Upload
dviertl
View
220
Download
0
Embed Size (px)
Citation preview
8/2/2019 Review Radiation Cemo
1/15
REVIEW
www.nature.com/clinicalpractice/onc
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
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
86 NATURE CLINICAL PRACTICE ONCOLOGY FEBRUARY 2007 VOL 4 NO 2
8/2/2019 Review Radiation Cemo
2/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 87
www.nature.com/clinicalpractice/onc
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.
8/2/2019 Review Radiation Cemo
3/15
REVIEW
88 NATURE CLINICAL PRACTICE ONCOLOGY SEIWERT ET AL. FEBRUARY 2007 VOL 4 NO 2
www.nature.com/clinicalpractice/onc
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.
8/2/2019 Review Radiation Cemo
4/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 89
www.nature.com/clinicalpractice/onc
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
8/2/2019 Review Radiation Cemo
5/15
REVIEW
90 NATURE CLINICAL PRACTICE ONCOLOGY SEIWERT ET AL. FEBRUARY 2007 VOL 4 NO 2
www.nature.com/clinicalpractice/onc
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.
8/2/2019 Review Radiation Cemo
6/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 91
www.nature.com/clinicalpractice/onc
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.
8/2/2019 Review Radiation Cemo
7/15
REVIEW
92 NATURE CLINICAL PRACTICE ONCOLOGY SEIWERT ET AL. FEBRUARY 2007 VOL 4 NO 2
www.nature.com/clinicalpractice/onc
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(
8/2/2019 Review Radiation Cemo
8/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 93
www.nature.com/clinicalpractice/onc
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
8/2/2019 Review Radiation Cemo
9/15
REVIEW
94 NATURE CLINICAL PRACTICE ONCOLOGY SEIWERT ET AL. FEBRUARY 2007 VOL 4 NO 2
www.nature.com/clinicalpractice/onc
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
8/2/2019 Review Radiation Cemo
10/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 95
www.nature.com/clinicalpractice/onc
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.
8/2/2019 Review Radiation Cemo
11/15
REVIEW
96 NATURE CLINICAL PRACTICE ONCOLOGY SEIWERT ET AL. FEBRUARY 2007 VOL 4 NO 2
www.nature.com/clinicalpractice/onc
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
8/2/2019 Review Radiation Cemo
12/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 97
www.nature.com/clinicalpractice/onc
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)
References
1 Steel GG and Peckham MJ (1979) Exploitable
mechanisms in combined radiotherapy-
chemotherapy: the concept of additivity. Int J Radiat
Oncol Biol Phys5: 8591
2 Brizel DM et al. (2000) Phase III randomized trial of
amifostine as a radioprotector in head and neck
cancer.J Clin Oncol18: 33393345
3 Buentzel J et al. (2006) Intravenous amifostine during
chemoradiotherapy for head-and-neck cancer:
a randomized placebo-controlled phase III study.
Int J Radiat Oncol Biol Phys64: 684691
4 Komaki R et al. (2004) Effects of amifostine
on acute toxicity from concurrent chemotherapy
and radiotherapy for inoperable non-small-cell lung
cancer: report of a randomized comparative trial.
Int J Radiat Oncol Biol Phys58: 13691377
5 Malik R et al. (2005) Meta-analysis of the effect of
amifostine on response rates in advanced non-small
cell lung cancer patients treated on randomized trials.
Int J Radiat Oncol Biol Phys63 (Suppl 1): S117
6 Sasse AD et al. (2006) Amifostine reduces side
effects and improves complete response rate during
radiotherapy: results of a meta-analysis. Int J Radiat
Oncol Biol Phys64: 784791
7 Grdina DJ et al. (2002) Radioprotectants: currentstatus and new directions. Oncology63 (Suppl 2):
S2S10
8 Stiff PJ et al. (2006) Palifermin reduces patient-
reported mouth and throat soreness and improves
patient functioning in the hematopoietic stem-cell
transplantation setting.J Clin Oncol [doi: 10.1200/
JCO.2005.02.8340]
9 Rosen LS et al. (2006) Palifermin reduces the
incidence of oral mucositis in patients with metastatic
colorectal cancer treated with fluorouracil-based
chemotherapy.J Clin Oncol24: 51945200
10 Giocanti N et al. (1993) DNA repair and cell cycle
interactions in radiation sensitization by the
topoisomerase II poison etoposide. Cancer Res53:
21052111
11 Hennequin C and Favaudon V (2002) Biological basis
for chemo-radiotherapy interactions. Eur J Cancer38:223230
12 Chou TC and Talalay P (1984) Quantitative analysis
of dose-effect relationships: the combined effects
of multiple drugs or enzyme inhibitors.Adv Enzyme
Regul22: 2755
13 Reynolds CP and Maurer BJ (2005) Evaluating
response to antineoplastic drug combinations in tissue
culture models. Methods Mol Med110: 173183
14 Teicher BA (2003) Assays for in vitro andin vivo
synergy. Methods Mol Med85: 297321
15 White DB et al. (2003) A new nonlinear mixture
response surface paradigm for the study of
synergism: a three drug example. Curr Drug Metab4:
399409
16 Coleman CN (1988) Hypoxia in tumors: a paradigm
for the approach to biochemical and physiologicheterogeneity.J Natl Cancer Inst80: 310317
17 Gray LH et al. (1953) The concentration of oxygen
dissolved in tissues at the time of irradiation as a
factor in radiotherapy. Br J Radiol26: 638648
18 Kumar P (2000) Tumor hypoxia and anemia: impact
on the efficacy of radiation therapy. Semin Hematol
37: 48
19 Overgaard J et al. (1989) Misonidazole combined with
split-course radiotherapy in the treatment of invasive
carcinoma of larynx and pharynx: report from the
DAHANCA 2 study. Int J Radiat Oncol Biol Phys16:
10651068
20 Moulder JE and Rockwell S (1984) Hypoxic fractions
of solid tumors: experimental techniques, methods
8/2/2019 Review Radiation Cemo
13/15
REVIEW
98 NATURE CLINICAL PRACTICE ONCOLOGY SEIWERT ET AL. FEBRUARY 2007 VOL 4 NO 2
www.nature.com/clinicalpractice/onc
of analysis, and a survey of existing data. Int J Radiat
Oncol Biol Phys10: 695712
21 Terasima T and Tolmach LJ (1963) X-ray sensitivity
and DNA synthesis in synchronous populations of
HeLa cells. Science140: 490492
22 Fowler JF and Lindstrom MJ (1992) Loss of local
control with prolongation in radiotherapy. Int J Radiat
Oncol Biol Phys23: 457467
23 Trott KR and Kummermehr J (1985) What is known
about tumour proliferation rates to choose between
accelerated fractionation or hyperfractionation?
Radiother Oncol3: 19
24 Krause M et al. (2005) Decreased repopulation
as well as increased reoxygenation contribute to
the improvement in local control after targeting of
the EGFR by C225 during fractionated irradiation.
Radiother Oncol76: 162167
25 Grillo-Ruggieri F and Mantello G (2004) Is one Gy
equal to one Gy after treatment interruptions? Rays
29: 275278
26 Schmidt-Ullrich RK et al. (1999) Molecular
mechanisms of radiation-induced accelerated
repopulation. Radiat Oncol Investig7: 321330
27 West CM et al. (1997) The independence of intrinsic
radiosensitivity as a prognostic factor for patient
response to radiotherapy of carcinoma of the cervix.Br J Cancer76: 11841190
28 Deacon J et al. (1984) The radioresponsiveness of
human tumours and the initial slope of the cell survival
curve. Radiother Oncol2: 317323
29 Dey S et al. (2003) Low-dose fractionated radiation
potentiates the effects of paclitaxel in wild-type and
mutant p53 head and neck tumor cell lines. Clin
Cancer Res9: 15571565
30 Nix PA et al. (2004) Radioresistant laryngeal cancer:
beyond the TNM stage. Clin Otolaryngol Allied Sci29:
105114
31 Smith BD and Haffty BG (1999) Molecular markers
as prognostic factors for local recurrence and
radioresistance in head and neck squamous cell
carcinoma. Radiat Oncol Investig7: 125144
32 Aebersold DM et al. (2001) Involvement of the
hepatocyte growth factor/scatter factor receptor
c-met and of Bcl-xL in the resistance of oropharyngeal
cancer to ionizing radiation. Int J Cancer96: 4154
33 Uchida D et al. (2001) Role of HGF/c-met system
in invasion and metastasis of oral squamous cell
carcinoma cellsin vitro and its clinical significance. Int
J Cancer93: 489496
34 Khodarev NN et al. (2004) STAT1 is overexpressed
in tumors selected for radioresistance and confers
protection from radiation in transduced sensitive cells.
Proc Natl Acad Sci USA101: 17141719
35 Bennett CB et al. (1993) Lethality induced by a single
site-specific double-strand break in a dispensable
yeast plasmid. Proc Natl Acad Sci USA15: 1317
36 Ward JF (1998) Nature of lesions formed by ionising
radiation. In DNA damage and repair: DNA repair
in higher eukaryotes, 6584 (Eds Nickoloff JA andHoekstra MF). Totowa, NJ: Humana Press
37 Begg AC (1990) Cisplatin and radiation: interaction
probabilities and therapeutic possibilities. Int J Radiat
Oncol Biol Phys19: 11831189
38 Yang LX et al. (1995) Production of DNA double-
strand breaks by interactions between carboplatin
and radiation: a potential mechanism for
radiopotentiation. Radiat Res143: 309315
39 Sinclair WK and Morton RA (1966) X-ray sensitivity
during the cell generation cycle of cultured Chinese
hamster cells. Radiat Res29: 450474
40 Terasima T and Tolmach LJ (1961) Changes in x-ray
sensitivity of HeLa cells during the division cycle.
Nature190: 12101211
41 Wilson GD et al. (2006) Biologic basis for combining
drugs with radiation. Semin Radiat Oncol16: 29
42 Hei TK et al. (1994) Taxol and ionizing radiation:
interaction and mechanisms. Int J Radiat Oncol Biol
Phys29: 267271
43 Stromberg JS et al. (1995) Lack of radiosensitization
after paclitaxel treatment of three human carcinoma
cell lines. Cancer75: 22622268
44 Vaupel P (2004) Tumor microenvironmental
physiology and its implications for radiation oncology.
Semin Radiat Oncol14: 198206
45 Semenza GL (2003) Targeting HIF-1 for cancer
therapy. Nat Rev Cancer3: 721732
46 Milas L et al. (1995) Tumor reoxygenation as a
mechanism of taxol-induced enhancement of tumor
radioresponse.Acta Oncol34: 409412
47 Kim JJ and Tannock IF (2005) Repopulation of cancer
cells during therapy: an important cause of treatment
failure. Nat Rev Cancer5: 516525
48 Liang K et al. (2003) The epidermal growth factor
receptor mediates radioresistance. Int J Radiat Oncol
Biol Phys57: 246254
49 Bonner JA et al. (2006) Radiotherapy plus cetuximab
for squamous-cell carcinoma of the head and neck.
N Engl J Med354: 567578
50 Spring PM et al. (2004) Low dose fractionatedradiation potentiates the effects of taxotere in nude
mice xenografts of squamous cell carcinoma of head
and neck. Cell Cycle3: 479485
51 Vokes EE and Weichselbaum RR (1990) Concomitant
chemoradiotherapy: rationale and clinical experience
in patients with solid tumors.J Clin Oncol8: 911934
52 Richmond RC (1984) Toxic variability and radiation
sensitization by dichlorodiammineplatinum(II)
complexes in Salmonella typhimurium cells. Radiat
Res99: 596608
53 Yang LX et al. (1995) Irradiation enhances cellular
uptake of carboplatin. Int J Radiat Oncol Biol Phys33:
641646
54 Amorino GP et al. (1999) Radiopotentiation by the oral
platinum agent, JM216: role of repair inhibition. Int J
Radiat Oncol Biol Phys44: 399405
55 Moreland NJ et al. (1999) Modulation of drug
resistance mediated by loss of mismatch repair by
the DNA polymerase inhibitor aphidicolin. Cancer Res
59: 21022106
56 Dolling JA et al. (1999) Cisplatin-modification of
DNA repair and ionizing radiation lethality in yeast,
Saccharomyces cerevisiae. Mutat Res433: 127136
57 Lawrence TS et al. (1997) Fluoropyrimidine-radiation
interactions in cells and tumors. Semin Radiat Oncol
7: 260266
58 McGinn CJ and Lawrence TS (2001) Recent
advances in the use of radiosensitizing nucleosides.
Semin Radiat Oncol11: 270280
59 Pinedo HM and Peters GF (1988) Fluorouracil:
biochemistry and pharmacology.J Clin Oncol6:
16531664
60 Sawada N et al. (1999) X-ray irradiation inducesthymidine phosphorylase and enhances the efficacy
of capecitabine (Xeloda) in human cancer xenografts.
Clin Cancer Res5: 29482953
61 Hui YF and Reitz J (1997) Gemcitabine: a cytidine
analogue active against solid tumors.Am J Health
Syst Pharm54: 162170
62 Crane CH et al. (2002) Is the therapeutic index
better with gemcitabine-based chemoradiation than
with 5-fluorouracil-based chemoradiation in locally
advanced pancreatic cancer? Int J Radiat Oncol Biol
Phys52: 12931302
63 Blackstock AW et al. (2005) Initial pulmonary toxicity
evaluation of chemoradiotherapy (CRT) utilizing 74 Gy
3-dimensional (3-D) thoracic radiation in stage III
8/2/2019 Review Radiation Cemo
14/15
REVIEW
FEBRUARY 2007 VOL 4 NO 2 SEIWERT ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 99
www.nature.com/clinicalpractice/onc
non-small cell lung cancer (NSCLC): a Cancer and
Leukemia Group B (CALGB) randomized phase II trial
[abstract #7060]. Presented at the 2005 ASCO annual
meeting, Orlando, FL
64 Talamonti MS et al. (2006) A multi-institutional phase
II trial of preoperative full-dose gemcitabine and
concurrent radiation for patients with potentially
resectable pancreatic carcinoma.Ann Surg Oncol13:
150158
65 Lawrence TS et al. (2003) The mechanism of action of
radiosensitization of conventional chemotherapeutic
agents. Semin Radiat Oncol13: 1321
66 Lawrence TS et al. (1997) Delayed radiosensitization
of human colon carcinoma cells after a brief exposure
to 2',2'-difluoro-2'-deoxycytidine (Gemcitabine). Clin
Cancer Res3: 777782
67 Shewach DS and Lawrence TS (1996) Gemcitabine
and radiosensitization in human tumor cells. Invest
New Drugs14: 257263
68 Bischof M et al. (2002) Interaction of pemetrexed
disodium (ALIMTA, multitargeted antifolate) and
irradiationin vitro. Int J Radiat Oncol Biol Phys52:
13811388
69 Bischof M et al. (2003) Radiosensitization by
pemetrexed of human colon carcinoma cells in
different cell cycle phases. Int J Radiat Oncol BiolPhys57: 289292
70 Seiwert TY et al. (2005) A phase I dose-escalating
study of combination pemetrexed-based
chemotherapy and concomitant radiotherapy for
locally advanced or metastatic non-small cell lung or
esophageal cancer [abstract #7062]. Presented at the
2005 ASCO annual meeting, Orlando, FL
71 Vokes EE et al. (1992) Hydroxyurea with concomitant
radiotherapy for locally advanced head and neck
cancer. Semin Oncol19: 5358
72 Kuo ML et al. (1997) The interaction of hydroxyurea
and ionizing radiation in human cervical carcinoma
cells. Cancer J Sci Am3: 163173
73 Prados MD et al. (1998) Radiation therapy and
hydroxyurea followed by the combination of 6-
thioguanine and BCNU for the treatment of primary
malignant brain tumors. Int J Radiat Oncol Biol Phys
40: 5763
74 Leyden D et al. (2000) Hydroxyurea and trimidox
enhance the radiation effect in human pancreatic
adenocarcinoma cells.Anticancer Res20: 133138
75 Schiff PB and Horwitz SB (1980) Taxol stabilizes
microtubules in mouse fibroblast cells. Proc Natl
Acad Sci USA77: 15611565
76 Hennequin C et al. (1995) S-phase specificity of cell
killing by docetaxel (Taxotere) in synchronised HeLa
cells. Br J Cancer71: 11941198
77 Steel GG (1994) Cell synchronization unfortunately
may not benefit cancer therapy. Radiother Oncol32:
9597
78 Ingram ML and Redpath JL (1997) Subadditive
interaction of radiation and Taxolin vitro. Int J Radiat
Oncol Biol Phys37: 1139114479 Heinrich MC et al. (1998) DNA cross-linker-
induced G2/M arrest in group C Fanconi anemia
lymphoblasts reflects normal checkpoint function.
Blood91: 275287
80 Sugiyama K et al. (2000) UCN-01 selectively
enhances mitomycin C cytotoxicity in p53 defective
cells which is mediated through S and/or G(2)
checkpoint abrogation. Int J Cancer85: 703709
81 Budach W et al. (2002) Mitomycin C in combination
with radiotherapy as a potent inhibitor of tumour cell
repopulation in a human squamous cell carcinoma.
Br J Cancer86: 470476
82 Wouters BG et al. (1999) Tirapazamine: a new drug
producing tumor specific enhancement of platinum-
based chemotherapy in non-small-cell lung cancer.
Ann Oncol10 (Suppl 5): S29S33
83 Brown JM and Lemmon MJ (1990) Potentiation by the
hypoxic cytotoxin SR 4233 of cell killing produced by
fractionated irradiation of mouse tumors. Cancer Res
50: 77457749
84 Lartigau E and Guichard M (1995) Does tirapazamine
(SR-4233) have any cytotoxic or sensitizing effect on
three human tumour cell lines at clinically relevant
partial oxygen pressure? Int J Radiat Biol67: 211216
85 Lambin P et al. (1992) The effect of the hypoxic cell
drug SR-4233 alone or combined with the ionizing
radiations on two human tumor cell lines having
different radiosensitivity. Radiother Oncol24: 201204
86 Brown JM and Koong A (1991) Therapeutic
advantage of hypoxic cells in tumors: a theoretical
study.J Natl Cancer Inst83: 178185
87 Brown JM (1993) SR 4233 (tirapazamine): a new
anticancer drug exploiting hypoxia in solid tumours.
Br J Cancer67: 11631170
88 Brown JM (1999) The hypoxic cell: a target for
selective cancer therapyeighteenth Bruce F Cain
Memorial Award lecture. Cancer Res59: 58635870
89 Wouters BG et al. (2001) Mitochondrial dysfunction
after aerobic exposure to the hypoxic cytotoxin
tirapazamine. Cancer Res61: 14515290 Patel M et al. (2003) Plasma and cerebrospinal fluid
pharmacokinetics of intravenous temozolomide in
non-human primates.J Neurooncol61: 203207
91 Hickman MJ and Samson LD (1999) Role of DNA
mismatch repair and p53 in signaling induction of
apoptosis by alkylating agents. Proc Natl Acad Sci
USA96: 1076410769
92 Roos W et al. (2004) Apoptosis triggered by DNA
damage O6-methylguanine in human lymphocytes
requires DNA replication and is mediated by p53 and
Fas/CD95/Apo-1.Oncogene23: 359367
93 Hermisson M et al. (2006) O6-methylguanine
DNA methyltransferase and p53 status predict
temozolomide sensitivity in human malignant glioma
cells.J Neurochem96: 766776
94 Wick W et al. (2002) Prevention of irradiation-induced
glioma cell invasion by temozolomide involves
caspase 3 activity and cleavage of focal adhesion
kinase. Cancer Res62: 19151919
95 Beauchesne P (2002) Promising survival and
concomitant radiation plus temozolomide followed by
adjuvant temozolomide.J Clin Oncol20: 31803181
96 Wedge SR et al. (1997) In vitro evaluation of
temozolomide combined with X-irradiation.
Anticancer Drugs8: 9297
97 van Rijn J et al. (2000) Survival of human glioma cells
treated with various combination of temozolomide
and X-rays. Int J Radiat Oncol Biol Phys47: 779784
98 Salama JK (2004) Intensity-modulated radiation
therapy in gynecologic malignancies. Curr Treat
Options Oncol5: 97108
99 Ma BB et al. (2003) Combined-modality treatment
of solid tumors using radiotherapy and moleculartargeted agents.J Clin Oncol21: 27602776
100 Ang KK et al. (2004) Epidermal growth factor receptor
and response of head-and-neck carcinoma to
therapy. Int J Radiat Oncol Biol Phys58: 959965
101 Pal SK and Pegram M (2005) Epidermal growth factor
receptor and signal transduction: potential targets for
anti-cancer therapy.Anticancer Drugs16: 483494
102 Dent P et al. (1999) Radiation-induced release of
transforming growth factor alpha activates the
epidermal growth factor receptor and mitogen-
activated protein kinase pathway in carcinoma cells,
leading to increased proliferation and protection
from radiation-induced cell death. Mol Biol Cell10:
24932506
8/2/2019 Review Radiation Cemo
15/15
REVIEW
www.nature.com/clinicalpractice/onc
103 Chinnaiyan P et al. (2005) Mechanisms of enhanced
radiation response following epidermal growth factor
receptor signaling inhibition by erlotinib (Tarceva).
Cancer Res65: 33283335
104 Bandyopadhyay D (1998) Physical interaction
between epidermal growth factor receptor and DNA-
dependent protein kinase in mammalian cells.J Biol
Chem273: 15681573
105 Dittmann KH et al. (2001) Characterization of the amino
acids essential for the photo- and radioprotective
effects of a Bowman-Birk protease inhibitor-derived
nonapeptide. Protein Eng14: 157160
106 Milas Let al. (2000) In vivo enhancement of tumor
radioresponse by C225 antiepidermal growth factor
receptor antibody. Clin Cancer Res6: 701708
107 Bonner JA et al. (2000) Enhanced apoptosis with
combination C225/radiation treatment serves as the
impetus for clinical investigation in head and neck
cancers.J Clin Oncol18 (Suppl): 47S53S
108 Folkman J (2006) Angiogenesis.Annu Rev Med57:
118
109 Jain RK (2005) Normalization of tumor vasculature: an
emerging concept in antiangiogenic therapy. Science
307: 5862
110 Wachsberger P et al. (2003) Tumor response to
ionizing radiation combined with antiangiogenesis orvascular targeting agents: exploring mechanisms of
interaction. Clin Cancer Res9: 19571971
111 Murata Ret al. (1997) An antiangiogenic agent
(TNP-470) inhibited reoxygenation during fractionated
radiotherapy of murine mammary carcinoma. Int J
Radiat Oncol Biol Phys37: 11071113
112 Mauceri HJ et al. (1998) Combined effects of
angiostatin and ionizing radiation in antitumour
therapy. Nature394: 287291
113 Ning S et al. (2002) The antiangiogenic agents
SU5416 and SU6668 increase the antitumor effects
of fractionated irradiation. Radiat Res157: 4551
114 Hanna NNet al. (2000) Antitumor interaction
of short-course endostatin and ionizing radiation.
Cancer J6: 287293
115 Birchmeier C et al. (2003) Met, metastasis, motility
and more. Nat Rev Mol Cell Biol4: 915925
116 Lal B et al. (2005) Targeting the c-Met pathway
potentiates glioblastoma responses to gamma-
radiation. Clin Cancer Res11: 44794486
117 Senzer N et al. (2005) Updated response and survival
data for TNFerade combined with chemoradiation in
the treatment of locally advanced pancreatic cancer
(LAPC) [abstract #4097]. Presented at the 2005 ASCO
annual meeting, Orlando, FL
118 Russo SM et al. (2001) Enhancement of radiosensitivity
by proteasome inhibition: implications for a role of
NF-kappaB. Int J Radiat Oncol Biol Phys50: 183193
119 Shinohara ET et al. (2005) Enhanced radiation
damage of tumor vasculature by mTOR inhibitors.
Oncogene24: 54145422
120 Nishimura Y (2004) Rationale for chemoradiotherapy.
Int J Clin Oncol9: 414420
121 Pigott Ket al. (1995) Where exactly does failure occur
after radiation in head and neck cancer? Radiother
Oncol37: 1719
122 Shukovsky LJ (1970) Dose, time, volume
relationships in squamous cell carcinoma of the
supraglottic larynx.Am J Roentgenol Radium Ther
Nucl Med108: 2729
123 Cook JAet al. (2004) Oxidative stress, redox, and the
tumor microenvironment. Semin Radiat Oncol14:
259266
124 Milosevic M et al. (2004) The human tumor
microenvironment: invasive (needle) measurement of
oxygen and interstitial fluid pressure. Semin Radiat
Oncol14: 249258
125 Roh HD et al. (1991) Interstitial hypertension in
carcinoma of uterine cervix in patients: possible
correlation with tumor oxygenation and radiation
response. Cancer Res51: 66956698
126 Taghian AG et al. (2005) Paclitaxel decreases the
interstitial fluid pressure and improves oxygenation in
breast cancers in patients treated with neoadjuvantchemotherapy: clinical implications.J Clin Oncol23:
19511961
127 Koukourakis MI et al. (2002) Hypoxia-inducible
factor (HIF1A and HIF2A), angiogenesis, and
chemoradiotherapy outcome of squamous cell head-
and-neck cancer. Int J Radiat Oncol Biol Phys53:
11921202
128 Suwinski R and Withers HR (2003) Time factor and
treatment strategies in subclinical disease. Int J
Radiat Biol79: 495502
129 Holsinger FC et al. (2003) Epidermal growth factor
receptor blockade potentiates apoptosis mediated by
Paclitaxel and leads to prolonged survival in a murine
model of oral cancer. Clin Cancer Res9: 31833189
130 Knecht Ret al. (2003) EGFR antibody-supplemented
TPE-chemotherapy: preclinical investigations to a
novel approach for head and neck cancer induction
treatment.Anticancer Res23: 47894795
131 Niwa H et al. (2003) Antitumor effects of epidermal
growth factor receptor antisense oligonucleotides
in combination with docetaxel in squamous cell
carcinoma of the head and neck. Clin Cancer Res9:
50285035
132 Cohen EE (2005) Integration of Gefitinib (G), into a
Concurrent Chemoradiation (CRT) Regimen Followed
by G Adjuvant Therapy in Patients with Locally
Advanced Head and Neck Cancer (HNC)a Phase II
Trial [abstract #5506].J Clin Oncol 23 (Suppl): 16S
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.