Alkylating agents Platinating agents Antimetabolites Topoisomerase inhibitors

www.rwww.radbioladbiol.ucla.ed.ucla.eduu

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Interaction of RT with CT Interaction of RT with CT and other Agentsand other Agents

Bill McBrideBill McBrideDept. Radiation OncologyDept. Radiation Oncology

David Geffen School MedicineDavid Geffen School MedicineUCLA, Los Angeles, Ca.UCLA, Los Angeles, [email protected]@mednet.ucla.edu


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• Alkylating agentsAlkylating agents• Platinating agentsPlatinating agents• AntimetabolitesAntimetabolites• Topoisomerase inhibitorsTopoisomerase inhibitors• Anti-microtubular agentsAnti-microtubular agents• MiscellaneousMiscellaneous

Classes of Chemotherapy Classes of Chemotherapy AgentsAgents


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•Alkylating agentsAlkylating agents• Nitrogen mustard derivatives: Nitrogen mustard derivatives: cyclophosphamide, cyclophosphamide, chlorambucil, melphalan, ifosfamide, mechlorethaminechlorambucil, melphalan, ifosfamide, mechlorethamine

• Ethylenimines: Ethylenimines: Thiotepa and HexamethylmelamineThiotepa and Hexamethylmelamine

• Nitrosoureas: Nitrosoureas: BCNU (carmustine), CCNU (lomustine), BCNU (carmustine), CCNU (lomustine), StreptozocinStreptozocin

• Alkylsulfonates: Alkylsulfonates: BusulfanBusulfan

• Hydrazines and Triazines: Hydrazines and Triazines: altretamine, altretamine, procarbazine, dacarbazine, temodarprocarbazine, dacarbazine, temodar

• Highly reactive alkyl groups (e.g. —CHHighly reactive alkyl groups (e.g. —CH22Cl) Cl) covalently bind to intracellular covalently bind to intracellular macromolecule, such as DNAmacromolecule, such as DNA

• Bifunctional crosslink are more effective Bifunctional crosslink are more effective (interstrand DNA crosslinks)(interstrand DNA crosslinks)

• Limited cell cycle specificity, carcinogenicLimited cell cycle specificity, carcinogenic

Classes of AgentsClasses of Agents


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• Platinating agentsPlatinating agents• Cisplatin, Carboplatin, oxiplatinCisplatin, Carboplatin, oxiplatin• Exist in 2+ oxidation state with 4 groups Exist in 2+ oxidation state with 4 groups

that interact with DNA (95% intrastrand 5% that interact with DNA (95% intrastrand 5% interstrand cross-linkages)interstrand cross-linkages)

• Nausea, vomiting, kidney toxicity, less Nausea, vomiting, kidney toxicity, less myelosuppression than with alkylating myelosuppression than with alkylating agentsagents



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•AntimetabolitesAntimetabolites• Purine/pyrimidine analogsPurine/pyrimidine analogs•5-FU, cytosine arabinoside, gemcitabine, 5-FU, cytosine arabinoside, gemcitabine, iododeoxyuridineiododeoxyuridine

• AntifolatesAntifolates•MethotrexateMethotrexate

• interfere with normal cell function (e.g. interfere with normal cell function (e.g. DNA synthesis)DNA synthesis)

• Cell cycle specific, tend to cause DNA Cell cycle specific, tend to cause DNA damage and block repair, less carcinogenic damage and block repair, less carcinogenic than alkylating agentsthan alkylating agents



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•Topoisomerase inhibitorsTopoisomerase inhibitors• Topo I inhibitorsTopo I inhibitors

• Camptothecin derivatives such as topotecan, Camptothecin derivatives such as topotecan, irinotecan (CPT11)irinotecan (CPT11)

• Topo II inhibitors Topo II inhibitors • Epipodophyllotoxins such as etoposide, Epipodophyllotoxins such as etoposide, teniposideteniposide

• Topo II inhibitors plus other effectsTopo II inhibitors plus other effects• Anthracyclines such as daunorubicin, doxorubicin Anthracyclines such as daunorubicin, doxorubicin (Adriamycin), idarubicin, epirubicin(Adriamycin), idarubicin, epirubicin

• Topoisomerases relax dsDNA to allow Topoisomerases relax dsDNA to allow replication/transcription by single (I) or replication/transcription by single (I) or double (II) strand nick. DSBs form when double (II) strand nick. DSBs form when the replication fork meets the DNA/topo the replication fork meets the DNA/topo cleavable complex - in S phasecleavable complex - in S phase



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• Antimicrotubular agentsAntimicrotubular agents• Vinca alkaloidsVinca alkaloids• Taxanes: paclitaxel (Taxol), docetaxel Taxanes: paclitaxel (Taxol), docetaxel

(Taxotere)(Taxotere)• Bind to tubulins (different site) and Bind to tubulins (different site) and

inhibit microtubular disassemblyinhibit microtubular disassembly• Cause G2M arrestCause G2M arrest



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OthersOthers

• Proteasome InhibitorsProteasome Inhibitors • Bortezumib, Velcade, PS-341Bortezumib, Velcade, PS-341• Boronic acid dipeptideBoronic acid dipeptide• Inhibits proteasome core chymotryptic activity reversiblyInhibits proteasome core chymotryptic activity reversibly• Effective in drug refractory multiple myelomaEffective in drug refractory multiple myeloma• CausesCauses

– Cell cycle arrestCell cycle arrest– Apoptosis of cancer cellsApoptosis of cancer cells– ImmunosuppressionImmunosuppression– Anti-inflammatoryAnti-inflammatory– Anti-angiogenesisAnti-angiogenesis– Downregulation of NF-Downregulation of NF-B (and many other signal B (and many other signal transduction molecules)transduction molecules)

• Radiosensitizer and chemosensitizerRadiosensitizer and chemosensitizer


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Chemotherapeutic ConsiderationsChemotherapeutic Considerations

•PharmacokineticsPharmacokinetics•Concentration of metabolites Concentration of metabolites over timeover time• Absorption, Distribution, Absorption, Distribution, Metabolism, EliminationMetabolism, Elimination

•PharmacodynamicsPharmacodynamics•Cellular response to drugCellular response to drug


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• PharmacokineticsPharmacokinetics• Concentration of metabolites over Concentration of metabolites over timetime• Normally measured by the area under the Normally measured by the area under the concentration/time curveconcentration/time curve

• However, maintaining a certain level may However, maintaining a certain level may be more important for some drugs than be more important for some drugs than othersothers• Continuous delivery better than bolus Continuous delivery better than bolus

• Topo I inhibitors, anti-Topo I inhibitors, anti-metabolites, taxanesmetabolites, taxanes


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•PharmacokineticsPharmacokinetics• Absorption, Distribution, Metabolism, Absorption, Distribution, Metabolism, EliminationElimination• AbsorptionAbsorption

• Depends on route of administrationDepends on route of administration• Intravenous route preferred for Intravenous route preferred for pharmacokinetic reasonspharmacokinetic reasons

• Oral is best for some eg TemozolomideOral is best for some eg Temozolomide• Regional delivery may be more effective Regional delivery may be more effective (glioma)(glioma)

• Influenced by physical form and barriers to Influenced by physical form and barriers to penetration/absorption e.g. blood-brain penetration/absorption e.g. blood-brain barrierbarrier

• DistributionDistribution• Requires blood/fluid flow to Requires blood/fluid flow to organs/tissues/tumororgans/tissues/tumor

• Diffusion kineticsDiffusion kinetics• Size and chemical formSize and chemical form• Protein and tissue binding, lipid Protein and tissue binding, lipid solubility, pH, etc.solubility, pH, etc.


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•PharmacokineticsPharmacokinetics•MetabolismMetabolism• Phase 1 active metabolites often produced in liverPhase 1 active metabolites often produced in liver• Phase II inactive metabolites produced by Phase II inactive metabolites produced by conjugationconjugation

• Some drugs requires activation (cyclophosphamide)Some drugs requires activation (cyclophosphamide)• Influenced by genetic polymorphisms (5-FU - Influenced by genetic polymorphisms (5-FU - dihydropyrimidine dehydrogenase deficiency is toxic dihydropyrimidine dehydrogenase deficiency is toxic and high thymidylate synthase levels decrease and high thymidylate synthase levels decrease efficacy)efficacy)

• Liver function affects metabolism Liver function affects metabolism •ExcretionExcretion• Primarily in kidney or biliary tractPrimarily in kidney or biliary tract• Phase I active metabolites (carboplatin) or Phase Phase I active metabolites (carboplatin) or Phase II metabolites (doxorubicin) can give toxicityII metabolites (doxorubicin) can give toxicity

• Kidney function affects clearanceKidney function affects clearance• Influenced by protein and tissue binding, lipid Influenced by protein and tissue binding, lipid solubility, pH, etc.solubility, pH, etc.•Doxorubicin slow release is due to high lipid solubilityDoxorubicin slow release is due to high lipid solubility


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• PharmacodynamicsPharmacodynamics• Cellular response to drug Cellular response to drug depends ondepends on• MicroenvironmentMicroenvironment• Cell cycle phaseCell cycle phase• Drug resistance mechanismsDrug resistance mechanisms• Intracellular metabolismIntracellular metabolism• Sensitivity to cell death/survival Sensitivity to cell death/survival pathwayspathways

• Difficult to get predictors from Difficult to get predictors from in vitro survival datain vitro survival data


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MicroenvironmentMicroenvironment

0.001

0.01

0.1

1

10

0 50 100 150 200 250

Surviving fraction

µg/ml bleomycin

AeratedAerated

Bleomycin, Bleomycin, procarbazine,dactinomyciprocarbazine,dactinomycinn

HypoxicHypoxic

less sensitiveless sensitive

10

µM mitomycin

Aerated

Mitomycin C, misonidazole, metronidazole, etanidazole, tirapazamine, doxorubicin

Hypoxic

more sensitivemore sensitive

0.001

0.01

0.1

1

10

0 2 4 6 8Surviving fraction


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Cell CycleCell Cycle

G1/S phaseG1/S phaseAlkylating Alkylating Agents, Agents,

CisplatinCisplatin

M PhaseM PhaseAlkylatingAlkylating

AgentsAgentsG2 phaseG2 phasePaclitaxelPaclitaxelBleomycinBleomycin

S phaseS phaseDocetaxelDocetaxel

MethotrexateMethotrexateAra-C, 6TG,Ara-C, 6TG,HydroxyureaHydroxyureaVinblastineVinblastineDoxorubicinDoxorubicin

G0 - quiescenceG0 - quiescence


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MechanismMechanismDecreased uptakeDecreased uptakeIncreased effluxIncreased efflux

Decrease in drug Decrease in drug activationactivation

Increase in drug Increase in drug catabolismcatabolism

Increase or decrease in Increase or decrease in levels of target levels of target moleculemolecule

Alterations in target Alterations in target moleculemolecule

Inactivation by binding Inactivation by binding to sulfhydryls (e.g. to sulfhydryls (e.g. glutathione)glutathione)

Increased DNA repairIncreased DNA repair

Decreased ability to Decreased ability to undergo apoptosisundergo apoptosis

DrugsDrugsMethotrexate, melphalan, Methotrexate, melphalan,

cisplatincisplatinAnthracyclines, vinca Anthracyclines, vinca

alkaloids, etoposide, alkaloids, etoposide, taxanestaxanes

Many antimetabolitesMany antimetabolitesMany antimetabolitesMany antimetabolitesMethotrexate, topoisomerase Methotrexate, topoisomerase

inhibitorsinhibitors

Methotrexate, other Methotrexate, other antimetabolites, antimetabolites, topoisomerase inhibitors, topoisomerase inhibitors, GleevecGleevec

Alkylating agents, cisplatin, Alkylating agents, cisplatin, anthracyclinesanthracyclines

Alkylating agents, cisplatin, Alkylating agents, cisplatin, anthracyclines, etoposideanthracyclines, etoposide

Alkylating agents, cisplatin, Alkylating agents, cisplatin, anthracyclines, etoposideanthracyclines, etoposide

Mechanisms of Drug ResistanceMechanisms of Drug Resistance


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Mechanisms of Drug ResistanceMechanisms of Drug Resistance

• Impaired drug influxImpaired drug influx•passive diffusion passive diffusion •energy & temperature independentenergy & temperature independent

•facilitated diffusion facilitated diffusion •transport carrier on membrane transport carrier on membrane •energy & temperature independentenergy & temperature independent

•active transport active transport •carrier-mediated processcarrier-mediated process•energy & temperature dependentenergy & temperature dependent•reduced folate carrier - mutation?reduced folate carrier - mutation?•Melphalan Melphalan binding affinity for drug binding affinity for drug and and number of transport sites / slower number of transport sites / slower carrier mobilitycarrier mobility


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Mechanisms of Drug ResistanceMechanisms of Drug Resistance• Increased drug effluxIncreased drug efflux• Many natural drugs/derivatives (taxanes, Many natural drugs/derivatives (taxanes, vinca alkaloids, anthracyclines) have vinca alkaloids, anthracyclines) have shared mechanisms of resistance, e.g. shared mechanisms of resistance, e.g. substrates for membrane-based ATPase-substrates for membrane-based ATPase-dependent proteins (pumps)dependent proteins (pumps)

• P-glycoprotein (P-glycoprotein (mdr1mdr1))• High levels in kidney & adrenals; High levels in kidney & adrenals; intermediate in lung, liver, colon and intermediate in lung, liver, colon and rectumrectum

• Co-specificity with proteasome enzymesCo-specificity with proteasome enzymes• InhibitorsInhibitors• Calcium channel blockers (verapamil)Calcium channel blockers (verapamil)• Cyclosporin ACyclosporin A• Tariquidar, zosuquidar (phase 1/2)Tariquidar, zosuquidar (phase 1/2)


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Summary of Drug TherapySummary of Drug Therapy

• Plethora of cytotoxic agentsPlethora of cytotoxic agents• Selective (not exclusive) targets - Selective (not exclusive) targets - proliferating cellsproliferating cells

• Major problem: drug resistanceMajor problem: drug resistance• Principal mechanismsPrincipal mechanisms

• altered membrane transport (P-glycoprotein);altered membrane transport (P-glycoprotein);• altered target enzyme (mutated topoisomerase II)altered target enzyme (mutated topoisomerase II)• decreased drug activationdecreased drug activation• increased drug degradation (e.g. altered increased drug degradation (e.g. altered expression of drug-metabolizing enzyme)expression of drug-metabolizing enzyme)

• drug inactivation (conjugation with glutathione)drug inactivation (conjugation with glutathione)• drug interactionsdrug interactions• enhanced DNA repair; failure to apoptose (e.g. enhanced DNA repair; failure to apoptose (e.g. mutation of p53)mutation of p53)


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How Effective is CT - and how How Effective is CT - and how is it best combined with RT?is it best combined with RT?

• Responses are often referred to as PR or CR. Responses are often referred to as PR or CR. – Defined by the endpoint - Defined by the endpoint - pathology/imaging/clinicalpathology/imaging/clinical

– If a tumor has 10If a tumor has 101010 cells, a PR may decrease this cells, a PR may decrease this to 2x10to 2x1099, which is not much of an improvement., which is not much of an improvement.

• Patients in complete remission can have anywhere Patients in complete remission can have anywhere between 0-10between 0-1099 cells as a tumor burden. If 10yr cells as a tumor burden. If 10yr relapse-free survival is 30% without and 40-45% relapse-free survival is 30% without and 40-45% with adjuvant chemotherapy, as is the case in with adjuvant chemotherapy, as is the case in early breast cancer regimens, Withers calculated early breast cancer regimens, Withers calculated that this represents about 2 logs of tumor cell that this represents about 2 logs of tumor cell kill – easy to achieve with RT.kill – easy to achieve with RT.

• Neoadjuvant chemotherapy may cause accelerated Neoadjuvant chemotherapy may cause accelerated tumor repopulation! Concomitant delivery of drugs tumor repopulation! Concomitant delivery of drugs with RT is often better than sequential delivery. with RT is often better than sequential delivery.


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Therapeutic IndexTherapeutic Index

• Need to increase therapeutic indexNeed to increase therapeutic index • Bone marrow major toxicityBone marrow major toxicity• Normally treat to MTD, except for Normally treat to MTD, except for palliative cases (5-FU for palliative cases (5-FU for advanced colorectal Ca)advanced colorectal Ca)

• Some tumors are drug Some tumors are drug ““resistantresistant”” others are others are ““sensitivesensitive”” but recur - but recur - are the cancer stem cells being are the cancer stem cells being killed? Many seem to have enhanced killed? Many seem to have enhanced drug efflux pumps…..drug efflux pumps…..


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Combination TherapiesCombination Therapies• CT combinationsCT combinations

− Different classes of agents Different classes of agents with minimally overlapping with minimally overlapping toxicitiestoxicities

• RT plus CTRT plus CT• Adjuvant therapy (P-glycoprotein Adjuvant therapy (P-glycoprotein

inhibitors)inhibitors)• Biological targeting + CT/RTBiological targeting + CT/RT


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Chemotherapy and RadiationChemotherapy and Radiation•Combination of chemotherapy and Combination of chemotherapy and radiation can increase cure rate, but radiation can increase cure rate, but also the potential for normal tissue also the potential for normal tissue toxicitytoxicity

•Dose Enhancement Ratio (DER)Dose Enhancement Ratio (DER)• Dose of radiation alone to produce an Dose of radiation alone to produce an effect divided by dose of radiation to effect divided by dose of radiation to give same effect in combination with druggive same effect in combination with drug

•Therapeutic Gain FactorTherapeutic Gain Factor• Ratio of DER for tumor to DER of dose-Ratio of DER for tumor to DER of dose-limiting normal tissuelimiting normal tissue


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Synergy vs. AdditivitySynergy vs. Additivity

Claims for synergy are often made if SClaims for synergy are often made if S11 = S = SAA x x SSBB

but this is only true if there is no but this is only true if there is no shoulder.shoulder.Tannock et al: The Basic Science of Oncology 4th Tannock et al: The Basic Science of Oncology 4th Ed.Ed.

SS11

0 1 2 3 4 5 6

Drug A + BDrug A + B

10-3

10-2

10-1

1

X??DDAA

0 1 2 3 4 5 6

DDAA

SSAA

1010-3-3

1010-2-2

1010-1-1

11 Drug ADrug A

1010-3-3

1010-2-2

1010-1-1

11 Drug BDrug B

DDBBSSBB

0 1 2 3 4 5 6

DDBB


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Dose of Agent B

Dose of Agent A

Supra-additiveSynergistic

Envelope of

Additivity

SubadditiveProtectiveAntagonistic

After Steel and Peckham, 1959

Isobologram AnalysisIsobologram Analysis


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ChemoRTChemoRT• Meta-analyses have shown that Meta-analyses have shown that chemotherapy (concomitant, neoadjuvant, chemotherapy (concomitant, neoadjuvant, adjuvant) improves survival in non-adjuvant) improves survival in non-metastatic HNSCC (other than NPC) by 4.4% metastatic HNSCC (other than NPC) by 4.4% at 5yrs. at 5yrs. – Bourhis et al PASCO 22:488, 2004Bourhis et al PASCO 22:488, 2004

• Concomitant gives an absolute benefit of Concomitant gives an absolute benefit of 6.5-8% at 5yrs, irrespective of 6.5-8% at 5yrs, irrespective of fractionation scheme although altered fractionation scheme although altered fractionation gives a survival advantage, fractionation gives a survival advantage, and is better than neoadjuvant. Platinum-and is better than neoadjuvant. Platinum-based regimens best. It comes with an based regimens best. It comes with an increase in early and late toxicity.increase in early and late toxicity.– Pignon et al IJROBP 69: S112, 2007 Pignon et al IJROBP 69: S112, 2007


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• Randomized Phase III Trial of Sequential Randomized Phase III Trial of Sequential Chemoradiotherapy Compared With Concurrent Chemoradiotherapy Compared With Concurrent Chemoradiotherapy in Locally Advanced Nonsmall-Cell Chemoradiotherapy in Locally Advanced Nonsmall-Cell Lung Cancer Lung Cancer

• Fournel et al Fournel et al Journal of Clinical OncologyJournal of Clinical Oncology, 23; 5910-, 23; 5910-5917, 2005.5917, 2005.

• Two hundred five patients were randomly assigned. PretreatmentTwo hundred five patients were randomly assigned. Pretreatment

characteristics were well balanced between the two arms. Therecharacteristics were well balanced between the two arms. There were were six toxic deaths in the sequential arm and 10 in the concurrentsix toxic deaths in the sequential arm and 10 in the concurrent arm. arm. Median survival was 14.5 months in the sequential arm andMedian survival was 14.5 months in the sequential arm and 16.3 16.3 months in the concurrent arm (log-rank test months in the concurrent arm (log-rank test PP = .24). = .24). Two-,Two-, 3-, and 3-, and 4-year survival rates were better in the concurrent4-year survival rates were better in the concurrent arm arm (39%, 25%, (39%, 25%, and 21%, respectively) than in the sequentialand 21%, respectively) than in the sequential arm (26%, 19%, and arm (26%, 19%, and 14%, respectively). 14%, respectively). Esophageal toxicity wasEsophageal toxicity was significantly more significantly more frequent in the concurrent arm than in thefrequent in the concurrent arm than in the sequential arm (32% sequential arm (32% vv 3%)3%). CONCLUSION: Although not statistically significant, clinically . CONCLUSION: Although not statistically significant, clinically importantimportant differences in the median, 2-, 3-, and 4-year survival differences in the median, 2-, 3-, and 4-year survival ratesrates were observed, with a trend in favor of concurrent were observed, with a trend in favor of concurrent chemoradiationchemoradiation therapy, therapy, suggesting that is the optimal strategy for suggesting that is the optimal strategy for patientspatients with locally advanced NSCLCwith locally advanced NSCLC..


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• Chemoradiation in the management of esophageal cancer.Chemoradiation in the management of esophageal cancer.• Kleinberg L, , Forastiere AA. . J Clin Oncol. 2007 Sep 10;25(26):4110-7 2007 Sep 10;25(26):4110-7• The combination of chemotherapy, fluorouracil and cisplatin, and The combination of chemotherapy, fluorouracil and cisplatin, and radiation has improved outcome for patients with esophageal cancer. radiation has improved outcome for patients with esophageal cancer. A randomized controlled trial confirmed a long-term survival A randomized controlled trial confirmed a long-term survival benefit when this chemotherapy was added to radiotherapy for benefit when this chemotherapy was added to radiotherapy for squamous cell carcinoma, but the approach has not been definitively squamous cell carcinoma, but the approach has not been definitively assessed in patients with adenocarcinoma. Preoperative assessed in patients with adenocarcinoma. Preoperative chemoradiotherapy has been tested in numerous phase II studies and chemoradiotherapy has been tested in numerous phase II studies and underpowered or flawed phase III studies. Nevertheless, underpowered or flawed phase III studies. Nevertheless, collectively, the evidence strongly suggests that preoperative collectively, the evidence strongly suggests that preoperative chemoradiotherapy improves outcome, and thus, this strategy has chemoradiotherapy improves outcome, and thus, this strategy has become a standard treatment option. Attempts to improve outcome by become a standard treatment option. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing the intensifying conventional cytotoxic drugs or increasing the radiation dose have not been successful. Camptothecin and taxane-radiation dose have not been successful. Camptothecin and taxane-based regimens combined with radiation have altered the toxicity based regimens combined with radiation have altered the toxicity profile, but substantial improvement in survival outcomes has yet profile, but substantial improvement in survival outcomes has yet to be demonstrated. to be demonstrated. Future improvements will likely require the Future improvements will likely require the incorporation of targeted agents that add minimally to existing incorporation of targeted agents that add minimally to existing toxicity, the use of molecular predictors of response to toxicity, the use of molecular predictors of response to individualize selection of the chemotherapeutic regimen, and early individualize selection of the chemotherapeutic regimen, and early identification of responders such that therapy might be altered identification of responders such that therapy might be altered dynamically.dynamically.


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• Phase III Study of Concurrent Chemoradiotherapy Versus Phase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free SurvivalPositive Effect on Overall and Progression-Free Survival

• Lin et al.Lin et al. Journal of Clinical Oncology Journal of Clinical Oncology 21: 631-637, 2003 21: 631-637, 2003• Two cycles of concurrent chemotherapyTwo cycles of concurrent chemotherapy with cisplatin 20 with cisplatin 20

mg/mmg/m22/dy plus fluorouracil 400 mg/m/dy plus fluorouracil 400 mg/m22/d by 96-hour/d by 96-hour continuous continuous infusion during the weeks 1 and 5 of RT. Median follow-up of infusion during the weeks 1 and 5 of RT. Median follow-up of 65 months, 26.2% (3765 months, 26.2% (37 of 141) and 46.2% (66 of 143) of of 141) and 46.2% (66 of 143) of patients developed tumor relapsepatients developed tumor relapse in the CCRT and RT-alone in the CCRT and RT-alone groups, respectively. The 5-year overallgroups, respectively. The 5-year overall survival rates were survival rates were 72.3% for the CCRT arm and 54.2% for the72.3% for the CCRT arm and 54.2% for the RT-only arm (RT-only arm (PP = .0022). The 5-year progression-free survival= .0022). The 5-year progression-free survival rates were rates were 71.6% for the CCRT group compared with 53.0% for71.6% for the CCRT group compared with 53.0% for the RT-only the RT-only group (group (PP = .0012). Although = .0012). Although significantly more toxicitysignificantly more toxicity was was noted in the CCRT arm, including leukopenia and emesisnoted in the CCRT arm, including leukopenia and emesis,,

compliance with the combined treatment was good. The secondcompliance with the combined treatment was good. The second

cycle of concurrent chemotherapy was refused by nine patientscycle of concurrent chemotherapy was refused by nine patients

and was delayed for 1 week for another nine patients. and was delayed for 1 week for another nine patients.


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• ASTRO 2007: Temozolomide (Temodar) Offers Long-Term Survival for Glioblastoma

• Mirimanoff

• 10.9% at two years for patients getting radiation alone, compared with 27.2% for those getting radiation and the medication. At three years, the corresponding rates were 4.4% and 16.4%. At four years, the rates were 3% and 12.1%.The differences were significant at P<0.0001.

• Patients (48% of total) with a methylated methylguanine methyl transferase (MGMT) promoter, …. had a four-year survival of 22.1% if they had the combination therapy, compared to 5.2% for radiation alone. The difference was significant at P=0.04.


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• Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy.chemoradiotherapy.

• Br J Cancer. 2008 May 20;98(10):1670-4. Epub 2008 May 13. 2008 May 20;98(10):1670-4. Epub 2008 May 13. • Yoshikawa R, , Nakano Y, , Tao L, , Koishi K, , Matsumoto TMatsumoto T, , Sasako MSasako M, , Tsujimura TTsujimura T, , Hashimoto-Tamaoki THashimoto-Tamaoki T, , Fujiwara YFujiwara Y..

• The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a critical component of the Hedgehog (Hh) signalling pathway, which is essential for critical component of the Hedgehog (Hh) signalling pathway, which is essential for morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As data were not available on the role of Gli-1 expression in oesophageal cancer data were not available on the role of Gli-1 expression in oesophageal cancer progression, we analysed whether it could be used to predict disease progression progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was associated with lymph-node metastasis, distant metastasis, and CRT, and was further correlated with the absence of both Gli-1 nuclear expression and residual further correlated with the absence of both Gli-1 nuclear expression and residual tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-node metastasis, and six out of seven died within 13 months. Furthermore, patients node metastasis, and six out of seven died within 13 months. Furthermore, patients with Gli-1 nuclear-positive cancers showed significantly poorer prognoses than with Gli-1 nuclear-positive cancers showed significantly poorer prognoses than those without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS those without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS 0 vs 54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%, 0 vs 54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%, P=0.001). P=0.001). Our study provides the first evidence that Gli-1 nuclear expression is a Our study provides the first evidence that Gli-1 nuclear expression is a strong and independent predictor of early relapse and poor prognosis in ESCC after strong and independent predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that Hh signal activation might promote cancer CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT.regrowth and progression after CRT.


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• Halogenated pyrimidinesHalogenated pyrimidines• 5-iododeoxyuridine (IudR), 5-bromo-5-iododeoxyuridine (IudR), 5-bromo-deoxyuridine (BrdU)deoxyuridine (BrdU)

• Activity is dependent on amount of Activity is dependent on amount of incorporation into DNAincorporation into DNA

• Blocks DNA repair and sensitize to RTBlocks DNA repair and sensitize to RT• Limited clinical usefulness due to Limited clinical usefulness due to toxicitytoxicity

Radiation SensitizersRadiation Sensitizers


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Exploiting Low Tumor Exploiting Low Tumor Oxygenation with Hypoxic Oxygenation with Hypoxic

CytotoxinsCytotoxins


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Capillary

150

O2 O2 O2

Hypoxia Causes Resistance to Radiation Hypoxia Causes Resistance to Radiation

and Anticancer Drugsand Anticancer Drugs

100500

Distance from Capillary (µm)

.

Surviving Fraction

Radiation / Chem. Drug

Combined

Hypoxic Cytotoxin

Hypoxic cytotoxins should have an at least additive effect with RT


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Radiosensitization by Targeting HypoxiaRadiosensitization by Targeting Hypoxia•Anemia has a -ve effect on RT outcomeAnemia has a -ve effect on RT outcome•Blood transfusionsBlood transfusions•EPO potentiates tumor growth!!!!EPO potentiates tumor growth!!!!

•Hyperbaric oxygenHyperbaric oxygen• Pure oxygen at 3 atmospheresPure oxygen at 3 atmospheres• Small patient numbers, unconventional Small patient numbers, unconventional fxfx

•Perfluorocarbon emulsionsPerfluorocarbon emulsions• oxygen carrying capacity of bloodoxygen carrying capacity of blood

•Efaproxiral: synthetic modifier of Efaproxiral: synthetic modifier of hemaglobinhemaglobin

•ARCONARCON• AR = accelerated radiation for AR = accelerated radiation for proliferation; CO = carbogen (95% Oproliferation; CO = carbogen (95% O22; ; 5% CO5% CO22) for chronic hypoxia; N = ) for chronic hypoxia; N = nicotinamide (vitamin B3 analogue) nicotinamide (vitamin B3 analogue) for acute hypoxiafor acute hypoxia


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Randomized HBO StudiesRandomized HBO Studies

Medical Research Council


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RadiosensitizersRadiosensitizers

• Radiosensitizers such as Radiosensitizers such as nitroimidazoles can nitroimidazoles can ““mimicmimic”” oxygen oxygen and fix damageand fix damage– Associated with some toxicity and there were Associated with some toxicity and there were

only rarely efforts to determine if the tumors only rarely efforts to determine if the tumors were hypoxic in advance of treatmentwere hypoxic in advance of treatment

– However there have been positive trials……However there have been positive trials…… • DAHANCA 5 trial using nimorazole in treatment of advanced squamous cell carcinoma of the head and neck


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Radiation SensitizersRadiation Sensitizers

• Hypoxia meta-analysis (Overgaard)Hypoxia meta-analysis (Overgaard)• 10,602 patients, 82 trials, HBO vs 10,602 patients, 82 trials, HBO vs sensitizers vs carbogen vs blood sensitizers vs carbogen vs blood transfusionstransfusions

• Greatest benefit in head & neck (largest Greatest benefit in head & neck (largest group?)group?)

• Hypoxia problem Hypoxia problem in squamous cell in squamous cell carcinomas, carcinomas, in adenocarcinomasin adenocarcinomas

• Improvement in local control = 5%; Improvement in local control = 5%; survival = 3%; survival = 3%; complication rate = complication rate = 0.6% (NS)0.6% (NS)

Selection for patients with hypoxic tumors would help!!!!


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And a meta-analysis by Jens Overgaard has shown significantly improved survival and

loco-regional control

Journal of Clinical Oncology, 25: pp. 4066-4074, 2007


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•Produce vasoconstriction or alter Produce vasoconstriction or alter metabolism causing reduction in metabolism causing reduction in oxygen concentration in oxygen concentration in tissue/organtissue/organ • sodium cyanide, carbon monoxide, sodium cyanide, carbon monoxide, epinephrine, histamine, serotoninepinephrine, histamine, serotonin

•Scavenge free radicalsScavenge free radicals• sulfhydryl compoundssulfhydryl compounds• dimethyl sulfoxide (DMSO), superoxide dimethyl sulfoxide (DMSO), superoxide dismutase enzymes (SODs)dismutase enzymes (SODs)

•Hydrogen atom donation to Hydrogen atom donation to facilitate direct repair to a facilitate direct repair to a radical site on DNAradical site on DNA

• glutathione, cysteine, WR compoundsglutathione, cysteine, WR compounds

Radiation ProtectorsRadiation Protectors


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WR compoundsWR compounds• WR-638 (cystaphos)WR-638 (cystaphos)

• Oral tablets carried by Soviet troopsOral tablets carried by Soviet troops• Requires intravenous or intraperitoneal Requires intravenous or intraperitoneal administrationadministration

• WR-1607WR-1607• Effective radioprotector: dose of 10 mg/kgEffective radioprotector: dose of 10 mg/kg• CardiotoxicityCardiotoxicity• Marketed as d-CON (rat poison)Marketed as d-CON (rat poison)

• WR-2721 (amifostine)WR-2721 (amifostine)• Phosphorothioate -- prodrugPhosphorothioate -- prodrug• Dephosphorylation (alkaline phosphatase) Dephosphorylation (alkaline phosphatase) WR-1065WR-1065• Differential protection in normal tissues (bone Differential protection in normal tissues (bone marrow, gut, salivary glands > lungs > brain)marrow, gut, salivary glands > lungs > brain)

• For complete benefit, need to increase radiation For complete benefit, need to increase radiation dose?dose?

• Clinical trials: some benefit -- RTOG phase III for Clinical trials: some benefit -- RTOG phase III for xerostomiaxerostomia

• Toxicity still an issue, as is fear of protecting Toxicity still an issue, as is fear of protecting tumortumor

NHNH22CHCH22CHCH22SPOSPO33HNaHNa

Radiation ProtectorsRadiation Protectors

CHCH33(CH(CH22))99NHCHNHCH22SSOSSO33HH


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RadioprotectorsRadioprotectors

• Thiols can protect either by Thiols can protect either by – scavenging free radicals scavenging free radicals

RSH + RSH + ..OH RS OH RS .. H2O H2O– hydrogen atom donation to hydrogen atom donation to radicals in target molecules radicals in target molecules (chemical repair)(chemical repair)

X X .. + RSH XH + RS + RSH XH + RS .. RSRS.. Is recycled by the glutathione Is recycled by the glutathione redox cycleredox cycle


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RadioprotectorsRadioprotectors

CHO cells

control

DTT 25mmol

WR-151326

Cysteamine10mmol

Radioprotectors such as WR-Radioprotectors such as WR-27212721(Ethyol:Amifostine), which (Ethyol:Amifostine), which contain contain thiol/sulfhydryl/SH groups thiol/sulfhydryl/SH groups workworkin experimental systems, butin experimental systems, butclinically are associated clinically are associated with with side-effects if given side-effects if given systemically. May be useful systemically. May be useful if given locally or to if given locally or to prevent second cancers, which prevent second cancers, which seems to need a lower dose seems to need a lower dose than for radioprotectionthan for radioprotection


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Questions:Questions: Interaction of Radiotherapy with other AgentsInteraction of Radiotherapy with other Agents


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151. Temozolomide (Temodar) is an151. Temozolomide (Temodar) is an– Alkylating agentAlkylating agent– Platinating agentPlatinating agent– AntimetaboliteAntimetabolite– Topoisomerase inhibitorTopoisomerase inhibitor– Anti-microtubular agentAnti-microtubular agent

#1 – It is most effective if the O-6-It is most effective if the O-6-methylguanine transferase (MGMT) DNA methylguanine transferase (MGMT) DNA repair enzyme is silenced by methylation. repair enzyme is silenced by methylation.


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152. 5-Fu is an152. 5-Fu is an– Alkylating agentAlkylating agent– Platinating agentPlatinating agent– AntimetaboliteAntimetabolite– Topoisomerase inhibitorTopoisomerase inhibitor– Anti-microtubular agent Anti-microtubular agent

#3 – 5-fluorouracil is a pyrimidine 5-fluorouracil is a pyrimidine analoganalog


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153. Which of the following has its 153. Which of the following has its action adversely affected by action adversely affected by hypoxiahypoxia– Bleomycin Bleomycin – ProcarbazineProcarbazine– DactinomycinDactinomycin– DoxorubicinDoxorubicin

#4 – hypoxia causes resistance to hypoxia causes resistance to doxorubicin but together they can result doxorubicin but together they can result in severe cardiotoxicityin severe cardiotoxicity


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154. Which of the following is true 154. Which of the following is true for the multiple drug resistance for the multiple drug resistance protein mdr1protein mdr1– It blocks drug influx into tumor It blocks drug influx into tumor cellscells

– It is expressed only in tumor cellsIt is expressed only in tumor cells– It increases drug eflux from a cell It increases drug eflux from a cell – It increases drug half-lifeIt increases drug half-life

#3 – it is the prototypical ATP-binding cassette (ABC) transporter that pump transport of various substances out of cells, including many chemotherapeutic agents


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155. The dose enhancement ratio is155. The dose enhancement ratio is– The dose of drug that is needed to enhance The dose of drug that is needed to enhance the effect of RTthe effect of RT

– The dose of radiation that is needed with The dose of radiation that is needed with the drug to that without the drug for a the drug to that without the drug for a given isoeffectgiven isoeffect

– The dose of radiation alone to the dose of The dose of radiation alone to the dose of radiation with drug that is needed for a radiation with drug that is needed for a given isoeffectgiven isoeffect

– The tumor control probability with drug The tumor control probability with drug plus radiation divided by that for plus radiation divided by that for radiation alone radiation alone

#3 – with radiation we work with isoeffective levels where possible


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156. The meta-analysis by Overgaard on 156. The meta-analysis by Overgaard on the role of hypoxia in RT indicated the role of hypoxia in RT indicated thatthat– Sensitizers made no difference to Sensitizers made no difference to overall outcomeoverall outcome

– Hypoxia is more of a problem with Hypoxia is more of a problem with adenocarcinomas than SCCadenocarcinomas than SCC

– An overall improvement of about 5% An overall improvement of about 5% in local control in HNSCC for in local control in HNSCC for sensitizers in combination with RTsensitizers in combination with RT

– Sensitizers in tumors in all sites Sensitizers in tumors in all sites were equally affected were equally affected #3 – data from over 10,000 patients were

analysed


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157. Which of the following is true 157. Which of the following is true about Amifostine?about Amifostine?– It is FDA approved as a It is FDA approved as a radioprotector for all normal radioprotector for all normal tissuestissues

– It is given orally or topicallyIt is given orally or topically– It needs to be dephosphorylated to It needs to be dephosphorylated to be activebe active

– It has shown efficacy in Phase III It has shown efficacy in Phase III clinical trials protecting against clinical trials protecting against mucositis in HNSCC mucositis in HNSCC

#3 – Commonly known as WR2721 or WR1065 in active form. Also known by its Ethyol trade name. It is given intravenously and is FDA-approved for mucositis in HNSCC, but not Phase III


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Slides Not Referred to in Slides Not Referred to in AudioAudio


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CisplatinCisplatin

• Most commonly used drug with RTMost commonly used drug with RT• Forms DNA-DNA and DNA-protein inter- Forms DNA-DNA and DNA-protein inter- and intra-strand crosslinks, inhibiting and intra-strand crosslinks, inhibiting DNA replication and RNA transcriptionDNA replication and RNA transcription

• DNA distortion leads to binding of MSH DNA distortion leads to binding of MSH and HMG and other proteinsand HMG and other proteins

• ATM and ATR, CHK1 and 2 activated for ATM and ATR, CHK1 and 2 activated for cell cycle arrestcell cycle arrest

• With RT, fixation of DNA damage, less With RT, fixation of DNA damage, less repair, more apoptosisrepair, more apoptosis


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5-FU5-FU• Thymidine phosphorylase –converts 5-FU to Thymidine phosphorylase –converts 5-FU to FdUrd, which thymidine kinase converts into FdUrd, which thymidine kinase converts into FdUMP, which inhibits thymidine synthase and FdUMP, which inhibits thymidine synthase and DNA synthesis and repair.DNA synthesis and repair.– May be major mechanism for continuous May be major mechanism for continuous infusioninfusion

• At the RNA level, uridine phosphorylase At the RNA level, uridine phosphorylase transforms 5-FU into FdUrd, which uridine transforms 5-FU into FdUrd, which uridine kinase converts into 5-FU monophosphate that kinase converts into 5-FU monophosphate that becomes di- and tri-phosphate, which is a becomes di- and tri-phosphate, which is a substrate for RNA polymerase, leading to substrate for RNA polymerase, leading to decreased mRNA stability.decreased mRNA stability.– May work best with bolus infusion May work best with bolus infusion


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GemcitabineGemcitabine

• Pyrimidine analogPyrimidine analog– Depletion of deoxynucleoside Depletion of deoxynucleoside triphosphate pool. Incorporation triphosphate pool. Incorporation into DNA inhibits DNA synthesis into DNA inhibits DNA synthesis and repairand repair

– HR importantHR important– Does not work with loss of MLH1Does not work with loss of MLH1


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ChemoRTChemoRT

123 patients123 patients64 Gy RT64 Gy RTversusversus50 Gy RT 50 Gy RT with 4 cycleswith 4 cyclesof 5-FU - CDDPof 5-FU - CDDP

Al-Sarraf et al, JCO, 1997


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Evaluation of early and late toxicities in chemoradiation Evaluation of early and late toxicities in chemoradiation trials.trials.Bentzen SMBentzen SM, , Trotti ATrotti AJ Clin Oncol.J Clin Oncol. 2007 Sep 10;25(26):4096-103 2007 Sep 10;25(26):4096-103Combined chemoradiotherapy is increasingly becoming a standard of care Combined chemoradiotherapy is increasingly becoming a standard of care for the nonoperative management of a variety of solid malignancies. A for the nonoperative management of a variety of solid malignancies. A string of randomized controlled phase III trials have shown string of randomized controlled phase III trials have shown statistically significant and clinically relevant improvements in statistically significant and clinically relevant improvements in outcome, ostensibly without any apparent increase in late toxicity. outcome, ostensibly without any apparent increase in late toxicity. However, However, the reliability and the sensitivity of toxicity reporting in the reliability and the sensitivity of toxicity reporting in most trials are questionable. Audits and phase IV studies suggest that most trials are questionable. Audits and phase IV studies suggest that the chemoradiotherapy success comes at a price in terms of late the chemoradiotherapy success comes at a price in terms of late toxicity. toxicity. This review presents some of the challenges in recording, This review presents some of the challenges in recording, analyzing, and reporting toxicity data. METHODS for summarizing analyzing, and reporting toxicity data. METHODS for summarizing toxicity are reviewed, and a new investigational metric, the TAME toxicity are reviewed, and a new investigational metric, the TAME reporting system, is discussed. The need for special vigilance in the reporting system, is discussed. The need for special vigilance in the era of molecular-targeted agents is emphasized because of the era of molecular-targeted agents is emphasized because of the possibility that unexpected serious adverse events with a low incidence possibility that unexpected serious adverse events with a low incidence may occur. Finally, we discuss how progress in molecular pathology and may occur. Finally, we discuss how progress in molecular pathology and radiation biology may provide novel opportunities for stratifying radiation biology may provide novel opportunities for stratifying patients according to risk of adverse effects, interventional targets patients according to risk of adverse effects, interventional targets for reducing or treating adverse effects, and surrogate markers of for reducing or treating adverse effects, and surrogate markers of normal-tissue injury.normal-tissue injury.


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Hypoxic CytotoxinsHypoxic Cytotoxins• QuinonesQuinones

– Mitomycin CMitomycin C• Differential between hypoxic and oxic cells poorDifferential between hypoxic and oxic cells poor• Requires very low levels of oxygen for maximum Requires very low levels of oxygen for maximum cytotoxicitycytotoxicity

• NitroaromaticsNitroaromatics• Benzotriazine di-N-oxidesBenzotriazine di-N-oxides

– TirapazamineTirapazamine• Good differential between oxic and hypoxic cellsGood differential between oxic and hypoxic cells• Phase III clinical trials with cisplatinPhase III clinical trials with cisplatin• Phase II with RTPhase II with RT


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Mechanism of Hypoxic Cytotoxicity Mechanism of Hypoxic Cytotoxicity of Tirapazamineof Tirapazamine

2

O

NN

N NH

O

1 e + H- +

NN

N NH

O

OH

2Reductase

TPZ

Hypoxia

*

*

*

TPZ Radical

.

2

-OO2

M. BrownM. Brown


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Tirapazamine is Toxic Tirapazamine is Toxic for Hypoxic Cells for Hypoxic Cells in vitroin vitro

10000100010010110-5

10-4

10-3

10-2

10-1

100

Tirapazamine Conc (M)Surviving Fraction

HCR= 300

hypoxiahypoxiaairair


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Lung Cancer

CervixCancer

Head & Neck Cancer

Tirapazamine has shown Clinical Tirapazamine has shown Clinical Efficacy when Combined with XRT or Efficacy when Combined with XRT or

ChemotherapyChemotherapy

Currently off the market! ....toxicity issues.


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RadiosensitizersRadiosensitizers

From Zeman, 2000


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• NitroimidazolNitroimidazoleses

misonidazolemisonidazole

CHCH22CH(OH)CHCH(OH)CH22OCHOCH33

NN

NN

NONO22

etanidazoleetanidazole

CHCH22CONH CHCONH CH22 CH CH22OHOH

NN

NN

NONO22

metronidazolemetronidazole

CHCH22CHCH22OHOH

NN

NN

CHCH33OO22NN

OO

nimorazolenimorazole

CHCH22CHCH22NN

NN

NN

OO22NN


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Misonidazole: Misonidazole: good sensitization in vitro and in vivo good sensitization in vitro and in vivo preclinical modelspreclinical models

O Air Air + Misonidazole (1 mmol dm-3) Air + Misonidazole (10 mmol dm-3) Nitrogen Nitrogen + Misonidazole (1 mmol dm-3) Nitrogen + Misonidazole (10 mmol dm-3)

X-rays X-rays ++

1 mg/g 1 mg/g misomiso

TCDTCD5050 = 43.8 Gy = 43.8 Gy24.1 Gy24.1 Gy

Sensitizer Sensitizer enhancement enhancement ratio = 1.8 ± ratio = 1.8 ±

0.10.1

100100

00

% tumors controlled

% tumors controlled

DoseDose2020 3030 4040 5050 6060

X-rays X-rays onlyonly


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AgentAgent Number of Number of TrialsTrials

SignificanSignificant benefitt benefit

Non-Non-significansignificant benefitt benefit

No benefitNo benefit

MisonidazoleMisonidazole 3939 44 44 3131

Clinical TrialsClinical Trials

Clinic:Clinic: dose-limiting toxicity dose-limiting toxicity -- peripheral neuropathy -- peripheral neuropathy (reduced tolerated dose)(reduced tolerated dose)

Documents

Alkylating agents Platinating agents Antimetabolites Topoisomerase inhibitors