Tumors as Organs: Biologically Augmenting Radiation Therapy by Inhibiting Transforming Growth Factor β Activity in Carcinomas
Transforming growth factor β (TGFβ) plays critical roles in regulating a plethora of physiological processes in normal organs, including morphogenesis, embryonic development, stem cell differentiation, immune regulation, and wound healing. Though considered a tumor suppressor, TGFβ is a critical mediator of tumor microenvironment, in which it likewise mediates tumor and stromal cell phenotype, recruitment, inflammation, immune function, and angiogenesis. The fact that activation of TGFβ is an early and persistent event in irradiated tissues and that TGFβ signaling controls effective DNA damage resp...
Source: Seminars in Radiation Oncology - September 20, 2013 Category: Cancer & Oncology Authors: Shisuo Du, Mary Helen Barcellos-Hoff Source Type: research

Characterization of the Stem Cell Niche and Its Importance in Radiobiological Response
Normal tissues are organized hierarchically with a small number of stem cells, able to self-renew and give rise to all the differentiated cells found in the respective specialized tissues. The undifferentiated, multipotent state of normal stem cells is codetermined by the constituents of a specific anatomical space that hosts the normal stem cell population, called the “stem cell niche.” Radiation interferes not only with the stem cell population but also with the stem cell niche, thus modulating a complex regulatory network. There is now mounting experimental evidence that many solid cancers share this hierarc...
Source: Seminars in Radiation Oncology - September 20, 2013 Category: Cancer & Oncology Authors: Frank Pajonk, Erina Vlashi Source Type: research

Introduction: Tumor as an Organ
In this issue of Seminars in Radiation Oncology, we focus on the theme of tumors as dysfunctional organs. Hanahan and Weinberg have pointed out in their most recent “Hallmarks of Cancer” review that tumors contain communities of cells and stromal elements that work in concert to promote tumor cell growth, angiogenesis, invasion, and metastasis as well as immune system evasion. The features of this microenvironment also influence the efficacy of therapy. As such, an understanding of the tumor microenvironment is highly relevant to the development of new therapeutic targets. The cover of this special issue highli...
Source: Seminars in Radiation Oncology - September 20, 2013 Category: Cancer & Oncology Authors: Mark W. Dewhirst Source Type: research

Understanding the Tumor Microenvironment and Radioresistance by Combining Functional Imaging With Global Gene Expression
The objective of this review is to present an argument for performing joint analyses between functional imaging with global gene expression studies. The reason for making this link is that tumor microenvironmental influences on functional imaging can be uncovered. Such knowledge can lead to (1) more informed decisions regarding how to use functional imaging to guide therapy and (2) discovery of new therapeutic targets. As such, this approach could lead to identification of patients who need aggressive treatment tailored toward the phenotype of their tumor vs those who could be spared treatment that carries risk for more no...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Mark W. Dewhirst, Jen-Tsan Chi Source Type: research

Cell Death–Stimulated Cell Proliferation: A Tissue Regeneration Mechanism Usurped by Tumors During Radiotherapy
The death of all the cancer cells in a tumor is the ultimate goal of cancer therapy. Therefore, much of the current effort in cancer research is focused on activating cellular machinery that facilitates cell death such as factors involved in causing apoptosis. However, recently, a number of studies point to some counterintuitive roles for apoptotic caspases in radiation therapy as well as in tissue regeneration. It appears that a major function of apoptotic caspases is to facilitate tissue regeneration and tumor cell repopulation during cancer therapy. Because tumor cell repopulation has been shown to be important for loca...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Mary A. Zimmerman, Qian Huang, Fang Li, Xinjiang Liu, Chuan-Yuan Li Source Type: research

Inhibiting Vasculogenesis After Radiation: A New Paradigm to Improve Local Control by Radiotherapy
Tumors are supported by blood vessels, and it has long been debated whether their response to irradiation is affected by radiation damage to the vasculature. We have shown in preclinical models that, indeed, radiation is damaging to the tumor vasculature and strongly inhibits tumor angiogenesis. However, the vasculature can recover by colonization from circulating cells, primarily proangiogenenic CD11b+ monocytes or macrophages from the bone marrow. This secondary pathway of blood vessel formation, known as vasculogenesis, thus acts to restore the tumor vasculature and allows the tumor to recur following radiation. The sti...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Brown J. Martin Source Type: research

Radiation as an Immune Modulator
Radiation therapy is currently one of the most widely utilized treatment strategies in the clinical management of cancer. Classically, radiation therapy was developed as an anticancer treatment on the basis of its capacity to induce DNA double strand breaks in exposed cancer cells, ultimately resulting in tumor cell death. Recently, our understanding of radiation effects has expanded widely in terms of the consequences of radiation-induced tumor cell death and the pertinent cells, signaling pathways, and molecular sensors that modify the tumor response to radiation. It is now well accepted that inflammation plays a complex...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Byron Burnette, Ralph R. Weichselbaum Source Type: research

Optimization of Tumor Radiotherapy With Modulators of Cell Metabolism: Toward Clinical Applications
Most solid tumors are characterized by unstable perfusion patterns, creating regions of hypoxia that are detrimental to radiotherapy treatment response. Because postsurgical radiotherapy, alone or in combination with other interventions, is a first-line treatment for many malignancies, strategies aimed at homogeneously increasing tumor pO2 have been the focus of intense research over the past decades. Among other approaches of demonstrable clinical and preclinical utility, this review focuses on those directly targeting oxygen consumption to redirect oxygen from a metabolic fate to the stabilization of radiation-induced DN...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Pierre Danhier, Christophe J. De Saedeleer, Oussama Karroum, Géraldine De Preter, Paolo E. Porporato, Bénédicte F. Jordan, Bernard Gallez, Pierre Sonveaux Source Type: research

The Roles of Reactive Oxygen Species and Autophagy in Mediating the Tolerance of Tumor Cells to Cycling Hypoxia
Tumor hypoxia (low oxygenation) causes treatment resistance and poor patient outcome. A substantial fraction of tumor cells experience cycling hypoxia, characterized by transient episodes of hypoxia and reoxygenation. These cells are under a unique burden of stress, mediated by excessive production of reactive oxygen species (ROS). Cellular components damaged by ROS can be cleared by autophagy, rendering cycling hypoxic tumor cells particularly vulnerable to inhibition of autophagy and its upstream regulatory pathways. Activation of the PERK-mediated signaling arm of the unfolded protein response during hypoxia plays a cri...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Marianne Koritzinsky, Bradly G. Wouters Source Type: research

Tumors as Organs: Biologically Augmenting Radiation Therapy by Inhibiting Transforming Growth Factor β Activity in Carcinomas
Transforming growth factor β (TGFβ) plays critical roles in regulating a plethora of physiological processes in normal organs, including morphogenesis, embryonic development, stem cell differentiation, immune regulation, and wound healing. Though considered a tumor suppressor, TGFβ is a critical mediator of tumor microenvironment, in which it likewise mediates tumor and stromal cell phenotype, recruitment, inflammation, immune function, and angiogenesis. The fact that activation of TGFβ is an early and persistent event in irradiated tissues and that TGFβ signaling controls effective DNA damage resp...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Shisuo Du, Mary Helen Barcellos-Hoff Source Type: research

Characterization of the Stem Cell Niche and Its Importance in Radiobiological Response
Normal tissues are organized hierarchically with a small number of stem cells, able to self-renew and give rise to all the differentiated cells found in the respective specialized tissues. The undifferentiated, multipotent state of normal stem cells is codetermined by the constituents of a specific anatomical space that hosts the normal stem cell population, called the “stem cell niche.” Radiation interferes not only with the stem cell population but also with the stem cell niche, thus modulating a complex regulatory network. There is now mounting experimental evidence that many solid cancers share this hierarc...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Frank Pajonk, Erina Vlashi Source Type: research

Introduction: Tumor as an Organ
In this issue of Seminars in Radiation Oncology, we focus on the theme of tumors as dysfunctional organs. Hanahan and Weinberg have pointed out in their most recent “Hallmarks of Cancer” review that tumors contain communities of cells and stromal elements that work in concert to promote tumor cell growth, angiogenesis, invasion, and metastasis as well as immune system evasion. The features of this microenvironment also influence the efficacy of therapy. As such, an understanding of the tumor microenvironment is highly relevant to the development of new therapeutic targets. The cover of this special issue highli...
Source: Seminars in Radiation Oncology - September 7, 2013 Category: Cancer & Oncology Authors: Mark W. Dewhirst Source Type: research

Cancer Control and Complications of Salvage Local Therapy After Failure of Radiotherapy for Prostate Cancer: A Systematic Review
The National Comprehensive Cancer Network guidelines currently endorse salvage local therapy as a reasonable alternative to observation or androgen-deprivation therapy for select men with a biopsy-proven local recurrence after definitive radiation for prostate cancer. Patients being considered for salvage therapy should have had localized disease at presentation, a prostate-specific antigen 10 years at recurrence, and a negative metastatic workup. In this systematic review, we synthesize the current literature describing the oncologic efficacy and toxicity profile of salvage brachytherapy, prostatectomy, cryotherapy, and h...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Arti Parekh, Powell L. Graham, Paul L. Nguyen Source Type: research

Adjuvant Versus Salvage Radiotherapy for High-Risk Prostate Cancer Patients
Radiotherapy (RT) after prostatectomy may potentially eradicate any residual localized microscopic disease in the prostate bed. The current dilemma is whether to deliver adjuvant RT solely on the basis of high-risk pathology (pT3 or positive margins), but in the absence of measurable prostate-specific antigen, or whether early salvage radiotherapy (SRT) would yield equivalent outcomes. Although the results of current randomized trials answering this very question remain years away, the best evidence to date supports early SRT as the better strategy. In terms of SRT, the pooled evidence reveals that one should initiate RT a...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Christopher R. King Source Type: research

Picking the Optimal Duration of Hormonal Therapy in Men With High-Risk and Locally Advanced Prostate Cancer Treated With Radiotherapy
The optimal duration of hormonal therapy when combined with radiation for men with high-risk and locally advanced prostate cancer remains under active study. Based on the results of randomized controlled trials, durations of androgen suppression therapy of at least 6 months have been shown to prolong survival in men with Gleason score 7 prostate cancer, irrespective of clinical stage. For men with locally advanced prostate cancer and 2 high-risk factors (particularly Gleason 8-10 tumors with evidence of extracapsular extension or seminal vesicle invasion on digital rectal examination) or pelvic nodal involvement, longer du...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: James W. Denham, Allison Steigler Source Type: research

Management of Prostate Cancer in Elderly Men
Elderly men comprise a large percentage of men diagnosed with prostate cancer (PrCa). Although localized PrCa is often indolent, older men tend to be diagnosed with higher-stage disease and are more likely to die from PrCa than younger men. Multiple factors other than age play an important role in determining who will benefit from active treatment, such as comorbid conditions, life expectancy, and tumor characteristics. Careful consideration of such factors can help prevent the overtreatment of elderly men with low-risk disease and undertreatment of elderly men with high-risk disease. Management decisions should be individ...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Shelly X. Bian, Karen E. Hoffman Source Type: research

Hypofractionation for Clinically Localized Prostate Cancer
This manuscript reviews the clinical evidence for hypofractionation in prostate cancer, focusing on data from prospective trials. For the purposes of this manuscript, we categorize hypofractionation as moderate (2.4-4 Gy per fraction) or extreme (6.5-10 Gy per fraction). Five randomized controlled trials have evaluated moderate hypofractionation in>1500 men, with most followed for>4-5 years. The results of these randomized trials are inconsistent. No randomized trials or other rigorous comparisons of extreme hypofractionation with conventional fractionation have been reported. Prospective single-arm studies of extrem...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Alvin R. Cabrera, W. Robert Lee Source Type: research

Comparing Dosimetric, Morbidity, Quality of Life, and Cancer Control Outcomes After 3D Conformal, Intensity-Modulated, and Proton Radiation Therapy for Prostate Cancer
New radiation technologies have been developed and adopted for clinical use in prostate cancer treatment in response to a need to deliver dose-escalated radiation therapy while minimizing treatment-related morbidity. The goal of this article is to examine the currently available evidence comparing dosimetric and patient outcomes of newer versus older radiation technologies in prostate cancer. Overall, although a body of dosimetry studies have demonstrated the ability of newer versus older technologies (intensity-modulated radiation therapy vs 3-dimensional conformal radiation therapy; proton vs intensity-modulated radiatio...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Kevin A. Pearlstein, Ronald C. Chen Source Type: research

How Can I Help Myself? A Critical Review of Modifiable Behaviors, Medications, and Complementary Alternative Medicine for Men Receiving Radiotherapy for Prostate Cancer
Men receiving radiation for prostate cancer frequently want to know what steps they can take to optimize their chance of cure and reduce their risk of side effects. A variety of modifiable behaviors, medications, and complementary alternative medicine interventions have been investigated in this regard. In this review, we summarize data on tobacco use, exercise, statins and aspirin, and vitamins. There is limited randomized data supporting any of the interventions and additional studies are needed before clinicians can confidently inform their patients regarding what steps to take to improve their outcomes. (Source: Semina...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Yolanda D. Tseng, Neil E. Martin Source Type: research

Prognostic Factors for Newly Diagnosed Prostate Cancer and Their Role in Treatment Selection
Adenocarcinoma of the prostate is extremely heterogeneous, ranging from an indolent chronic illness to an aggressive rapidly fatal systemic malignancy. The classic prognostic factors of tumor stage, prostate specific antigen level, and Gleason score have been used for over a decade to categorize patients at the time of diagnosis into broad risk groups that help to determine appropriate management. Although the grouping of patients into favorable, intermediate, and high-risk categories has become standard, and the categories continue to define distinct prognostic subgroups, considerable heterogeneity exists within each risk...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Juanita Crook, Ana Fernandez Ots Source Type: research

Multidisciplinary Care and Management Selection in Prostate Cancer
The management of prostate cancer is complicated by the multitude of treatment options, the lack of proven superiority of one modality of management, and the presence of physician bias. Care at a multidisciplinary prostate cancer clinic offers patients the relative convenience of consultation with physicians of multiple specialties within the confines of a single visit and appears to serve as a venue in which patients can be counseled regarding the risks and benefits of available therapies in an open and interactive environment. Physician bias may be minimized in such an environment, and patient satisfaction rates are high...
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Ayal A. Aizer, Jonathan J. Paly, Jason A. Efstathiou Source Type: research

Prostate Cancer: Where We Have Been, Where We Are, and Where We Are Going
In this issue of Seminars in Radiation Oncology, experts provide systematic reviews of evidence and clarifying discussion on clinically relevant issues in prevention, detection, and staging, and prognosis, management of nonmetastatic newly diagnosed and recurrent prostate cancer. It is a privilege for me to be able to serve as the guest editor for this issue where the contributors are personal friends, colleagues, and outstanding physician scientists. (Source: Seminars in Radiation Oncology)
Source: Seminars in Radiation Oncology - June 10, 2013 Category: Cancer & Oncology Authors: Anthony V. D'Amico Source Type: research

Place of Proton Radiotherapy in Future Radiotherapy Practice
We describe the steps in health technology assessment and the potential design of preclinical and clinical trials to define the role of proton therapy in the future. (Source: Seminars in Radiation Oncology)
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Daniel Zips, Michael Baumann Source Type: research

Evolution of Technology to Optimize the Delivery of Proton Therapy: The Third Generation
The evolution of proton therapy technology will lead to a new generation of systems that allow for greater accuracy and precision of the dose delivery and will be more compact. We envision that over the next 10-15 years, the quality of deliverable proton dose distributions in the patient will be pushed nearly toward the physical limit of proton therapy. Those future proton therapy systems will fit into treatment rooms of similar size as today's conventional radiation treatment rooms. At the same time, due to technological advancements, the cost of proton therapy will come down to the cost of advanced photon therapy. We dis...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Jacob Flanz, Thomas Bortfeld Source Type: research

Health Economic Controversy and Cost-Effectiveness of Proton Therapy
Owing to increasing healthcare costs, there is a need to examine whether the benefits of new technologies are worth the extra cost. In proton therapy, where the evidence in favor is limited, it is heavily debated whether the expected benefit justifies the higher capital and operating costs. The aim of this article was to explore the existing methodologies of economic evaluations (EEs) of particle therapy and recommend an approach for future data collection and analysis. We reviewed the published literature on health economics of proton therapy using accepted guidelines on performing EE. Different cost strategies were asses...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Yolande Lievens, Madelon Pijls-Johannesma Source Type: research

Controversies in Clinical Trials in Proton Radiotherapy: The Present and the Future
Proponents of proton radiotherapy have cited the dose distribution characteristics of proton beams as evidence of its superiority over photon radiotherapy. Outcomes after photon radiotherapy remain suboptimal owing to poor local control and normal-tissue toxicity in many clinical indications. Critics of proton radiotherapy have noted the relative lack of prospective data from clinical trials showing a benefit for proton radiotherapy despite its theoretical advantages. Questions remain with regard to physical uncertainties in proton dose delivery and variations in their radiobiological effect in different tissues and tumors...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Robert C. Miller, Mark Lodge, Mohammad Hassan Murad, Bleddyn Jones Source Type: research

Clinical Controversies: Proton Radiation Therapy for Brain and Skull Base Tumors
Proton radiotherapy offers distinct physical properties that could lead to an improvement of dose distribution with subsequent reduction of integral dose to the patient. This supports the potential use of proton beams in tumors close to sensitive structures, such as the skull base and the brain. In the present manuscript, the literature on proton therapy for brain and skull base tumors is critically reviewed and compared with results obtained with modern photon techniques. Treatment planning comparisons demonstrate that dose distributions within the target are comparable. In terms of normal tissue dose distribution, proton...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Stephanie E. Combs, Normand Laperriere, Michael Brada Source Type: research

Clinical Controversies: Proton Therapy for Thoracic Tumors
Photon and proton therapy techniques have both improved dramatically over the past decade. As a result, high radiation doses can be delivered while sparing organs at risk. However, in many series, older proton techniques have been compared with contemporary photon techniques, hampering a fair comparison. By virtue of their physical properties and because of modern 4-dimensional and imaging evolution, protons show theoretical superiority compared with photons. Current nonrandomized studies suggest that protons may indeed spare organs at risk much better that the best available photon techniques, leading to fewer side effect...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Dirk De Ruysscher, Joe Y. Chang Source Type: research

Clinical Controversies: Proton Therapy for Prostate Cancer
Proton therapy has been used in the treatment of prostate cancer for several decades, and interest surrounding its use continues to grow. Proton-based treatment techniques have evolved significantly over this period, and several centers now routinely use technologies such as pencil-beam scanning. However, whether the theoretical dosimetric advantages of the proton beam translate into clinically meaningful improvements for prostate cancer patients is unknown, and outcomes from single-arm experiences using whole courses of proton beam therapy in the treatment of early-stage prostate cancer have shown mixed results when compa...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Kent W. Mouw, Alexei Trofimov, Anthony L. Zietman, Jason A. Efstathiou Source Type: research

Clinical Controversies: Proton Therapy for Pediatric Tumors
Despite the claim in the published literature, the introduction of proton therapy for children is not analogous to the evolution of conformal photon irradiation relying on the understanding of the impact of altered dose distributions. The differences in radiobiological effect when comparing photons with protons mean that we are comparing a known entity with an unknown entity: the dose-volume histogram for proton therapy might mean something substantially different from the dose-volume histogram for photon therapy. The multifaceted difference between the 2 modalities supports the argument for careful evaluation, follow-up, ...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Thomas E. Merchant Source Type: research

Physics Controversies in Proton Therapy
The physical characteristics of proton beams are appealing for cancer therapy. The rapid increase in operational and planned proton therapy facilities may suggest that this technology is a “plug-and-play” valuable addition to the arsenal of the radiation oncologist and medical physicist. In reality, the technology is still evolving, so planning and delivery of proton therapy in patients face many practical challenges. This review article discusses the current status of proton therapy treatment planning and delivery techniques, indicates current limitations in dealing with range uncertainties, and proposes possi...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Martijn Engelsman, Marco Schwarz, Lei Dong Source Type: research

Biological Considerations When Comparing Proton Therapy With Photon Therapy
This article discusses the controversies associated with these 3 issues when comparing proton and photon therapy. (Source: Seminars in Radiation Oncology)
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Harald Paganetti, Peter van Luijk Source Type: research

Proton Therapy: The Present and the Future
The aim of most advances in radiotherapy is to improve disease control, survival, and quality of life, and with technological developments, it is achieved by equitoxic dose escalation or simply by more targeted therapy, reducing treatment-induced side effects. Photon radiotherapy technology, in therapeutic use since the discovery of X-rays, has progressed in leaps and bounds to offer sophisticated treatments, delivering defined doses of radiation with a high level of precision to tumors visualized with modern imaging. As good as the photon techniques are, delivered by a variety of highly sophisticated linear accelerators a...
Source: Seminars in Radiation Oncology - April 1, 2013 Category: Cancer & Oncology Authors: Michael Brada, Thomas Bortfeld Source Type: research