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Www.radbiol.ucla.edu WMcB2008 Interaction of RT with CT and other Agents Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles,

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Presentation on theme: "Www.radbiol.ucla.edu WMcB2008 Interaction of RT with CT and other Agents Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles,"— Presentation transcript:

1 WMcB2008 Interaction of RT with CT and other Agents Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca.

2 WMcB2008 Alkylating agentsAlkylating agents Platinating agentsPlatinating agents AntimetabolitesAntimetabolites Topoisomerase inhibitorsTopoisomerase inhibitors Anti-microtubular agentsAnti-microtubular agents MiscellaneousMiscellaneous Classes of Chemotherapy Agents

3 WMcB2008 Alkylating agentsAlkylating agents Nitrogen mustard derivatives: cyclophosphamide, chlorambucil, melphalan, ifosfamide, mechlorethamineNitrogen mustard derivatives: cyclophosphamide, chlorambucil, melphalan, ifosfamide, mechlorethamine Ethylenimines: Thiotepa and HexamethylmelamineEthylenimines: Thiotepa and Hexamethylmelamine Nitrosoureas: BCNU (carmustine), CCNU (lomustine), StreptozocinNitrosoureas: BCNU (carmustine), CCNU (lomustine), Streptozocin Alkylsulfonates: BusulfanAlkylsulfonates: Busulfan Hydrazines and Triazines: altretamine, procarbazine, dacarbazine, temodarHydrazines and Triazines: altretamine, procarbazine, dacarbazine, temodar Highly reactive alkyl groups (e.g. —CH 2 Cl) covalently bind to intracellular macromolecule, such as DNAHighly reactive alkyl groups (e.g. —CH 2 Cl) covalently bind to intracellular macromolecule, such as DNA Bifunctional crosslink are more effective (interstrand DNA crosslinks)Bifunctional crosslink are more effective (interstrand DNA crosslinks) Limited cell cycle specificity, carcinogenicLimited cell cycle specificity, carcinogenic Classes of Agents

4 WMcB2008 Platinating agentsPlatinating agents Cisplatin, Carboplatin, oxiplatinCisplatin, Carboplatin, oxiplatin Exist in 2+ oxidation state with 4 groups that interact with DNA (95% intrastrand 5% interstrand cross-linkages)Exist in 2+ oxidation state with 4 groups that interact with DNA (95% intrastrand 5% interstrand cross-linkages) Nausea, vomiting, kidney toxicity, less myelosuppression than with alkylating agentsNausea, vomiting, kidney toxicity, less myelosuppression than with alkylating agents Classes of Agents

5 WMcB2008 AntimetabolitesAntimetabolites Purine/pyrimidine analogsPurine/pyrimidine analogs 5-FU, cytosine arabinoside, gemcitabine, iododeoxyuridine5-FU, cytosine arabinoside, gemcitabine, iododeoxyuridine AntifolatesAntifolates MethotrexateMethotrexate interfere with normal cell function (e.g. DNA synthesis)interfere with normal cell function (e.g. DNA synthesis) Cell cycle specific, tend to cause DNA damage and block repair, less carcinogenic than alkylating agentsCell cycle specific, tend to cause DNA damage and block repair, less carcinogenic than alkylating agents Classes of Agents

6 WMcB2008 Topoisomerase inhibitorsTopoisomerase inhibitors Topo I inhibitorsTopo I inhibitors Camptothecin derivatives such as topotecan, irinotecan (CPT11)Camptothecin derivatives such as topotecan, irinotecan (CPT11) Topo II inhibitorsTopo II inhibitors Epipodophyllotoxins such as etoposide, teniposideEpipodophyllotoxins such as etoposide, teniposide Topo II inhibitors plus other effectsTopo II inhibitors plus other effects Anthracyclines such as daunorubicin, doxorubicin (Adriamycin), idarubicin, epirubicinAnthracyclines such as daunorubicin, doxorubicin (Adriamycin), idarubicin, epirubicin Topoisomerases relax dsDNA to allow replication/transcription by single (I) or double (II) strand nick. DSBs form when the replication fork meets the DNA/topo cleavable complex - in S phaseTopoisomerases relax dsDNA to allow replication/transcription by single (I) or double (II) strand nick. DSBs form when the replication fork meets the DNA/topo cleavable complex - in S phase Classes of Agents

7 WMcB2008 Antimicrotubular agentsAntimicrotubular agents Vinca alkaloidsVinca alkaloids Taxanes: paclitaxel (Taxol), docetaxel (Taxotere)Taxanes: paclitaxel (Taxol), docetaxel (Taxotere) Bind to tubulins (different site) and inhibit microtubular disassemblyBind to tubulins (different site) and inhibit microtubular disassembly Cause G2M arrestCause G2M arrest Classes of Agents

8 WMcB2008 Others 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 arrest –Apoptosis of cancer cells –Immunosuppression –Anti-inflammatory –Anti-angiogenesis –Downregulation of NF-  B (and many other signal transduction molecules) Radiosensitizer and chemosensitizerRadiosensitizer and chemosensitizer

9 WMcB2008 Chemotherapeutic Considerations PharmacokineticsPharmacokinetics Concentration of metabolites over timeConcentration of metabolites over time Absorption, Distribution, Metabolism, EliminationAbsorption, Distribution, Metabolism, Elimination PharmacodynamicsPharmacodynamics Cellular response to drugCellular response to drug

10 WMcB2008 PharmacokineticsPharmacokinetics Concentration of metabolites over timeConcentration of metabolites over time Normally measured by the area under the concentration/time curveNormally measured by the area under the concentration/time curve However, maintaining a certain level may be more important for some drugs than othersHowever, maintaining a certain level may be more important for some drugs than others Continuous delivery better than bolusContinuous delivery better than bolus Topo I inhibitors, anti-metabolites, taxanesTopo I inhibitors, anti-metabolites, taxanes

11 WMcB2008 PharmacokineticsPharmacokinetics Absorption, Distribution, Metabolism, EliminationAbsorption, Distribution, Metabolism, Elimination AbsorptionAbsorption Depends on route of administrationDepends on route of administration Intravenous route preferred for pharmacokinetic reasonsIntravenous route preferred for pharmacokinetic reasons Oral is best for some eg TemozolomideOral is best for some eg Temozolomide Regional delivery may be more effective (glioma)Regional delivery may be more effective (glioma) Influenced by physical form and barriers to penetration/absorption e.g. blood-brain barrierInfluenced by physical form and barriers to penetration/absorption e.g. blood-brain barrier DistributionDistribution Requires blood/fluid flow to organs/tissues/tumorRequires blood/fluid flow to organs/tissues/tumor Diffusion kineticsDiffusion kinetics Size and chemical formSize and chemical form Protein and tissue binding, lipid solubility, pH, etc.Protein and tissue binding, lipid solubility, pH, etc.

12 WMcB2008 PharmacokineticsPharmacokinetics MetabolismMetabolism Phase 1 active metabolites often produced in liverPhase 1 active metabolites often produced in liver Phase II inactive metabolites produced by conjugationPhase II inactive metabolites produced by conjugation Some drugs requires activation (cyclophosphamide)Some drugs requires activation (cyclophosphamide) Influenced by genetic polymorphisms (5-FU - dihydropyrimidine dehydrogenase deficiency is toxic and high thymidylate synthase levels decrease efficacy)Influenced by genetic polymorphisms (5-FU - dihydropyrimidine dehydrogenase deficiency is toxic and high thymidylate synthase levels decrease efficacy) Liver function affects metabolismLiver function affects metabolism ExcretionExcretion Primarily in kidney or biliary tractPrimarily in kidney or biliary tract Phase I active metabolites (carboplatin) or Phase II metabolites (doxorubicin) can give toxicityPhase I active metabolites (carboplatin) or Phase II metabolites (doxorubicin) can give toxicity Kidney function affects clearanceKidney function affects clearance Influenced by protein and tissue binding, lipid solubility, pH, etc.Influenced by protein and tissue binding, lipid solubility, pH, etc. Doxorubicin slow release is due to high lipid solubilityDoxorubicin slow release is due to high lipid solubility

13 WMcB2008 PharmacodynamicsPharmacodynamics Cellular response to drug depends onCellular response to drug depends on MicroenvironmentMicroenvironment Cell cycle phaseCell cycle phase Drug resistance mechanismsDrug resistance mechanisms Intracellular metabolismIntracellular metabolism Sensitivity to cell death/survival pathwaysSensitivity to cell death/survival pathways Difficult to get predictors from in vitro survival dataDifficult to get predictors from in vitro survival data

14 WMcB2008 Microenvironment Surviving fraction µg/ml bleomycin Aerated Bleomycin, procarbazine,dactinomycin Hypoxic less sensitive 10 µM mitomycin Aerated Mitomycin C, misonidazole, metronidazole, etanidazole, tirapazamine, doxorubicin Hypoxic more sensitive Surviving fraction

15 WMcB2008 Cell Cycle G1/S phase Alkylating Agents, Cisplatin M Phase AlkylatingAgents G2 phase PaclitaxelBleomycin S phase DocetaxelMethotrexate Ara-C, 6TG, HydroxyureaVinblastineDoxorubicin G0 - quiescence

16 WMcB2008 Mechanism Decreased uptake Increased efflux Decrease in drug activation Increase in drug catabolism Increase or decrease in levels of target molecule Alterations in target molecule Inactivation by binding to sulfhydryls (e.g. glutathione) Increased DNA repair Decreased ability to undergo apoptosis Drugs Methotrexate, melphalan, cisplatin Anthracyclines, vinca alkaloids, etoposide, taxanes Many antimetabolites Methotrexate, topoisomerase inhibitors Methotrexate, other antimetabolites, topoisomerase inhibitors, Gleevec Alkylating agents, cisplatin, anthracyclines Alkylating agents, cisplatin, anthracyclines, etoposide Mechanisms of Drug Resistance

17 WMcB2008 Mechanisms of Drug Resistance Impaired drug influxImpaired drug influx passive diffusionpassive diffusion energy & temperature independentenergy & temperature independent facilitated diffusionfacilitated diffusion transport carrier on membranetransport carrier on membrane energy & temperature independentenergy & temperature independent active transportactive transport carrier-mediated processcarrier-mediated process energy & temperature dependentenergy & temperature dependent reduced folate carrier - mutation?reduced folate carrier - mutation? Melphalan  binding affinity for drug and  number of transport sites / slower carrier mobilityMelphalan  binding affinity for drug and  number of transport sites / slower carrier mobility

18 WMcB2008 Mechanisms of Drug Resistance Increased drug effluxIncreased drug efflux Many natural drugs/derivatives (taxanes, vinca alkaloids, anthracyclines) have shared mechanisms of resistance, e.g. substrates for membrane-based ATPase-dependent proteins (pumps)Many natural drugs/derivatives (taxanes, vinca alkaloids, anthracyclines) have shared mechanisms of resistance, e.g. substrates for membrane-based ATPase-dependent proteins (pumps) P-glycoprotein (mdr1)P-glycoprotein (mdr1) High levels in kidney & adrenals; intermediate in lung, liver, colon and rectumHigh levels in kidney & adrenals; intermediate in lung, liver, colon and rectum 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)

19 WMcB2008 Summary of Drug Therapy Plethora of cytotoxic agentsPlethora of cytotoxic agents Selective (not exclusive) targets - proliferating cellsSelective (not exclusive) targets - proliferating 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 expression of drug- metabolizing enzyme)increased drug degradation (e.g. altered 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. mutation of p53)enhanced DNA repair; failure to apoptose (e.g. mutation of p53)

20 WMcB2008 How Effective is CT - and how 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 - pathology/imaging/clinical –If a tumor has cells, a PR may decrease this to 2x10 9, which is not much of an improvement. Patients in complete remission can have anywhere between cells as a tumor burden. If 10yr relapse- free survival is 30% without and 40-45% with adjuvant chemotherapy, as is the case in early breast cancer regimens, Withers calculated that this represents about 2 logs of tumor cell kill – easy to achieve with RT.Patients in complete remission can have anywhere between cells as a tumor burden. If 10yr relapse- free survival is 30% without and 40-45% with adjuvant chemotherapy, as is the case in early breast cancer regimens, Withers calculated that this represents about 2 logs of tumor cell kill – easy to achieve with RT. Neoadjuvant chemotherapy may cause accelerated tumor repopulation! Concomitant delivery of drugs with RT is often better than sequential delivery.Neoadjuvant chemotherapy may cause accelerated tumor repopulation! Concomitant delivery of drugs with RT is often better than sequential delivery.

21 WMcB2008 Therapeutic Index Need to increase therapeutic indexNeed to increase therapeutic index Bone marrow major toxicityBone marrow major toxicity Normally treat to MTD, except for palliative cases (5-FU for advanced colorectal Ca)Normally treat to MTD, except for palliative cases (5-FU for advanced colorectal Ca) Some tumors are drug “resistant” others are “sensitive” but recur - are the cancer stem cells being killed? Many seem to have enhanced drug efflux pumps…..Some tumors are drug “resistant” others are “sensitive” but recur - are the cancer stem cells being killed? Many seem to have enhanced drug efflux pumps…..

22 WMcB2008 Combination Therapies CT combinationsCT combinations −Different classes of agents with minimally overlapping toxicities RT plus CTRT plus CT Adjuvant therapy (P-glycoprotein inhibitors)Adjuvant therapy (P-glycoprotein inhibitors) Biological targeting + CT/RTBiological targeting + CT/RT

23 WMcB2008 Chemotherapy and Radiation Combination of chemotherapy and radiation can increase cure rate, but also the potential for normal tissue toxicityCombination of chemotherapy and radiation can increase cure rate, but also the potential for normal tissue toxicity Dose Enhancement Ratio (DER)Dose Enhancement Ratio (DER) Dose of radiation alone to produce an effect divided by dose of radiation to give same effect in combination with drugDose of radiation alone to produce an effect divided by dose of radiation to give same effect in combination with drug Therapeutic Gain FactorTherapeutic Gain Factor Ratio of DER for tumor to DER of dose-limiting normal tissueRatio of DER for tumor to DER of dose-limiting normal tissue

24 WMcB2008 Synergy vs. Additivity Claims for synergy are often made if S 1 = S A x S B but this is only true if there is no shoulder. Tannock et al: The Basic Science of Oncology 4th Ed. S1S1S1S Drug A + B X ? DADADADA DADADADA SASASASA Drug A Drug B DBDBDBDB SBSBSBSB DBDBDBDB

25 WMcB2008 Dose of Agent B Dose of Agent A Supra-additive Synergistic Envelope of Additivity Subadditive Protective Antagonistic After Steel and Peckham, 1959 Isobologram Analysis

26 WMcB2008

27 WMcB2008 ChemoRT Meta-analyses have shown that chemotherapy (concomitant, neoadjuvant, adjuvant) improves survival in non-metastatic HNSCC (other than NPC) by 4.4% at 5yrs.Meta-analyses have shown that chemotherapy (concomitant, neoadjuvant, adjuvant) improves survival in non-metastatic HNSCC (other than NPC) by 4.4% at 5yrs. –Bourhis et al PASCO 22:488, 2004 Concomitant gives an absolute benefit of 6.5-8% at 5yrs, irrespective of fractionation scheme although altered fractionation gives a survival advantage, and is better than neoadjuvant. Platinum-based regimens best. It comes with an increase in early and late toxicity.Concomitant gives an absolute benefit of 6.5-8% at 5yrs, irrespective of fractionation scheme although altered fractionation gives a survival advantage, and is better than neoadjuvant. Platinum-based regimens best. It comes with an increase in early and late toxicity. –Pignon et al IJROBP 69: S112, 2007

28 WMcB2008 Randomized Phase III Trial of Sequential Chemoradiotherapy Compared With Concurrent Chemoradiotherapy in Locally Advanced Nonsmall-Cell Lung CancerRandomized Phase III Trial of Sequential Chemoradiotherapy Compared With Concurrent Chemoradiotherapy in Locally Advanced Nonsmall-Cell Lung Cancer Fournel et al Journal of Clinical Oncology, 23; , 2005.Fournel et al Journal of Clinical Oncology, 23; , Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P =.24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P =.24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.

29 WMcB2008 Chemoradiation in the management of esophageal cancer. Chemoradiation in the management of esophageal cancer. Kleinberg L, Forastiere AA. J Clin Oncol Sep 10;25(26): Kleinberg L, Forastiere AA. J Clin Oncol Sep 10;25(26): Kleinberg LForastiere AAJ Clin Oncol. Kleinberg LForastiere AAJ Clin Oncol. The combination of chemotherapy, fluorouracil and cisplatin, and radiation has improved outcome for patients with esophageal cancer. A randomized controlled trial confirmed a long-term survival benefit when this chemotherapy was added to radiotherapy for squamous cell carcinoma, but the approach has not been definitively assessed in patients with adenocarcinoma. Preoperative chemoradiotherapy has been tested in numerous phase II studies and underpowered or flawed phase III studies. Nevertheless, collectively, the evidence strongly suggests that preoperative chemoradiotherapy improves outcome, and thus, this strategy has become a standard treatment option. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing the radiation dose have not been successful. Camptothecin and taxane-based regimens combined with radiation have altered the toxicity profile, but substantial improvement in survival outcomes has yet to be demonstrated. Future improvements will likely require the incorporation of targeted agents that add minimally to existing toxicity, the use of molecular predictors of response to individualize selection of the chemotherapeutic regimen, and early identification of responders such that therapy might be altered dynamically. The combination of chemotherapy, fluorouracil and cisplatin, and radiation has improved outcome for patients with esophageal cancer. A randomized controlled trial confirmed a long-term survival benefit when this chemotherapy was added to radiotherapy for squamous cell carcinoma, but the approach has not been definitively assessed in patients with adenocarcinoma. Preoperative chemoradiotherapy has been tested in numerous phase II studies and underpowered or flawed phase III studies. Nevertheless, collectively, the evidence strongly suggests that preoperative chemoradiotherapy improves outcome, and thus, this strategy has become a standard treatment option. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing the radiation dose have not been successful. Camptothecin and taxane-based regimens combined with radiation have altered the toxicity profile, but substantial improvement in survival outcomes has yet to be demonstrated. Future improvements will likely require the incorporation of targeted agents that add minimally to existing toxicity, the use of molecular predictors of response to individualize selection of the chemotherapeutic regimen, and early identification of responders such that therapy might be altered dynamically.

30 WMcB2008 Phase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free SurvivalPhase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free Survival Lin et al. Journal of Clinical Oncology 21: , 2003Lin et al. Journal of Clinical Oncology 21: , 2003 Two cycles of concurrent chemotherapy with cisplatin 20 mg/m 2 /dy plus fluorouracil 400 mg/m 2 /d by 96-hour continuous infusion during the weeks 1 and 5 of RT. Median follow-up of 65 months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients developed tumor relapse in the CCRT and RT-alone groups, respectively. The 5-year overall survival rates were 72.3% for the CCRT arm and 54.2% for the RT-only arm (P =.0022). The 5- year progression-free survival rates were 71.6% for the CCRT group compared with 53.0% for the RT-only group (P =.0012). Although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis, compliance with the combined treatment was good. The second cycle of concurrent chemotherapy was refused by nine patients and was delayed for 1 week for another nine patients.Two cycles of concurrent chemotherapy with cisplatin 20 mg/m 2 /dy plus fluorouracil 400 mg/m 2 /d by 96-hour continuous infusion during the weeks 1 and 5 of RT. Median follow-up of 65 months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients developed tumor relapse in the CCRT and RT-alone groups, respectively. The 5-year overall survival rates were 72.3% for the CCRT arm and 54.2% for the RT-only arm (P =.0022). The 5- year progression-free survival rates were 71.6% for the CCRT group compared with 53.0% for the RT-only group (P =.0012). Although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis, compliance with the combined treatment was good. The second cycle of concurrent chemotherapy was refused by nine patients and was delayed for 1 week for another nine patients.

31 WMcB2008 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< 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.

32 WMcB2008 Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer May 20;98(10): Epub 2008 May 13. Br J Cancer May 20;98(10): Epub 2008 May 13. Br J Cancer. Br J Cancer. Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, Tsujimura T, Hashimoto-Tamaoki T, Fujiwara Y. Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, Tsujimura T, Hashimoto-Tamaoki T, Fujiwara Y. Yoshikawa RNakano YTao LKoishi KMatsumoto TSasako MTsujimura T Hashimoto-Tamaoki TFujiwara Y Yoshikawa RNakano YTao LKoishi KMatsumoto TSasako MTsujimura T Hashimoto-Tamaoki TFujiwara Y 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 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 progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was 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-node metastasis, and six out of seven died within 13 months. Furthermore, patients 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 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). 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 CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT. 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 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 progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was 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-node metastasis, and six out of seven died within 13 months. Furthermore, patients 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 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). 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 CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT.

33 WMcB2008 Halogenated pyrimidinesHalogenated pyrimidines 5-iododeoxyuridine (IudR), 5-bromo-deoxyuridine (BrdU)5-iododeoxyuridine (IudR), 5-bromo-deoxyuridine (BrdU) Activity is dependent on amount of incorporation into DNAActivity is dependent on amount of incorporation into DNA Blocks DNA repair and sensitize to RTBlocks DNA repair and sensitize to RT Limited clinical usefulness due to toxicityLimited clinical usefulness due to toxicity Radiation Sensitizers

34 WMcB2008 Exploiting Low Tumor Oxygenation with Hypoxic Cytotoxins

35 WMcB2008 Capillary 150 O2O2 O2O2 O2O2 Hypoxia Causes Resistance to Radiation and Anticancer Drugs Distance from Capillary (µm). Surviving Fraction Radiation / Chem. Drug Combined Hypoxic Cytotoxin Hypoxic cytotoxins should have an at least additive effect with RT

36 WMcB2008 Radiosensitization 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 atmospheres Pure oxygen at 3 atmospheres Small patient numbers, unconventional fx Small patient numbers, unconventional fx Perfluorocarbon emulsionsPerfluorocarbon emulsions  oxygen carrying capacity of blood  oxygen carrying capacity of blood Efaproxiral: synthetic modifier of hemaglobinEfaproxiral: synthetic modifier of hemaglobin ARCONARCON AR = accelerated radiation for proliferation; CO = carbogen (95% O 2 ; 5% CO 2 ) for chronic hypoxia; N = nicotinamide (vitamin B3 analogue) for acute hypoxia AR = accelerated radiation for proliferation; CO = carbogen (95% O 2 ; 5% CO 2 ) for chronic hypoxia; N = nicotinamide (vitamin B3 analogue) for acute hypoxia

37 WMcB2008 Randomized HBO Studies Medical Research Council

38 WMcB2008 Radiosensitizers Radiosensitizers such as nitroimidazoles can “mimic” oxygen and fix damageRadiosensitizers such as nitroimidazoles can “mimic” oxygen and fix damage –Associated with some toxicity and there were only rarely efforts to determine if the tumors were hypoxic in advance of treatment –However there have been positive trials…… DAHANCA 5 trial using nimorazole in treatment of advanced squamous cell carcinoma of the head and neck

39 WMcB2008 Radiation Sensitizers Hypoxia meta-analysis (Overgaard)Hypoxia meta-analysis (Overgaard) 10,602 patients, 82 trials, HBO vs sensitizers vs carbogen vs blood transfusions10,602 patients, 82 trials, HBO vs sensitizers vs carbogen vs blood transfusions Greatest benefit in head & neck (largest group?)Greatest benefit in head & neck (largest group?) Hypoxia problem  in squamous cell carcinomas,  in adenocarcinomasHypoxia problem  in squamous cell carcinomas,  in adenocarcinomas Improvement in local control = 5%;  survival = 3%;  complication rate = 0.6% (NS)Improvement in local control = 5%;  survival = 3%;  complication rate = 0.6% (NS) Selection for patients with hypoxic tumors would help!!!!

40 WMcB2008 And a meta-analysis by Jens Overgaard has shown significantly improved survival and loco-regional control Journal of Clinical Oncology, 25: pp , 2007

41 WMcB2008 Produce vasoconstriction or alter metabolism causing reduction in oxygen concentration in tissue/organProduce vasoconstriction or alter metabolism causing reduction in oxygen concentration in tissue/organ sodium cyanide, carbon monoxide, epinephrine, histamine, serotoninsodium cyanide, carbon monoxide, epinephrine, histamine, serotonin Scavenge free radicalsScavenge free radicals sulfhydryl compoundssulfhydryl compounds dimethyl sulfoxide (DMSO), superoxide dismutase enzymes (SODs)dimethyl sulfoxide (DMSO), superoxide dismutase enzymes (SODs) Hydrogen atom donation to facilitate direct repair to a radical site on DNAHydrogen atom donation to facilitate direct repair to a radical site on DNA glutathione, cysteine, WR compoundsglutathione, cysteine, WR compounds Radiation Protectors

42 WMcB2008 WR compounds WR-638 (cystaphos)WR-638 (cystaphos) Oral tablets carried by Soviet troopsOral tablets carried by Soviet troops Requires intravenous or intraperitoneal administrationRequires intravenous or intraperitoneal administration 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)  WR-1065Dephosphorylation (alkaline phosphatase)  WR-1065 Differential protection in normal tissues (bone marrow, gut, salivary glands > lungs > brain)Differential protection in normal tissues (bone marrow, gut, salivary glands > lungs > brain) For complete benefit, need to increase radiation dose?For complete benefit, need to increase radiation dose? Clinical trials: some benefit -- RTOG phase III for xerostomiaClinical trials: some benefit -- RTOG phase III for xerostomia Toxicity still an issue, as is fear of protecting tumorToxicity still an issue, as is fear of protecting tumor NH 2 CH 2 CH 2 SPO 3 HNa Radiation Protectors CH 3 (CH 2 ) 9 NHCH 2 SSO 3 H

43 WMcB2008 Radioprotectors Thiols can protect either byThiols can protect either by –scavenging free radicals RSH +. OH RS. H2O –hydrogen atom donation to radicals in target molecules (chemical repair) X. + RSH XH + RS. RS. Is recycled by the glutathione redox cycle

44 WMcB2008 Radioprotectors CHO cells control DTT 25mmol WR Cysteamine 10mmol Radioprotectors such as WR-2721 (Ethyol:Amifostine), which contain thiol/sulfhydryl/SH groups work in experimental systems, but clinically are associated with side-effects if given systemically. May be useful if given locally or to prevent second cancers, which seems to need a lower dose than for radioprotection

45 WMcB2008 Questions: Interaction of Radiotherapy with other Agents

46 WMcB Temozolomide (Temodar) is an –Alkylating agent –Platinating agent –Antimetabolite –Topoisomerase inhibitor –Anti-microtubular agent It is most effective if the O-6-methylguanine transferase (MGMT) DNA repair enzyme is silenced by methylation. #1 – It is most effective if the O-6-methylguanine transferase (MGMT) DNA repair enzyme is silenced by methylation.

47 WMcB Fu is an –Alkylating agent –Platinating agent –Antimetabolite –Topoisomerase inhibitor –Anti-microtubular agent 5-fluorouracil is a pyrimidine analog #3 – 5-fluorouracil is a pyrimidine analog

48 WMcB Which of the following has its action adversely affected by hypoxia –Bleomycin –Procarbazine –Dactinomycin –Doxorubicin hypoxia causes resistance to doxorubicin but together they can result in severe cardiotoxicity #4 – hypoxia causes resistance to doxorubicin but together they can result in severe cardiotoxicity

49 WMcB Which of the following is true for the multiple drug resistance protein mdr1 –It blocks drug influx into tumor cells –It is expressed only in tumor cells –It increases drug eflux from a cell –It 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

50 WMcB The dose enhancement ratio is –The dose of drug that is needed to enhance the effect of RT –The dose of radiation that is needed with the drug to that without the drug for a given isoeffect –The dose of radiation alone to the dose of radiation with drug that is needed for a given isoeffect –The tumor control probability with drug plus radiation divided by that for radiation alone #3 – with radiation we work with isoeffective levels where possible

51 WMcB The meta-analysis by Overgaard on the role of hypoxia in RT indicated that –Sensitizers made no difference to overall outcome –Hypoxia is more of a problem with adenocarcinomas than SCC –An overall improvement of about 5% in local control in HNSCC for sensitizers in combination with RT –Sensitizers in tumors in all sites were equally affected #3 – data from over 10,000 patients were analysed

52 WMcB Which of the following is true about Amifostine? –It is FDA approved as a radioprotector for all normal tissues –It is given orally or topically –It needs to be dephosphorylated to be active –It has shown efficacy in Phase III clinical trials protecting against 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

53 WMcB2008 Slides Not Referred to in Audio

54 WMcB2008 Cisplatin Most commonly used drug with RTMost commonly used drug with RT Forms DNA-DNA and DNA-protein inter- and intra- strand crosslinks, inhibiting DNA replication and RNA transcriptionForms DNA-DNA and DNA-protein inter- and intra- strand crosslinks, inhibiting DNA replication and RNA transcription DNA distortion leads to binding of MSH and HMG and other proteinsDNA distortion leads to binding of MSH and HMG and other proteins ATM and ATR, CHK1 and 2 activated for cell cycle arrestATM and ATR, CHK1 and 2 activated for cell cycle arrest With RT, fixation of DNA damage, less repair, more apoptosisWith RT, fixation of DNA damage, less repair, more apoptosis

55 WMcB FU Thymidine phosphorylase –converts 5-FU to FdUrd, which thymidine kinase converts into FdUMP, which inhibits thymidine synthase and DNA synthesis and repair.Thymidine phosphorylase –converts 5-FU to FdUrd, which thymidine kinase converts into FdUMP, which inhibits thymidine synthase and DNA synthesis and repair. –May be major mechanism for continuous infusion At the RNA level, uridine phosphorylase transforms 5-FU into FdUrd, which uridine kinase converts into 5-FU monophosphate that becomes di- and tri- phosphate, which is a substrate for RNA polymerase, leading to decreased mRNA stability.At the RNA level, uridine phosphorylase transforms 5-FU into FdUrd, which uridine kinase converts into 5-FU monophosphate that becomes di- and tri- phosphate, which is a substrate for RNA polymerase, leading to decreased mRNA stability. –May work best with bolus infusion

56 WMcB2008 Gemcitabine Pyrimidine analogPyrimidine analog –Depletion of deoxynucleoside triphosphate pool. Incorporation into DNA inhibits DNA synthesis and repair –HR important –Does not work with loss of MLH1

57 WMcB2008 ChemoRT 123 patients 64 Gy RT versus 50 Gy RT with 4 cycles of 5-FU - CDDP Al-Sarraf et al, JCO, 1997

58 WMcB2008 Evaluation of early and late toxicities in chemoradiation trials.Bentzen SM, Trotti AJ Clin Oncol Sep 10;25(26): Bentzen SM Trotti AJ Clin Oncol.Bentzen SM Trotti AJ Clin Oncol. Combined chemoradiotherapy is increasingly becoming a standard of care for the nonoperative management of a variety of solid malignancies. A string of randomized controlled phase III trials have shown statistically significant and clinically relevant improvements in outcome, ostensibly without any apparent increase in late toxicity. However, the reliability and the sensitivity of toxicity reporting in most trials are questionable. Audits and phase IV studies suggest that the chemoradiotherapy success comes at a price in terms of late toxicity. This review presents some of the challenges in recording, analyzing, and reporting toxicity data. METHODS for summarizing toxicity are reviewed, and a new investigational metric, the TAME reporting system, is discussed. The need for special vigilance in the era of molecular-targeted agents is emphasized because of the possibility that unexpected serious adverse events with a low incidence may occur. Finally, we discuss how progress in molecular pathology and radiation biology may provide novel opportunities for stratifying patients according to risk of adverse effects, interventional targets for reducing or treating adverse effects, and surrogate markers of normal-tissue injury.

59 WMcB2008 Hypoxic Cytotoxins QuinonesQuinones –Mitomycin C Differential between hypoxic and oxic cells poorDifferential between hypoxic and oxic cells poor Requires very low levels of oxygen for maximum cytotoxicityRequires very low levels of oxygen for maximum cytotoxicity NitroaromaticsNitroaromatics Benzotriazine di-N-oxidesBenzotriazine di-N-oxides –Tirapazamine 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

60 WMcB2008 Mechanism of Hypoxic Cytotoxicity of Tirapazamine 2 O N N N NH O 1 e + H - + N N N NH O OH 2 Reductase TPZ Hypoxia * * * TPZ Radical. 2 - O O 2 M. Brown

61 WMcB2008 Tirapazamine is Toxic for Hypoxic Cells in vitro Tirapazamine Conc (  M) Surviving Fraction HCR = 300 hypoxia air

62 WMcB2008 Lung Cancer Cervix Cancer Head & Neck Cancer Tirapazamine has shown Clinical Efficacy when Combined with XRT or Chemotherapy Currently off the market!....toxicity issues.

63 WMcB2008 Radiosensitizers From Zeman, 2000

64 WMcB2008 NitroimidazolesNitroimidazoles misonidazole CH 2 CH(OH)CH 2 OCH 3 N N NO 2 etanidazole CH 2 CONH CH 2 CH 2 OH N N NO 2 metronidazole CH 2 CH 2 OH N N CH 3 O2NO2NO2NO2N O nimorazole CH 2 CH 2 N N N O2NO2NO2NO2N

65 WMcB2008 Misonidazole: good sensitization in vitro and in vivo preclinical 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 + 1 mg/g miso TCD 50 = 43.8 Gy 24.1 Gy Sensitizer enhancement ratio = 1.8 ± % tumors controlled Dose X-rays only

66 WMcB2008 Agent Number of Trials Significant benefit Non- significant benefit No benefit Misonidazole Clinical Trials  Clinic: dose-limiting toxicity -- peripheral neuropathy (reduced tolerated dose)


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