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1.  Analysis of Gene Expression Using Gene Sets Discriminates Cancer Patients with and without Late Radiation Toxicity 
PLoS Medicine  2006;3(10):e422.
Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%–10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity.
Methods and Findings
Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization.
X-ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier.
Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.
Expression profiling can discriminate between groups of patients with and without severe late radiotherapy toxicity but not (yet) predict individual responses.
Editors' Summary
More than half the people who develop cancer receive radiotherapy as part of their treatment. That is, tumor cells are destroyed by exposing them to a source of ionizing radiation such as X-rays. Ionizing radiation damages the genetic material of cancer cells so that they can no longer divide. Unfortunately, it also damages nearby normal cells, although they are less sensitive to radiation than the cancer cells. Radiotherapists minimize how much radiation hits normal tissues by carefully aiming the X-rays at the tumor. Even so, patients often develop side effects such as sore skin or digestive problems during or soon after radiotherapy; the exact nature of the side effects depends on the part of the body exposed to the X-rays. In addition, a few patients develop severe late radiation toxicity, months or years after their treatment. Like early toxicity, late toxicity occurs in the normal tissues near the tumor site. For example, in prostate cancer—a tumor that forms in a gland in the male reproductive system that lies between the bladder and the end of the gut (the rectum)—late radiation toxicity affects rectal, bladder, and sexual function in 5%–10% of patients.
Why Was This Study Done?
It is not known why some patients develop late radiation toxicity, and it is impossible to predict before treatment which patients will have long-term health problems after radiotherapy. It would be useful to know this, because radiation levels might be reduced in those patients, while larger doses of radiation could be given to patients at low risk of late complications to ensure a complete eradication of their cancer. One theory is that some patients are genetically predisposed to develop severe late radiation toxicity. In other words, their genetic make-up makes it more likely that their tissues develop long-term complications after radiation damage. In this study, the researchers looked for markers of a genetic predisposition for late radiation toxicity by comparing radiation-induced changes in the pattern of cellular proteins in patients who had late radiation toxicity after radiotherapy with the changes seen in patients who did not develop such complications.
What Did the Researchers Do and Find?
The researchers recruited 38 patients who had been treated successfully with radiotherapy for prostate cancer two years previously. Of these, 21 had developed severe late radiation toxicity. They isolated lymphocytes (a type of immune system cell) from the patients' blood, stimulated the lymphocytes to divide, exposed them to X-rays, and analyzed the pattern of genes active in these cells—their gene expression profile—before and after irradiation. The researchers found that irradiation induced the expression of numerous genes in the lymphocytes, including many well-known radiation-responsive genes. They then used an analytical process called “random cross-validation” to look for a gene expression profile (or molecular signature) that was associated with late radiation toxicity. They report that a signature based on the radiation response of 50 individual genes correctly classified 63% of the patient population in terms of whether the patient had developed late radiation toxicity. A signature based on the radiation response of gene sets containing genes linked by function or cellular localization correctly classified 86% of the patient population.
What Do These Findings Mean?
Gene expression profiling identified groups of patients who had had severe late radiation toxicity pretty well, particularly when sets of related genes were used to classify the patients. The approach was not so good, however, at identifying individual patients who had had problems, being correct and certain only half the time. Additional studies are needed, therefore, before this promising approach can be used clinically to predict patient responses to radiotherapy. Overall, the study supports the idea that some patients are genetically predisposed to develop late radiation toxicity, and it also provides clues about which cellular pathways help to determine late radiation toxicity. Most of the genes and gene sets that discriminated between the patients with and without late radiation toxicity are involved in protein metabolism, apoptosis (a special sort of cell death), and stress signaling networks (pathways that protect cells from damage). This information, if confirmed, might help researchers to develop therapeutic interventions to minimize late radiation toxicity in vulnerable individuals.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Cancer Institute patient information on radiotherapy and on prostate cancer
American Cancer Society information on radiation therapy
Cancer Research UK patient information on radiotherapy
Wikipedia pages on radiotherapy (note that Wikipedia is a free online encyclopedia that anyone can edit)
PMCID: PMC1626552  PMID: 17076557
2.  Normal tissue protection for improving radiotherapy: Where are the Gaps? 
Translational cancer research  2012;1(1):35-48.
Any tumor could be controlled by radiation therapy if sufficient dose were delivered to all tumor cells. Although technological advances in physical treatment delivery have been developed to allow more radiation dose conformity, normal tissues are invariably included in any radiation field within the tumor volume and also as part of the exit and entrance doses relevant for particle therapy. Mechanisms of normal tissue injury and related biomarkers are now being investigated, facilitating the discovery and development of a next generation of radiation protectors and mitigators. Bringing recent research advances stimulated by development of radiation countermeasures for mass casualties, to clinical cancer care requires understanding the impact of protectors and mitigators on tumor response. These may include treatments that modify cellular damage and death processes, inflammation, alteration of normal flora, wound healing, tissue regeneration and others, specifically to counter cancer site-specific adverse effects to improve outcome of radiation therapy. Such advances in knowledge of tissue and organ biology, mechanisms of injury, development of predictive biomarkers and mechanisms of radioprotection have re-energized the field of normal tissue protection and mitigation. Since various factors, including organ sensitivity to radiation, cellular turnover rate, and differences in mechanisms of injury manifestation and damage response vary among tissues, successful development of radioprotectors/mitigators/treatments may require multiple approaches to address cancer site specific needs. In this review, we discuss examples of important adverse effects of radiotherapy (acute and intermediate to late occurring, when it is delivered either alone or in conjunction with chemotherapy, and important limitations in the current approaches of using radioprotectors and/or mitigators for improving radiation therapy. Also, we are providing general concepts for drug development for improving radiation therapy.
PMCID: PMC3411185  PMID: 22866245
Acute radiation effects; radiotherapy; radiation mitigator; radioprotector; oral mucositis; lung fibrosis; radiation-induced brain damage
3.  Radiation Survivors: Understanding and exploiting the phenotype following fractionated radiation therapy 
Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing that cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145 and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multi-fraction (MF) radiation of 0.5, 1 and/or 2 Gy fraction to 10 Gy total dose, and a single dose (SD) of 5 and 10 Gy. The resulting changes in mRNA, miRNA and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell cycle arrest, TGF-β, survival and apoptotic signal transduction. The radiation-induced stress response will set-forth a unique platform for exploiting the effects of radiation therapy as “focused biology” for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome.
PMCID: PMC3552079  PMID: 23175523
4.  Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes 
Breast Cancer Research  2005;7(5):R690-R698.
Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects.
Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes obtained from breast cancer patients before radiotherapy. Acute reactions were assessed in 108 of these patients on the last treatment day. Late morbidity was assessed after 7 years of follow-up in some of these patients. The Radiation Therapy Oncology Group (RTOG) morbidity score system was used for both assessments.
Radiosensitivity values obtained using the in vitro test showed no relation with the acute or late adverse skin reactions observed. There was no evidence of a relation between acute and late normal tissue reactions assessed in the same patients. A positive relation was found between the treatment volume and both early and late side effects.
After radiation treatment, a number of cells containing major changes can have a long survival and disappear very slowly, becoming a chronic focus of immunological system stimulation. This stimulation can produce, in a stochastic manner, late radiation-related adverse effects of varying severity. Further research is warranted to identify the major determinants of normal tissue radiation response to make it possible to individualize treatments and improve the outcome of radiotherapy in cancer patients.
PMCID: PMC1242135  PMID: 16168114
5.  56Fe ion irradiation enhances angiogenesis and other inter-cellular determinants of carcinogenesis risk 
Journal of Radiation Research  2014;55(Suppl 1):i124-i126.
In the assessment of radiogenic cancer risk from space flight, it is imperative to consider effects not only on the creation of cancer cells (initiation) but also on cell–cell interactions that play an important and often decisive role in the promotion and progression phases. Autopsy results confirm that most adults carry fully malignant tumors that are held in check at a small size and will never become symptomatic [ 1, 2]. This introduces the possibility that cosmic radiation may significantly influence cancer risk through alteration of the bottleneck inter-tissue interactions responsible for maintaining this dormant state. One such bottleneck is the growth limitation imposed by the failure of the tumor to induce blood vessels (angiogenesis). Other deciding events are the ability of a tumor to proliferate and invade. We have previously shown that proton radiation, the most prevalent radiation in space, has a suppressive effect on all three of these functional responses. It down-regulates angiogenic genes like VEGF and HIF-1α and impairs cell invasion and tumor growth [ 3]. We decided to test these responses after 56Fe irradiation, an HZE radiation type present in the cosmic environment with presumably high carcinogenic potential [ 4].
Human microvascular endothelial cells (HMVEC) and normal human dermal fibroblast (NHDF) cells were irradiated with different doses of 56Fe ion radiation (1 GeV/n) at Brookhaven National Laboratory and RNA was extracted 6 h later. Genomic-wide array analysis was done on the isolated RNA through the Agilent Platform. It was observed that several pro-angiogenic genes like VEGF, IL-6 and HIF-1α were significantly up-regulated after treatment with 56Fe ion radiation (Fig.  1). These results were also confirmed at the mRNA and protein levels with the human and murine lung cancer lines, A549 and LLC, respectively. Additional verification of modulation of these key genes was also observed when lungs of C57BL/6 mice treated with 56Fe ion radiation showed an increase in VEGF and MMP9 mRNA and protein expression 6 h post-irradiation (Fig.  2). Cell invasion was shown to be increased by 56Fe ion radiation in various cell types, including fibroblast, tumor and endothelial progenitor cells. 56Fe ion irradiation also modulated functional processes crucial to angiogenesis. It enhanced the ability of untargeted (bystander) endothelial cells to invade and proliferate in response to factors produced by targeted fibroblast or cancer cells in vitro. Results also carry over to in vivo. C57BL/6 mice exposed to whole-body irradiation with 0.2 Gy dose of 56Fe and injected subcutaneously with LLC tumor cells showed a significant augmentation in tumor growth and growth rate in the irradiated group. Additionally, nude mice exposed to whole-body 56Fe radiation and injected intravenously with A549 cancer cells 3 h post-irradiation demonstrated a significant enhancement in lung colonization capacity when compared with the sham-irradiated control mice injected.
These results together suggest cell and tissue-level responses to 56Fe irradiation may act to overcome major cancer progression-level bottlenecks including those related to angiogenesis, cell proliferation and invasion. This is of significant concern for cancer risk estimations pertinent to NASA as achieving these cancer hallmark processes can make the difference between a radiation-induced cancer cell progressing to a clinically detectable cancer in astronauts or not. In conclusion, we demonstrate a strong radiation quality dependence for space radiation carcinogenesis risk manifested through influences on intercellular interactions in the progression phase of carcinogenesis. Fig. 1.Heatmaps of selected differentially regulated major angiogenesis genes after proton and 56Fe ion radiation in HMVECs and NHDF. Cells were treated with either 0, 0.5, 1 or 2 Gy of proton radiation or 0, 0.2, 0.4 or 1 Gy of 56Fe ion dose. Among the major regulated genes were VEGF, HIF-1A and IL-6; they were down-regulated by proton radiation and up-regulated by iron radiation. Fig. 2.Immunofluorescence images of lungs of C57BL/6 mice treated with 0, 0.2 or 1 Gy of 56Fe ion dose and stained 6 h later. Pro-angiogenic factors VEGF and MMP9 were increased in mice that received the 56Fe ion treatment.
PMCID: PMC3941549
6.  Imaging in Radiation Oncology: A Perspective 
The Oncologist  2010;15(4):338-349.
This paper reviews the integration of imaging and radiation oncology, and discusses challenges and opportunities for improving the practice of radiation oncology with imaging.
An inherent goal of radiation therapy is to deliver enough dose to the tumor to eradicate all cancer cells or to palliate symptoms, while avoiding normal tissue injury. Imaging for cancer diagnosis, staging, treatment planning, and radiation targeting has been integrated in various ways to improve the chance of this occurring. A large spectrum of imaging strategies and technologies has evolved in parallel to advances in radiation delivery. The types of imaging can be categorized into offline imaging (outside the treatment room) and online imaging (inside the treatment room, conventionally termed image-guided radiation therapy). The direct integration of images in the radiotherapy planning process (physically or computationally) often entails trade-offs in imaging performance. Although such compromises may be acceptable given specific clinical objectives, general requirements for imaging performance are expected to increase as paradigms for radiation delivery evolve to address underlying biology and adapt to radiation responses. This paper reviews the integration of imaging and radiation oncology, and discusses challenges and opportunities for improving the practice of radiation oncology with imaging.
PMCID: PMC3227970  PMID: 20413639
Image-guided radiation therapy; Imaging; Radiation oncology
7.  Prediction of clinical toxicity in locally advanced head and neck cancer patients by radio-induced apoptosis in peripheral blood lymphocytes (PBLs) 
Head and neck cancer is treated mainly by surgery and radiotherapy. Normal tissue toxicity due to x-ray exposure is a limiting factor for treatment success. Many efforts have been employed to develop predictive tests applied to clinical practice. Determination of lymphocyte radio-sensitivity by radio-induced apoptosis arises as a possible method to predict tissue toxicity due to radiotherapy. The aim of the present study was to analyze radio-induced apoptosis of peripheral blood lymphocytes in head and neck cancer patients and to explore their role in predicting radiation induced toxicity. Seventy nine consecutive patients suffering from head and neck cancer, diagnosed and treated in our institution, were included in the study. Toxicity was evaluated using the Radiation Therapy Oncology Group scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Radiation-induced apoptosis increased in order to radiation dose and fitted to a semi logarithmic model defined by two constants: α and β. α, as the origin of the curve in the Y axis determining the percentage of spontaneous cell death, and β, as the slope of the curve determining the percentage of cell death induced at a determined radiation dose, were obtained. β value was statistically associated to normal tissue toxicity in terms of severe xerostomia, as higher levels of apoptosis were observed in patients with low toxicity (p = 0.035; Exp(B) 0.224, I.C.95% (0.060-0.904)). These data agree with our previous results and suggest that it is possible to estimate the radiosensitivity of peripheral blood lymphocytes from patients determining the radiation induced apoptosis with annexin V/propidium iodide staining. β values observed define an individual radiosensitivity profile that could predict late toxicity due to radiotherapy in locally advanced head and neck cancer patients. Anyhow, prospective studies with different cancer types and higher number of patients are needed to validate these results.
PMCID: PMC2827476  PMID: 20109191
8.  Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy 
Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy.
Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide.
Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis.
A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.
PMCID: PMC3117708  PMID: 21645372
9.  CDDO-Me Protects Normal Lung and Breast Epithelial Cells but Not Cancer Cells from Radiation 
PLoS ONE  2014;9(12):e115600.
Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs). In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF) = 1.3), and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs) with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients.
PMCID: PMC4275221  PMID: 25536195
10.  Practice-Based Evidence to Evidence-Based Practice: Building the National Radiation Oncology Registry 
Journal of Oncology Practice  2013;9(3):e90-e95.
Successful implementation of the National Radiation Oncology Registry should improve the quality of care for patients with cancer treated with radiation.
The National Radiation Oncology Registry (NROR), sponsored by the Radiation Oncology Institute and the American Society for Radiation Oncology, is designed to collect standardized information on cancer care delivery among patients treated with radiotherapy in the United States and will focus on patients with prostate cancer. Stakeholders were engaged through a forum that emphasized the need for patient-centered outcomes, minimal data burden, and maximal connectivity to existing registries and databases. An electronic infrastructure is under development to provide connectivity across radiation oncology and hospital information systems. The NROR Gateway features automatic abstraction as well as aggregation of treatment and outcome data. The prostate cancer data dictionary provides standardized elements in four domains: facility, physician, patient, and treatment. The pilot phase will consist of clinical centers chosen to provide a representative mix of radiation treatment modalities, facility types, population-based settings, and regional locations. The initial set of radiation practice metrics includes physician board certification and maintenance, ordering of staging scans, active surveillance discussion, dose prescriptions for low-risk/high-risk disease, radiation fields for low-risk/high-risk disease, image-guided radiation therapy use, androgen deprivation therapy use, post-brachytherapy implant computed tomography dosimetry, collection of toxicity assessments, and longitudinal patient follow-up. The NROR pilot study will provide the framework for expansion to a nationwide electronic registry for radiation oncology.
PMCID: PMC3651578  PMID: 23942508
11.  Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008 
Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational endpoints that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans.
PMCID: PMC2978526  PMID: 19723641
translational clinical studies; image-guided radiation therapy; radiosurgery; metastasis; tumor markers
12.  Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials 
Radiation Oncology Journal  2014;32(3):103-115.
To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.
PMCID: PMC4194292  PMID: 25324981
Radiation normal tissue injury; Protectors; Mitigators
13.  DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy 
Frontiers in Oncology  2013;3:113.
Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single-strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress – a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.
PMCID: PMC3650303  PMID: 23675572
DNA double-strand breaks; ionizing radiation; homologous recombination repair; radiosensitization; cancer
14.  Novel Approaches of Chemoradiotherapy in Unresectable Stage IIIA and Stage IIIB Non-Small Cell Lung Cancer 
The Oncologist  2012;17(5):682-693.
Improvements in both locoregional and distant disease control are needed to improve the overall survival outcome of patients with non-small cell lung cancer. This article reviews several strategies that are currently under investigation, including newer chemotherapy agents, targeted therapy, and novel radiation schedules.
Learning Objectives:
After completing this course, the reader will be able to: Describe the current status of phase II trials with novel agents in order to distinguish the role of phase III trials in determining the role of novel agents.Describe target therapy in stage III non-small cell lung cancer and discuss the status of personalized medicine in stage III disease.State the current standard for thoracic radiation therapy and the current status of hypofractionated, adaptive radiotherapy and proton therapy and evaluate the recent radiation therapy oncology group (RTOG) 0617 trial.
This article is available for continuing medical education credit at
Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease, and appropriate patients are candidates for chemoradiotherapy with curative intent. The optimal treatment paradigm is currently undefined. Concurrent chemoradiotherapy, compared with sequential chemotherapy and thoracic radiation therapy (TRT), results in superior overall survival outcomes as a result of better locoregional control. Recent trials have revealed efficacy for newer chemotherapy combinations similar to that of older chemotherapy combinations with concurrent TRT and a lower rate of some toxicities. Ongoing phase III trials will determine the roles of cisplatin and pemetrexed concurrent with TRT in patients with nonsquamous histology, cetuximab, and the L-BLP25 vaccine. It is unlikely that bevacizumab will have a role in stage III disease because of its toxicity. Erlotinib, gefitinib, and crizotinib have not been evaluated in stage III patients selected based on molecular characteristics. The preliminary results of a phase III trial that compared conventionally fractionated standard-dose TRT (60 Gy) with high-dose TRT (74 Gy) revealed an inferior survival outcome among patients assigned to the high-dose arm. Hyperfractionation was investigated previously with promising results, but adoption has been limited because of logistical considerations. More recent trials have investigated hypofractionated TRT in chemoradiotherapy. Advances in tumor targeting and radiation treatment planning have made this approach more feasible and reduced the risk for normal tissue toxicity. Adaptive radiotherapy uses changes in tumor volume to adjust the TRT treatment plan during therapy, and trials using this strategy are ongoing. Ongoing trials with proton therapy will provide initial efficacy and safety data.
PMCID: PMC3360908  PMID: 22531360
Targeted therapy; Bevacizumab; Epidermal growth factor receptor; Cetuximab; Radiation therapy; Hypofractionation; High-dose thoracic radiation therapy; Adaptive radiotherapy
15.  Gene Expression Signatures That Predict Radiation Exposure in Mice and Humans 
PLoS Medicine  2007;4(4):e106.
The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation.
Methods and Findings
We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans.
We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.
John Chute and colleagues report that gene expression patterns in peripheral blood mononuclear cells from mice and humans reflect prior radiation exposure.
Editors' Summary
Everyone living on earth is constantly exposed to low levels of ionizing radiation—energy in the form of waves or particles that is powerful enough to strip electrons out of atoms and to break chemical bonds in important biomolecules. These low levels of ionizing radiation come from radioactive chemicals in the ground and cosmic rays, for example, and are relatively harmless. Occasionally, though, individuals are exposed to larger amounts of ionizing radiation, often as a result of medical tests and treatments but sometimes through the accidental or deliberate release of radioactive chemicals. These larger doses, which permanently damage or kill cells, can cause radiation sickness, a condition characterized by bone marrow failure, gut problems, susceptibility to bacterial infections, and other symptoms that develop days or months after exposure to ionizing radiation. Particularly large doses can be lethal but even moderate doses can increase an individual's risk of developing cancer later in life.
Why Was This Study Done?
Some of the effects of ionizing radiation can be reduced if suitable treatment is started immediately after exposure. Unfortunately, it takes several days to estimate the amount of ionizing radiation to which an individual has been exposed. It would be useful to measure personal exposures more quickly, especially in emergency situations where ideally doctors would be able to distinguish rapidly and accurately between the “worried well” and exposed individuals. As cells respond to irradiation by altering the expression of some genes, the researchers in this study investigated whether gene expression profiling (a molecular biology technique that catalogues all the genes expressed by a cell) can be used to define a set of gene expression changes—called a metagene—that differentiates between irradiated and non-irradiated cells.
What Did the Researchers Do and Find?
The researchers exposed mice to no ionizing radiation, a low dose that causes no medical problems, an intermediate dose that damages blood cells, or a lethal dose. Six hours later, they isolated blood cells from the mice, and catalogued which genes each sample expressed. Using this information, the researchers identified and validated metagenes that accurately distinguished between blood samples from non-irradiated and irradiated animals and between samples from animals exposed to different radiation doses. The researchers then developed a metagene for human radiation exposure using blood samples taken from patients before and after total body irradiation given as part of their medical treatment. This metagene correctly identified 18 of 20 pre-irradiation samples and 17 of 20 post-irradiation samples. Finally, the researchers tested whether the radiation metagenes developed in mice could distinguish between samples taken from irradiated and non-irradiated people. Although the high-dose mouse metagene correctly identified all of the samples from healthy donors as being non-irradiated, it correctly identified only two-thirds of the pre-irradiated samples from patients.
What Do These Findings Mean?
These findings indicate that metagenes can be generated that recognize different levels of radiation exposure in mice and people. In the mouse study a metagene was identified that correctly identified in all cases whether a sample came from a non-irradiated mouse or an animal exposed to the lowest dose of radiation. This result suggests that it might be possible to use a metagene to identify exposed individuals among thousands of “worried well” after a radiation emergency. First, however, the mouse and human metagenes identified here need to be refined to improve their accuracy and then validated in more people. The current high-dose mouse metagene may be bad at identifying non-irradiated patients, for example, because of gene expression changes that are a result of the patients' underlying disease or previous medical treatments. By studying additional patients, it might be possible to improve the accuracy of the metagene by taking these radiation-independent changes into account. Finally and more generally, these findings suggest that the metagene approach could be used to monitor people's exposure to other dangerous environmental agents.
Additional Information.
Please access these Web sites via the online version of this summary at
US Environmental Protection Agency offers information on understanding radiation and factsheets on ionizing radiation
MedlinePlus provides links to information on radiation exposure and pages on radiation sickness
US Centers for Disease Control and Prevention has information on emergency preparedness and response to radiation emergencies
Wikipedia has pages on ionizing radiation, radiation poisoning, and expression profiling (note that Wikipedia is a free online encyclopedia that anyone can edit)
PMCID: PMC1845155  PMID: 17407386
16.  Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy 
Journal of Thoracic Disease  2014;6(4):287-302.
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.
PMCID: PMC3968552  PMID: 24688774
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
17.  Current concepts in clinical radiation oncology 
Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.
PMCID: PMC3935099  PMID: 24141602
Radiotherapy; IMRT/IGRT; Particle therapy; Targeted therapy; Biomarkers; Personalized medicine
18.  AB 59. Re-irradiation with 3D-conformal radiotherapy in patients with lung cancer. Report in two cases 
Journal of Thoracic Disease  2012;4(Suppl 1):AB59.
There are cases of patients with Lung cancer, which have received radiation therapy in mediastinum and the tumor mass (45-50 Gy) and after uncertain period in their life, they need re-irradiation due to recurrent tumor mass which is close to previous radiation field. 3D Conformal Radiotherapy, the last years, is used always and more, because of the minimal dangerous of radiation myelitis. Re-irradiation of patients with lung cancer and the role of 3D Conformal radiotherapy in the overall-survival and the quality of life in these patients.
Patients and methods
68 years-old patient with lung cancer of the right upper lob, was irradiated 3 years ago, and he was referred to our department with recurrent tumor mass, close to previous radiation field. Patient has received 45 Gy, total dose, in mediastinum and the tumor mass, with anterior-posterior fields (in different department of radiation oncology). We have taken mention of the fields and doses which have received the spinal cord, heart and unilateral lung. After CT simulation, determination of the clinical target volume(CTV) of the tumor mass, determination of the organ at risk (OAR), 2D-3D treatment planning, the patient was irradiated with 2.500 cGy (10 fractions with 250 cGy/fraction) conformal RT, with linear accelerator with MLC-multilieaf collimator (in the recurrent tumor mass). The medical physics were used 3 radiation fields for avoidance the irradiation of spinal cord and the other organ at risk. The second patient, woman, 58 years old, with lung cancer was irradiated 2 years ago, in the mediastinum due to dyspneia from tumor mass in the mediastinum and the left middle lob. She was received 30 Gy in 10 fractions with 3 Gy/Fr. The patient was re-irradiated due to reccurrence, after CT simulation and 3D Conformal treatment planning, with linear accelerator with MLC. She was received 20 Gy in the tumor mass with 20 Gy/Fr in 10 fractions. It was also done the Dose Volume histogram (DVH) from the medical physics. They have taken care for the dose limitations in the organs at risk. There were also used 3 fields for radiation treatment.
In the two patients who was re-irradiated in the follow-up after 1, 2, 3, 4, 5, 6, 7 months there was not appearance toxicity from the organs at risk such as spinal cord, heart, unilateral lung. The respiratory function was better. There was not appearance of radiation myelitis (or Chermitte’s syndrome) sudden electric-like shocks extending down the spine with head flexion usually resolves spontaneously). Patients did not showed to have complications such as acute pericarditis, pulmonary fibrosis, radiation pneumonitis. The CT-of thorax showed decrease of the recurrent mass.
With 3D Conformal RT succeed in maximum therapeytical radiation dose for the re-irradiation, in the patients with recurrent mass and lung cancer, without overcame the dose limitations of the organ at risk. So, increase the overall- survival in the re-irradiated patients and improves their quality of life.
PMCID: PMC3537399
19.  Strategies for optimizing the response of cancer and normal tissues to radiation 
Nature reviews. Drug discovery  2013;12(7):526-542.
Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment and the delivery of image-guided radiation therapy, acute toxicity and potential long-term side effects often limit the ability to deliver a sufficient dose of radiation to control tumours locally. In the past two decades, a better understanding of the hallmarks of cancer and the discovery of specific signalling pathways by which cells respond to radiation have provided new opportunities to design molecularly targeted therapies to increase the therapeutic window of radiation therapy. Here, we review efforts to develop approaches that could improve outcomes with radiation therapy by increasing the probability of tumour cure or by decreasing normal tissue toxicity.
PMCID: PMC3906736  PMID: 23812271
20.  Quantitative analysis of tumor shrinkage due to chemotherapy and its implication for radiation treatment planning in limited-stage small-cell lung cancer 
The optimal timing of chemoradiotherapy in limited-stage small-cell lung cancer (LS-SCLC) hasn’t been established, although evidence from studies supported that patients can benefit from early radiation therapy. The purpose of this study was to quantify tumor shrinkage in response to induction chemotherapy (IC), evaluate the impact of tumor shrinkage on radiation dosimetric parameters and determine its implication for the timing of radiation therapy for patients with LS-SCLC.
Twenty patients with LS-SCLC who were treated with IC followed by concomitant radiation therapy were investigated retrospectively. Ten patients received 1 cycle of IC, and 10 patients received 2 cycles of IC. Pre-IC CT imaging was coregistered with a simulation CT, and virtual radiation plans were created for pre- and post-IC thoracic disease in each case. The changes in the gross target volume (GTV), planning target volume (PTV) and dosimetric factors associated with the lungs, esophagus and heart were analyzed.
The mean GTV and PTV for all of the patients decreased by 60.9% and 40.2%, respectively, which resulted in a significant reduction in the radiation exposure to the lungs, esophagus and heart. Changes in the PTV and radiation exposure of normal tissue were not significantly affected by the number of chemotherapy cycles delivered, although patients who received 2 cycles of IC had a greater decrease in GTV than those who received only 1 cycle of IC (69.6% vs. 52.1%, p = 0.273).
Our data showed that targeting the tumor post-IC may reduce the radiation dose to normal tissue in patients with LS-SCLC. However, the benefit to the normal tissue was not increased by an additional cycle of IC. These findings suggest that the first cycle of chemotherapy is very important for tumor shrinkage and that initiating thoracic radiation therapy at the second cycle of chemotherapy may be a reasonable strategy for timing of radiation therapy in LS-SCLC treatment.
PMCID: PMC3851276  PMID: 24040865
Small-cell lung cancer; Chemotherapy; Radiation therapy; Treatment planning
21.  Randomized Noninferiority Trial of Reduced High-Dose Volume Versus Standard Volume Radiation Therapy for Muscle-Invasive Bladder Cancer: Results of the BC2001 Trial (CRUK/01/004) 
To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer.
Methods and Materials
In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years).
Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population.
In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.
PMCID: PMC3753507  PMID: 23958147
22.  Acute toxicity of second generation HIV protease-inhibitors in combination with radiotherapy: a retrospective case series 
There is little data on the safety of combining radiation therapy and human immunodeficiency virus (HIV) protease inhibitors to treat cancers in HIV-positive patients. We describe acute toxicities observed in a series of HIV-positive patients receiving modern radiation treatments, and compare patients receiving HIV protease inhibitors (PI) with patients not receiving HIV PIs.
By reviewing the clinical records beginning January 1, 2009 from the radiation oncology department, we identified 29 HIV-positive patients who received radiation therapy to 34 body sites. Baseline information, treatment regimen, and toxicities were documented by review of medical records: patient age, histology and source of the primary tumor, HIV medication regimen, pre-radiation CD4 count, systemic chemotherapy, radiation therapy dose and fractionation, irradiated body region, toxicities, and duration of follow-up. Patients were grouped according to whether they received concurrent HIV PIs and compared using Pearson's chi-square test.
At baseline, the patients in the two groups were similar with the exception of HIV medication regimens, CD4 count and presence of AIDS-defining malignancy. Patients taking concurrent PIs were more likely to be taking other HIV medications (p = 0.001) and have CD4 count >500 (p = 0.006). Patients taking PIs were borderline less likely to have an AIDS-defining malignancy (p = 0.06). After radiation treatment, 100 acute toxicities were observed and were equally common in both groups (64 [median 3 per patient, IQR 1-7] with PIs; 36 [median 3 per patient, IQR 2-3] without PIs). The observed toxicities were also equally severe in the two groups (Grades I, II, III respectively: 30, 30, 4 with PIs; 23, 13, 0 without PIs: p = 0.38). There were two cases that were stopped early, one in each group; these were not attributable to toxicity.
In this study of recent radiotherapy in HIV-positive patients taking second generation PIs, no difference in toxicities was observed in patients taking PIs compared to patients not taking PIs during radiation therapy. This suggests that it is safe to use unmodified doses of PIs and radiation therapy in HIV cancer patients, and that it is feasible to use PIs as a radiosensitizer in cancer therapy, as has been suggested by pre-clinical results.
PMCID: PMC3064638  PMID: 21414215
23.  Renal cell carcinoma treated with stereotactic radiotherapy with histological change confirmed on autopsy: a case report 
BMC Research Notes  2014;7:270.
Treatment of primary renal cell carcinoma using radiotherapy with curative intent is rare, because renal cell carcinoma is generally regarded as a radiation-resistant tumor. Recently, stereotactic body radiation therapy has been radically applied for cancers in various organs including renal cell carcinoma. However, there were few reports describing pathological changes of renal cell carcinoma post stereotactic body radiation therapy. This is the first report we are aware of documenting late histological effects of stereotactic body radiation therapy on renal cell carcinoma and surrounding normal tissue.
Case presentation
A right renal tumor was identified in a Japanese 70-year-old man on follow-up computed tomography for his chronic hepatitis. T1N0M0 renal cell carcinoma was clinically diagnosed as the tumor was 3 cm in diameter and well-enhanced with intravenously infused contrast material in the arterial phase on computed tomography. No metastases in regional lymph nodes or distant sites were evident. Stereotactic body radiation therapy was selected as an alternative therapy to surgery because of his poor liver function. A total dose of 60 Gy in 10 fractions over 12 days was delivered using a 10-megavolt X-ray. The renal tumor gradually decreased in size and partial response had been achieved at 2 years after completing stereotactic body radiation therapy. Hepatocellular carcinoma was identified during follow-up in the patient and he died of progression of hepatocellular carcinoma with hepatic failure 2.5 years after completing stereotactic body radiation therapy. Autopsy was done and it showed almost complete necrosis of tumor tissues with a small amount of viable renal carcinoma cells. These pathological findings suggested marked effects of stereotactic body radiation therapy on clear cell renal cell carcinoma.
Our case demonstrates a good pathological response with small foci of remnant viable cancer cells after stereotactic body radiation therapy of 60Gy in 10 fractions for small renal cell carcinoma. Although further experiences and longer follow-up are mandatory to conclude the optimal treatment schedule and efficacy of stereotactic body radiation therapy for renal cell carcinoma, stereotactic body radiation therapy may represent a novel less-invasive option for the treatment of primary renal cell carcinoma.
PMCID: PMC4008414  PMID: 24767701
Renal cell carcinoma; Stereotactic body radiation therapy; Histological effect; Autopsy
24.  Combined Hyperthermia and Radiotherapy for the Treatment of Cancer 
Cancers  2011;3(4):3799-3823.
Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an integral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, cardiac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threatening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy.
PMCID: PMC3763397  PMID: 24213112
heat shock proteins; radiotherapy; hyperthermia; cancer; hypoxia
25.  Factors predicting radiation pneumonitis in locally advanced non-small cell lung cancer 
Radiation Oncology Journal  2011;29(3):181-190.
Thoracic radiotherapy is a major treatment modality of stage III non-small cell lung cancer. The normal lung tissue is sensitive to radiation and radiation pneumonitis is the most important dose-limiting complication of thoracic radiation therapy. This study was performed to identify the clinical and dosimetric parameters related to the risk of radiation pneumonitis after definitive radiotherapy in stage III non-small cell cancer patients.
Materials and Methods
The medical records were reviewed for 49 patients who completed definitive radiation therapy for locally advanced non-small cell lung cancer from August 2000 to February 2010. Radiation therapy was delivered with the daily dose of 1.8 Gy to 2.0 Gy and the total radiation dose ranged from 50.0 Gy to 70.2 Gy (median, 61.2 Gy). Elective nodal irradiation was delivered at a dose of 45.0 Gy to 50.0 Gy. Seven patients (14.3%) were treated with radiation therapy alone and forty two patients (85.7%) were treated with chemotherapy either sequentially or concurrently.
Twenty-five cases (51.0%) out of 49 cases experienced radiation pneumonitis. According to the radiation pneumonitis grade, 10 (20.4%) were grade 1, 9 (18.4%) were grade 2, 4 (8.2%) were grade 3, and 2 (4.1%) were grade 4. In the univariate analyses, no clinical factors including age, sex, performance status, smoking history, underlying lung disease, tumor location, total radiation dose and chemotherapy were associated with grade ≥2 radiation pneumonitis. In the subgroup analysis of the chemotherapy group, concurrent rather than sequential chemotherapy was significantly related to grade ≥2 radiation pneumonitis comparing sequential chemotherapy. In the univariate analysis with dosimetric factors, mean lung dose (MLD), V20, V30, V40, MLDipsi, V20ipsi, V30ipsi, and V40ipsi were associated with grade ≥2 radiation pneumonitis. In addition, multivariate analysis showed that MLD and V30 were independent predicting factors for grade ≥2 radiation pneumonitis.
Concurrent chemotherapy, MLD and V30 were statistically significant predictors of grade ≥2 radiation pneumonitis in patients with stage III non-small cell lung cancer undergoing definitive radiotherapy. The cutoff values for MLD and V30 were 16 Gy and 18%, respectively.
PMCID: PMC3429901  PMID: 22984669
Non-small cell lung cancer; Radiation therapy; Radiation pneumonitis; Dosimetric factor

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