oncology || principles of radiation oncology

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Principles of RadiationOncology

Timothy J. Kinsella, Jason Sohn, and Barry Wessels

he medical specialty of radiation oncology has evolvedsignificantly over the past 50 years, having begun as asubspecialty within diagnostic radiology in the 1930s

and 1940s. Today, more than 50% of newly diagnosed cancerpatients receive radiation therapy, typically as a part of curative combined modality treatment with surgery and/orchemotherapy. Additionally, a majority of patients whopresent with metastatic disease or who develop metastasesfollowing initial cancer treatment require palliative radiationtherapy. As such, the radiation oncologist plays a major rolein the management of most adult cancers and certain groupsof pediatric and adolescent cancers. The intent of this chapteris to provide an overview of radiation biology, newerapproaches to radiation treatment planning, the use of specialized applications of radiation therapy, and the mecha-nisms of drug–radiation interactions leading to radiosensiti-zation, as well as the evolving area of targeted radiationtherapy. It is hoped that this overview provides the necessaryfundamental knowledge of radiation oncology for the reader (particularly nonradiation oncologists) to then betterunderstand the rationale for the use of radiation therapy inspecific cancers as detailed in other chapters throughout thistextbook.

The Biologic Basis of Radiation Oncology

The Concept of Therapeutic Ratio

Shortly after the turn of the last century, radiation therapybegan as a new modality for cancer treatment based on thediscovery of X-rays by Roentgen and radium by the Curies.The pioneering use of X-rays and radium in the first twodecades of the 20th century involved the use of large singledoses of radiation therapy delivered in short treatment inter-vals, which, although resulting in a reduction of the tumormass, was also associated with severe acute and late normaltissue toxicities. The concept of radiation dose fractionation(i.e., the use of smaller radiation doses given in multiple, typically daily, fractions) over several weeks evolved from anin vivo experiment in the 1920s using the testes of a rabbit asa model system for tumor proliferation.1 These early Frenchradiobiologists found that multiple radiation treatments com-pared to a large single dose of radiation resulted in sterility(the desired effect) without producing severe injury to the surrounding scrotum. The initial clinical use of radiation dosefractionation was then applied to patients with head and neck

cancers as early as the 1930s, with improved tumor responsesand reduced acute and late normal tissue toxicities.2,3 Thus,the concept of a therapeutic ratio or index for radiationtherapy was initially recognized more than 75 years ago.

The concept of the therapeutic ratio for radiation therapy,which compares the radiation dose–response curves for bothtumor control rates and normal tissue(s) complication rates,is illustrated in three separate panels in Figure 3.1. The upperpanel represents a theoretical optimal therapeutic ratio,where the tumor control curve lies always to the left of thenormal tissue complication curve, whereas the middle panelshows an unacceptable therapeutic ratio in which the tumorcontrol and normal tissue complication curves are reversed.Obviously, it would be easy to recommend the clinical use ofradiation therapy for this idealized situation depicted in theupper panel. Conversely, in the middle panel, the radiationoncologist would need to carefully weight the type (acute,late) and grade (severity) of expected normal tissue(s) compli-cations before recommending radiation therapy. Indeed, asillustrated in the section on radiation treatment planning(later in this chapter), the current use of three-dimensionalconformal radiation treatment (3-D CRT), intensity-modulated radiation treatment (IMRT) planning, and imageguided radiation therapy (IGRT) allows the radiation oncolo-gist to quantitate the dose–volume histograms for eachnormal tissue included in the treatment volume so as tochange an unacceptable therapeutic ratio (middle panel) tothe bottom panel in Figure 3.1, which is the most realisticgraph of tumor control and normal tissue injury as a functionof radiation dose as found in many clinical settings. In actu-ality, for most common solid cancers the curves are not par-allel, and the tumor control curve for most solid tumors isless steep than the normal tissue injury curves. Actualdose–response curves derived from in vivo experimental dataor from clinical trials in humans are often more variable thanthe illustration in the bottom panel of Figure 3.1, particularlydepending on the tumor type. Indeed, as is presented in otherchapters on specific tumor types throughout this textbook, itis only by carefully designed and controlled clinical trials thatthe concept of a therapeutic ratio for radiation therapy can bequantitated for a specific tumor type.

Radiation Interactions with Biologic Materials

Ionizing radiation deposits energy as it trasverses varioustypes of biologic materials or media (e.g., air, soft tissue, bone)within a human. The interaction of ionizing radiation with

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these biologics is a random process, with the frequency anddensity of energy deposition termed the linear energy trans-fer (LET). As human cells and tissues (as well as tumors) areprincipally considered to be dilute aqueous (water) solutionscontaining biomolecules, the localized but randomly distrib-uted energy depositions from ionizing radiation can haveeither direct effects on important biomolecules such as DNA

or indirect effects produced by intermediate radiation prod-ucts resulting from interactions with water, which consti-tutes up to 90% of a cell or tissue as calculated on a weightbasis. The most highly reactive species produced by the radi-olysis of water is the hydroxyl radical (•OH), although thereare many other types of free radicals produced by ionizingradiation, including DNA free radicals resulting from directionizations. These free radicals are generated within 10-2 to10-12 seconds and subsequently cause chemical damage toDNA. It has been determined that ionizing radiation-inducedcell killing in mammalian cells (including human tumorcells) results from a greater contribution (@70%) of initial indi-rect ionizing effects on water than direct effects on essentialbiomolecules, principally DNA. These ionizing radiation-produced free radicals are highly reactive chemically withinthe cell and undergo a cascade of reactions to either acquirenew electrons or to rid themselves of unpaired electrons, typ-ically resulting in breakage of chemical bonds in DNA in verylocalized areas, called clusters, or multiply damaged sites.Because DNA is considered to be the most essential cellularbiomolecule, the types of DNA damage caused by thissequence of initial energy deposition, production of free rad-icals and subsequent clustered breakage of chemical bondscan include DNA single-strand breaks (SSB), DNA double-strand breaks (DSB), DNA crosslinks, and DNA base damage.The creation of a DSB and, more specifically, an unrepairedDSB is considered the most cytotoxic DNA lesion resultingfrom ionizing radiation damage.4,5 The molecular and bio-chemical processes involved in ionizing radiation damage andrepair in human normal and malignant tissues are reviewedin the next section.

At the cellular level, the biologic effects of these initialphysical interactions of ionizing radiation with biologic mate-rials and the secondary chemical effects (i.e., DNA effects)can result in a cell’s loss of reproductive capability. Func-tionally, the consequence of this reproductive loss can resultin terminal differentiation, accelerated senescence, necrosis,or apoptosis.6,7 A cell that has been lethally damaged by ion-izing radiation may undergo a few cell divisions before death,and this lethally damaged cell’s progeny are also destined todie. In the radiation biology laboratory, the radiation sensi-tivity of a cell (both normal and malignant) can be quanti-tated by analysis of cell survival curves. A radiation survivalcurve plots the fraction of cells surviving on a log scaleagainst the radiation dose given (in cGy or Gy) on a linearscale (Figure 3.2). Survival is determined by the ability of acell to form a macroscopic colony, usually defined as morethan 50 cells (@5–6 cell divisions). A typical radiation survivalcurve for a mammalian cell population has an initial “shoul-der” in the low-dose region (up to 1–3Gy), followed by a ter-minal exponential slope. The importance of this exponentialrelation is that, for a given radiation dose increment, a con-stant proportion (not a constant number) of cells are killed byionizing radiation.6,7 The shoulder region indicates a reducedefficiency of cell killing or, conversely, a higher efficiency ofrepair of sublethal or potentially lethal ionizing radiationdamage. The resulting survival curve for mammalian cellsbased on a standard clonogenic survival assay is bestdescribed by a linear quadratic (LQ) model, according to thefollowing formula:

S e D D= - +( )a b 2

“Desirable” Probability of Tumor control

Normal TissueComplication Tumor Control

“Acceptable” Risk of Normal Tissue Complication

UnacceptableTherapeutic

Ratio

95%

50%

5%

40 60 80

Pro

babi

lity

of E

ffect

Total Dose (Gy)


Tumor Control

Normal Tissue Complication


AcceptableTherapeutic

Ratio

95%

50%

5%

40 60 80

Pro

babi

lity

of E

ffect

Total Dose (Gy)


Tumor Control Normal TissueComplication


OptimalTherapeutic

Ratio

95%

50%

5%

40 60 80

Pro

babi

lity

of E

ffect

Total Dose (Gy)

FIGURE 3.1. The concept of therapeutic ratio for radiation therapyunder conditions in which the relationship between the normaltissue tolerance and tumor control dose–response curves is optimal(upper panel), unacceptable (middle panel), and acceptable (lowerpanel).

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where S = surviving fraction, a = initial “repairable” radiationdamage, b = irrepairable radiation damage, and D = ionizingradiation dose measured in grays (Gy).

Interestingly, this two-parameter (a, b) exponential modelis reproduced when multiple fractions of ionizing radiationare given to either a normal or malignant cell population ifthe time interval between radiation doses (fractions) is suffi-cient to allow for initial radiation damage repair (usually 1–3hours). However, the differential effects of ionizing radiationon cell kill in a malignant versus a normal cell population arenot completely explained by this LQ model or any othermathematical model, as discussed later.

The discussion on radiation interactions at the cellularlevel so far has concerned sparsely ionizing radiation (lowLET), such as produced by photons or high-energy electronsthat are generated by linear accelerators used clinically formost cancers treated today. High linear energy transfer (high-LET) radiation can also be used clinically and involves the useof charged particles such as alpha particles and pi mesons.Additionally, intermediate-LET sources such as neutrons andprotons are also used clinically, with a recent resurgence ofinterest in proton radiation therapy in the United States andJapan.8,9 Because of these different LET radiation sources, theparameter of relative biologic effectiveness (RBE) is used inexperimental radiation biology and clinical radiation therapy.The RBE is the dose ratio of different LET sources to producethe same biologic effect. Typically, with high- or inter-mediate-LET radiation, the radiation survival curve has areduced or absent “shoulder” and a steeper exponential slope.The general explanation of the change in radiation survival(a, b parameters) with use of intermediate- to high- and inter-mediate-LET radiations compared to low-LET radiation isthat the ionizing energy deposition is so dense with high- andintermediate-LET radiations that the DNA damage cannot berepaired as efficiently. There may also be less effect from theoxygenation state of a cell or tissue with high LET. However,as discussed later, the advantage of intermediate- and high-LET radiations in the radiation survival curve may not beeasily translated to the clinic, as one must carefully weightthe RBE of the tumor and the RBE of normal tissues. Thus,the therapeutic gain for a specific tumor and specific dose-

limiting normal tissues may not be improved with high- orintermediate-LET radiation compared to low-LET radiation.Clinically, this is clearly the case for neutron beam irradia-tion, based on the past 20 years of human testing. As such,the recent renewed interest in proton beam irradiation shouldbe tempered until prospective clinical data are available forspecific patient groups in which proton beam treatments arecompared to the standard of use of photons from conventionallinear accelerators.9

Molecular and Cellular Radiation Biology

Repair of Ionizing Radiation Damage: Cellular and Molecular Mechanisms

As mentioned, ionizing radiation can cause a variety of lesionsthrough direct interactions with DNA or, more commonly,through damage induced in adjacent water molecules withina cell or adjacent cells. These damages to DNA include damageto the deoxyribose backbone, base damage, single-strandbreaks (SSBs), and double-strand breaks (DSBs).4 Because expo-sure to ionizing radiation was inevitable during evolution,human cells have developed multiple repair pathways tohandle the diverse types of DNA damage created by ionizingradiation.5 Understanding these complex and sometimesredundant repair pathways in human cells has been a majorfocus in radiation biology during the past 10 to 15 years thatwill continue in the future.10 These studies on radiation repairpathways also have many links to ionizing radiation effects onthe cell cycle, which is discussed later in this chapter.

Repair of Base Damage and DNASingle-Strand Breaks

Repair of ionizing radiation-induced base damage involves a sequence of biochemical processes termed base excisionrepair (BER). DNA single-strand breaks (SSBs) are one of themost common lesions occurring in human cells, either spon-taneously or as intermediates of enzymatic repair of basedamage during BER. In BER, a single damaged base or locallymultiply damaged bases are recognized and removed by spe-cific glycosylases, resulting in apurinic or apyrimidinic (AP)sites that require cleavage by an AP endonuclease, followedby resynthesis using the complementary strand as a template,and finally by ligation of the repaired strand.11,12 Ionizing radi-ation-induced DNA SSB repair is completed in steps similarto BER, in which a normal DNA strand serves as a templatefor repair. When DNA SSBs caused directly by ionizing radi-ation or arising as BER intermediates are not promptly andefficiently processed, the presence of clusters of damaged sitesand of stalled replication forks can then result in DSBs.4

The availability of cellular models characterized by defi-ciencies in specific DNA repair proteins have proved to begood models to clarify the molecular mechanisms underlyingBER and SSB repair.10 For example, it has been shown thattransfection of the human gene XRCC1 (X-ray repair cross-complementing gene 1) can correct mouse cells that have adeficiency in rejoining DNA SSB induced by ionizing radia-tion and alkylating agents. The XRCC1 protein acts as a scaf-folding protein, which binds tightly to at least three otherfactors involved in BER and DNA SSB repair mechanisms

a Cell Kill

b Cell Kill

(linear scale)

a/b Ratio

S = e–(aD + bD 2)

Dose (Gy)

Su

rviv

ing

Fra

ctio

n(lo

g sc

ale)

FIGURE 3.2. Log-linear illustration of in vitro radiation survival ofa typical human cancer cell line showing an initial shoulder (a cellkill) at lower doses (usually 1–2Gy) followed by a terminal slope (B-cell kill) at higher doses (≥3Gy).

including DNA ligase III, DNA polymerase b, and poly (ADP-ribose) polymerase (PARP).12 The importance of XRCC1 in theresponse of a human cell population to DNA damage has beenthe subject recently of several studies evaluating whetherpolymorphism of the human XRCC1 gene contributes sig-nificantly to an increased cancer risk in selected popula-tions.12 Indeed, a genetic change in a single amino acid atcodon 399 has been linked to an increased risk of several typesof gastrointestinal cancers (gastric, pancreatic, colorectal) aswell as breast cancer. Additionally, functional analysis ofthese polymorphisms suggest that these variants of XRCC1may contribute to a hypersensitivity to ionizing radiation.12

Repair of DNA Double-Strand Breaks

It is well recognized that the most important lesion causedby ionizing radiation is a DSB.4,5 Unrepaired or misrepairedDSBs can produce chromosomal deletions, translocations,and acentric/dicentric chromosomes, which result in celllethality or genetic instability. Unlike repair of DNA SSBwhere the complementary normal DNA strand serves as atemplate, DSB repair is a more complicated process and caninvolve homologous recombination (HR) or nonhomologousend joining (NHEJ). Typically, ionizing radiation inducesDNA DSBs where one or both DNA ends have a protrudingDNA single-strand overhang. It is known from genetic andbiochemical studies in radiosensitive yeast mutants that onlyone unrepaired (or misrepaired) DSB can result in cellularlethality.5,10 The induction of DSBs by ionizing radiationshows a linear function with dose whereas the kinetics ofunrepaired (unrejoined) DSBs has a linear quadratic (a, b) rela-tionship with dose.13 With low radiation doses, the quadraticcomponent is insignificant. Thus, the survival curve for aDSB repair-proficient cell would have an initial “shoulder” (acomponent) at low radiation doses followed by a terminalexponential slope (b component), as previously illustrated inFigure 3.2. In contrast, the “shoulder” region is normally notobserved in DSB repair-deficient cells, such as normal skinfibroblasts or normal lymphocytes from patients affectedwith the autosomal recessive disease ataxia telangiectasia(AT). DSB repair (including both HR and NHEJ) is presumablythe fundamental process that mechanistically explains thepreviously described cellular responses to ionizing radiationdamage termed sublethal damage repair (SLDR) and poten-tially lethal damage repair (PLDR).4 However, in spite ofnumerous attempts to define DSB repair and survival follow-ing ionizing radiation in mathematical terms (such as the LQmodel), other contributing factors such as cell-cycle check-points, hypoxia, genetic background diversity (polymor-phism), induction of apoptosis, and bystander effects (e.g.,autocrine or paracrine pathways) may significantly influencethe survival response of a cell or tissue (including normal andmalignant). These complex genetic and biochemical interac-tions are not easily simulated by mathematical modeling.

Homologous recombination (HR) is one of two majorrepair pathways in humans for repair of ionizing radiation-induced DSB. There are three general mechanisms for HR-mediated DSB repair.5,14,15 Two of the HR mechanisms,termed gene conversion and break-induced homology, requirehomology with a separate DNA molecule (Figure 3.3). Theother HR mechanism, single-strand annealing, requires onlylocal homology on one end of the DSB (Figure 3.4). All three

HR mechanisms require a 3¢-DNA single-strand overhang (3¢-PSS). During gene conversion and break-induced replication,3¢-PSSs are created on both ends of a DSB. One then annealsto a homologous region on a sister chromatid, a homologouschromosome, or elsewhere to other chromosomes. New DNAsynthesis is next initiated at the 3¢-ends and proceeds to the3¢-PSS on the other end of the DSB. At this point, HR canproceed in two different directions, including (a) a Hollidayjunction (gene conversion), which results from the 3¢-PSSannealing to the newly synthesized strand (Figure 3.3A), or (b)the replication fork proceeds until the end of the chromosomewithout encountering the other end of the DSB (break-induced replication; Figure 3.3B). The third HR mechanism,single-strand annealing, can be synthesis-dependent or

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Gene conversion withcrossing-over

Holliday junctionresolution

Break-induced replication

A B

FIGURE 3.3. Various pathways of homologous recombination (HR).After 3¢-Protruding DNA Single Strand (3¢-PSS) are created (arrow-heads), they invade a homologous region on another DNA molecule.Replication fork capture (A) results in the formation of a Hollidayjunction, with its subsequent resolution either with crossing-over(shown) or in the absence of cross-over events. When no replicationfork capture occurs (B), the recombination follows the break-inducedreplication pathway.

5¢

5¢

5¢

5¢ 5¢3¢

5¢ 3¢

5¢

5¢3¢3¢ PSS/3¢ PSS

3¢ 3¢

3¢

DNA ligase,mismatch repair

Endonuclease

Endonuclease (FEN-1)

FIGURE 3.4. Single-strand annealing repairs double-strand breaks(DSBs) that contain both ends having 3¢-PSS. Flap endonuclease (FEN-1) removes the misplaced DNA strand.

-independent (Figure 3.4). Both types of single-strand anneal-ing utilize local homology on the 3¢-PSSs of both ends of theDSB. Annealing of the two 3¢-PSSs results in a flap of onestrand with synthesis-independent annealing or in a gap withsynthesis-dependent annealing. The flap is subsequentlyremoved by a 3¢Æ5¢ exonuclease or a flap endonuclease whilea gap is filled by a DNA polymerase.

All three HR mechanisms require the gene products (pro-teins) of the RAD52 epistasis group (RAD50, 51, 52, 54, 57,58, and 59) as well as participation of the gene products.15 TheMre11 protein is thought to be a primary sensor of ionizingradiation induced DSB with subsequent recruitment of Rad50and Xrs2 proteins in yeast and the Nijmegen breakage syn-drome (Nbs1) protein in humans (Figure 3.5). The resultingcomplex of Mre11, Rad50, and Nbs1 is believed to generate3¢-PSS DNA lesions where several homologues of the yeastRAD51 gene (Figure 3.5) next interact with each other in acomplex process to facilitate DNA strand migration, inva-sion, and finally repair.

In contrast, nonhomologous end joining (NHEJ) recombi-national repair does not require extended homology betweenthe ends of a DSB. DSB rejoining can proceed with a limitednumber of base pairings at the site of the break. In humans,the complex of repair proteins for NHEJ involves Ku70, Ku80,DNA-dependent protein kinase catalytic subunit (DNAPKcs), DNA ligase IV, and X-ray cross-complementation(XRCC) 4. According to a current model (Figure 3.6), theKu70–Ku80 dimer initially binds to the ends of a DSB, andthis dimer acts as a helicase to result in local unwinding atthe DSB end.15 DNA PKcs is then recruited near the sites ofeach end of the DSB followed by the XRCC4/DNA ligase IVcomplex to repair DSBs created by restriction enzymes. NHEJcan be divided into several pathways, depending on the typeof DNA lesion detected. Rejoining of DNA DSB containingfour base pair complementary ends created by restrictionendonucleases is very efficient and precise. However, whenthe DSB ends are not complementary, repair is less efficientand may result in small insertions or deletions in the repairof noncomplementary (difficult) DSBs.

It is not clearly understood how human cells choose thepathway for DSB repair.10 Two models have been proposed to

explain how a cell might regulate whether HR or NHEJ path-ways are used following ionizing radiation-induced DSBs.According to the first model, NHEJ is the major pathwayactive during the G1 and early S phases of the cell cycle.16 Assister chromatids occur during late S and G2 phases, HR is themajor DSB repair pathway at these cell-cycle phases.5 Thesecond model involves a direct competition for DNA DSBends between the sensors of NHEJ and HR (see Figures 3.5,3.6). Evidence for the first model is derived from murine scidcells, which lack NHEJ but can repair DSBs during the G2

phase via HR pathways.17 Evidence for the second model isfound in human cells where the human Rad52 protein andthe Ku70–Ku80 protein complex have been shown to competeto protect DNA DSB ends against exonuclease activity.18

Additionally, the p53 tumor suppressor gene also appears toplay a role in a human cell decision between NHEJ and HRfollowing ionizing radiation damage.10 It has been shown thathuman cells lacking functional p53 (either by null mutationsor by mutant p53 expression) display up to 20-fold-higherrates of HR following ionizing radiation damage than cellsexpressing wild-type p53. Because p53 regulates the tran-scription and posttranslational activity of RAD51, it may bethat the Rad51 protein plays a pivotal role in channeling DSBrepair via the NHEJ pathway. Thus, these data suggest thatthe choice between NHEJ and HR is a function of cell-cyclephase, homologue availability, and the genetic background ofa cell (e.g., p53 status).

The consequences of incomplete or faulty DNA repair ofionizing radiation damage may result in carcinogenesis inhuman normal cells or in the development of ionizing radia-tion resistance in human tumor cells. A number of geneswhose products are involved in DSB repair have been foundmutated in many different human cancers. For example, lossof heterozygosity (LOH) of RAD51, RAD52, and RAD54 havebeen found in human breast carcinomas. Additionally, nearlytwo-thirds of human pancreas cancers have overexpression of


FIGURE 3.5. Proteins involved in the homologous recombination(HR) pathways of DSB repair: homology search and strand invasion.Taken from combined data obtained on yeast and vertebrate models.

FIGURE 3.6. A model for nonhomologous end joining (NHEJ)involving DNA-PK. The Ku80/Ku70 complex senses and binds toDSB ends and recruits DNA-PKcs. Ku-associated helicase activity(WRN in the presence of RP-A?) is activated, and the Ku-complexmigrates into the double helix with the Ku80 protein heading first inthe 5¢-direction of the broken end of DNA. It is speculated that,depending on the type of the DSB, either the XRCC4/DNA ligase IVcomplex or other proteins (i.e., nucleases and recombinases) arerecruited to aid in the rejoining of the four broken ends of DNA.

the Rad51 protein, which could lead to cellular resistance toionizing radiation damage and the development of tumor heterogeneity.

There is an ongoing search for new proteins responsiblefor ionizing radiation-induced DNA damage detection andrepair.10,15 During the past decade, several important DNArepair genes were discovered, mutations of which led todefects in DNA repair and extreme sensitivity to ionizingradiation. The X-ray cross-complementing (XRCC) geneswere identified in humans and subsequently nine geneticcomplementation groups were recognized. As mentioned previously, the product of the XRCC1 gene was found to beimportant for DNA SSB repair. XRCC2 and XRCC3 geneproducts are part of the RAD51 family and are essential forthe HR pathway in DNA DSB repair. XRCC4 to XRCC7 genesinitially appeared to be involved in the NHEJ pathway forDNA DSB repair and were later sequenced to reveal thatXRCC4 was DNA ligase IV, XRCC5 was Ku80, XRCC6 wasKu70, and XRCC7 was found to be DNA PKcs. Mutantswithin the XRCC8 complementation group show phenotypicsimilarities with ataxia telangiectasia (AT) and the Nijmegenbreakage syndrome (NBS) with extreme sensitivity to ioniz-ing radiation and to topoisomerase 1 inhibitors. Finally, theXRCC9 gene (also called Fanconi anemia G group) showsmarked sensitivity to ionizing radiation and DNA crosslink-ing agents as well as spontaneous chromosome instability.

During the past few years, the RAD24 gene groupmembers were identified to also include RAD9, RAD17,MEC3, and DDC1 genes. The products of this RAD24 epistaxis group appear to have regulatory roles that connectionizing radiation-induced DNA repair and cell-cycle pro-gression. It is also recognized that products of the tumor sup-pressor genes such as BRCA1, ATM, and p53 interact withRAD50 and RAD51 gene products to complete the complexprocess of DNA DSB damage recognition and repair.

Clearly, the field of DNA DSB repair is complex and is anarea of intense research for the discipline of radiation oncol-ogy.5,10,15 Although our knowledge of these complex inter-actions leading to DNA DSB repair is probably still quiterudimentary, translational radiation biologists/oncologistsare beginning to explore how some of these genes or proteinproducts might be therapeutic targets for modifying the ion-izing radiation response in resistant human cancers. Thesetranslational approaches to novel “targeted” therapy in radi-ation oncology are discussed later in this chapter. The effectson ionizing radiation damage and repair on cell-cycle check-points are described in the next subsection.

Ionizing Radiation Effects on the Cell Cycle

It has been known for several decades that ionizing radiationleads to a prolongation of the cell cycle and can result in an arrest in the G1, G2, and S phases.7,19,20 Because ionizingradiation causes a variety of DNA damage, it was initiallyinferred that these cell-cycle arrests (now called checkpoints)were essential for the repair of these different types of DNAdamage. However, over the past 10 to 15 years, the biology ofthe cell cycle has become better understood as a complex butfinely regulated process involving many factors, particularlythe cyclins and cyclin-dependent kinases (CDKs).19 Progres-sion through the cell cycle is promoted by a number of CDKsthat are complexed with specific regulatory proteins called

cyclins, and these complexes drive the cell cycle. Addition-ally, there are a corresponding number of cell-cycle inhibitoryproteins (CDKIs), which serve as negative regulators of thecell cycle. To date, at least nine structurally related CDKshave been identified along with more than 20 cyclins. The CDK–cyclin complexes themselves are activated byphosphorylation at specific sites, although not all theseCDK–cyclin complexes have clearly defined cell-cycle regu-latory roles. It is also now recognized that the G0 phase is not a “quiescent” phase as initially termed. Indeed, cellulargrowth functions occur during G0, and subsequent entry fromG0 into the cell cycle (G1) is tightly regulated at the restric-tion point. This point is thought to divide the early and lateG1 phase of the cell cycle. A current model of the human cellcycle and the major cyclins, CDKs, and CDKIs is depicted inFigure 3.7.

The arrest of cells at the G1 checkpoint following ioniz-ing radiation damage is best understood at the present time.The retinoblastoma tumor suppressor gene product (Rb)governs the G1–S phase transition.21 In its active state, Rb ishypophosphorylated and forms an inhibitory complex withthe E2F transcription factors. The activity of Rb is modulatedby the sequential phosphorylation by CDK 4/6–cyclin D andCDK2–cyclin E. An ionizing radiation-induced G1 arrestresults from a specific CDKI, p21waf1/cip1, which prevents keyevents such as the phosphorylation of RB and activation ofE2F transcription factors. Importantly, p21waf1 is induced atthe transcriptional level by wild-type p53, which accumulatesin irradiated cells and causes a cell-cycle arrest in both G1 andG2.22,23 While the p53-mediated G1 arrest is primarily due to the induction of p21, a p53-mediated G2 arrest involvesinduction of both p21 and 14-3-3 s, a protein that normallysequesters cyclin B–Cdc2 complexes in the nucleus.

Following recovery of a G1 checkpoint, cyclin E binds toCDK2, and this active complex completely hyperphosphory-lates Rb (pRb), which releases the E2F complex and fully acti-vates the E2F transcription factors.24 The irradiated cell thenproceeds into S-phase transcription of a range of targetsinvolved in chemotherapy-based radiosensitization. Thesedrug–radiation targets include ribonucleotide reductase (RR),thymidylate synthase (TS), and thymidine kinase (TK). Theinteractions of radiosensitizing drugs such as RR inhibitors(gemcitabine, hydroxyurea) and TS inhibitors (fluoropyrim-idines), as well as drugs activated by TK (fluoropyrimidines,halogenated pyrimidine analogues), are used clinically toenhance radiation cytotoxicity. These drug–radiation combi-nations are discussed later in this chapter (see followingsection on Mechanisms of Interaction with ConventionalChemotherapy).

Early in S phase, cyclins D and E are targeted by ubiqui-tination for proteasome degradation. The production of cyclinA and the subsequent complex of cyclin A–CDK2 enables S-phase progression, with the production of other enzymesand proteins involved in DNA synthesis, including histones and proliferating cell nuclear antigen (PCNA). Ionizing radia-tion can also induce an S-phase (or replication) checkpoint,which involves activation of ataxia telangiectasia mutated(ATM) and ATM and Rad-3 related (ATR) kinases with sub-sequent activation of Chk1 and Chk2.25 The phosphorylation(activation) of Chk1 and Chk2 inhibits phorylation of Cdc2and blocks progression into G2 and entry into mitosis (Mphase).

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A clear understanding of the role of the G2 checkpoints toionizing radiation damage and repair is lacking at the presenttime.26 From genetic studies in yeast using Saccharomycescerevisiae, the RAD9, RAD17, RAD24, and MEC3 genes arerequired for a G2 arrest. In human cells, the DNA mismatchrepair proteins MLH1 and MSH2 also appear to play a role inthe G2 arrest following ionizing radiation damage.27 Based onthe dramatic increase in our understanding of ionizing radia-tion effects on G1 and S-phase checkpoints over the past fewyears, it is anticipated that the signaling pathways for recog-nition of ionizing radiation damage during G2 and M will bebetter understood in the near future.19

Ionizing Radiation-Induced Apoptosis

It is well established that a principal mechanism of cell deathfollowing ionizing radiation damage involves necrosis.6,7

More recently, radiation research has also focused on apopto-sis as an alternative cell death mechanism following ionizingradiation.6,7 Apoptosis is an active, energy-dependent processin which the cell participates in its own destruction (i.e., programmed cell death).28 Apoptosis is characterized mor-phologically by cell shrinkage, cell membrane blebbing, chro-matin condensation, and finally by fragmentation intoapoptotic bodies. The molecular sequence or cascade of apo-ptosis involves the early release of cytochrome C from mito-chondria, activation of an apoptotic protease-activating factor(Apaf-1), activation of caspase 9, and subsequent cleavage ofdownstream (effector) caspases in a self-amplifying cascade.The apoptotic cascade degrades several essential cellular proteins including b-actin, laminin, and polyadenosine 5¢-diphosphate-ribosyl polymerase (PARP).29 This cascade is regulated by members of the Bcl-2 family of proteins, which are either antiapoptotic (Bcl-2, Bcl-xL, Bcl-W) orproapoptotic (BAD, Bax, Bak).28,29 Bcl-2 or Bcl-xL proteins bind and inhibit Apaf-1, which prevents the activation of caspases. However, in the presence of excess Bax, Bcl-2 maybe displaced from Apaf-1, allowing caspase cleavage and activation.

The effects of ionizing radiation on apoptosis and cell-cycle arrests are interrelated, as evidenced by the central roleof p53.30 In addition to the effects of ionizing radiation-induced p53 protein expression on both the G1 arrest and G2 arrest as detailed in the prior section, p53 is also criticalin the induction of apoptosis. For example, human tumorcells with certain mutations in the p53 gene are resistant toundergoing apoptosis following ionizing radiation. Anotherexample of this interrelationship of cell-cycle arrest and apo-ptosis following ionizing radiation damage is demonstrated inisogenic human colon cancer cell lines that differ only in theirp21 protein status. Wild-type p21 cells undergo a G1 and G2

cell-cycle arrest with enhanced clonogenic survival followingionizing radiation, whereas cells lacking the p21 protein donot undergo these cell-cycle arrests and proceed to apoptosis.

Ionizing Radiation Interaction with Oxygen

It has long been recognized that cellular and tissue oxygena-tion is a major determinant of radiosensitivity.31,32 For severaldecades, oxygen was considered to be a radiation dose modi-fier as in vitro/in vivo radiobiology data suggested that theoxygen enhancement ratio (OER) is 2.5–3.0 for low-LET radiation (X-rays, photons) and 1.5–2.0 for intermediate-LETradiation (protons). More recently, experimental and limitedclinical data suggest that the OER for both low- and inter-mediate-LET radiation are lower at lower doses typically useddaily in treating human cancers. Although the underlyingmechanism of the oxygen-modifying effect is not exactlyknown, the leading model suggests that cellular oxygen actsas a radiosensitizer by forming radicals such as peroxides inDNA, resulting in a fixation or persistence of ionizing radia-tion (IR) damage.

It is now known that two different forms of hypoxia existin human cancers. Chronic hypoxia results from a tumor out-growth of its blood supply, and variable levels or gradients ofchronically low oxygen tension exist beyond the physiologicdiffusion distance of oxygen through the interstitial (extra-vascular) tissue compartment.33 It is hypothesized that these


FIGURE 3.7. Current model of the cell cycle.The cell cycle is regulated by cyclins, cyclin-dependent kinases (CDKs), and cyclin-depen-dent kinase inhibitors (CDKIs). The cell cycleis divided into four distinct phases: G1, S, G2,and M. G0 represents exit from the cell cycle inwhich the cell performs its routine functions,including the important function of cellgrowth. The progression of cell through the cellcycle is driven by CDKs, which are positivelyand negatively regulated by cyclins and CDKIs,respectively. The resection point governs thetransition point beyond which a cell’s progres-sion through the cell cycle is independent ofexternal stimuli.

chronic hypoxic tumor areas (volumes) contain clonogenicand radioresistant hypoxic tumor cells. It is also recognizedthat reoxygenation of these chronically hypoxic tumor cellscan occur, at least experimentally.33,34 A second type of tumorhypoxia also exists and is termed acute or perfusion-limitedhypoxia. Acute tumor hypoxia results from transient alter-ations in tumor vasculature.34

Over the past decade, several clinical studies have demon-strated that hypoxic tissue (defined as areas of oxygen tensionless than 2.5mmHg) exist in up to 50% to 60% of a widerange of locally advanced solid tumors including primarybrain tumors, soft tissue sarcomas, and melanoma as well ascarcinomas of the breast, head and neck, pancreas, andcervix.35 Although trials of several hypoxic radiosensitizershave been negative, it is now realized that proper patient(tumor) selection was not performed in the design of thesetrials.36 Current trials such as the accelerated radiotherapy,carbogen, and nicotinamide (ARCON) trials in Europe, par-ticularly in head and neck cancer and bladder cancers, areselecting patients with biochemically confirmed hypoxictumors for testing this approach.37

Hypoxia also causes altered gene expression in humantumors with associated changes in tumor microenvironment.The best characterized transcription factor is hypoxia-inducible factor 1 (HIF-1).38 The changes in gene expressionin hypoxic tumors are similar to changes in normal cells toadapt to a hypoxic stress such as trauma and subsequentwound healing. However, these hypoxia-regulated genes,when upregulated in human tumors, lead to resistance notonly to radiation therapy but also to different types of

chemotherapy.39 The clinical targeting of HIF-1a to selec-tively kill or inhibit hypoxic tumor cells is now in early trials using drugs such as radamycin.39 The advantage of targeting HIF-1 is the observed rapid response to changes in oxygenation, making it a good target for both acute and chronic hypoxic tumor cells. Such new targetedapproaches in radiation oncology are discussed later in thischapter.

Radiation Treatment Planning

Three-Dimensional Conformal Radiation Therapy

Since computers were used for single plane treatment plan-ning in the 1970s to 1980s, treatment planning systems havebecome further developed along with advances in computerhardware. These dramatic increases in computing power haveallowed multiplane treatment planning to become practical.Once the planning systems became capable of handling largeamounts of computed tomography (CT)-derived patient data,calculation algorithms were developed to account for the fullscattering component of radiation transport in various humantissues.

The development of accurate three-dimensional dose cal-culations and 3-D rendering of patient anatomy provided thetool to sculpt a tumoricidal dose distribution conformed to atumor (target) volume and to minimize dose to all othernormal tissue (Figure 3.8). From these considerations, theterm 3-D conformal radiation therapy (3-D CRT) gained rapid

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FIGURE 3.8. A tumor in the pancreas wastreated with three-dimensional (3-D) conformalradiation therapy (CRT). Organs spared werekidneys, liver, spinal cord, and small bowel.Five noncoplanar beams were used for treat-ment. Each beam was conformed to the targetvolume with multileaf collimator as shownabove to maximize the conformity. Three-dimensional rendering can assist the planner tooptimize the beam angle.


FIGURE 3.9. International Commission on Radiation Units andMeasurements (ICRU) reports 50 and 62 introduced the volume definitions for radiation therapy treatment planning (see References41, 42). Outer ring, block aperture; second from outer ring, planningtarget volume; third ring, clinical target volume; inside ring, grosstarget volume.

utility and acceptance.40 Once dose could be highly conformedto the target volume, the margin of the target had to be moreaccurately determined; this has been accomplished by usingmultimodality imaging and carefully defining treatment andnormal treatment volumes. The International Commissionon Radiation Units and Measurements (ICRU) Reports 50 and 62 introduced the definition of volumes (Figure 3.9).41,42

The gross target volume (GTV) is defined as the clinically palpable volume or, more typically, as visualized by imaging.It may consist of the primary tumor, metastatic lymph-adenopathy, and local tumor extension. The clinical targetvolume (CTV) includes the tissue surrounding the GTV thatmight have microscopic malignant disease or “at-risk”regional lymph nodes. More than one CTV can be defined.The planning target volume (PTV) includes GTV and/or CTVplus a margin to account for variations in treatment delivery,including variations in treatment setup, patient motionduring treatment, and organ motion. These ICRU reports alsoreviewed the definition of normal organs to be spared. Organsat risk (OAR) are defined as critical normal tissues, such asthe spinal cord, whose radiation sensitivity may significantlyinfluence treatment planning and/or the prescribed dose.After planning has been performed, a dose–volume histogram(DVH) can be generated from the plan (Figure 3.10). The DVHprovides the information: dose versus volume of a specifiedorgan. This information is very useful for radiobiologicstudies. However, it does not provide spatial dose informa-

FIGURE 3.10. Three-dimensional treatment planning provided a tool for analyzing dose distribution in various organs interested. This toolis very useful in the analysis of the biologic consequences of the optimized irradiation.

tion. It can be used to complement the graphic isodose dis-plays used in treatment planning by comparing the amountof dose given to specified organ volume. High dose confor-mity can enable the radiation oncologist to seek dose escala-tion to the target volume for possibly better radiobiologicadvantages and an improved therapeutic gain, as previouslydescribed in Figure 3.1.

Intensity-Modulated Radiation Therapy

Three-dimensional CRT is used to optimize the radiationdelivery to irregularly shaped volumes by manually settingindividual beam angles. Intensity-modulated radiationtherapy (IMRT) is a new approach to 3-D CRT. Clinical defi-nition of complex treatment volumes often requires concavedose distributions. IMRT has been found to be most useful inthis regard.43 Radiation dose delivery to a target volume byIMRT is performed by the superposition of multiple “beam-lets” from each treatment angle. Full dose uniformity isachieved by the summation of individual beams of small fieldsize where the central axis is frequently blocked by complexmultileaf collimator (MLC) patterns. The dose is figurativelypainted in by discrete amounts wherever needed to maintaindose uniformity in a defined volume. Typically, in the opti-mization process using IMRT for radiation dose delivery, therelevant physical and geometric information of the irradiatedobject and radiation source serve as input data. Then, dosedistribution may be calculated using the input data forvolumes that have specific geometric characteristics. Thisdose calculation is known as a forward treatment planningprocess. However, an inverse treatment planning process isused to create IMRT plans. The inverse planning processessentially starts with a precise prescription of the goals of anideal plan, and the planning system optimizes input data tomeet these conditions. In addition to the availability of thephysical parameters of the irradiated object (tumor volume),the relevant information about the capabilities and specifica-tions of the available treatment machine may be inserted intothe planning system. After the physician prescribes thedesired doses to the different volumes including GTV, PTV,and adjacent dose-limiting normal tissues, the inverse plan-ning system provides a delivery method to execute the pre-scription accurately with a specific treatment machine. Theresultant computerized solutions appear as radiation intensi-ties from the sources as a function of source location, whichresults in a dose function that is used in the delivery of tar-geted irradiation.

As shown in Figure 3.11, this head and neck treatmentplan provides a sample of IMRT inverse planning process. Thisspecific case shows a target volume for a patient with a base-of-tongue primary cancer where the GTV has been outlinedand resulting in a corresponding PTV with expanded marginsgenerated around it. The PTV has been prescribed to a uniformdose distribution of 7,200cGy. Regional “at-risk” lymphnodes are also treated to the minimum dose of 5,400cGy.Here, there are unique features of IMRT compared to the con-ventional radiation therapy, in that the IMRT can deliver dif-ferent doses to multiple targets simultaneously. This methodmay eliminate the necessity of boost plans to deliver differentdoses to multiple targets. The fractional doses per day to phys-ically defined target volumes can be made to vary. The dailydoses should be selected carefully in view of the radiobiologic

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consideration. Most clinical experience is based on the samefractional doses, although total doses specific to multipletarget sites and critical structures may be different.

Critical normal tissues such as the spinal cord and rightparotid can be “spared” (see Figure 3.11) to doses of 4,300 and 2,200cGy, which should result in no significant late toxicities. Once all objectives are determined, the inversetreatment planning system is able to optimize the dose dis-tributions that satisfy the initial objectives. Most planningsystems have used an intermediate step before giving a deliv-erable plan with a delivery machine. This intermediate stepprovides users with several options: which treatment deliv-ery machine is being selected, how many intensity levels areto be used, and what is the basic prescription of multiplebeam directions (gantry angles).

Current IMRT delivery methods have been implementedby MLCs installed on conventional linear accelerators,tomotherapy, and physical beam modulators.44 Multileaf col-limators include conventional MLCs that accompany theinstallation on most modern linear accelerators and specifi-cally designed MLCs which have been attached to the gantryfor IMRT use. There are two methods used for deliveringmodulated beams using MLCs: step-and-shoot and slidingwindow techniques.44 The step-and-shoot method deliversdose to the target by a series of small beams. At each gantryangle, MLCs constantly form a series of segments to delivera modulated beam. During the time of MLC movementsbetween segments, the radiation beams are cycled to an offposition automatically by the programmed accelerator soft-ware without further human interaction. However, thesliding window technique starts with all leaves closed fromone side of a radiation field and opens the leaves in a dynamicpattern. The speed of each pair of leaves depends on the doseintensity desired. The radiation beams are continually onduring the MLC movement.

Image-Guided Radiation Therapy

In the past, large target margins and treatment volume wereused to accommodate the positioning error and organ motionassociated with radiation therapy treatment. Because highlyconformal radiation therapy can now be delivered, accuratetarget determinations (i.e., CTV, GTV, PTV) have become avery important issue. Various image modalities can nowguide highly conformal therapy such as IMRT by locating thetarget before daily fractionated radiation therapy. Ultrasoundimaging is often used for internal target positioning, mostlyfor localized prostate cancers.45 However, because the ultra-sound cannot penetrate air or bone, its use is limited tocertain anatomic sites. Additionally, ultrasound, similar toCT, does not provide any functional information on tumorbiology.

Traditionally, the determination of tumor volumes forradiation treatment planning, as well as determiningresponses following radiation therapy, has been limited toimaging techniques such as CT and magnetic resonanceimaging (MRI) scanning. Based on these scanning techniques,we now can deliver higher radiation doses using 3-D CRT andIMRT techniques in certain situations such as localizedprostate cancer46 and head and neck cancers,47 which trans-late into improved local tumor control and survival. With the

clinical development of positron emission tomography (PET),single-photon emission computed tomography (SPECT), andmagnetic resonance spectroscopy (MRS), radiation oncolo-gists are attempting to integrate these function imaging tech-niques into radiation treatment planning. This evolving fieldof image-guided radiation therapy (IGRT) holds the potentialto radically alter the way radiation therapy is used to treatcancer over the next decade. A comprehensive overview wasrecently published.48

Specialized Applications of Radiation Therapy

Systemic Radiation Therapy

Targeted radiation therapy combines principles of systemicand local therapy. Advantages of these approaches are to treatdisease in multiple locations and to target microscopic sub-clinical disease. The rate of the uptake and retention of

radioactivity to kill tumor cells relative to that of the normaltissues determines the efficiency of this treatment approach.

Systemic radiation therapy can be categorized into twoforms: radioimmunotherapy and systemic unsealed radiationtherapy.49,50 Radioimmunotherapy uses antibodies, antibodyfragments, or compounds as carriers to guide radiation to thetarget(s). The systemic unsealed radiation therapy can beadministered by intravenous, oral, intratumoral, peritoneal,or intrathecal routes. These approaches are intended to con-centrate the radioactivity into the target(s) and to deliver atherapeutic radiation dose. The applications of radioim-munotherapy are currently under way to treat lymphomas,leukemias, and some solid tumors with 131I, 90Y, 153Lu, 186Re,and several alpha-emitting radionuclides.49 Other forms ofsystemic radiation therapy often use electron-emittingradioactive material. The most typical treatments using 131I,89Sr, 32P, and 153Sm are for hyperthyroidism, differentiatedthyroid cancer, painful skeletal metastases, polycythemiavera, malignant cysts, and neuroendocrine tumors.50 These


FIGURE 3.11. The orthogonal images for a head and neck cancershow the dose distribution from an intensity-modulated radiationtreatment (IMRT) plan with nine beams at equally spaced gantry

angles. Markedly reduced doses to the spinal cord (4,300cGy) and theright parotid (2,200cGy) are noted, while delivering 7,200cGy to theprimary tumor and 5,400cGy to the at-risk lymph nodes.

treatments are usually well tolerated without causing long-term effects, such as cancer or infertility. Several ongoing andnew initiatives to explore the use of targeted therapy to beused as conditioning regimens for bone marrow transplantinstead of nonspecific total-body irradiation show strongpotential for reducing the side effects associated with thetransplant process.51

Brachytherapy

Brachytherapy is the clinical procedure that inserts smallencapsulated radioactive sources into the treatment (tumor)volume. Radioactive sources are continuously irradiating thetreatment volume by an exponentially decaying dose rate.From each source, the therapeutic range is usually in the mil-limeter (mm) to centimeter (cm) range. Therefore, it providesa superior localization of dose to the tumor volume comparedto the conventional external radiation therapy. There are two different methods in brachytherapy: an intracavitaryapproach where radioactive sources are implanted in bodycavities in close proximity of the treatment volume, and aninterstitial approach in which the sources are directlyimplanted in the treatment volume. Typically, the intracavi-tary implant is temporary. On the other hand, interstitialimplant can be temporary or permanent. Most gynecologictumors have been treated with brachytherapy using long-lived 137Ce sources.52 Recently, more brachytherapeutic appli-cations to other anatomic sites have been introduced. Thesenew applications include prostate seed implant for localizedprostate cancers, intravascular irradiation to prevent coronaryartery restenosis, and “mammo-site” breast irradiation asbriefly discussed next.

Palladium-103 and 125I seeds are used for the prostate seedimplant procedure.53,54 Accurate seed placement within theprostate, the most important task, is achieved by using trans-rectal ultrasonography, which provides accuracy and preci-sion. The treatment procedure requires extensive treatmentplanning to localize each source and produce a combined plan for all sources. There are usually two steps to completethe treatment planning process for permanent seed implants:preplanning the target volume and intraoperative planning.Preplanning is performed with ultrasound images acquiredbefore the surgery. Based on this plan, the strength of theseeds to be ordered, the number, and proposed seed placementmay be preplanned. The premise of intraoperative planning isthat preplanning is not necessary. All planning can be donein the operating room with real-time images. Advantages ofthe preplanning approach include: preevaluation of whetherthis treatment can be deliverable, more planning time tooptimize the seed placement for ideal dose distribution, andminimization of ordering unnecessary seeds. The dosimetricgoals of prostate cancer implant therapy are to deliver suffi-cient dose to the prostate and to spare the rectum, bladder,and other adjacent critical structures. These goals areachieved with optimizing the strength and the number ofseeds.54

Intravascular brachytherapy has been introduced to treatcoronary restenosis.55,56 After a percutaneous coronary trans-luminal angioplasty (PCTA) is performed to reopen the block-age within the coronary artery, a radioactive source (192Ir, 125I,90Sr, or 32P) may be positioned in the area of the restenosis.Depending on the selection of radioactive source, the treat-

ment time varies from 3 to 25 minutes.55 Due to the presenceof the radiation-delivering catheter, minimizing the treatmenttime to restore maximum blood flow is a factor for consider-ation of source selection as well as other factors; other factorsinclude the dose distribution in inhomogeneous tissue (calci-fied plaque versus normal tissue), and the artery diameter.56

Mammo-site brachytherapy is considered as an alterna-tive to a standard 5-week external radiation therapy coursefor breast cancers.57,58 This procedure shortens the treatmenttime to just 5 days. A specific device has been designed forthis procedure, consisting of a hollow catheter to which aninflatable balloon is attached. It is temporarily implanted into the lumpectomy site. Beads of radioactive iridium areinserted into the catheter within the inflated balloon, whichhelps the catheter to be centered so that the dose can be uni-formly delivered to the lumpectomy surface. The actual treat-ment takes typically two 15-minute sessions per day for 5days. The catheter stays in place over the entire course oftreatment. The preliminary clinical results with respect tolocal control and breast cosmesis are encouraging.58

Intraoperative Radiotherapy

Intraoperative radiation therapy (IORT) delivers a large singledose of 10 to 20Gy to a tumor bed following surgical resec-tion, during which the normal organs are physically movedout of the pathway of the radiation beam.59 Intraoperativeradiation therapy using X-ray beams was first described morethan 80 years ago. However, refinements in techniques forIORT delivery and the generation of relevant large animal andhuman data on normal tissue tolerances to these large singledoses of radiation therapy have ushered in a modern era forIORT.60,61 It is now widely used for abdominal, pelvic, andretroperitoneal carcinomas and sarcomas as well as for somethoracic malignancies, extremity sarcomas, and head andneck cancers. The clinical experience to these tumor sitesfrom large cancer centers throughout the world was recentlysummarized.62 Linear accelerators designed for external radi-ation therapy have been adapted to deliver electron beamswith IORT applicators, which collimate the electron beamsaccording to the size and the slope of the treating area.Presently, dedicated mobile IORT machines are also used.These machines generate electron beams only. Therefore,shielding issues are minimal, and the machines are designedto be suitable for use in regular operating rooms.

Stereotactic Radiation Therapy

Stereotactic radiosurgery has been used worldwide as aprimary or secondary procedure to treat both malignant andbenign tumors. Typically, patients with brain metastases aretreated following delivery of whole-brain irradiation.63,64 Theclinical results including appropriate patient selection arediscussed in detail in the chapter on Brain Metastases. Thetarget (tumor) volumes for this procedure are small, typicallyless than 30cm3 (less than 4cm diameter). To achieve thisgoal, intracranial stereotactic positioning systems aredesigned to achieve accurate target localization and have alsoenabled effective nonsurgical treatment of arteriovenous mal-formations, acoustic neuromas, and primary brain tumors, inaddition to brain metastases.

Stereotactic radiation therapy to well-defined intracraniallesions can be performed in single or multiple fractions. The

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type of tumor can determine the choice of fractionation.63,64

Most centers perform radiosurgery on an outpatient basis.Treatment process starts with the fixation of a stereotacticframe on the patient’s skull. Light sedation and local anes-thetic applied before frame fixation are adequate for thepatient’s comfort throughout the treatment day. The patient with the frame goes through contrast-enhanced CTand/or MRI imaging with thin serial cuts (1–2mm thick) takenin the region of the tumor. These scans are imported into atreatment planning software, where image segmentation isperformed for volumetric evaluation and three-dimensionalreconstruction.

There are two approaches for stereotactic radiosurgery:linear accelerator based and the gamma knife. With the firstapproach, tertiary micro-multileaf collimator and circularcones have been developed and adapted to a standard linearaccelerator where 6MV photons are typically used. The conesizes for linear-based stereotactic radiosurgery range from 0.5to 3.5cm. The second technical approach to stereotacticradiosurgery uses the gamma knife (Elekta). This machineuses 201 cobalt sources (60Co) and collimates the radiationbeams using specially designed cranial helmets with 201 aper-tures and four different diameters (4, 8, 14, and 18mm). Thetreatment is delivered with a combination of these helmetsto conform the radiation distribution.

Whether a linear accelerator or a gamma knife is used, theradiation beams are arranged to intersect at a common pointwithin the brain. The beam intersection volume is deter-mined by the collimation system selected to encompass thetarget, and this produces a high-dose falloff just outside the intersection volume. Therefore, precise determination ofthe target volume is very important to deliver effective dosesto the tumor(s). Noncoplanar arc beams are often used withlinear accelerator-based stereotactic radiosurgery compared tostationary beams with the gamma knife.

Heavy Charged Particle Radiation Therapy

Heavy charged particles have two distinct characteristicscompared to photons or electrons.8 Dose distributions arehighly localized, and the shallow depth sparing effect is significant due to the domination of the Bragg peak. Thisshallow depth sparing is much more significant than high-energy photons generated by linear accelerators. Additionally,the depth dose after the Bragg peak diminishes nearly to zero.As the Bragg peak depth depends on the incident energy,varying the energy of the primary beam can easily modulatethe maximum dose depth. In addition to the advantage indepth dose distribution, the lateral dose gradient is significantat the beam edge.

As previously discussed, heavy charged particles also havea higher radiobiological effectiveness (RBE) and lower oxygenenhancement ratio (OER) because of higher linear energytransfer (LET). These factors may provide more radiobiologicadvantages in addition to the physics described above.Recently, isocentrically mounted proton therapy machinesare emerging as a competitive radiation therapy modality, asdose conformality has become more of a central issue.8,9 It ispossible that the new, clinically oriented proton therapymachines can deliver conformal radiation to the target thatwill be superior to the current IMRT methods using linear

accelerators. However, carefully designed clinical trials areneeded to evaluate these potential advantages to proton beamradiation therapy. For small targets, gamma knife irradiationwith full frame immobilization represents the current “goldstandard” by which other irradiation modalities are to bemeasured and compared.

Drug–Radiation Interactions and NewApproaches to “Targeted” Radiation Therapy

Mechanisms of Interaction with Conventional Chemotherapy

The concomitant use of conventional chemotherapy agentssuch as the fluoropyrimidines and the platinum analoguesduring radiation therapy is the standard of care for neoadju-vant, postoperative adjuvant and definitive therapy in thetreatment of locally advanced cancers of the head and neck,lung, and throughout the gastrointestinal tract, includingesophageal, gastric, pancreas, rectal, and anal cancers. Theresults of various Phase 3 clinical trials of concomitant com-bined modality therapy using these drugs are reviewedthroughout this textbook under the disease-specific sites.Indeed, the success of these concomitant combined modalitytreatments for the locally advanced cancers is probably themost significant advances in cancer therapy during the past 10 to 15 years.65–67 Surprisingly, in spite of such success,the cellular and molecular mechanisms of interaction result-ing in tumor radiosensitization remain poorly understood.Although an in-depth review of our current understanding of the greater than additive interactions of conventionalchemotherapy drugs is beyond the scope of the chapter, the reader is referred to three recent reviews.65–67 A briefoverview of these drug–radiation interactions is summarizedas follows.

5-Fluorouracil (5-FU) is clearly the most commonly useddrug as a radiosensitizer, with the principal mechanism ofsensitization related to inhibition of thymidylate synthase(TS) with subsequent progression through the G1 checkpoint(restriction point) into S phase with altered (perturbed)triphosphate pools and reduced DNA repair.68 As such,tumors with high levels (overexpression) of TS, which areknown to be clinically resistant to 5-FU cytotoxicity, areprobably also resistant to 5-FU-based radiosensitization. Twoother enzymes involved in nucleoside metabolism includingdihydropyrimidine dehydrogenase (DPD), a 5-FU catabolicenzyme, and thymidine phosphorylase (TP) may also be keyregulators of fluoropyrimidine radiosensitization, includingthe use of oral prodrugs such as UFT and capecitabine.66

Chemotherapy drugs that target ribonucleotide reductase(RR), the rate-limiting enzyme in deoxynucleotide metabo-lism, can also result in clinical radiosensitization.66,67

These drugs include hydroxyurea (HU) and gemcitabine(dFdCyd). It is known that ionizing radiation can cause a posttranscriptional overexpression of RR69 and that the mechanism of radiosensitization appears to be progressioninto S phase under altered triphosphate pools (particularlydATP).70

The platinum analogues, including cisplatin, carboplatin,and oxaliplatin, are also commonly used as clinical radiosen-sitizers in head and neck cancers, non-small cell lung cancers,


bladder cancers, and locally advanced cervical cancers.Several potential mechanisms of drug–radiation interactionswith the platinum analogues have been proposed, includingenhanced formation of toxic platinum–DNA adducts andcrosslinks in the presence of IR free radicals; cell-cycle arrestat G2/M with reduced DNA repair; and enhanced cellularplatinum uptake by IR.68

Although the enhanced local control and improved sur-vival rates have convinced the oncology community to con-sider these concomitant combined modality approaches as the current standard of care for many locally advanced solid tumors, there is also an enhancement in both acute (e.g.,mucositis, myelosuppression) and late (e.g., esophageal,bowel strictures) normal tissue toxicities. Thus, more care-fully designed clinical trials are still needed to measure thetherapeutic gain and to test in patients the proposed mecha-nisms of these drug–radiation interactions leading toradiosensitization using noninvasive imaging techniquesincluding PET and MR spectroscopy. Even in this era of mo-lecularly targeted therapy, the oncology community shouldnot overlook the success of these drug–radiation interactionsand should continue to study the molecular targets of theseleading to radiosensitization.

Mechanisms of Interaction with Bioreductive Drugs

As discussed earlier, hypoxic tumor cells exist in manycommon solid tumors and represent a therapeutically resis-tant tumor cell population that may limit the curability ofthese tumors to different chemotherapy drug classes as wellas to radiation therapy. However, the presence of thesehypoxic cell populations in tumors also represents anexploitable difference to enhance the therapeutic gain asnormal tissues do not have such acute and/or chronicallyhypoxic cells. One approach to exploit hypoxia for a thera-peutic gain is to use bioreductive drugs with radiation therapyto selectively kill the hypoxic cell population.

The development of bioreductive drugs has been an areaof extensive preclinical research and clinical testing for morethan 25 years, but even today there are no clinically provenbioreductive drugs approached in the United States for usewith radiation therapy alone nor with chemoradiotherapy.Two recent review articles detailed the development andtesting of these various nitroheterocyclic compounds.71,72 Atthe present time, nimorazole is used in some European coun-tries as a radiosensitizer in head and neck cancers based on aPhase III trial,73 and tirapazamine is in Phase II and III testingcombined with radiotherapy alone, cisplatin-basedchemotherapy, and combined cisplatin/radiation therapy inthe United States.72

Growth Factor Receptor Targeting for Radiosensitization

Over all the past several years, the potential therapeutic tar-geting of growth factor receptors on tumor cells is an area of active preclinical research and early clinical testing. Twokey targets to enhance radiosensitization in human cancersare the epidermal growth factor (EGF) family and vascularendothelial growth factor (VEGF). For a comprehensive dis-

cussion of these approaches to radiosensitization, the readeris referred to two recent reviews.74,75

The epidermal growth factor receptor family has fourtransmembrane receptor tyrosine kinases, including HER2,HER3, HER4, and epidermal growth factor receptor (EGFR),which are involved in cell proliferation and survivalresponses, mediated through ligand binding. EGRF is knownto be overexpressed in a majority of several tumors includingnon-small cell lung cancer, head and neck cancers, andglioblastoma multiforme. Clinical studies confirm that EGRFoverexpression is associated with clinical radioresistance inthese tumors. HER2 overexpression in breast cancer is alsoassociated with clinical radioresistance. Thus, targeting theEGFR family clearly has the potential for radiosensitization.The preliminary results of a Phase III clinical trial comparingradiation therapy + the chimeric monoclonal antibody againstEGRF (Cetuximab, Erbitux; ImClone Systems, New York,NY, and Bristol-Myers Squibb Company, Princeton, NJ, USA)were recently reported showing improved local control andsurvival at 2 and 3 years.76 Although encouraging, several criticisms in trial design and the lower than expected localcontrol and survival data in the radiation therapy alone,necessitate further clinical testing.

A second developmental area of tumor targeting involvestargeting the tumor vasculature. It is recognized that tumorprogression during radiation therapy is a major reason for radi-ation failures. The ability of a tumor to progress during radi-ation therapy is dependent on the continued formation of newtumor blood vessels. Consequently, by targeting tumor vas-culature, one attempts to disrupt the proangiogenic balancebetween the tumor and its endothelial and vascular stromalcells.75 Because VEGF is an important proangiogenic tumorgrowth factor, a considerable amount of emphasis has beenplaced on VEGF inhibition in preclinical testing with radia-tion therapy using protein- or receptor-targeted antibodies orusing VEGF receptor signaling inhibitors including thecyclooxygenase 2 inhibitors.77

Two other approaches that attempt to target tumorgrowth and enhance tumor response to ionizing radiationinvolve targeting tumor oncogenes such as Ras78 and thenuclear transcription factor NF-KB.79 As no clinical data areavailable on these potential targeted therapies, the reader isreferred to two recent reviews of the preclinical research andproposed clinical testing.78,79

Targeting DNA Repair for TumorRadiosensitization

As reviewed previously in this chapter, recent advances in our understanding of DNA repair have shown genetic and epigenetic changes in several common human cancers, whichresult in alterations in IR damage recognition and damagerepair processes. DNA mismatch repair (MMR) is a postrepli-cational process whose genes/proteins are not only capable ofrecognizing and processing single DNA base-pair mismatchesand insertion-deletion loops during DNA replication, but alsoDNA adducts resulting from several types of chemotherapydrugs including the platinum analogues, alkylating/methyl-ating drugs including procarbazine and temozolomide, andvarious nucleoside analogues including the fluoropyrim-idines, gemcitabine, and the purine analogues, 6-thioguanine(6-TG) and 6-mercaptopurine (6-MP).80 MMR is also involved

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in processing IR damage.81 As such, MMR-deficient humantumors resulting from genetic defects [e.g., human nonpoly-posis colorectal cancers (HNPCC)] or from epigenetic silenc-ing (methylation) of hMLH1 and hMSH2 genes (e.g., found in15%–30% of colon, gastric, endometrial, high-grade glioma,and ovarian and breast cancers) show clinical resistance tothese chemotherapeutic agents as well as IR.80–82 Oneapproach to target these MMR-deficient human cancers forradiosensitization involves the use of the halogenated thymi-dine analogues such as iododeoxyuridine (IUdR), which areincorporated into DNA in place of thymidine and enhanceDNA damage following IR exposure. MMR-deficient tumorcells fail to effectively remove IUdR DNA, unlike normal(MMR+) cells, allowing for preferential tumor radiosensitiza-tion without enhancing normal tissue toxicity as recentlyshown in vivo.83 A clinical trial of this approach using an oralprodrug of IUdR (IPdR) and radiation therapy in MMR-deficient (“resistant”) human cancers is ongoing.

Another potential area for “targeted” radiosensitizationinvolves the use of inhibitory drugs or proteins directed atdouble-strand break repair. As stated earlier, RAD51 is over-expressed in several clinically radioresistant tumors such aspancreas cancer. Additionally, ionizing radiation treatmentcan induce expression of RAD51 RNA and RAD51 protein-mediated homologous recombination of double-strand breaksin both normal and human tumor cells. At present, imatnibmesylate (Gleevac; Novartis) is a potential candidate for clinical testing of inhibiting RAD51 at its tyrosine 315 phos-phorylating site.84

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