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t is very timely that the topic of innovative techniques inradiation therapy has been chosen for an Issue of Seminars

n Radiation Oncology. The practice of radiation oncology hasade significant progress in the last few years, and yet, just asany obstacles have been overcome, new challenges haveresented and are as yet unmet. In this guest editorial, we aimo do 3 things: (1) briefly to set the overall historical scenend highlight key past developments, (2) to summarize theey points made by our valued contributors and add our owncientific perspective on the situation today, and (3) to “fu-ure gaze” and set out the wish list for the long-term future.

ntroduction:arly History and Briefverview of This Compilation

he practice of radiation therapy is now some 110 years old,aving started the year after the German physicist professorilhelm Röntgen discovered the x-ray on November 8, 1895

n Würzburg. All those years ago, radiotherapy relied onow-energy poorly penetrating x-rays; there was no conceptf accurate dosimetry, no certain knowledge of the geograph-cal location of the tumor, no understanding of treatmentlanning, and little expectation of ability to determine prog-osis. In short, the “science” was somewhat hit and miss,robably literally as well as metaphorically.1-6

In the first 50 to 60 years of radiotherapy, many of theseissing elements were the subject of intense study so that by

he mid-20th century there was a well-understood system ofadiation dosimetry, elementary, 2-dimensional, treatmentlanning by hand, embryonic megavoltage therapy with co-alt irradiation and with the first generation of linear accel-rators and classical tomography to add to planar x-radiologyor crude section imaging of x-ray attenuation. Importantly,

ddress reprint requests to Professor Steve Webb, Institute of Cancer Research,University of London, Head of Department, Head of Radiotherapy PhysicsResearch, Joint Department of Physics, Royal Marsden NHS Trust, Downs

tRoad, Sutton, Surrey, SM2 5PT, UK. E-mail: Steve.Webb@icr.ac.uk

053-4296/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.semradonc.2006.04.001

he multidisciplinary subject of radiation oncology estab-ished itself, relying on the skills of clinicians, physicists,ngineers, and radiographers. Professional societies had beenstablished,7 and there were specialty publications, albeit inmbryonic form. The use of electrons had become estab-ished, but, with that exception, radiotherapy was still basedn photon irradiation.4

Although single-photon emission computed tomographySPECT) and positron emission tomography (PET) devel-ped in the 1960s, they were at that time not harnessed foradiotherapy planning; 1972 is generally regarded as a land-ark year in which commercial x-ray computed tomography

CT) became available and within only a very few years waseing harnessed to treatment planning. This revolutionizedoth diagnosis and therapy. Albeit that functional tomo-raphic imaging actually preceded this event, its impact inveryday radiation therapy was minimal throughout the restf the 20th century and is only now becoming a seriousontender for assisting the determination of the planningarget volume.8 Understanding the functional behavior ofissues is crucial to future development and one of the topicse selected to have covered in this issue.9

Computerized treatment planning began in the 1960s.ntil CT became available and even shortly thereafter, plan-ing was largely 2-dimensional. Three-dimensional planningid not seriously evolve until the 1980s when the subject ofonformal radiotherapy, first mooted by Takahashi as longgo as the 1940s, became the focus of serious study.10-13 Itas in the 1980s that personal computers and minicomput-

rs became fast enough to take care of treatment-planningalculations in almost real time (with the exception of coursef Monte-Carlo calculations), and at the same time inverselanning for conformal therapy was in its developmentaltages.14,15 Treatment planning is therefore the focus of an-ther of our contributing articles.16

Intensity-modulated radiation therapy (IMRT), first sug-ested by Brahme around 1982,17 had just a handful of work-rs developing rudimentary concepts by the late 1980s early990s.18 There was no equipment to deliver IMRT other than

he metal compensator so the theory somewhat ran ahead of

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he delivery abilities. In 1992, this changed19 with the an-ouncement of the NOMOS MIMiC, which dominatedlargely American) modulated radiotherapy for some threeears between the first irradiations at Baylor in 1994 and therst full-course irradiations by other techniques in 1997 no-ably at Memorial Sloan Kettering Cancer Institute, Nework, NY. The idea to harness a multileaf collimator (MLC)

nto the delivery of IMRT in either step-and-shoot mode orynamic mode, although possible in a few research organi-ations around 1993, did not become clinically establishedntil about 1997. From about 2000, systems to plan andeliver IMRT in the clinic were becoming routinely avail-ble.14,15,20-22 Another of our contributed articles reviews thelinical implementation of IMRT, and this can be linkedcross to the separate review of planning and optimizationpproaches.23

Although most IMRT has relied on the use of the NOMOSIMiC or the MLC-based techniques, two radically alterna-

ive approaches were simultaneously and independently de-eloped starting in about 1992. These were (spiral) tomo-herapy,24 first used to treat a patient in August 2002 and theobotic Accuray Cyberknife (Sunnyvale, CA).25 Both havenique features that endear them to their supporters andackle erstwhile difficult issues. For example, tomotherapy isdeal for delivering multifocal high-dose whole-body irradi-tion, something difficult with C-arm linac-based IMRT. Theyberknife is, in principle, idealized for image-feedback–ased correction for intrafraction motion. Another of ourontributing article concentrates in this area of alternativeechnology for IMRT.26

This leads us nicely to the topic of understanding, measur-ng, and controlling for interfraction and intrafraction organ

otion. In many ways, photon IMRT is already optimized forhe (unreal) static patient and the challenge for the next fewears is to develop image-guided radiotherapy and specifi-ally image-guided intensity-modulated radiation therapyIG-IM-RT).27 The welcome addition of 4-dimensional x-rayT, cone-beam megavoltage computed tomography (MVCT)nd kilovoltage computed tomography (kVCT), and a largeumber of methods to measure organ motion or surrogatesor organ motion has opened up the possibility to reduce orradicate artificially generated margins and so improve theherapeutic ratio. We must remember that margins do notxist in biology. They are inventions to cope with a previ-usly insoluble problem. The goal is to treat the diseasedissue at exactly where it is at all instances of therapy and thiss a burgeoning research topic. Another of our contributionsocuses on this area.28

The idea to introduce radioactive materials directly intoumor sites or on the patient’s skin surface is very old, goingack to the days when radium was in use. The two mainsystems” of dosimetry, the Paris and the Manchester sys-ems, were the bedrock of this subject for many years, withadiotherapy surgeons implanting wires and hairpins andlaques as best they could and with little image guidance.osimetry rules existed for placement, but postsurgical do-

imetry was largely based on the manual use of Sievert inte-

ral curves and the like together with drawings and crude p

lanar and shadow-shift x-rays made in theater by the phys-cist. Results were often very successful, and this science ofrachytherapy grew up in parallel with the use of externaleams of x-rays. This has now been revolutionized in that allhe components used to improve external-beam therapy haveeen marshaled to assist brachytherapy. Thus, 3-dimensional

mage guidance and planning, optimization, afterloading,nd high-dose-rate treatment including pulsed treatmentsre all recent developments that would be unrecognizable tohe brachytherapist of some 30 years ago.2 Another of ourrticles concentrates on this area.29

Particle therapy is numerically speaking the Cinderella ofur area. If we exclude the use of electrons (which tend to besed alongside photons and grouped with them as conven-ional radiotherapy), then the use of heavy charged particless rare. There have been some 40,801 patients treated withrotons and 5,611 with heavier ions [2005 Particle Therapyo-Operative Group (PTCOG) figures], but numerically

hese treatments are just noise in the worldwide treatment ofillions of patients for over more than a century with pho-

ons. Yet, paradoxically, the dose distributions obtainableith charged particles are indisputably superior to any

chievable with photons, and it is argued that although ac-elerating equipment is initially expensive, it can last longer,eliver particles to multiple gantries, and possibly not workut much more expensive if the sums are done properly.30

ecause there are only tens of facilities worldwide (again setgainst thousands for photon therapy), there have been fewrials and progress has been somewhat harder to assess givenhis numerical disparity.14,15 A group leading in both protonnd ion therapy has contributed here to update our under-tanding.31

Finally, physical dose is just a surrogate for biological ef-ect, and the subject of radiobiology has developed alongsidehysical techniques. There are models and data for predict-

ng tumor control probability and normal-tissue complica-ion probability from 3-dimensional dose distributions, buthe subject is still not fully understood and to some extent itan only grow as clinical trials of 3-dimensional Conformaladiation Therapy (CFRT) and IMRT are performed and cor-elated with biological outcome. The exponents of clinicaliological modeling are enthusiastic, but it has to be said sore its critics. A contributing article presents the current po-ition.32

In many ways, the age of the generalist radiotherapist,hysicist, and radiographer has gone, now replaced by thoseho will specialize in just one or two areas within their dis-

ipline. At one time, we considered it was possible for somef us to overview the whole field quite effectively,14,15,21,22 butow we are increasingly convinced this is impossible. Spe-ialists usually make more progress than generalists, but ahallenge will be to ensure we do not develop a Babel ofanguages and subcultures that are not mutually understand-ble.

he Position Todayodern radiation therapy is going through a very interesting

hase as several new technologies are being developed and

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Introduction 195

ecoming available for clinical use. In this issue of Seminars inadiation Oncology, we and our coauthors have highlightedight example technologies to show this trend. Although theyre from the mainstream of current development in radiationherapy, they do not represent a unique or definitive choicend indeed any reader might select a different set of eightreas including intraoperative radiotherapy, targeted radio-uclide therapy, radiochemotherapy, nonionizing treatmentodalities such as high-intensity focused ultrasound, biolog-

cal markers for radiation response, and so on. Some recentextbooks, with less space restriction, have been able to have wider coverage.10,11,22,27

Functional imaging is starting to find broad application inadiotherapy planning and treatment follow-up. Tradition-lly, nuclear medicine has been used to image radio-iodine–abeled compounds in planar and SPECT scans. The use ofadio-fluorine-labeled fluoro-deoxy-glucose (FDG) for imag-ng metabolism with PET is showing promise to influencearget volume definition greatly. New markers for cell-levelunction such as proliferation and hypoxia are being ex-loited and used to determine prescriptions based on doseainting to tailor the dose distribution based on intrinsiconuniformity of functional signal. Magnetic resonance–ased functional imaging techniques based on cellular mark-rs and perfusion are also starting to be evaluated in thelinical setting. In this issue, Grégoire, Bol, Geets, and Lee9

iscuss the use of PET to improve planning for head and neckquamous-cell carcinoma. The planning of IMRT is generallyy inverse techniques but James M. Galvin (this issue, pp12-217) reviews alternatives to these.16

IMRT has seen rapid development in the past decade withonsequent rapidly increasing clinical use. Sites such as pros-ate, prostate plus nodes, liver, breast, lung, head, and neckow have IMRT as part of the accepted standard for clinicalanagement. Data from trials, particularly phase-2 dose-es-

alation studies, are becoming available to enable evaluationf the consequences of the dose shaping available with IMRT.en Haken and Lawrence23 discuss the clinical role of IMRT,articularly in relation to prostate and head and neck treat-ent.Although most IMRT is delivered by using conventional

inear accelerators and MLCs, there is great interest in com-eting technology to deliver modulated dose distributionsnd to use imaging to monitor the treatment delivery process.lternatives to the MLC have been considered including (1)

he use of MLC jaws-only to shape multisegment field mod-lations and (2) the use of tomotherapy binary collimators,uch as the NOMOS MIMiC. Other, more revolutionary ap-roaches redesign the whole radiation delivery system. Twof the most common commercially available examples are thei-Art Tomotherapy system and the image-guided robotic

inac. The Hi-Art (Tomotherapy Inc., Madison, WI) systemses a multislice CT geometry for dose delivery and incorpo-ates a MVCT delivery verification system. The robotic linacAccuray, Sunnyvale, CA) approach uses kV orthogonal ra-iographs in conjunction with external marker tracking bysing intrared light. Fenwick, Tomé, Soisson, Mehta, and

ackie26 review the state of the art of such approaches. t

Radiotherapy of moving tumors is discussed by Jiang.28

he general approach to this problem has been to useargins to encompass the extent of organ motion, in much

he same way that margins are used to account for system-tic differences in mean position between planning andreatment and to account for random day-to-day setupariations. This approach results in the irradiation of po-entially large volumes of normal tissue and a consequentevere limit on the maximum dose that may be delivered tohe target without compromising surrounding normal tis-ues. Gating techniques are starting to be applied based onontrolling the patient’s breathing by using voluntaryreath hold and systems such as the Active Breathing Co-rdinator. Other techniques involve acquiring 4-dimen-ional tomographic data for planning to determine thepatiotemporal characterists of organ motion and thus tonable an intelligent margin recipe to be applied. Treat-ent delivery approaches involve imaging during irradia-

ion and gating the delivery system accordingly. Often themaging technique used is kilovoltage x-ray imaging ofnternal anatomy or the use of external markers, such ashe Varian Realtime Position Management (RPM) system,o image the patient exterior as a surrogate for internalnatomy motion. Tracking the target is another technol-gy reviewed.Brachytherapy, as a treatment modality, has undergoneuch development in recent years. The development ofigh-dose rate treatment in brachytherapy has led to changes

n the ways in which this treatment technique is used com-ared with low- and medium-dose rate regimens, includingeduction in overall dose administered and the use of frac-ionation. Another area of development has been the use ofomputer-based calculations based on the American Associ-tion of Physicists in Medicine (AAPM) task group 43 recom-endations, which effectively accounts for the dose from all

ources. The planning systems allow better visualization ofose distributions in 2 dimensions and 3 dimesions and areften available with optimization algorithms to allow the usero shape the dose distribution. The development of 3-dimen-ional image-based treatment planning coupled with imageusion also allows for better dose optimization and improvedource location. Brachytherapy is discussed by Hoskin andownes.29

The use of charged hadrons for radiation therapy offersany potential advantages over the more traditionallysed photons and electrons because of the physical char-cteristics of the Bragg energy-deposition curve, whicheaks at the end of particle range. The increased capitalost of the delivery systems compared with photon andlectron delivery systems has meant hadron treatment fa-ilities are relatively scarce by comparison although someispute the financial arguments. Notwithstanding, newenters are coming on line around the world, prompted inart by the inarguably improved dose distributionschieveable. Hadron therapy is generally separated intoroton, light ion, and light-heavy ion treatments. Theeavier the ion, the greater the density of energy deposi-

ion close to the Bragg peak and hence the greater the

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elative biological effect. Radiation therapy with chargedarticles is discussed by Schulz-Ertner, Jäkel, and Schle-el.31

Jackson, Yorke, and Rosenzweig32 comment on our un-erstanding of the relationship between physical dose de-

ivered and treatment outcome and present a binomialodel for analyzing the results of radiotherapy studies.he first stages of trying to model the dosimetric and volu-etric dependence of normal tissues to radiotherapy treat-ents were based on schemes to reduce dose-volume his-

ograms to equivalent dose to whole organs or to fractionsf an organ receiving a given dose.33 Authors presentedarameter recommendations for these models.34 Withreater clinical experience, our evidence for the radiationesponse characteristics of organs has developed withore sophisticated models.35

Having now set some historical context and reviewed theurrent position we turn our attention to the far future.

rystal-ball Gazeo the Long-term Future:he Ideal That We Would Like

t is said that they only ask you to predict the future if you areeriously old and/or will not be around to know if you wereorrect. Hopefully, we will work many more years to contrib-te to the subject and live long enough to see if some of theollowing come true.

Ahead of crystal-ball gazing, it should be reiterated thathis is a very unscientific process. Scientists are trained totudy and analyze situations, report their findings, and stopt that. Predicting the future is a risky business, albeit onehat people like to request.36-38 Those who predict futurerends are sometimes not popular with colleagues because, atest, they look puffed up and at worst ridiculous. However,his being said, we shall attempt to propose what should ben ideal scenario for radiotherapy. At worst, this should bentertaining and at best it might spawn some new researchreas. Because this cannot be a nicely structured essay, pointsre provided to stimulate response. “Future gazing” is not theame process as stating the likely short-term developmentsrom the current situation. It is, instead, bold, radical, andoday completely unthinkable. It might also be faintly ridic-lous to suggest this could happen.Let us divide the chain of radiotherapy as follows: diagno-

is of disease, planning treatment, delivering treatment, andssessing response.

iagnosis of Disease● The role of diagnosis will continue to evolve, with bet-

ter, more-thorough screening programs establishing thepresence of disease at increasingly earlier stages with aconsequent shift in the stage profile at which diseasesare treated and greater focus on cancer survival issues.

● Diagnosis of disease will be based on a battery of imag-ing techniques and tests. The normal population will be

monitored by implanted electronic biosensor devices

that will signal early-onset disease to room-based mon-itors that will automatically contact a doctor through theInternet.38

● Three-dimensional imaging will become fully integratedinto the clinician’s armory. The doctor will order 3-di-mensional anatomic imaging, 3-dimensional functionalimaging (SPECT, PET, and magnetic resonance imag-ing), blood tests, and visual assessment and combinesuch information.

● Telemedicine will play an increasing role in diagnosis.Image data will be stored centrally and be accessiblefrom anywhere in the world. The doctor may call inter-nationally for opinion. Doctors may not even be local tothe patient’s residence or hospital but fully networkedthroughout the world.

● The prevailing climate will be dependent on knowledgeof organ function not just its attenuation of x-rays.

lanning Treatment● Treatment planning will become individualized, based

on the patient’s measured radiosensitivity and tissue re-sponse to radiation measured by using tissue assays andfunctional imaging.

● Functional imaging data will be merged with anatomicalimaging data. Sometimes the contours determined fromdifferent imaging modalities will conflict so intelligentrules (eg, fuzzy logic) must continue to be developed fordeciding the contour to use.

● Tissue contouring will be automatic with only minorintervention from humans to quality assure the resultsand to tune the contours.

● Contouring will be done for all important organs notjust the organs at risk. This will allow us to create adatabase of response.

● As with imaging, treatment will become multimodality,with competing plans with photons, electrons, protons,and heavy ions produced. These external radiations maybe combined with brachytherapy, radionuclides, andtargeted drug therapies. Treatment will be genuinelyindividualized, and class solutions will become a thingof the past.

● Multiple plans will be created by computer that will nota priori fix the treatment modality or beam parameters(number and orientation). Hence, as well as differentradiation modalities, plans will be made for a variety ofbeam number and orientation, coplanar and noncopla-nar. For all these situations, different cost functions willalso be tried.

● Planning will be fully 4-dimensional. Ideally, noninva-sive tomographic data will be collected regularly andoften throughout the treatment period and used for re-planning. Patients will be replanned at intervals throughtheir treatment after assessment of tumor change of ge-ometry or functional status. Gone will be the concept ofa “day 1 plan” used for each subsequent fraction. Planscould be changed throughout the treatment fractions to

respond to changing clinical conditions.

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Introduction 197

● Dose calculations will all be by Monte-Carlo methods.There will be no need for approximate analytical doseengines and all the dose terminology in use today.

● Dosimetric outcomes will be displayed in many newways and used to predict biological outcome. As ourunderstanding of the dose-volume effects of organs de-velops, treatment plans will be evaluated directly interms of likely treatment outcomes rather thandosimetry.

elivering Treatment● All treatment facilities will feature truly integrated imag-

ing feedback into the delivery process.● The default goal will be to correctly treat the moving

target. Margins will be a thing of the past.● Before all fractions of radiotherapy, 3-dimensional to-

mographic imaging will deliver information to reposi-tion the patient accommodating interfraction dailychanges. If patient translations are not sufficient for cor-rection and rotations have occurred, then suitable re-planning will take care of this.

● Some form of 4-dimensional imaging will take placecontinuously through all treatment fractions. Eithersome implanted marker will be monitored directly orsome external surrogate marker with its motion corre-lated to that of the internal organ. Strategies will bedeveloped to optimize the tradeoff between informationacquisition to guide treatment accuracy and extra imag-ing dose entailed.

● Radiotherapy delivery equipment will respond to theposition of the moving target intrafraction. Because itcannot do this instantaneously, intelligent predictorswill be used to point to the correct target location.

● Both C-arm and robotic linacs will be able to deliverIMRT at a much higher dose rate than at present. Flat-tening filters will be a thing of the past with their effectembodied in suitable fluence modulation. Robotic ra-diotherapy will also be spatially modulated. Possiblymultiple robots in the same room will be able to dosepaint the patient just as multiple robots work on carproduction lines.

● Every developed country will have at least one particleaccelerator facility based in a hospital to act as a nationalreferral center but also to make the assessment of thescientific need for such facilities less dependent on his-torical geographical location and national choices.

● As described under planning treatment, patients maywell be allocated to multiple modality treatment (pho-tons and heavy particles).

● Molecular genetics may combine with radiotherapy forsynergistic response. Concomitant therapy will take ona new meaning.

ssessing Response● All patients will have tissue samples taken to enable

treatment outcome to be related to biological mecha-

nism. 1

● All patient dose, treatment outcome, and tissue assaydata will be automatically stored in a central database forfuture recovery and analysis.

● Patients will fill in patient-specific symptom and re-sponse data via the Internet from home to an onlinedatabase.

● Symptom data and dose data will be brought together intrials databases to refine the biological models of out-come.

● Post-treatment data collection will be the standard rou-tine practice not the exception. Data will be coordinatedthrough international trials.

onclusionill this happen? And when? Skeptics will say this is over-

lown hope and hype. Yet, if one had asked a medical phys-cist in say 1940 to predict the situation in 2006, how manyould have foreseen the developments summarized earlier

hat are the subject of this issue? At that time, there were noomputers in medicine. Only the x-ray could give a roughdea of tumor location. Megavoltage x-rays were unheard of.rtificial isotopes were little used for imaging. Control ofotion equated to “stop motion (masks) or ignore motion

use margins).” Planning still used overlays of isodoses onelluloid sheets and mechanical adders with wheels and cogs.oday’s radiotherapy and its associated physical basis areost sophisticated and very well developed; 1940’s radio-

herapy has been swept away. Yet many problems are un-olved, and much protocol and technique has the smell ofvolution not revolution about it. Why should we overcher-sh the technology of today? In 2050, it should be signifi-antly different and the challenge is to work on what mayoday seem problems impossible to solve.

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