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Radiation response modifiers
This document discusses radiation response modifiers in cancer treatment, emphasizing the relationship between radiation dose, tumor response, and normal tissue damage. It highlights strategies to enhance therapeutic efficacy, such as hypoxic cell sensitizers, novel chemotherapy agents, and concurrent chemoradiation approaches while addressing challenges like treatment toxicity and anemia. The document also mentions the evolving role of radioprotectors and advanced treatment methods, noting that while some preclinical candidates show promise, their success in phase III trials has been mixed.
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Radiation response modifiers
- 1. RADIATION RESPONSE MODIFIERS Dr. HimanshuShekhar Mekap MD, Radiation oncology
- 2. INTRODUCTION • In RadiationTherapy There is a clear Dose- Response relationship. • Unfortunately damage to normal tissue also increases as the radiation dose increases. • Substantial effort has been made to modify these dose response relationships & increase the separation between tumour tissue & normal tissue dose response curves.
- 3. RADIATION RESPONSE 1.THERAPEUTIC RATIO:TCP/NTCP 2.EFFICACY/TOXICITY PROFILE OF CHEMICAL MODIFIER
- 4.
- 5. THE OXYGEN EFFECT OER RADIATIONDOSE IN HYPOXIA RADIATION DOSE IN AIR The response of cells to radiation is strongly dependent upon oxygen Addition of molecular O₂ to target free radicals produces altered chemical str. That are potentially lethal
- 6. OVERCOMING TUMOR HYPOXIA AUGMENTATION OF TUMOROXYGENATION 1.HYPERBARIC OXYGEN & RT 2.CARBOGEN WITH/WITHOUT NICOTINAMIDE 3.CORRECTION OF ANEMIA SENSITIZATION OF HYPOXIC CELLS 1.MISONIDAZOLE 2.NIMORAZOLE PHARMACOLOGIC TARGETING OF HYPOXIC CELLS 1.MITOMYCIN C 2.PORFIROMYCIN 3.TIRAPAZAMINE
- 7. BENEFIT HEAD & NECK, CERVIX NOBENEFIT CNS,LUNGS, BLADDER,SKIN FAILURE NONCONVENTIONAL HYPOFRACTIONATED REGIMENS, PATIENT COMPLIANCE,EXPENSIVE HYPERBARIC OXYGEN AND RT
- 8. CARBOGEN WITH/WITHOUT NICOTINAMIDE RATIONALE CO₂ RIGHT SHIFTSTHE OXYHEMOGLOBIN CURVE RATIONALE NICOTINAMIDE ENHANCES TUMOR BLOOD FLOW (Preclinical) NICOTINAMIDE ADMINISTERED 1 TO 1.5 HOURS PRIOR TO RT AT 60 TO 80 mg/kg. FAILURE- 1.NAUSEA & VOMITING 2.COMPLIANCE 3.HYPERBARIC CHAMBERS
- 9. MISONIDAZOLE DAHANCA-2 STUDY 626 Pts.,doubleblind randomized, 11gm/m² RESULT: Significant improvement in pharynx subgroup as compared to larynx. Significant NEUROTOXICITY NIMORAZOLE DAHANCA-5 Study PHASE III,1.2 gm/m² Supraglottic Larynx & Pharynx RESULT:Improved locoregional control & disease free survival (49% vs 33%) P=0.002 META-ANALYSIS: >11,000 Pts. In 91 Randomized trials- RESULT: IMPROVED LOCOREGIONAL TUMOR CONTROL MOSTLY IN HEAD AND NECK CA, BUT NO IMPROVEMENT IN OVERALL SURVIVAL (IN DENMARK NIMORAZOLE HAS BECOME PART OF THE STANDARD RT IN HEAD AND NECK CANCER) HYPOXIC CELL RADIOSENSITIZERS
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- 11. MODIFICATION BASED ON HEMOGLOBIN Itis well established that haemoglobin conc. Is an important prognostic factor for the response to radiotherapy especially squamous cell ca.(Overgaard et al,1989) Patients with low haemoglobin levels have a reduced locoregional tumour control & survival probability Tumor hypoxia clearly is one of the major factors
- 12. ANEMIA & CONCENTRATIONOF HEMOGLOBIN • Thomas GM et al, 1st time showed the potential benefit of increasing haemoglobin conc. to 11 gm/dl By blood transfusion In advanced ca. cervix with improved survival. • DAHANCA study group had failed to show any benefit of transfusion in head & neck ca. • Hoskin pj,Robinson et al, hv failed to show any benefit of erythropoietin in correction of anemia in head & neck cancer Pts.
- 13. TARGETING OF HYPOXICCELLS METABOLISED IN REGIONS OF LOW O₂ CONC. PREFERENTIALLY CYTOTOXIC TO HYPOXIC CELLS MITOMYCIN C DEFINITIVE NONSURGICAL MANAGEMENT OF CA. ANUS YALE University- 195 Head & neck ca. 68 Gy with/without MMC on days 1 & 43 of RT RESULT- Locoregional RFS (54% to 76%,P=0.003) BUT OS not significant PORFIROMYCIN- derivative, but showed inferior results as compared to MMC IN 5 yr Loco-Regional Relapse Free Survival but no difference in OS. TIRAPAZAMINE HEADSTART STUDY(Phase III) RT+CISPLATIN/TPZ vs CISPLATIN NO DIFFERENCE Rischin et al, showed benefit of TIRAPAZAMINE in tumor hypoxia in Loco-Regional Failure.
- 14. STRATEGIES CHEMOTHERAPY & IRRADIATION SPATIAL COOPERATION CYTOTOXIC ENHANCEMENT INDEPENDENT TOXICITIES PROTECTIONOF NORMAL TISSUES BIOLOGIC COOPERATION TEMPORAL MODULATION
- 15. SPATIAL COOPERATION • Chemotherapyacts systemically & Radiotherapy acts locoregionally. • Sequential therapy is best example • Example- Adjuvant CT→RT in Breast cancer RT in bulky disease in Lymphoma PCI in small cell lung cancer INDEPENDENT TOXICITY • Normal tissue toxicity is the main dose limiting factor. • CT Regimen with a toxicity profile different from RT. • Increased tumor cell kill with minimal combined tissue toxicity. • Example- Adriamycin is not used with breast RT. • BLEOMYCIN is not used with lung RT.
- 16. CYTOTOXIC ENHANCEMENT • COMBINEDmodality therapy leads to Interaction at molecular/cellular level resulting in greater antitumor effect on the basis of additive actions. PROTECTION OF NORMAL TISSUES • Technical improvements in radiation delivery • Chemical or biologic agents. • Example- AMIFOSTINE protects against xerostomia in head & neck ca.(limited success)
- 17. BIOLOGIC COOPERATION Independent targetingof subpopulations of cells within the tumor itself EXAMPLE- TIRAPAZAMINE as it targets hypoxic sub populations of cells which are radioresistant TEMPORAL MODULATION Implies therapeutics that target the FOUR R”S of Radiotherapy Repair,Repopulation,Redistribution,Reoxygenation between fractionated radiation treatments
- 18. INCREASING INITIAL RADIATIONDAMAGE INHIBITION OF CELLULAR REPAIR COUNTERACTING HYPOXIA ASSOCIATED TUMOR RADIORESISTANCE INHIBITION OF TUMOR CELL REPOPULATION CELL CYCLE REDISTRIBUTION DRUG- RADIATION INTERACTIONS
- 19. INCREASING INITIAL RADIATIONDAMAGE • Radiation induces lesions in DNA molecule such as SSBs, DSBs, DNA-DNA crosslinks. • Drugs such as halogenated pyrimidines incorporate into DNA & make it more susceptible to radiation damage. INHIBITION OF CELLULAR REPAIR- • Many chemotherapeutic agents interact with cellular repair mechanisms & inhibit Repair for e.g- Halogenated pyrimidines, Gemcitabine in Pre clinical studies.
- 20. COUNTERACTING HYPOXIA ASSOCIATED TUMORRADIORESISTANCE- CT Preferentially kill proliferating cells,primarily found in well oxygenated regions of the tumor, as these regions are close to blood vessels. Destruction of tumor cells in these areas leads to an increased oxygen supply to hypoxic regions Massive loss of cells after chemotherapy lowers the interstitial pressure which allows re- establishment of blood supply.
- 21. CELL CYCLE REDISRIBUTION •Cytotoxic action of CT or RT depends on position of cells in cell cycle. • Cells in G₂ & M phase were approx. 3 times more sensitive than S phase. Example- 1. Taxanes can block transition of cells through Mitosis resulting in cell accumulation in G₂ & M phase. 2. elimination of the Radioresistant S- phase cells e.g, Fludarabine & Gemcitabine. 3. Accumulation of cells in G₂ & M phase by parasynchronous movement
- 22. INHIBITION OF TUMORCELL REPOPULATION • Repopulation- the cell loss after each fraction of radiation during radiation therapy induces compensatory cell regeneration. • The rate of cell proliferation in tumors treated by RT is higher than that in untreated tumors. This treatment induced cell proliferation is termed accelerated repopulation. • Chemotherapeutic drugs, because of their cyto toxic or cytostatic activity reduce the rate of proliferation when given concurrently with RT.
- 23. PLATINUM COMPOUNDS Potent radiosensitizer formany years MECHANISMS-1. Inhibition of DNA synthesis 2. Inhibition of transcription elongation by DNA interstrand crosslinks. 3.Inhibition of repair of radiation induced DNA damage. 1.CISPLATIN 2.OXALIPLATIN 3.CARBOPLATIN 4.SATRAPLATIN
- 24. ANTIMETABOLITES 5-FLUOROURACIL Target the radioresistantcells in S phase. Used as bolus infusion, or continuous infusion Mechanism of Radiosensitization -1. Incorporation into RNA 2. Inhibition of thymidilate synthase 3. Direct incorporation into DNA CAPECITABINE Oral Prodrug of 5 FU. Its converted to its cytotoxic form by thymidine phosphorylase RATIONALE- 1. thymidine phosphorylase is overexpressed in tumor tissues. 2. Radiation stimulates expression of thymidine phosphorylase.
- 25. ANTIMETABOLITES GEMCITABINE Nucleoside analogue, actsas a potent radiosensitizer, S phase specific. Mechanism- ↓DeoxyNTP Direct incorporation into DNA Drug induced apoptosis. Preclinical evidence suggests that it’s a potent Radiosensitiser PEMETREXED NOVEL multitargeted agent inhibiting multiple folate requiring enzymes. Shown synergistic activity with RT due to interference with DNA synthesis. Radiosensitization is not cell cycle phase specific. Shown encouraging results in NSCLC
- 26. ALKYLATING AGENTS TEMOZOLOMIDE 2nd generation orallyacting Unique in its ability to cross BBB. Radiosensitization- inhibition of DNA repair 1st line therapy in GBM concurrent with RT TOPOISOMERASE I INHIBITOR TOPOTECAN,IRINOTECAN MECHANISMS-1. Inhibition of Repair 2. Redistribution ino G₂ phase. 3.Conversion of RT induced SSBs into DSBs.
- 27. ANTIMICROTUBULES TAXANES MECHANISMS 1.Cellular arrest inG₂M phase of the cell cycle. 2.Induction of apoptosis. 3.Reoxygenation of tumor cells. 1.PACLITAXEL 2.DOCETAXEL
- 28. CHEMORADIATION THERAPY AS STANDARDOF CARE HEAD & NECK (LOCALLY ADVANCED) CISPLATIN,5FU, CARBOPLATIN, CETUXIMAB DEFINITIVE/ POST-OP. CONCURRENT LRC/DFS,OS BENEFIT ORGAN PRESERVE GLIOBLASTOMA MULTIFORME TEMOZOLOMIDE DEFINITIVE/ POST-OP. CONCURRENT OVERALL SURVIVAL LOCALLY ADVANCED NSCLC CISPLATIN,CARBOPL ATIN, ETOPOSIDE,PACLITA XEL DEFINITIVE CONCURRENT, SEQUENTIAL OVERALL SURVIVAL LIMITED STAGE SMALL CELL LUNG CA CISPLATIN/ETOPOSI DE DEFINITIVE CONCURRENT OVERALL SURVIVAL ESOPHAGEAL CA. CISPLATIN/5FU PRE-OP./ DEFINITIVE CONCURRENT LOCAL CONTROL,OS
- 29. CHEMORADIATION THERAPY AS STANDARDOF CARE GASTRIC CA. 5FU POST-OP. CONCURRENT OVERALL SURVIVAL PANCREATIC CA. 5FU,GEMCITABINE POST-OP./ DEFINITIVE CONCURRENT LOCOREGIONAL CONTROL,POSSIBLY SURVIVAL LOCALLY ADVANCED RECTAL CANCER 5FU,CAPECITABINE PRE-OP. CONCURRENT IMPROVED SPHINCTER PRESERVATION,OS ANAL CA. 5FU,MITOMYCIN C DEFINITIVE CONCURRENT IMPROVED COLOSTOMY FREE SURVIVAL CA. CERVIX CISPLATIN,5FU DEFINITIVE CONCURRENT OVERALL SURVIVAL BLADDER CA. CISPLATIN,5FU DEFINITIVE CONCURRENT BLADDER PRESERVATION
- 30. LONG-TERM TOXICITY OFCOMBINED CHEMORADIATION THERAPY BLEOMYCIN PULMONARY FIBROSIS/PNEUMONITIS ACTINOMYCIN-D HEPATOPATHY DOXORUBICIN CARDIOMYOPATHY METHOTREXATE LEUKOENCEPHALOPATHY CISPLATIN SENSORINEURAL HEARING LOSS
- 31. CTRT IN HEAD& NECK CANCER INT 0099, 1998 RT(70Gy) vs. RT(70Gy) + Cisplatin(100mg/m²) with adj. cisplatin+5-FU At 5 yr PFS(58% vs 29%), DFS(74% vs 46%), OS(67% vs37%) favours CT/RT arm. p<0.001 RTOG 9111, 2003 3 ARM-( Glottic & supraglottic) –RT vs sequential CT/RT vs concurrent CT/RT NO Diff. in OS, but Concurrent arm had superior local control & highest organ preservation EORTC 22931, 2004 Post-op. RT(66Gy) vs. post- op. CTRT (66Gy+cisplatin) 5 yr OS(53% vs 40%), PFS (47% vs. 36%), LRC (82% vs. 69%) p<0.05 MACH-NC Meta analysis 93 randomised trials in Head & Neck- 17,346 Patients CT/RT Provides absolute 5- yr OS BENEFIT OF 6.5%, whereas induction CT showed only 2.4%
- 32. CTRT IN CARCINOMACERVIX GOG-120, 1999 IIB-IVA; 3 ARMS; RT+ CISPLATIN vs. RT+CISPLATIN/5FU/HU vs. RT+HU IMPROVED PFS & OS IN BOTH CISPLATIN ARMS P<0.005 GOG-123, 1999 IB( TUMORS ≥4cm.) RT vs. RT+ cisplatin IMPROVED PFS(P<0.001) & IMPROVED OS(P<0.008) IN CISPLATIN ARM INTERGROUP 0107, 2000 I-IIA( POST HYSTERECTOMY) WITH HIGH RISK, RT vs. RT+CISPLATIN/5FU IMPROVED PFS (P=0.003) & IMPROVED OS(P=0.008) IN CTRT ARM RTOG 9001, 1999 IB-IIA(≥5cm. Or +ve pelvic nodes), IIB-IVA EFRT vs CTRT IMPROVED 5 yr DFS (P<0.001)& IMPROVED 5 yr OS(P=0.004) IN CISPLATIN ARM
- 33. CETUXIMAB AS RADIOSENSITIZER Themedian duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03) James A Bonner, K. Kian Ang, M.D., Ph.D. N Engl J Med 2006; 354:567-578 February 9, 2006
- 34. RTOG-0522 INITIAL RESULTS REPORTEDAT ASCO-2011 • The randomized trial conducted by the RTOG sought to determine if adding cetuximab to a chemoradiotherapy treatment regimen would improve progression-free and overall survival for patients with Stage III-IV head and neck squamous cell cancers. Show No Survival Benefits by the Addition of Cetuximab to Chemoradiation Treatment for Patients with Locally Advanced Head and Neck Cancer
- 35. RADIOPROTECTORS AMIFOSTINE is theonly Radioprotective drug approved by U.S.FDA for prevention of xerostomia in head & neck ca. MECHANISMS- 1.Free radical scavenging 2. Hydrogen atom donation to facilitate DNA repair RTOG PHASE III trial demonstrated efficacy of amifostine in reducing xerostomia in head & neck ca. receiving RT FAILURE- 1.Possible tumor protection 2. Loss of therapeutic gain
- 36. RADIOPROTECTORS PALIFERMIN KERATINOCYTE GROWTH FACTOR issynthesised predominantly by mesenchymal cells Preclinical models-potential to ameliorate radiation effects in oral mucosa,skin,intestine,lung & urinary bladder Spielberger et al,2004 Randomised,placebo controlled,double blinded phase III Patients receiving total body irradiation & high dose chemotherapy in preparation for peripheral blood progenitor cell transplantation- Significant reduction in incidence & duration of oral mucositis
- 37. HYPERTHERMIA RATIONALE – 1. CANlead to Reoxygenation, which further improves Radiation Response. 2. Inhibits repair of both sublethal & potentially lethal damage through its effect in inactivating crucial DNA repair pathways. 3. With Hyperthermia,there is no difference in sensitivity between aerobic & hypoxic cells. 4. Direct cytotoxicity. RADIATION + HYPERTHERMIA- COMPLEMENTARY EFFECTS (S-PHASE →Radioresistant-Radiosensitive)
- 38. PHASE III TRIALS AUTHORSITE TREATMENT CR% LC% OS% Valdagni ,1993 HEAD & NECK RT 41 24 _ RT+HT 83* 69 _ Vernon,1996 BREAST RT 41 _ 40 RT+HT 59* _ 40 Sneed,1998 BRAIN RT _ _ 15 RT+HT _ _ 31*
- 39. PHASE III TRIALS AUTHORSITE TREATMENT CR% LC% OS% Van der zee,2000 CERVIX RT 57 41 27 RT+HT 83* 61* 51* Jones,2005 CHEST WALL RT 42 25 23 RT+HT 66* 48* 21 Hua,2011 NASOPHARY NX RT+CT 81 79 63 RT+HT+CT 96* 91* 73*
- 40. TAKE HOME MESSAGE •The chemical modification of radiation response both for enhancing treatment efficacy & reducing therapy induced toxicity remains an area of active investigation. • Promising candidates identified in preclinical & early phase trials have been less successful in randomised phase III settings. • Attempts to improve treatment efficacy by augmenting tumor oxygen delivery have a mixed record of success.
- 41. TAKE HOME MESSAGE •The use of drugs that are preferentially cytotoxic to hypoxic cells holds promise , although improved tools to identify those patients most likely to benefit from targeted therapy are needed. • However, apart from the use of radiosensitizer NIMORAZOLE in Denmark, none of these treatments have become part of standard radiation therapy.
- 42. TAKE HOME MESSAGE •The use of radioprotectors is more controversial. Proof of chemical radioprotection has been established in salivary glands but not elsewhere. There is possibility of radioprotection in tumor as well. • The combination of chemotherapy & radiation has become a common strategy in locally advanced cancers with emphasis on concurrent delivery.
- 43. TAKE HOME MESSAGE •Improvements in treatment outcome in terms of both local control & survival have been achieved with traditional chemotherapeutic agents such as cisplatin & 5FU. • In the era of new RT technologies, monoclonal antibodies & novel chemotherapeutic agents are associated with significant cost profiles. In this regard hyperthermia is relatively inexpensive,given the results already achieved further investigation warranted.