Review Radiation Cemo

8/2/2019 Review Radiation Cemo

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The concurrent chemoradiation paradigmgeneral principlesTanguy Y Seiwert*, Joseph K Salama and Everett E Vokes

INTRODUCTION

Three clinical rationales support the use ofchemotherapy delivered concurrently withradiation. First, concomitant chemoradio-therapy can be used with organ-preservingintent, resulting in improved cosmesis andfunction compared with surgical resection withor without adjuvant treatment. Second, chemo-therapy can act as a radiosensitizer, improving

the probability of local control and, in somecases, survival, by aiding the destruction of radi-oresistant clones (Table 1). Third, chemotherapygiven as part of concurrent chemoradiationmay act systemically and potentially eradicatedistant micrometastases.

CLINICAL APPLICATIONDISEASE

ENTITIES

Currently, concomitant chemoradiotherapy iswidely used in the treatment of solid tumors.In almost all malignancies in which loco-regional control is necessary, concurrent chemo-radiotherapy is either an established treatmentmodality or is actively being investigated.The optimum schedules, synergistic combi-nation of agents, and integration of targetedtherapies are also areas of active investigation.Chemoradiotherapy combinations for individualdiseases with their specific indications and limita-tions are beyond the scope of this article; however,an overview of the most common uses is shownin Table 1. In the next issue of this journal, theapplication of chemoradiotherapy in head andneck cancer will be detailed, exemplifying some

of the principles outlined here.

THEORETICAL FRAMEWORK FOR

THERAPYTHE STEEL PARADIGM

In 1979, Steel and Peckham introduced a theo-retical framework to describe the interaction ofcytotoxic chemotherapy and radiotherapy.1 Theterm spatial cooperation is used to describethe scenario whereby radiotherapy acts loco-regionally, and chemotherapy acts against distantmicrometastases, without interaction between

During the past 20 years, the advent of neoadjuvant, primary, and adjuvantconcurrent chemoradiotherapy has improved cancer care dramatically.Significant contributions have been made by technological improvementsin radiotherapy, as well as by the introduction of novel chemotherapyagents and dosing schedules. This article will review the rationale for theuse of concurrent chemoradiotherapy for treating malignancies. Themolecular basis and mechanisms of action of combining classic cytotoxicagents (e.g. platinum-containing drugs, taxanes, etc.) and novel agents

(e.g. tirapazamine, EGFR inhibitors and other targeted agents) withradiotherapy will be examined. This article is part one of two articles.In the subsequent article, the general principles outlined here will beapplied to head and neck cancer, in which the impact of concurrentchemoradiotherapy is particularly evident.

KEYWORDS chemoradiation, cytotoxic, radiation, resistance, synergistic

TY Seiwert is a fellow in the Department of Medicine, University of ChicagoCancer Research Center, JK Salama is an instructor in the Departmentof Radiation and Cellular Oncology, Pritzker School of Medicine, TheUniversity of Chicago, and EE Vokes is the John E Ultmann Professorof Medicine and Radiation and Cellular Oncology, and Director of theHematology/Oncology Section in the Department of Medicine, PritzkerSchool of Medicine, The University of Chicago, IL, USA.

Correspondence*University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 606371470, USA

[email protected]

Received 20 March 2006 Accepted 18 September 2006

www.nature.com/clinicalpractice

doi:10.1038/ncponc0714

REVIEW CRITERIAThe information for this Review was compiled using the PubMed andMEDLINE databases for articles published until 15 June 2006. Electronic early-release publications were also included. Only articles published in Englishwere considered. The search terms used included chemoradiotherapy orchemoradiation in association with the following search terms: reviews,radiosensitizer, concurrent, mechanism, molecular, cell cycle, cytotoxicchemotherapy, hypoxia, targeted therapies, radioresistance, cisplatin,tirapazamine, carboplatin, oxaliplatin, 5-FU, gemcitabine, capecitabine,pemetrexed, paclitaxel, mitomycin C, hydroxyurea, temozolomide,amifostine, palifermin, EGFR, Met, STAT 1, and VEGF. Full articles wereobtained and references were checked for additional material when appropriate.References were chosen based on the best clinical or laboratory evidence, especiallyif the work had been corroborated by published work from other centers. Prioritywas given to studies in high impact factor journals when available.

SUMMARY

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the agents (Figure 1). This cooperative effectrequires the agents to have non-overlappingtoxicity profiles in order that both modali-ties can be used at effective doses withoutincreasing normal tissue effects. When combinedconcurrently with radiotherapy, however, fewchemotherapeutic agents meet this criterion,because limited single-agent activity or toxicity-driven dose reductions preclude the deliveryof systemic dosing schedules. Many trials of

concomitant chemoradiotherapy, however, havedemonstrated decreased incidence of distantmetastases compared with radiation alone. Thisevidence could indicate that chemotherapy deliv-ered at radiosensitizing doses has some systemicspatial cooperative effect, or that the improvedlocal control of chemoradiotherapy decreasessubsequent metastases.

The second interaction between radiation andchemotherapy is radiation sensitization, which iseither additive or supra-additive: the interaction

within the radiation field leads to increasedkilling of cells (cytotoxic activity) either to thesame degree as (additive) or more than (supra-additive) using both modalities sequentially(Figures 1 and 2).Strictly speaking, radiosensi-tizers shouldnt have inherent cytotoxic activity.The hypoxic cell sensitizers (e.g. misonidazole),and thymidine analogs (e.g. bromodeoxyuridine)are examples of true radiosensitizers; however,the radiosensitizers most commonly used today

(cisplatin, 5-fluorouracil [5-FU], and taxanes) dohave inherent cytotoxic activity and can increasedamage to normal tissues, with a true benefitachieved only if the increase in antitumor effect islarger than the normal tissue damage (Figure 3).

Infra-additivedrugs possess radioprotectiveproperties that lessen the cytoxic effect of radia-tion on the tumor and/or normal tissue. Ideally,such agents should be selective for normaltissue to allow administration of higher radia-tion doses. Several agents are being investigated

Table 1 Overview of disease entities and indications in which concurrent chemoradiotherapy is used.a

Disease entity Indication and treatment Commonly used agents Benefit

Upper aerodigestive tract cancers

Head and neck cancer Locally advanced HNCprimary or adjuvant treatment

Cisplatin, 5-FU, FHX,cetuximab

Improved organ preservation and survivalcompared with radiation alone

Non-small-cell lung cancer Stage IIIB, nonoperablenonmetastatic disease Cisplatin, carboplatin/paclitaxel, cisplatin/etoposide Curative approach in poor surgicalcandidates or IIIB disease

Small-cell lung cancer Limited stage disease Cisplatin/etoposide Curative in ~20% of patients

Esophageal cancer Locally advanced disease Cisplatin/5-FU Survival benefit, increased cure rates,organ preservation

Gastrointestinal malignancies

Rectal cancer Neoadjuvant 5-FU Improved sphincter preservation, decreasein local and distal failures

Anal cancer Mainstay of curative treatment 5-FU, MMC Improved organ preservation

Gastric cancer Adjuvant Cisplatin, 5-FU Some data indicate a survival benefit

Pancreatic cancer Adjuvant, unresectablelocoregionally advanced tumors

5-FU Improved locoregional control, possibly asurvival benefit

Cholangiocarcinoma Adjuvant, unresectablelocoregionally advanced tumors

5-FU Some data indicate a survival benefit

Gynecological and genitourinary cancers

Cervical cancer Primary modality Cisplatin, 5-FU, hydroxyurea Improved local and distal control,organ preservation

Bladder cancer Primary modality Cisplatin Improved local control

Other cancers

Glioblastoma Adjuvant Temozolomide Survival benefit

Sarcoma Neoadjuvant Doxorubicin Downstaging, improved organ preservation

aThis is a limited overview, and concurrent chemoradiotherapy is used in most solid tumors either as a standard treatment or investigationally. For further details pleaserefer to the organ-specific literature. Abbreviations: 5-FU, 5-fluorouracil; FHX, 5-FU, hydroxyurea and radiation; HNC, head and neck cancer; MMC, mitomycin C.


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and have shown promising early results withradiation alone, but for concurrent chemo-radiotherapy definitive phase III evidence doesnot currently support their routine use. One suchagent, amifostinean organic thiophosphatemight decrease cisplatin-induced or radiation-induced toxicity by acting as a scavenger of freeradicals, as well as by binding to and neutral-izing organoplatinums and alkylating agents,thereby preventing DNA adduct formation.Although decreased incidence of xerostomiain patients with head and neck cancer treatedwith radiotherapy alone was convincinglydemonstrated in a large trial,2 the benefit withconcurrent chemoradiotherapy remains unclear,as demonstrated by a phase III study showing nosignificant difference in xerostomia or mucositisrates.3 Although a single-institution trial of

patients with advanced lung cancer randomizedto receive concurrent cisplatin, etoposide, andtwice-daily radiation demonstrated a decreasein grade 12 esophagitis, grade 3 pneumonitis,and neutropenic fever, an increase in sneezing,dysgeusia (loss of taste), and more importantlyhypotension, was observed.4 In a larger phaseIII trial conducted by the Radiation TherapyOncology Group, addition of amifostine toradiotherapy did not demonstrate any differ-ence in grade 3 or greater esophagitis, although

patients had a statistically significant, althoughsmall (1.3%) decrease in weight loss.3 Concernsthat radiation protectors might have a tumorprotective effect has limited their use; however,two large meta-analyses did not confirm thisconcern.5,6 At doses lower than those used for

normal tissue protection, amifostine has beenshown to have antimutagenic properties.7The agent palifermin, a recombinant human

keratinocyte growth factor, reduces oralmucositis in patients undergoing radiation andchemotherapy for autologous stem-cell trans-plant and in metastatic colorectal cancer treatedwith 5-FU.8,9 This drug is currently undergoingphase III testing with concurrent chemoradio-therapy in patients with advanced head andneck cancer.

Determination of additive effects between

chemotherapy and radiation

The type of interaction between chemotherapyand radiotherapy within the radiation field(supra-additivity, additivity, or infra-additivity)can be determined. For this purpose, Steel andPeckham described the isobologram analysis,which is based on an isoeffect concept forchemoradiotherapy interaction (Figure 2).1Independent doseresponse curves for chemo-therapy and radiotherapy are necessary to createa plot, called an isobologram. The isobologramis generated by plotting the dose of each agent(i.e. chemotherapy and radiotherapy) againsteach other, which produces a cytotoxic effect(isoeffect) on the axes of increasing dose of eachagent. Two curves, named mode 1 and mode 2,can then be generated (Figure 2). The mode 1curve results from the assumption that radia-tion and chemotherapy act independently, andis created by plotting a given dose of radiationagainst the dose of chemotherapy needed toproduce an effect equal to the difference betweenthe chosen cytotoxic effect and the effect of thecurrent dose of radiation. The mode 2 curve

assumes that radiation and chemotherapy haveidentical mechanisms of action. Points on thiscurve are generated by plotting doses of radia-tion against the doses of chemotherapy needed toincrease the effect of the dose of radiation to thechosen cytotoxic effect. Multiple points on bothof these lines are obtained by varying the radia-tion dose and calculating the appropriate dosesof chemotherapy. Finally, the true (empiric)survival curve is generated for radiation andchemotherapy given in combination. The doses

No interaction

modalities work

independently

Chemotherapy

toxicities

Radiation

toxicities

Molecular level

Cellular level

Tissue level

Independent toxicities

Radiosensitization

Spatial cooperation In-field cooperation

Infra-additivity

(antagonism)a

Locoregional

control

AdditivitySupra-additivity

(synergism)

Chemotherapy:

distal control(out-of-field)

Radiation:

local control(in-field)

Synergistic toxicities

Figure 1 Rationale for adding chemotherapy to radiation. Spatial and in-fieldcooperation are the two idealized types of cooperation between radiation and

chemotherapy. Both mechanisms can contribute synergistically to clinical

benefit.aUsually not desirable as this could protect the tumor.


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of each agent needed to produce the chosen cyto-toxic effect are plotted. Points that fall below theenvelope between mode 1 and 2 curves indicatesupra-additivity, data points occurring within theenvelope (between the two curves) indicate addi-tivity, and data points above the envelope indi-

cate infra-additivity. Further details and samplecalculations are provided elsewhere.10,11Other methods exist to determine types of

additivity, including the median effect prin-ciple and the response surface approach, bothof which are described in detail elsewhere.1215Unfortunately, the concept of additivity is oflimited use in clinical practice, as preclinicalprediction of additivity does not translate wellinto clinical outcomes. The use of this methodis, therefore, limited to forming hypotheses,which need to be confirmed empirically.

Quantification of the chemotherapy

and radiation interaction

The radiosensitizing ability of a drug can beexpressed by the therapeutic ratio. This ratio isderived from sigmoid-shaped doseresponsecurves, calculated by plotting the response oftissues (both normal and tumor) on the ordi-nate axis versus the chemotherapy or radiationtherapy dose on the abscissa (Figure 3). Thetherapeutic ratio is defined as the quotient ofthe dose that produces a 50% tumor control rateand the dose that produces a 50% normal tissuetoxicity rate. When chemotherapy is combinedwith radiation, both normal tissue and tumorcontrol curves produced by radiation aloneshift to the left because of the chemotherapy-induced sensitization of cells. Ideally, radiationsensitizers should influence the tumor responsecurve more than the normal tissue curve, thusresulting in a greater than one therapeutic ratio.Similar to the concept of additivity, therapeuticratios are mainly hypothesis-forming and needto be tested empirically in phase I and II studies.Such preclinical data may help in the initial dose

schedule selection for phase I trials.

Mechanisms of radiation resistance or failure

Tumors have developed multiple strategies toresist radiation damage. Table 2 gives an over-view of the most widely accepted mechanisms.Simplistically, larger tumors have a stochasticchance that some cells will survive radiotherapy.Moreover, hypoxic tumor cells have increasedresistance to radiation; multiple studies havedemonstrated that hypoxic cells exhibit 2.53.0

times the resistance to radiotherapy damagecompared with normoxic cells.1620 As shown inFigure 4, the phases of the cell cycle significantlyinfluence the radiosensitivity of cells.21

1.0

0.5

0.0

0.0 0.5

Drug dose

RTdose

1.0

Supra-additivity

(synergism)

Infra-additivity(antagonistic effect)

Additivity envelope(area between the

mode 1 [upper] andmode 2 [lower] curves)

Figure 2Schematic example of an isobologram depicting the combinationof radiation and a systemic agent. Thex andyaxes show the isoeffective

levels for radiation and drug. The thick line is the line of additivity, and the

additivity envelope is based on the combined standard errors. Curves above

the envelope represent antagonistic effects and curves below the envelope

represent synergistic effects.1,41 Abbreviation: RT, radiotherapy.

100

0

Radiation dose (Gy)

Response/toxicityrat

e(%)

Normal tissue

Tumor

Figure 3Schematic doseresponse curves for tumor and normal tissuedamage with radiation. The offset between the two curves indicates the

therapeutic range. Chemoradiotherapy leads to a shift of both curves to the

left, ideally with a stronger shift of the tumor curve (as indicated by the longer

arrow), increasing overall efficacy of treatment (radiation enhancement).120


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One of the most commonly invoked under-lying mechanisms in treatment failure22,23 istumor cell repopulation, which results in a rapidgrowth between radiation fractions. Althoughincompletely understood, the stimulation ofgrowth factors and the selection of resistantclones lead to rapid emergence of treatmentresistance.22,24,25 In addition, rapidly prolif-erating tumors contain a high proportion ofradioresistant cells in the S phase of the cellcycle. For further information on repopulation,readers should refer to the excellent review bySchmidt-Ullrich et al.26

Certain tumors are intrinsically radio-

resistant, while others acquire mechanismsof radioresistance during treatment. Intrinsicradioresistance is seen when there is anincreased surviving fraction of tumor cells after2 Gy radiotherapy; this result is often depictedin a clonogenic radiation cell survival curveassay. Small increases in radioresistance leadto large, logarithmic decreases in final cell killafter radiotherapy. In some tumors, such evalu-ation in radioresistance in pretreatment biop-sies predicts for radiosensitivity and clinical

outcome, although these findings have so farnot been widely reproducible.27,28 Activationof certain prosurvival pathways that preventapoptosis can induce treatment resistance.Among the many pathways implicated aremutated p53,29 amplification of DNA repairgenes, increased levels of reactive oxygen speciesscavengers, and activation of prosurvival/poor-prognosis oncogenes such as EGFR,30,31 orc-MET(also known as MST1R).32,33 Recently,gene-expression profiling has identifiedthat radiation-resistant tumors overexpressmany genes related to interferon pathways orinduced by interferon itself, especiallySTAT1.

Radiosensitive cells transfected with STAT1demonstrated radioprotection after exposureto 3.0 Gy radiation.34

General mechanisms of chemotherapy

and radiotherapy interaction

Seven major interactions between chemotherapyand radiation will be explained here and are listedin Table 3. For most chemotherapeutic agentsseveral interactions apply at the same time.First, DNA damage can be induced by both

Table 2 Mechanisms of radioresistance.

Process affected Mechanism Comments

Large tumor cellburden

Tumor size is inversely correlated with tumor response.Radiation-induced cell kill is a random eventthe higherthe number of cells, the higher the chance of cellsescaping a lethal hit.121,122

Upfront or completion surgery should be considered toreduce tumor bulk or residual disease.

Tumor cellmicroenvironment/hypoxia

Oxygen is needed to generate ROS and other radicals withradiation. ROS are thought to be essential to the cytotoxiceffect from radiation (reviewed in Cook et al.123).

Hypoxia is present for two reasons:

1. increased interstitial pressure may causehypoperfusion, hypoxia and acidosis;124126

2. cancer-related anemia contributes to local hypoxia(HIF1 is a marker of tumor hypoxia).

Hypoxic cells are 2.53.0 times less radiation-sensitive thannormoxic cells.18,44

Both hypoxia and HIF1 are adverse prognostic factors.127

Chemotherapy can increase radiation effect:

1. through reoxygenation second to tumor shrinkage(e.g. with paclitaxel46);

2. by killing hypoxic cells selectively (e.g. withtirapazamine or mitomycin C);

3. through resensitization of hypoxic cells to radiation(nitroimidazolesin development).

Inherent oracquired tumorcell resistance

Multiple mechanisms are thought to contribute, includingmutated p5329, DNA repair gene amplification, increasedlevels of ROS scavengers, activation of prosurvival/poor-prognosis oncogenes (EGFR,100,101

c-MET32).

Delays or interruptions in radiotherapy are known to leadto the development of radioresistance and allow suchresistant cells to repopulate.

Repopulation Regrowth of tumor cells between doses of radiotherapyor chemotherapy. Accelerated repopulation might lead totreatment failure and emergence of true radioresistance(see row above).22

Accelerated radiation schemes are intended to preventrepopulation.128

Antimetabolites with activity in the S phase of the cell cycle(5-FU, hydroxyurea) also inhibit repopulation.

EGFR inhibitors can block cell proliferation betweenradiotherapy fractions.101

Abbreviations: 5-FU, 5-fluorouracil; HIF1, hypoxia-inducible factor 1-alpha; ROS, reactive oxygen species.


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chemotherapy and radiotherapy and synergy ispossible. Ionizing radiation induces DNA basedamage, alkali-labile sites, single-strand breaks, anddouble-strand breaks (DSBs). All of these errorscan be rapidly repaired except for DSBs, which ifnot repaired are considered lethal.35,36 The integra-tion of cisplatin into DNA or RNA in close prox-imity to a radiation-induced single-strand breakcan act synergistically to make the defect signifi-cantly more difficult to repair (Figure 5).37,38Second, chemotherapy can inhibit post-radiationdamage repair. DNA synthesis and repair sharecommon pathways, which provide the rationalefor using DNA synthesis inhibitors with radiationas a means of inducing cytotoxic damage to tumorcells. Agents affecting nucleoside and nucleotidemetabolism can inhibit the repair of radiation-induced DNA damage in patients, and are amongthe most potent radiation sensitizers. Examples of

such agents include the fluoropyrimidines,thymidine analogs, gemcitabine, and hydroxyurea.Third, administered concurrently, radiotherapyand chemotherapy often target different phases ofthe cell cycle and may cooperate to produce anadditive effect (i.e. cytokinetic cooperation/synchronization). The radiosensitivity of a cell isdependent on the phase of the cell cycle; cells inthe S phase are the most radioresistant, and cellsin the G2M phase of the cell cycle are the mostradiosensitive (Figure 4).39,40 In addition,

cytokinetic cooperation of S-phase-specific agents(e.g. camptothecins, 5-FU, hydroxyurea) is seen ifcells are exposed in close temporal proximityto radiation.41 Some drugs (e.g. taxanes) are able

to synchronize with the cell cycle of tumor cellsto allow increased efficacy of subsequent radio-therapy (called synchronization or cell-cyclepooling). This process was successfully shownin vitro, although the conceptespecially itsapplicability in vivoremains controver-sional.11,42,43 Fourth, the increased resistance ofhypoxic cells to radiation (Table 2) means thathypoxic cell sensitizers may be beneficial.18,44

Hypoxia is common in many cancers andwas shown to be a marker of aggressive clinicalbehavior and poor prognosis.45 Chemotherapycan help eliminate these resistant cells andincrease the efficacy of radiotherapy viamultiple mechanisms (Table 3). Tirapazamine,and potentially mitomycin C, preferentiallykill hypoxic cells. Additionally, paclitaxel,46and EGFR inhibitors,24 were shown to shrinktumors, thereby increasing perfusion andoxygenation and reducing radioresistant hypoxicareas. This hypoxic effect might be applicablefor many other agents. Fifth, repopulation ofrapidly proliferating tumors is usually mediatedby overexpression of growth factors and growthfactor receptors, as well as increased activity of

downstream signaling pathways, and the pres-ence of activating mutations in genes involved atall levels of the signaling pathways. Agents thattarget the S phase of the cell cycle, such as 5-FU,irinotecan, and hydroxyurea, as well as those thatinhibit proliferation and/or growth factor path-ways, such as EGFR inhibitors, may be effectivein preventing tumor cell repopulation, therebyradiosensitizing tumor cells.24,47

In addition to their antiproliferative effectsthat prevent tumor cell repopulation, EGFR

Most radiosensitive

Most radioresistant

Division

Taxanes

Vinca alkaloids

Etoposide

Vinca alkaloids

5-fluorouracil

Methotrexate

Hydroxyurea Doxorubicin

Cytarabine

Gemcitabine

Etoposide

Cell-cycle-independent: Platinating agents

Alkylating agents

G2

M

S

G0

G1 Bleomycin

Figure 4 Cell-cycle schematic and respective

sensitivity to chemotherapeutic agents.

Cell deathRepairRepair

Radiation-induced

single-strand breakaCisplatin adduct Cisplatin and radiation-

induced damage

Figure 5 Increased DNA damage by addition of cisplatin to radiation.aRadiation can also induce other DNA damage, of which double-strand breaks

are considered lethal.


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inhibitors and antiangiogenic agents can blocksignaling pathways that are responsible for

aggressive tumor biology, poor prognosis, andradioresistance. Although the exact mecha-nisms of various targeted therapies vary andare generally poorly understood, preclinical48and clinical49 data support the rationale forradiosensitizing properties as a consequenceof inhibiting the detrimental effects of theagents targets. Finally, some tumors resistantto standard chemoradiotherapy respond toalterations in radiation fractionation. Thisphenomenon, termed hyperradiation sensitivity,

is observed at radiation doses greater than 1 Gy.Preclinically, for both paclitaxel and docetaxel,

low-dose fractionated radiation can overcomeradioresistance.50 Clinical trials evaluating thistechnique are currently underway.

Specific mechanisms of chemotherapy

and radiotherapy interaction

Platinum analogsCisplatin is one of the most commonly useddrugs for concurrent chemoradiotherapy.Through interactions with nucleophilic sites onDNA and RNA, cisplatin introduces intrastrand

Table 3 Mechanisms of chemotherapy and radiotherapy interaction.

Process affected Mechanisma Drug examples

Increased radiationdamagea

Incorporation of chemotherapy drug into DNA/RNA 5-FU: incorporation into DNA, increasing susceptibilityto RT damage

Cisplatin: cross-links with DNA or RNA (intrastrand andinterstrand); works for both hypoxic and oxygenated

cells51

Inhibition of DNA repairprocessa

Interference with the DNA repair process afterradiation

Halogenated pyrimidines (e.g. 5-FU, bromodeoxyuridine,iododeoxyuridine)

Nucleoside analogs (e.g. gemcitabine, fludarabine)

Cisplatin

Methotrexate

Camptothecins and doxorubicin

Etoposide

Hydroxyurea

Carmustine, lomustine

Cell-cycle interference(cytokinetic cooperationand synchronization)a

Most cytotoxic chemotherapies as well as radiationare cell-cycle-specific, and proliferating cells are mostsusceptible

Accumulation of cells in the G2 and M phases(the most radiosensitive phases)

Elimination of radioresistant cells in the S phase

Taxanes lead to cell-cycle arrest via tubulin stabilization

Nucleoside analogs (e.g. gemcitabine, fludarabine),etoposide, methotrexate, hydroxyurea

Enhanced activityagainst hypoxic cellsa

Reoxygenation second to tumor shrinkage. Hypoxiccells are 2.53.0 times less radiation-sensitive thannormoxic cells18,44

Chemotherapy can help to eliminate hypoxic cells

Most chemotherapeutic agents; described in particularfor paclitaxel45

Tirapazamine, mitomycin (selective killing of hypoxic cells);nitroimidazoles (resensitize hypoxic cells to radiation)

Radiotherapyenhancement bypreventing repopulationa

Systemic therapy can slow or stop rapid proliferation,which could otherwise be the basis for repopulationphenomenon

Most chemotherapeutic agents, in particular:

Antimetabolites with activity in the S phase inhibitrepopulation (e.g. 5-FU, hydroxyurea)

EGFR inhibitors, which impede cell proliferation betweenRT fractions100

Inhibition of prosurvival

and poor prognosismarkersa

Targeted therapies (best demonstrated for EGFR

inhibition) block signaling pathways that might beresponsible for radioresistance and poor prognosis

EGFR inhibitorsshown for anti-EGFR antibody, PKI-

166 (small-molecule TKI), and EGFR antisense,129131

but on the basis of clinical experience likely to be a classeffect49,132

Hyperradiationsensitivityb

HNSCC cells resistant to standard-fraction CRT canbe resensitized to CRT by using smaller fraction sizes(


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and interstrand cross-links, thereby distorting theDNA structure, and blocking nucleotide replica-tion and transcription. Active in both hypoxicand well-oxygenated cells,51 several potentialmechanisms for cisplatin-mediated radiationsensitization were reported and summarized by

Wilson and co-workers.41

It has been proposedthat radiation induces free radicals and subse-quently the formation of toxic platinum inter-mediates, which increase cell killing.52 Moreover,ionizing radiation can increase cellular uptakeof platinum.53 Damage to DNA by ionizingradiation that typically would be repairable canbecome fixed and lethal through cisplatins free-electron-scavenging capacity. This inhibition ofDNA repair (Figure 5)54 leads to an increasedincidence of cell-cycle arrest and apoptotic celldeath after radiation.41,55

In vitro studies have shown that the mostsynergistic combination of cisplatin and radia-tion involves low doses of each,either of whichwould be insufficient to cause cell death if admin-istered alone. Cisplatin would seem to inhibitthe sublethal damage repair process implicatedin the recovery of insufficiently radiated cells.41Radiosensitization by cisplatin and carboplatinmay be limited to cells with an intact homo-logous recombination repair system,41,56 butradiosensitization is not impacted by hypoxia.Oxaliplatin, a cisplatin-related compound,has been shown to have activity in cisplatin-resistant systems and unaltered sensitivity inmutated mismatch-repair systems.49 Althoughless well studied, oxaliplatin is postulated tohave similar radiosensitization mechanismsto those of cisplatin.41

Antimetabolite-based chemoradiotherapy

5-fluorouracilThe halogenated pyrimidine nucleoside analog5-FU is used extensively with radiation.57,58 Thisanalog impedes nucleic acid synthesis throughthymidylate synthase inhibition, depleting the

pool of nucleotide triphosphates, leading to cell-cycle changes, DNA fragmentation, and ultimatelycell death.59 When 5-FU is incorporated into RNAand DNA it inhibits not only DNA synthesis, butalso transcription and protein synthesis. Optimal5-FU radiosensitization requires continuousadministration of the agent during radiationbecause of the need for continuous thymidy-late synthase inhibition, the short half-life ofplasma 5-FU and intracellular phosphorylated5-FU metabolites.

5-FU radiosensitization is postulated to occurby the agents effect on the proportion of cells inthe radioresistant S phase of the cell cycle.Whengiven in standard doses, 5-FU is able to kill cellsin the S phase. Additionally, at sublethal concen-trations, 5-FU pre-incubation is hypothesized to

radiosensitize tumor cells through changes inthe S-phase cell-cycle checkpoint, which allowinappropriate progression out of the S phaseinto the G2 phase. This conjecture is supportedby the fact that blocking the entry of cells intoS phase prevents radiosensitization for a similarpyrimidine analog, fluorodeoxyuridine.57,58Impaired repair of radiation-induced DSBsmight also contribute to 5-FU cytotoxicity andradiosensitization.57,58

Capecitabine

Capecitabine is an oral prodrug that is convertedto 5-FU via thymidine phosphorylase. Radiationhas been shown to preferentially increase tumorthymidine phosphorylase levels via induction oftumor necrosis factor. In a colon cancer fluoro-pyrimidine-resistant xenograft model, exposureto capecitabine before irradiation demonstrateda supra-additive effect compared with radiationalone.60 Clinical trials are actively exploring therole of the combination of capecitabine andradiation therapy.

GemcitabineGemcitabine is a widely used S-phase cell-cycle-specific pyrimidine analog that hinders DNAsynthesis and repair through depletion of deoxy-nucleoside triphosphates that are required by twoenzymes: DNA polymerase and ribonucleotidereductase. Gemcitabine has shown activity inmany solid tumors, either alone or in combina-tion with other agents (e.g. cisplatin or carbo-platin).61 Initial clinical studies of pancreaticand lung cancer demonstrated marked toxicityof gemcitabine-based chemoradiotherapy anddampened enthusiasm for the efficacy of this

drug, since only doses much lower than thoseused without radiation could be administeredsafely. Recent data from multi-institutionalstudies have shown that full doses of gemcit-abine can be delivered with aggressive conformalradiation techniques.6264

In preclinical models, the potent radio-sensitizing properties of gemcitabine weremost pronounced with exposure to low dosesof the agent at least 24 h before irradiation.Interestingly, sensitization persisted for up to


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48 h, and radiation exposure before exposureto gemcitabine did not lead to sensitization.These observations are consistent with the timeneeded to deplete deoxynucleoside triphosphates(dATP) and transition through the S phase ofthe cell cycle.6567 It seems that incorporation

of incorrect bases secondary to deoxynucleosidetriphosphate depletion and S-phase accumulationare the basis of the radiosensitizing propertiesof gemcitabine.65

PemetrexedThis compound is a novel multitargeted antifolatethat inhibits thymidylate synthase, dihydrofolatereductase, and glycinamide ribonucleotideformyl-transferase, all of which are key enzymesinvolved in nucleotide synthesis. Preclinical datasuggest synergistic antitumor activity of peme-

trexed and concurrent radiotherapy, and inter-ference with DNA synthesis is thought to be theprimary cytotoxic mechanism.68 Pemetrexedis not cell-cycle-specific as it shows equal effi-cacy in the G1 and S phases of the cell cycle.69Although the exact interaction of pemetrexedwith radiation is not fully understood, it hasbeen postulated that prolongation of the S phaseby radiation increases the intracellular drugexposure time and toxicity. Pemetrexed-basedchemoradiotherapy is in phase I clinical testingin several tumor types.70

HydroxyureaHydroxyurea acts as a radiation enhancer in vitroand in vivo51 and is useful for the treatment ofhead and neck cancer.71 This drug was previouslyused for squamous-cell carcinoma of the cervix(replaced by cisplatin)72 and gliomas (replacedby temozolomide),73 and was proposed for thetreatment of pancreatic cancer (replaced by 5-FUand potentially gemcitabine).74 Ribonucleotide-reductase inhibition prevents radiation-inducedDNA damage repair during nucleotide excision.Furthermore, hydroxyurea might also synchronize

cancer cells at the G1S checkpoint.74 The doubleaction of hydroxyurea of cell-cycle synchronizingand DNA damage repair inhibition has beensuggested as a mechanism for its more efficaciousaction as a radiation sensitizer at doses lowerthan for the ribonucleotide-reductase inhibitorsgemcitabine and trimidox.74 Antimetabolitessuch as hydroxyurea are selectively cytotoxicto cells that are in the relatively radioresistantS phase of the cell cycle, which might contributeto overcoming radioresistance.

Taxane-based chemoradiotherapy

Paclitaxel and docetaxel form high-affinity bondswith microtubules, promoting tubulin poly-merization and stabilization. At high doses, thesedrugs block prophase to metaphase progression,disrupting the centrosome network and thereby

causing cell death.75

Despite the structural simi-larities of these two agents, differences in excre-tion and cell-cycle tropism instigate differingtemporal interactions of paclitaxel and docetaxelwith radiation.76

Two mechanisms for paclitaxel and docetaxelradiosensitization have been proposed. Thestandard explanation is that cells remain inthe G2M phase of the cell cycle, leadingto synchronization (cell-cycle pooling) oftumor cells at a point of maximum radio-sensitivity,11,42 but it is still unclear whether

cell-cycle redistribution occurs, especiallyin vivo.43True synchronization in large tumorsseems unlikely, and may not increase the thera-peutic index as normal cells are also affected.77Alternatively, taxanes can induce tumorshrinkage, improving perfusion and subsequentreoxygenation. As hypoxic areas of the tumorare reoxygenated they become more sensitiveto radiation-induced cell kill.46 Paradoxically,low doses of taxanes may induce protectionagainst radiation via possible alterations insignal transduction pathways. Pretreatmentof a human laryngeal squamous cell line with7.5 nmol/l paclitaxel 6 h before irradiationinduced subadditive effects via G2 blockade.78Extensive single-agent and chemoradiotherapytaxane mechanisms are reviewed by Hennequinand Favaudon.11

Mitomycin-C-based chemoradiotherapy

Mitomycin C inhibits DNA and RNA synthesisby interfering with DNA cross-linking, prima-rily at the guanine and cytosine pairs. Althoughmitomycin C is not cell-cycle-specific, this agentis known to induce marked cell-cycle arrest at the

G2M transition.79,80 In combination with radia-tion, mitomycin C acts as a hypoxic cell sensitizerand is thought to prevent repopulation, althoughthe exact mechanism remains elusive.81

Tirapazamine-based chemoradiotherapy

Tirapazamine is the lead compound in a class thathas selective cytotoxic activity under hypoxic con-ditions (hypoxic cell cytotoxic).82 Hypoxic tumorcells that are relatively resistant to radiotherapyexhibit aggressive growth behavior, and portend


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a poor prognosis. Although widely recognized inits ability to enhance radiation,83 debate existsas to whether tirapazamines effects are addi-tive or supra-additive.84,85 Regardless, theor-etical models show that the killing of hypoxiccells might improve outcomes compared with

standard radiosensitizers.86

Tirapazamines approximately 100-foldincreased potency under anoxic conditionsoccurs via electron donation, which causesformation of transient oxidizing radicals. Innormoxic tissue these radicals quickly bindavailable molecular oxygen, re-establishingthe nontoxic parent compound. In the absenceof oxygen, however, these oxidizing radicalsinduce the formation of DNA radicals byextracting a proton from the C4 location of thedeoxyribose ring on the DNA.87 This process

can lead to cytotoxic DNA-strand breaks.Additionally, unknown mechanisms decreasetopoisomerase II activity in tirapazamine-treated cells.88 Although little or no cell killingis observed in normoxic cells, systemic sideeffects including fatigue, muscle cramps, andreversible ototoxicity were observed during theclinical administration of tirapazamine, andhave been attributed to a loss of mitochondrialmembrane potential.89

Temozolomide-based chemoradiotherapy

Temozolomide is an orally administered cyto-toxic alkylating agent, which readily crosses thebloodbrain barrier; 30% of plasma concentra-tions are achieved in the cerebrospinal fluid.90Commonly used to treat gliomas, temozolo-mide causes DNA damage by methylationof the O-6 position of guanine and activatesthe p53-controlled DNA damage responsepathway.91 Tumors with methylation of theO-6-methylguanine DNA-methyltransferase(MGMT), a p53 DNA damage repair enzyme,are preferentially radiosensitized.92,93 Temo-zolomide also inhibits signaling of radiation-

triggered cell migration and invasiveness94 anddecreases tumor cell repopulation.

The aim of combining temozolomide withradiation is the use of an intrinsically activeagent that has a different toxicity profile toradiation.95In a study by Wedge et al.,96 a glio-blastoma cell line with no MGMT activity wascompared with a colorectal cancer cell line withhigh repair activity. Temozolomide and radiationwere additive in the glioblastoma line, whereasantagonism was observed in the colorectal

cancer line. This finding is probably attributableto radiation induction of MGMT. Additionally,temozolomide and radiation showed additiveand supra-additive activity.97

Advances in radiotherapy

While most advances in concurrent chemoradio-therapy have focused on the integration of novelsystemic agents, recent technological improve-ments in radiotherapy have impacted directlyon concurrent chemoradiotherapy. Intensity-modulated radiation therapy (IMRT) has allowedbetter delivery of radiation to the target volumes,allowing sharp dose gradients between targetsand normal tissues. After clinical implementa-tion of IMRT, decreased acute gastrointestinal,skin, hematologic, and salivary toxicity rateswere reported, which improved the therapeutic

index of radiation.

98

These decreases in normaltissue toxicity could also improve the therapeuticindex of chemoradiation. Additionally, imple-mentation of image-guided radiotherapy vialinear accelerator-based kilovoltage techniques,and gating radiation delivery with the respira-tory cycle, will improve day-to-day targeting andpotentially decrease acute and chronic toxicitiesof chemoradiotherapy.Molecular-targeted therapies in

combination with chemoradiotherapy

In the past decade, the promises of molecular-targeted agents have increasingly come to frui-tion, and these agents have been combined withradiotherapy in an effort to optimize the thera-peutic index of drug dosing. Molecular-targetedtherapies are an attractive option combined withchemoradiotherapy because they are more specificfor the target and can inhibit radioresistance path-ways. An extensive review of molecular-targetedagents and their interaction with radiotherapy hasbeen published by Ma et al.99

EGFR-targeted therapies and chemoradiotherapy

The membrane-bound receptor tyrosine kinaseEGFR is activated upon binding of the ligand(transforming growth factor , epidermalgrowth factor), which induces dimerizationand subsequent phosphorylation of the intra-cellular EGFR tyrosine residues. Upon activation,intracellular signaling cascades mediate variouscellular responses important for tumor survivaland growthnamely, increased proliferation,invasion, angiogenesis, and metastasis, andconcomitant decreased apoptosis.


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EGFR (erbB1) and the EGFR family memberserbB24 are deregulated in head and neck,lung, breast, and colorectal cancers. IncreasedEGFR protein expression correlates withincreased tumor size, recurrence risk, and radio-resistance, and with decreased survival.100,101

Cell culture experiments of radiation-inducedEGFR expression and increased radioresistance,demonstrated by the addition of exogenousEGF, indicated a causal link between EGFR andradioresistance.102

Preclinical studies with the EGFR inhibi-tors cetuximab, gefitinib, and erlotinib showenhanced radiosensitivity leading to supra-additive efficacy both in vitro and in vivo.49,100,103Proposed mechanisms for radiosensitiza-tion via EGFR inhibitors include inhibitionof cell proliferation, impairment of DNA

damage repair,

104

attenuation of tumor neo-angiogenesis, inhibition of radiation-inducedEGFR nuclear import,105 and promotion ofradiation-induced apoptosis.106,107 In partic-ular, the antiproliferative effects of EGFR inhi-bition most likely prevent repopulation,100 amajor mechanism implicated in radioresistance.The other mechanisms may well have a role inthe supra-additivity of the anti-EGFR radiationcombination.

Antiangiogenic and anti-VEGF therapyin combination with radiationAngiogenesis is essential for sustained tumorgrowth, and many new cancer therapies aredirected against modification of the tumorvasculature.108,109 The process of angiogenesisis mediated by multiple proangiogenic andantiangiogenic factors, with VEGF having acentral role.108,109 Anti-VEGF agents fall intotwo broad categories: those that target the VEGRligand, such as bevacizumab, and those thattarget the receptor, such as PTK787 (an antibodyto VEGFR-2). Other antiangiogenic strategiesinclude antiangiogenic factor administration to

counterbalance proangiogenic stimuli, inhibitionof extracellular matrix degradation enzymes,integrin antagonists, and therapies with directendothelial cell toxicity.

Two mechanisms for radiosensitization withantiangiogenic agents have been proposed andcould exist in parallel.109,110 The traditionalview is that antiangiogenic destruction oftumor vessels leads to hypoxia and starvation,which paradoxically could also increase tumorresistance.111 Increasingly, however, findings

show that increases in blood flow, oxygen, anddrug delivery (i.e. a transient normalization ofthe abnormal structure and function of tumorvessels) is seen as the underlying mechanism ofantiangiogenic therapies.109

Radiosensitizing properties were first

reported for angiostatin when Weichselbaumand colleagues demonstrated that the combina-tion of angiostatin and radiation was synergisticand decreased radioresistance.112 These resultshave also been confirmed for antiangiogenicsmall-molecule tyrosine kinase inhibitors.113Additionally, endostatin showed additivity withradiation regarding tumor regression, growthinhibition, angiogenesis, and enhanced apop-tosis.114 These mechanisms could be caused byenhancement of tumor oxygenation, leading toincreased radiosensitivity, as well as direct tumor

growth delay.

110,112

Novel targeted therapies with radiosensitizingpropertiesReceptor tyrosine kinases other than EGFR arealso potential targets for novel radiosensitizers.Overexpression of c-Met has been linked to poorprognosis in many cancers,115 and synergismwith radiation has been described in glioblastomacell lines.116 Other receptor tyrosine kinases suchas insulin-like growth factor receptor or ephrinreceptors are additional candidates. Anotherinnovative strategy that has been tested in phase Iclinical trials is radiation-induced activation ofgene transcription. For example, TNFerade(GenVec, Gaithersburg, MD) is a replication-deficient adenovirus vector with an early growthresponse protein 1 (EGR1) radiation-induciblepromoter leading to intratumoral human tumornecrosis factor production. Initial applications ofthis agent in esophageal, rectal, and pancreaticcancer, as well as in sarcomas, have shown proofof principal, with extensive tumor necrosis as asign of activity.117 Additional studies in head andneck cancer are ongoing.

With the increasing understanding of cancerbiology, hundreds of novel targeted agents arescheduled to come into preclinical and clinicaldevelopment in the next decade. Among theseagents proteasome inhibitors, and agents thattarget mammalian target of rapamycin, haveshown promising results when combined withradiotherapy.118,119 For further information onthe interaction of targeted agents with radiation,readers are referred to the excellent review by Maand coauthors.99


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CONCLUSION

In summary, concurrent chemoradiotherapy is ahighly efficacious locoregional treatment optionfor solid tumors, which can be used alone orcombined with surgery or induction/consolidationchemotherapy. Through our increased under-

standing of the molecular basis of chemotherapyand radiation interactions, we have gained insightsinto how to best use and potentially combineagents with radiation, with benefits beginningto be seen in patients. Novel targeted therapiesand agents specific for hypoxic or radiated cellshold promise for further significant improve-ment of therapeutic ratios. Concurrent chemo-radiotherapy already offers excellent locoregionalcontrol with an acceptable toxicity profile for thetreatment of many locoregional advanced tumors.In the final article of this two-article series we will

examineusing the example of head and neckcancerspecific concurrent chemoradiotherapytreatment options and the underlying clinicalevidence. Head and neck cancer is often a loco-regionally confined disease, and this is exemplifiedby the profound impact and benefit that concurrentchemoradiotherapy can have for patients.

KEY POINTS

Concurrent chemoradiotherapy has improved

cancer care during the past two decades in

multiple diseases, and can be used in the

neoadjuvant, primary (definitive), or adjuvant

setting

Chemotherapy or targeted agents can increase

the efficacy of radiation

Radiosensitizing effects (interaction within the

radiation field) can be additive or supra-additive

Multiple mechanisms underlie radiosensitizing

properties of chemotherapeutic agents and

include increased radiation damage, inhibition

of DNA repair, cell-cycle synchronization,

increased cytotoxicity against hypoxic cells,

inhibition of prosurvival pathways, and

abrogation of rapid tumor cell repopulation

Radioresistance occurs through multiple

mechanisms, such as a large tumor burden,

hypoxia, rapid tumor cell repopulation, as well

as the constitutive or acquired activation of

radioresistance signaling pathways

In addition to the classic chemotherapeutic

agents with radiosensitizing properties (i.e.

cisplatin and paclitaxel), several novel agents

show promising interactions with radiation (e.g.

EGFR inhibitors, pemetrexed, tirapazamine, and

potentially several other targeted therapies)

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AcknowledgmentsThe authors would like to

acknowledge the generous

help of Dr Blase Polite

and Dr Samir Undevia in

reviewing organ-specific

data.

Competing interestsEE Vokes has declared

associations with the

following companies:

AstraZeneca, Bristol-Myers

Squibb, Eli Lilly, Genentech,

ImClone, OSI and sanofi-

aventis. See the article

online for full details of

the relationship. The other

authors declared they have

no competing interests.

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