Advances in Cancer Research: 92

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Smaller and more affordable cyclotrons are now in development, and if successful, this may result in the more widespread availability of proton-based radiotherapy in the coming decades. Cellular and tumor responses to radiation. In , while studying the histology of irradiated testes, Regaud recognized that undifferentiated cells spermatagonia were more radiosensitive than their more differentiated spermatozoid counterparts One year later, Bergoinie and Tribondeau expressed this same concept somewhat differently in their law 47 , which states that elevated radiosensitivity is seen in cells with higher mitotic activities and lower levels of established function differentiation.

Decades later in , Muller performed a series of experiments showing that chromosomes are the major target of X-ray—mediated cell killing. Puck was responsible for major developments that promoted the study of radiation effects on individual cells.

Throughout the s, he devised efficient methods for growing colonies from single human tumor cells that enabled clonogenic survival curves. Normal tissues were also subsequently studied using related clonogenic-based end points. Till and McCulloch developed a system whereby bone marrow cells were injected into lethally irradiated recipient animals, and resulting colonies formed in the animals' spleens. This allowed researchers to study the reproductive integrity of the injected cells after various treatments Another assay developed by Withers evaluated the viability of the intestinal clonogenic mucosal cells after irradiation Many groups have used cell culture techniques to study the basis of radiation resistance on a descriptive level.

For example, Weichselbaum and colleagues 50 irradiated cells derived from various tumors thought to be sensitive or resistant to radiation, but cell survival curve characteristics did not clearly correlate with clinical tumor behaviors.

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Further work showed potentially lethal damage repair PLDR to be among the most important factors for relating cell culture studies of human tumors to their clinical responses. Potentially lethal damage can be thought of as cellular injury damage that leads to cell death under some circumstances but not if conditions are modified to allow for repair.

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For example, osteogenic sarcoma tumors are generally thought to be resistant to radiation, and cells derived from these tumors have great capacity for PLDR after radiation Oxygen has also been shown to be a critically important determinant of cellular responsiveness to radiation. Early observations with model organisms such as Ascaris eggs and vegetable seeds suggested that low oxygen conditions promote resistance to irradiation. More recent studies have shown that tumor hypoxia can also select for more aggressive tumor cells, including those with p53 mutations Furthermore, hypoxia generates a broad range of signaling effects, including activation of the hypoxia-inducible transcription factor family of proteins that regulate a variety of downstream genes Many investigators have attempted to exploit the oxygen effect with a variety of clinical modalities 55 — 57 ; this is a subject of continuing research.

Modern developments in cellular and molecular biology have since confirmed that DNA damage mediates many of the lethal cellular effects of radiotherapy. Free radical scavenger agents, such as sulfhydryl-containing compounds, can counteract this oxidative damage. Such agents can render cells more radioresistant 60 , reduce radiation-associated chromosome abnormalities 61 , and reduce some radiation toxicities clinically Cells undergo a critical period after irradiation, which determines their fate: On the molecular level, radiation damage initiates very complex signaling cascades that result in a variety of responses including cell cycle arrest, induction of stress response genes, DNA repair, and apoptosis.

They act via phosphorylation of several downstream targets including the chromatin protein histone H2AX A simplified overview of some of the cellular pathways involved in response to ionizing radiation modified from ref. Although DNA damage is generally regarded to be the primary event leading to radiation-induced cell lethality, numerous non-DNA related mechanisms have recently been implicated in cellular responses to radiation. Two examples of this are radiation-induced ceramide production from plasma membrane—derived sphingomyelin and the activation of intracellular signaling pathways Radiation-induced signaling of epidermal growth factor receptor EGFR , for example, can have a prosurvival effect.

Pharmacologic inhibition of this effect can potentially be achieved with anti-EGFR antibodies 66 or chemical inhibitors of EGFR tyrosine kinase activity for example, gefitinib, and erlotinib. Another important recent discovery is the bystander effect, an intercellular signaling pathway described by several authors whereby irradiated cells exert effects on neighboring untreated cells 67 , These responses in neighboring cells consist of broad cellular changes including gene activation, induction of genomic instability, differentiation, and changes in apoptotic potential.

This occurs even when bystander cells are physically separated from the irradiated cells; therefore it seems to be mediated, at least in part, by diffusible substances The bystander effect emphasizes the need to consider the entire tumor microenvironment with modern studies of radiation effects, rather than concentrating on individual cells.

This notion has become particularly crucial, given that host stromal components within tumors are now known to contribute to radiation responsiveness also.

Experiments in mice have implicated host-derived blood vessels as a target of radiotherapy, in terms of both tumor control 70 and complications in normal tissues Many of these advances in our understanding of radiation effects are now leading to newer thinking in the design of targeted therapeutics 72 , Inhibitors of angiogenesis are also being considered as potential radiation modulators 74 , 75 , after the initial discoveries of angiostatin and endostatin by Folkman's laboratory 76 , Although advances such as these are encouraging, truly tumor-selective radiosensitizing compounds remain somewhat elusive Modern conceptual innovations in radiotherapy.

The earliest uses of radiotherapy in cancer management came as alternatives to surgical resection or as treatment for unresectable lesions. With the advances in diagnosis and improvements in treatment modalities, however, this paradigm has gradually shifted over the past century. Radiotherapy continues to have a role as monotherapy for some cancer presentations but is now more commonly used as a component of multimodality managements Fig. Part of this conceptual evolution is related to the perceptions of how cancers arise and spread.

From the late s onward, most clinicians had accepted the notion that cancer arises in a local site and spreads via a centrifugal pattern. This theory was most clearly communicated by Halsted 79 , and it predicts that cancers will spread primarily in a predictable, stepwise manner, from the primary tumor to the regional lymphatics and then systemically to distant sites.

For many decades, this philosophy shaped oncologic treatments, which heavily concentrated on both the tumor and contiguous regional lymphatics. This thinking was eventually challenged by the suggestion that tumors arise as one of two types—either permanently localized or capable of metastasizing early. This model was championed by Fisher 80 , and it suggested that metastasis is an early event that occurs even before detection of the primary mass.

This philosophy stressed a perceived need for early systemic therapies, and it de-emphasized the importance of local control. A third model was introduced in as the continuum or spectrum theory This model proposes that patterns of cancer spread are more complex than first thought, that they exist as a continuum of disease proclivities. It emphasizes that cancer cells develop metastatic potential as tumors grow during their clinical evolution and that the process of malignant progression facilitates the capacity of cancer cells to metastasize. This view is supported by clinical studies: For example, a recent clinical trial randomized melanoma patients to receive surgical resection with margins of 1 cm compared with 3 cm.

Introduction

Similar results were observed with early-stage non—small cell lung cancer; a trend toward lower survival rates was observed after limited lung resections compared with complete lobectomies In terms of radiotherapy, the spectrum theory is also supported by clinical outcome data. This was particularly true in trials of high-risk breast cancer, where women had mastectomy with or without radiotherapy to the chest wall and regional lymphatics. Even when chemotherapy was a part of the treatment, regional radiotherapy resulted in fewer distant metastases and improved survival rates 84 , Another major conceptual advance for radiotherapy has been its use in treatments aimed at organ preservation 87 , Many effective chemoradiotherapy regiments have allowed patients to be spared morbid procedures such as laryngectomy for head and neck tumors 89 and abdominoperineal resection for anal carcinomas Although it is possible that some these approaches may expose patients to slightly higher risk for tumor recurrence, most people believe that these small potential risks are offset by the large quality-of-life benefits.

When combined with radiotherapy, many common chemotherapeutic drugs have been shown to have additive tumor killing and in some situations actual synergy. It should be noted that chemotherapeutic drugs also usually increase treatment-related toxicity, so the net effect on therapeutic index can be variable. Platinum-based drugs are probably still the most commonly used agents in this setting. Radiotherapy elevates the cellular uptake of platinum drugs and increases the number of therapeutic platinum intermediates 91 , Several randomized clinical trials in advanced cervical cancer have shown a benefit to adding platinum-based chemotherapy to radiotherapy 93 — In one such trial, the addition of cisplatin significantly improved tumor control and survival rates, although this came at the expense of elevated toxic effects A similar trial with head and neck cancers showed that combinations of hyperfractioned radiotherapy and concurrent chemotherapy cisplatin and fluorouracil resulted in improved tumor control rates with comparable rates of complications to hyperfractioned radiotherapy alone Furthermore, several trials have shown the advantage of concurrent over sequential chemoradiotherapy, suggesting some degree of synergy in at least some situations Indirectly, these improvements have had major effects on how radiotherapy is practiced.

The progress in pediatric cancer treatments illustrates this nicely. Over the past 75 years, radiotherapy has been incorporated into the initial treatment of many childhood brain tumors that were once universally fatal.

The problem of long-term central nervous system side effects remains a major obstacle for survivors 98 , however, and many newer clinical trials are designed with this issue in mind. With medulloblastoma, for example, an ongoing Children's Oncology Group trial is taking maximal advantage of modern advances to reduce radiation toxicities.

Advances in radiological technologies and the integration of concomitant chemotherapies have allowed for reductions in irradiated brain volumes 99 , reductions in radiation dose , and better avoidance of critical normal organs , These changes are likely to have major effect on quality-of-life for these children.

One final conceptual advance worthy of mention is the management of metastases, which account for the great majority of cancer deaths. For most of the last century, treatment for metastatic cancers has generally consisted of systemic drugs, with local therapies reserved for palliative needs.

Tumor Immunology: Basic and Clinical Advances

We proposed in that distinct oligometastatic states may exist wherein a limited number of metastases at certain anatomic sites may be potentially curable with local therapies This idea is supported by surgical series that have produced cures after resection of limited metastases in the lung , liver , synchronous lung and liver , or adrenal gland Our group has combined this concept with newer image-guided, highly targeted SBRT techniques to treat metastases occurring in multiple five or fewer sites or organs Fig.

The ongoing clinical trial at the University of Chicago involves a dose escalation design to test the feasibility and efficacy of this approach Images from a y-old man who had previously completed treatment of limited-stage small cell lung cancer. He subsequently represented with a solitary metastasis of the left adrenal gland.

Orange shaded area, the target volume; colored numbers, dose per fraction delivered to that particular volume. CNS, central nervous system. The field of radiotherapy has undergone an amazing series of developments since its inception over a century ago. The biological discoveries over the past century have likewise been revolutionary.

In our opinion, however, the clinical practice of radiotherapy has thus far been influenced far less by these biological insights than by clinical advances and physics-based technologies. For example, methods for directly measuring DNA damage have yet to be applied clinically to assess radiation effects in tumor tissue or normal organs. And only recently have the extraordinary mechanistic discoveries regarding the molecular basis of DNA damage response and repair begun to affect clinical practice in meaningful ways. Looking forward, we believe that bringing laboratory discoveries and techniques to the clinic will be the key challenge facing our specialty.

We need to treat only those patients who can benefit from treatment and only to the extent that is necessary. Clinically applied molecular biology will make this possible.

Major Advances in the Treatment of Cancer

We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses. Skip to main content. Connell and Samuel Hellman. The first X-ray of Mrs. Advances in Perspective Pioneering of fractionated radiotherapy. Download figure Open in new tab Download powerpoint.

List of common cancers treated with radiotherapy. Summary and Conclusions The field of radiotherapy has undergone an amazing series of developments since its inception over a century ago. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Footnotes Received December 28, Accepted December 3, Med Care ; Mosby Year Book; University of Chicago Press; Madame Curie, a biography. Marie Curie, a life. Madame Curie and her world. Curies, cure, and culture. Perspect Biol Med ; Sur les principes radiophysiologiques de la radiotherapie des cancers.

Acta Radiol ; Sterilization rontgenienne totale et definitive, sans radiodermite, des testicules du Belier adulte: Compt Rend Soc de Biol ; Roentgen therapy of epitheliomas of the tonsillar region, hypopharynx, and larynx from to Principles of x-ray therapy of malignant diseases. Lancet ; 2: Historic milestones in radiobiology and radiation therapy. Semin Oncol ; 6: Quimby E, McComb W. Radiology ; Del Regato JA, Radiological oncologists: Dose, time and fractionation: Clin Radiol ; A new isoeffect curve for change in dose per fraction. Radiother Oncol ; 1: The evolution of the basic concepts underlying the practice of radiotherapy from to Tolerance of normal tissue to therapeutic irradiation.

Radiobiology for the Radiologist. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Radiother Oncol ; A Radiation Therapy Oncology Group RTOG phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Lancet ; Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase II study on stereotactic body radiotherapy of colorectal metastases.

Acta Oncol ; Phase III trial of high- vs. High-dose rate and low-dose rate intracavitary therapy for carcinoma of the uterine cervix. Final results of Osaka University Hospital. Cancer ; High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: Some early experiences in therapeutic radiology; formation of the American Radium Society. Hirsch IS, Holzknecht G. The principles and practice of Roentgen therapy. With dosage formulae and dosage table. Cathode-ray and roentgen-ray work in progress. AJR ; Lawrence E, Sloan D. High velocity mercury ions. Phys Rev ; Acceleration of electrons by magnetic induction.

Intensity modulated radiation therapy: Intensity-modulated radiation therapy, protons, and the risk of second cancers. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: How do protons compare with other conformal techniques? Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Regaud C, Blanc J. Actions des rayons X sur les diverses generations de la lignee spermatique: Bergonie' J, Tribandeau L.

Compt Rend Acad Sci Paris ; A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res ; Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. X-ray sensitivity of human tumor cells in vitro. Response of human osteosarcoma in vitro to irradiation: Factors of importance in radiosensitivity of tumors.

Br J Radiol ; 9: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature ; Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev ; Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol ; 6: Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer Suppl ; Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: The level of induced DNA double-strand breakage correlates with cell killing after X-irradiation.

Radiotherapy and cellular signalling. Lancet Oncol ; 2: Combined use of radioprotective and radiosensitizing drugs in experimental radiotherapy. Antimutagenic effects of amifostine: Semin Oncol ; Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol ; J Biol Chem ; Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis.

Advances in Cancer Therapy

Oncogene ; Epidermal growth factor receptor blockade with C modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res ; Mothersill C, Seymour C. Biological response to radiation therapy. Mothersill C, Seymour CB. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science ; With cancer being one of the most serious diseases of our times, I am confident that this book will meet the patients', physicians' and researchers' needs.

Pelus and Seiji Fukuda. Jordan and Pierre Sonveaux. By Varisa Pongrakhananon and Yon Rojanasakul. Shah, Elias Siores and Chronis Daskalakis. Huang and Shih-Ming Hsu. This is made possible by the EU reverse charge method. Edited by Oner Ozdemir. Edited by Cesar Lopez-Camarillo. Edited by Subhra Biswas. Edited by Kathryn Tonissen. Edited by Margarita Pesheva. Edited by Mariko Tomita. Edited by Doaa Hashad. Edited by Oliver Bathe. Edited by Faik Atroshi.

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