors, such as brain tumors, thoracic tumors, gastrointestinal cancer, and prostate cancer. SRT is used especially for the patients who are medically inoperable, unwilling to undergo surgery, or medicine inef f ective with tumor progression. Furthermore, SRT could be properly used as palliative treatment aiming at relieving local symptoms and pain, and eventually achieving a potential survival benef i t of several months. Besides, SRT combined with immunotherapy or other therapeutic modalities is in heated discussion. However, the weaknesses of SRT relate to the inevitable radiation-induced toxicities as well as the inaccessibility of prophylactic irradiation. In general, one ff aw cannot obscure the splendor of the jade.e emergence and development of SRT has opened the new era of precision radiation therapy, and SRT will probably step gloriously onto the remarkable stage for precision medicine.

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Shi-kai WU, Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing 100071, China. Tel: 86-10-66947196; E-mail: skywu4923@sina.com

Received 2015-11-12; accepted 2015-11-20