7. Fenwick Classical radiobiology

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7. Fenwick Classical radiobiology

7/16/2009• So it’s plausible that trials of hypoxia-modifiers show only 5%improvements in local control because in many patients earlyhypoxia is moderated by re-oxygenation.• A corollary is that very short schedules may run into problems withtumor control (as well as early reactions).NTD50 (Gy)3002702402101801501209060300Oxygen effect – Reoxygenation0 10 20 30 40 50duration (days)α/β = 10 GyData from a rat experiment (Moulder et al 1976), showing isoeffective doses (correctedto 2 Gy fractionation using α/β = 10 and 100 Gy) for 50% tumor control rates. For eitherα/β value, very short isoeffective schedules require elevated dose-levels.NTD50 (Gy)1201101009080706050403020100α/β = 100 Gy0 10 20 30 40 50duration (days)Oxygen effect - summary• Oxygen powerfully enhances radiation cell killing.• So poor outcomes are expected for hypoxic tumors.• Reducing tumor hypoxia by using modifiers such ashyperbaric oxygen or misonidazole leads to ~ 5%improvement in local control at several tumor sites.• Methods for identifying patients likely to benefit fromhypoxia-modifying treatments (those with high initialtumor hypoxia and limited reoxygenation) would allowhypoxia modification to be deployed more efficiently.• Very short schedules may not allow enough time forreoxygenation.4. Reassortment – cell cycle effects• Like chemotherapy, sensitivity of cells to radiation varieswith position in the cell cycle.• Unlike chemotherapy, cells are at their most resistant toradiation in S-phase, probably because of enhanced DNArepair through homologous recombination, survivalpotentially being an order of magnitude higher than for cellsin G1 and G2.• So after radiation, an increased percentage of cells will liein S-phase.• Together with cell-cycle blocks at checkpoints followingirradiation, this phenomenon has the potential to induce adegree of cell cycle synchrony amongst tumor clonogens.Reassortment – cell cycle effects• Synchrony might be exploitable by delivering a secondcytoxic agent dose at an optimal time after the first.• For instance, one cell cycle-time after irradiation manysurviving cells will be back in S-phase, and if they aretreated at that point using an agent with high S-phasesensitivity, enhanced cell kill might be achieved.• But disappointing results have been achieved using thisapproach, perhaps because cell cycle times withintumors are quite variable, causing synchrony to be lost.5. Radiosensitivity• Studies have found correlations between tumor cellradiosensitivity (eg surviving fraction after 2 Gy) and tumorcontrol rates, exploring variations between both differenttumor types and individuals.• Likewise, correlations have been found between normaltissue damage and fibroblast and lymphocyteradiosensitivities.• Given the correlations, it’s intuitively appealing to explorethe potential of dose individualisation based onradiosensitivity assays.• This approach is not yet very advanced, partly because cellsurvival can be difficult to measure rapidly for patients, andpartly because ...Radiosensitivity and the therapeutic window• Dose response curves are sigmoidal• Tumor response curves lie to the left of normal issue curves,and tend to be less steep.• Unless dose-individualisation is smart, overall control andcomplication rates can be very similar to conventional doseprescription,just distributed differently amongst patients.100%age control orcomplication rate0TumorcontrolprobabilityDoseNormaltissuecomplicationprobability7


7/16/2009Radiosensitivity and the therapeutic window• In particular, to individualise dose effectively, more thanjust a correlation (however good the p value) betweenoutcome and radiosensitivity is required.• Tests are needed which could identify patients who areparticularly likely to fail.• By targetting these specific patients with higher doses,their chances can be improved without raising thecomplication rate for the treatment as a whole nearly asmuch as if doses were raised for a larger, less focussedgroup.• Work is ongoing.6. Remote (?) cell kill – the bystander effect• Evidence is piling up that radiation damage is not acompletely local phenomenon – that is, some cells thatare damaged or killed after irradiation may have beentraversed by absolutely no photons or electrons.• Data comes from elaborate low-dose and microbeamstudies which deliver such low or highly-targetted dosesthat only relatively few cells are directly irradiated; andfrom simpler experiments irradiating cells in one part of aPetri dish and exploring the effect on cells elsewhere inthe dish.• Implication is that radiation action on one cell generateschemical messengers which damage other cells.• This is a change in paradigm ...6. Remote (?) cell kill – teatment impact Classical radiobiology – summary• Physically, the impact on treatment depends on thedistance the messenger will diffuse through tissue.• Belyakov et al (2005) has obtained a distance of ∼ 1mmin a reconstructed skin system.• Biochemically, the agent(s) involved presumably presentfurther targets for radiation modifiers...• The curvature of cell-survival plots means thathyperfractionation tilts damage away from endpoints withlower α/β ratios (often late complications), to those withhigher ratios (often tumor control).• An HNSCC meta-analysis found hyperfractionation gives~ 9% gain in local control cf conventional fractionation• Moderate (1-2 week) schedule acceleration usefully limitsaccelerated tumor repopulation, HNSCC meta-analysisshowing an ~ 8% gain• Little is gained from further acceleration, which requiresdose-reduction and still produces ~ 8% gain compared toconventional fractionationClassical radiobiology – summary• Tumor hypoxia-modifiers produce ~ 5% improvement inlocal control for several cancers.• Identifying patients likely to benefit from hypoxiamodifierswould allow more efficient deployment.• Very short schedules may limit reoxygenation.• Disappointing results have been achieved using cellsynchrony approaches.• Dose-individualisation generally requires predictiveassays with good sensitivity and specificity.• Bystander effects occurring on a 1 mm length-scale invivowill have limited physical impact on treatments.Classical radiobiologyThank you for your attention8

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