塞来昔布对宫颈癌HeLa细胞的放射增敏作用观察及机制探讨

目的观察环氧合酶2（COX-2）抑制剂塞来昔布对宫颈癌HeLa细胞的放射增敏作用,并探讨其机制。方法将对数生长期的HeLa细胞分为3组,阴性对照组单纯培养液培养,单纯放射组采用6MV的x线照射治疗,放射加药组先用20、40umol／L塞来昔布作用72h,再行x线照射。采用克隆形成实验测算细胞放射敏感性参数平均致死剂量（Do）、准域剂量（Dq）、2Gy照射存活分数（SF2）及放射增敏比（SERDo）,采用免疫细胞化学法检测HeLa细胞中的COX-2、VEGF—C。结果放射加药组Do、Dq和SF2值小于单纯放射组（P均〈0．05）,其SERDo由2．01±0．06增至2．41±0．08;与阴性对照组、单纯放射组比较,放射加药组HeLa细胞的COX-2、VEGF—C表达显著降低（P均〈0．05）。结论塞来昔布能增强宫颈癌HeLa细胞的放射敏感性,可能与下调宫颈癌细胞的COX-2、VEGF—C表达有关。     

Metabolic functional imaging for tumor radiosensitivity monitoring

Assessing tumor radiosensitivity before and during radiation therapy can be a crucial element in decision-making with regard to treatment. However, no known non-invasive test is available at present, which allows for a reliable evaluation of the radiosensitivity of a tissue subjected to radiotherapy. Among tests being evaluated, positron emission tomography (PET) is considered to be a promising method. The purpose of this review is to identify the tests and research paths that have recently been explored for the evaluation of tumor response to treatment after isotopic labeling revealed by nuclear imaging. The majority of the explored methodologies are based on the indirect evaluation of the radiosensitivity by cell proliferation or apoptosis, tissue oxygenation or hypoxia, intrinsic radiosensitivity of clonogenic cells, tumor metabolism and angiogenesis. The development of such methods would permit the adoption of a therapeutic regimen with respect to a given radiosensitivity of a tissue. Therefore, a given therapeutic strategy could be readjusted (by associating, for instance, a radiosensitizer of hypoxic cells) or even modified if it proved to be inadequate or when it presents an unfavorable cost-effectiveness ratio. We present here a critical review of the radiotracers revealed by nuclear imaging that are developed for radiosensitivity monitoring.     

Anti-tumor effect of pEgr-IFNγgene-radiotherapy in B16 melanoma-bearing mice

AIM: To construct a pEgr-IFNγ plasmid and to investigate its expression properties of interferon-γ (INF-γ) induced by irradiation and the effect of gene-radiotherapy on the growth of melanoma.METHODS: A recombined plasmid, pEgr-IFNγ, was constructed and transfected into B16 cell line with lipofectamine. The expression properties of pEgr-IFNγwere investigated by ELISA. Then, a B16 melanoma-bearing model was established in mice, and the plasmid was injected into the tumor tissue. The tumor received 20 Gy X-ray irradiation 36 h after injection, and IFN-γ expression was detected from the tumor tissue. A tumor growth curve at different time points was determined.RESULTS: The eukaryotic expression vector, pEgr-IFNγ,was successfully constructed and transfected into B16 cells.IFN-γ expression was significantly increased in transfected cells after X-ray irradiation in comparison with 0 Gy group (77.73-94.60 pg/mL, P＜0.05-0.001), and was significantly higher at 4 h and 6 h than that of control group after 2 Gy X-ray irradiation (78.90-90.00 pg/mL, P＜0.01-0.001).When the transfected cells were given 2 Gy irradiation 5 times at an interval of 24 h, IFN-γ expression decreased in a time-dependent manner. From d 3 to d 15 after IFNγ generadiotherapy, the tumor growth was significantly slower than that after irradiation or gene therapy alone.CONCLUSION: The anti-tumor effect of pEgr-IFNγgeneradiotherapy is better than that of genetherapy or radiotherapy alone for melanoma. These results may establish an important experimental basis for gene-radiotherapy of cancer.     

Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis

Ataxia-telangiectasia is a syndrome with many facets, involving a progressive cerebellar ataxia, immunodeficiency, cancer susceptibility, radiosensitivity, defects in DNA repair/processing, chromosomal breakage and rearrangements, elevated serum alphafetoprotein, and premature aging. Ataxia-telangiectasia is an autosomal recessive disorder, rare in outbred populations; carriers of the ataxia-telangiectasia gene may be as common as 1 in 60 and have subclinical radiosensitivity and cancer susceptibility. One estimate suggests that 8.8% of patients with breast cancer could be carriers of ataxia-telangiectasia. These carriers may be responsible for underestimating normal tolerance doses for radiation therapy by 15% to 20%; thus by preselecting and excluding carriers of ataxia-telangiectasia from cohorts of patients with cancer, conventional radiation doses might be increased so as to improve greatly the efficacy of radiotherapy. The genes for the 3 most common ataxia-telangiectasia complementation groups, which include 97% of tested families, have recently been localized to the long arm of chromosome 11.     

Role of radiotherapy in the management of hepatocellular carcinoma:A systematic review

Many patients with hepatocellular carcinoma(HCC) present with advanced disease,not amenable to curative therapies such as surgery,transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization(TACE) and radiation therapy. Especially TACE,delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy,has given favorable results on local control and survival. Radiotherapy,as a therapeutic modality of internal radiation therapy with radioisotopes,has also achieved efficacious tumor control in advanced disease. On the contrary,the role of external beam radiotherapy for HCC has been limited in the past,due to the low tolerance of surrounding normal liver parenchyma. However,technological innovations in the field of radiotherapy treatment planning and delivery,have provided the means of delivering radical doses to the tumor,while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy,evaluated for efficacy and safety for HCC,report encouraging results. In this review,we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.     

Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy

In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.KEYWORDS : Low Doses Fractionated Radiation Therapy (LDFRT), hyper-radiation sensitivity (HRS), induced radiation resistance (IRR), hyperfractionation, chemopotentiation, stereotactic body radiation therapy (SBRT), stereotactic ablative radiosurgery (SARS), stereotactic ablative radiotherapy (SABR), stereotactic radiosurgery (SRS), spatially fractionated GRID radiotherapy (SFGRT), lattice     

Enhancement of radiotherapy with DNA topoisomerase I-targeted drugs

Since its discovery more than a century ago, ionizing radiation has become a mainstay therapy for patients suffering from cancers. Currently, radiotherapy provides cure or palliative care for approximately one half of the cancer population. The anticancer efficacy of radiotherapy is, however, largely limited by its lack of tumor specificity and, consequently, normal tissue toxicity. There is an urgent need to develop systemic adjuncts that can enhance the efficacy and the selectivity of radiotherapy toward tumor cells. DNA topoisomerase I (TOP1)-targeted drugs such as camptothecin derivatives represent a novel class of chemotherapeutic agents that have recently been shown to be excellent radiation sensitizers. Combined modality therapy with TOP1-targeted drugs and radiotherapy represents a new promising cancer therapy. The mechanism of enhancement of radiotherapy by TOP1-targeted drugs is under intense investigation. Clinical trials using combinations of radiation and camptothecin derivatives are also currently ongoing in various solid tumors including brain, head and neck, and lung cancers. A better understanding of the radiosensitization (RS) mechanism of TOP1-targeted drugs is pivotal to their clinical application, as well as in guiding the development of better radiation sensitizers.     

Technical advances in external radiotherapy for hepatocellular carcinoma

Radiotherapy techniques have substantially improved in the last two decades. After the introduction of 3-dimensional conformal radiotherapy, radiotherapy has been increasingly used for the treatment of hepatocellular carcinoma(HCC). Currently, more advanced techniques, including intensity-modulated radiotherapy(IMRT), stereotactic ablative body radiotherapy(SABR), and charged particle therapy, are used for the treatment of HCC. IMRT can escalate the tumor dose while sparing the normal tissue even though the tumor is large or located near critical organs. SABR can deliver a very high radiation dose to small HCCs in a few fractions, leading to high local control rates of 84%-100%. Various advanced imaging modalities are used for radiotherapy planning and delivery to improve the precision of radiotherapy. These advanced techniques enable the delivery of high dose radiotherapy for early to advanced HCCs without increasing the radiation-induced toxicities. However, as there have been no effective tools for the prediction of the response to radiotherapy or recurrences within or outside the radiation field, future studies should focus on selecting the patients who will benefit from radiotherapy.     

Induction of cell death by radiotherapy

Ionising radiation remains one of the most effective tools in the therapy of cancer. It combines the properties of an extremely efficient DNA-damaging agent with a high degree of spatial specificity. Nonetheless, there remain considerable differences in the outcome for treatment of tumours of differing histological type treated by radiotherapy. Tumours arising from lymphoid or germ cells are significantly more radiocurable than most solid tumours of epithelial origin. The molecular mechanisms underlying such differences in cellular radiosensitivity are the subject of current research. When normal mammalian cells are subjected to stress signals--e.g. radiation, chemotherapeutic drugs, oxygen deficiency--a range of gene products involved in the sensing and signalling of such stresses are activated. The response of eukaryotic cells to ionising radiation includes activation of DNA repair pathways and cell cycle checkpoints, with subsequent full 'biological' recovery or cell death. Radiation induces two different modes of cell death termed mitotic or clonogenic cell death, and apoptosis. Until recent years, there was surprisingly little mechanistic understanding of the events following induction of physical damage by radiation and biological outcome for the cell. There have been recent major advances in our understanding of the signal transduction pathways involved in determining the fate of cells after irradiation.     

Radiosensitivity of dermal and tumor fibroblasts derived from the same patient

The in vitro radiosensitivity of dermal fibroblasts has been found to vary between individuals, and a number of studies have also shown that this parameter correlates with radiation-induced late injuries in clinical radiotherapy. In addition, certain genetic disorders are known to effect radiosensitivity, e.g. normal tissues of patients homozygous or heterozygous for the ataxia teleangiectasia gene show unusual sensitivity to radiation both in vivo and in vitro. Thus, it has been assumed that there is a genetically determined component resulting in a certain intrinsic cellular radiation response in an individual. To study this possible relationship between different cells of a specific patient, we established eight pairs of dermal and tumor fibroblast cultures. The donor patients had either adenocarcinoma of the uterus or squamous cell carcinoma (SCC) of the head and neck. The radiosensitivity of these strains was determined by a 96-well plate clonogenic assay, previously used by us for radiosensitivity testing of cancer cells. From a paired comparison, the values for the cell fraction surviving 2.0 Gy (SF₂), of both fibroblast strains, were found to be on the same level in five out of eight cases. In patient 6, the SF₂ of tumor fibroblasts was significantly higher than that of dermal fibroblasts (P = 0.0014). In two additional cases the tendency was the same, but not statistically significant. As groups, the two types of fibroblasts did not differ from each other, mean SF₂ values of 0.24 ± 0.07 and 0.21 ± 0.05, respectively. The SF₂ of tumor fibroblasts from SCC patients proved to be significantly higher than that of the adenocarcinoma patients (P = 0.030). These preliminary results indicate that the in vitro radiosensitivity of tumor fibroblasts correlates with normal cell sensitivity in many cases, but not in all. The radiosensitivity of tumor fibroblasts also seems to follow the level of in vitro radiosensitivity determined for the corresponding histological type of tumor cells. Further studies are needed to determine more closely the relationship between the radiosensitivities of tumor cells and tumor fibroblasts, thus evaluating the possibility of testing radiosensitivity from tumor fibroblasts in order to estimate tumor response. Received: 18 November 1997 / Accepted: 15 April 1998     

Comparative morphological studies of cervix cancer and adjacent tissue following preoperative intracavitary contact therapy using Cf-252 or Co-60

The effects of Cf-252 and Co-60 radiation have been compared by investigating radiation response and radiation pathomorphosis of the cervical carcinoma and surrounding normal tissue. The effectiveness of radiotherapy treatment was evaluated by comparison of Cf-252 and Co-60 irradiated patients (each arm 18 patients) with a non-irradiated control group (15 patients), suffering from epithelium carcinomas of the cervix uteri. The total dose in point A was 60 isoGy in either case given in 3 fractions at 28 days using the after-loading units "ANET" (neutrons) and "AGAT V" (gamma). Two to three weeks after irradiation, extended extirpation of the uterus and its adnexa was performed. The therapeutic effect was strongest in both comparative groups with superficially located exophytic forms of the cervical carcinoma and with carcinoma in situ. With invasive growth forms, signs of therapeutic pathomorphosis were found in both groups predominantly in the superficial tumor areas. However, the extent of the remaining tumor complexes was much greater with Co-60 than with Cf-252 radiation. Adenocarcinomas were more sensitive to Cf-252 independently of the invasion depth of the tumor. The observed alterations in the surrounding normal tissue of the uterus, both in the immediate proximity of the Cf-252 source (endometrium) and at some distance (myometrium, perimetrium) reflect the more severe alterations following irradiation as compared with Co-60. The lower values of the volume density of the tumor parenchyma remaining after radiotherapy and the high damage index (95.5%) give evidence for the pronounced biological and therapeutic effectiveness of high dose rate Cf-252-radiation. They allow to expect improvement of late results in the treatment of patients with epithelium carcinoma of the cervix uteri, and it seems to be reasonable to make further studies in that direction.     

Radiothérapie par rayonnement synchrotron

Radiation therapy is commonly used in the treatment of cancer. The normal tissue tolerance can be a limit to deliver enough dose to the tumor to be curative. The synchrotron beam presents some interesting physical properties, which could decrease this limitation. Synchrotron beam is a medium energy X-ray nearly parallel beam with high intensity. Three methods are under preclinical investigations: the microbeam, the minibeam and the stereotactic radiotherapy. The first two use a geometric irradiation effect called spatial fractioning. The last one use highly conformational irradiation geometry combined with a dose enhancement due to the presence of high-Z element in the target. Synchrotron radiotherapy preclinical experiments have shown some curative effect on rodent glioma models. Following these encouraging results a phase I/II clinical trial of iodinated enhanced stereotactic synchrotron radiotherapy is currently being prepared at the European Synchrotron Radiation Facility.     

Identification of candidate genes involved in the radiosensitivity of esophageal cancer cells by microarray analysis

SUMMARY.  Radiotherapy plays a key role in the control of tumor growth in esophageal cancer patients. To identify the patients who will benefit most from radiation therapy, it is important to know the genes that are involved in the radiosensitivity of esophageal cancer cells. Hence, we examined the global gene expression in radiosensitive and radioresistant esophageal squamous cell carcinoma cell lines. Radiosensitivities of 13 esophageal cancer cell lines were measured. RNA was extracted from each esophageal cancer cell line and a normal esophageal epithelial cell line, and the global gene expression profiles were analyzed using a 34 594-spot oligonucleotide microarray. In the clonogenic assay, one cell line (TE-11) was identified to be highly sensitive to radiation, while the other cell lines were found to be relatively radioresistant. We identified 71 candidate genes that were differentially expressed in TE-11 by microarray analysis. The up-regulated genes included CABPR, FABP5, DSC2, GPX2, NME, CBR3, DOCK8, and ABCC5, while the down-regulated genes included RPA1, LDOC1, NDN, and SKP1A. Our investigation provided comprehensive information on genes related to radiosensitivity of esophageal cancer cells; this information can serve as a basis for further functional studies.     

Anti-tumor effect of pEgr-IFNγ,gene-radiotherapy in B16 melanoma-bearing mice

AIM: To construct a pEgr-IFNγ Plasmid and to investigate its expression properties of interferon-γ (INF-γ) induced by irradiation and the effect of gene-radiotherapy on the growth of melanoma. METHODS: A recombined plasmid, pEgr-IFNγ, was constructed and transfected into B16 cell line with lipofectamine. The expression properties of pEgr-IFNγ were investigated by ELISA. Then, a B16 melanoma-bearing model was established in mice, and the plasmid wasinjected into the tumor tissue. The tumor received 20 Gy X-ray irradiation 36 h after injection, and IFN-γ expression was detected from the tumor tissue. A tumor growth curve at different time points was determined. RESULTS: The eukaryotic expression vector, pEgr-IFNγ, was successfully constructed and transfected into B16 cells. IFN-γ expression was significantly increased in transfected cells after X-ray irradiation in comparison with 0 Gy group (77.73-94.60 pg/mL, P<0.05-0.001), and was significantly higher at 4 h and 6 h than that of control group after 2 Gy X-ray irradiation (78.90-90.00 pg/mL, P<0.01-0.001).When the transfected cells were given 2 Gy irradiation 5 times at an interval of 24 h, IFN-y expression decreased in a time-dependent manner. From d 3 to d 15 after IFNγ generadiotherapy, the tumor growth was significantly slower than that after irradiation or gene therapy alone. CONCLUSION: The anti-tumor effect of pEgr-IFNγ generadiotherapy is better than that of genebherapy or radiotherapy alone for melanoma. These results may establish an important experimental basis for gene-radiotherapy of cancer.     

Vulvar cancer in a patient with Fanconi's anemia, treated with 3D conformal radiotherapy

Fanconi's anemia (FA) is rare autosomal recessive disorder characterized by aplastic anemia, congenital anomalies, and cancer susceptibility. FA patients have deficiencies in DNA repair pathways that cause cellular sensitivity to ionizing radiation and cross-link agents such as mitomycin C and diepoxybutane (DEB). If these patients survive until early adulthood, they are at high risk for developing solid tumors, most commonly squamous cell carcinoma of the oropharynx, esophagus, and vulva. Treatment of these solid tumors with radiotherapy is complicated by the increased risk of normal tissue toxicity. Three-dimensional (3D) conformal radiotherapy is a technique that uses CT images to more accurately target tumors and maximize the dose to the tumor volume while limiting the dose to normal tissue. This report describes application of 3D conformal radiotherapy techniques to the treatment of vulvar cancer in a patient with FA in an attempt to limit the normal tissue volume exposed to radiation.     

Interactions between radiotherapy and endocrine therapy in breast cancer

Whenever radiation therapy is given with curative intent there is the risk of serious damage to normal tissue. This risk increases with the dose of radiation, as does the probability of local tumour control. In the attempt to cure, the doses reach a level that inevitably causes some undesirable adverse effects, ranging from undetectable, or minimal, to unacceptably severe. Over the last few years, a number of reports have suggested that the prediction of normal tissue response after radiotherapy may be achieved by assays on samples withdrawn from the patients prior to treatment, although recent reports have described mixed results. The ability to predict tumour response to anti-hormones in patients with breast cancer has important implications with regard to treatment. Recent discoveries promise to provide individualized treatment options. However, there are no data to support that, used jointly, the combination of radiotherapy and hormone therapy may achieve an enhancement of breast cancer tumour response. Nowadays, development in cancer therapy is increasingly arising out of studies in basic science; its implementation in the hands of clinicians is improving the management of patients with cancer. In addition, as the biological aspects of irradiation and hormonal therapy offer an explanation, at least in part, for the outcome observed in patients with breast cancer after therapy, we have focused this review on trying to analyse the most relevant experimental research about the relative roles of radiotherapy and hormonal therapy, the corresponding side-effects and, taking into account recent advances, future areas of research that we consider of major importance in the field.     

Gastrointestinal radiation injury:Symptoms,risk factors and mechanisms

Ionising radiation therapy is a common treatment modality for different types of cancer and its use is expected to increase with advances in screening and early detection of cancer.Radiation injury to the gastrointestinal tract is important factor working against better utility of this important therapeutic modality.Cancer survivors can suffer a wide variety of acute and chronic symptoms following radiotherapy,which significantly reduces their quality of life as well as adding an extra burden to the cost of health care.The accurate diagnosis and treatment of intestinal radiation injury often represents a clinical challenge to practicing physicians in both gastroenterology and oncology.Despite the growing recognition of the problem and some advances in understanding the cellular and molecular mechanisms of radiation injury,relatively little is known about the pathophysiology of gastrointestinal radiation injury or any possible susceptibility factors that could aggravate its severity.The aims of this review are to examine the various clinical manifestations of post-radiation gastrointestinal symptoms,to discuss possible patient and treatment factors implicated in normal gastrointestinal tissue radiosensitivity and to outline different mechanisms of intestinal tissue injury.     

Gallbladder cancer: role of radiation therapy.

BACKGROUND/AIMS: Gallbladder carcinoma is characterized by late diagnosis, ineffective treatment and poor prognosis. These tumors were usually considered to be radioresistant. So far, the role of radiotherapy has not been adequately evaluated. The aim of this report is to assess the value of radiotherapy in carcinoma of the gallbladder. METHODOLOGY: We reviewed all publications concerning the role of radiation therapy in gallbladder carcinoma. External radiation therapy, intra-operative radiation therapy, and brachytherapy were evaluated in two groups in which the prognosis is quite different; a group operated on, with apparent complete resection of the tumor, and a palliative surgery group. RESULTS: It appears that gallbladder carcinomas are not as radioresistant as was formerly thought. Local control of the tumor and reduction of tumor size was reported in several publications. Collected data showed a slight improvement of survival after adjuvant or palliative radiotherapy, especially in the advanced stage of gallbladder carcinomas. It appears preferable to give a "boost" (15 Gy) to the gross lesion or residual lesion at operation (intra-operative irradiation or brachytherapy), and deliver an additional 45-50 Gy post-operatively. CONCLUSIONS: The results published encourage further trials in well defined populations. Radiotherapy seems to be a safe procedure, morbidity is minimal, and a slight effect on survival is observed after curative or palliative surgical procedures.     

质子刀放射治疗肝细胞癌的研究进展

随着对正常组织耐受能力的研究的不断深入和放疗技术的发展,针对大部分肝细胞癌（HCC）患者伴有的肝硬化,肿瘤体积大、多发且伴有血管浸润,甚至出现门静脉癌栓等现状,放射治疗便成为HCC降级治疗及辅助治疗的重要手段。其中质子刀（PBT）作为一种较新型的放疗方法取得了较为显著的临床效果。介绍了PBT治疗HCC的生物学特性及其临床疗效和毒性副作用。前期的研究结果表明PBT对于局部照射剂量具有良好的控制作用,可降低对健康肝细胞及周围正常组织的毒性。但目前的临床研究显示PBT应用于HCC也存在着一些禁忌证,值得进一步界定。     

Hepatocellular carcinoma with portal vein tumor thrombosis: Improved treatment outcomes with external beam radiation therapy

The treatment of advanced hepatocellular carcinoma (HCC) associated with portal vein tumor thrombosis (PVTT) is very challenging because of HCC's grave prognosis. Despite many efforts to improve the treatment results, patient survival has been limited to several months. In this situation, radiotherapy has been considered as an alternative treatment modality because of the growth of knowledge about the radiotolerance of normal tissue and the advances of radiotherapy techniques such as three dimensional conformal radiotherapy, intensity modulated radiotherapy, stereotactic body radiotherapy and proton therapy. More restoration of the liver function and longer survival of the patients can be achieved by the better response after radiotherapy. However, considering the high risk of intrahepatic advanced tumor or extrahepatic dissemination by PVTT at disease presentation, a combination of radiation therapy and systemic agents will be desirable. Therefore, performing prospective randomized clinical trials is important to assess the benefits of radiotherapy and to develop combination treatment strategies.