CURRENT STANDARDS & FUTURE DIRECTIONS FOR PROSTATE CANCER RADIATION THERAPY

CURRENT STANDARDS & FUTURE DIRECTIONS FOR PROSTATE CANCER RADIATION THERAPYCURRENT STANDARDSRadiotherapy TechniqueTarget VolumeDose EscalationIGRT MethodsCombination with Androgen Deprivation Therapy (ADT)FUTURE DIRECTIONSParticle Beam TherapyHypofractionation ConceptsSimultaneous integrated boostApplication of spacer to protect the rectal wallCurrent standardsRadiotherapy Techniques Prostate cancer result study group (2012)For localized prostate cancer RT superior to RP in all defined risk groups. Brachytherapy for low & select intermediate risk EBRT + Brachytherapy for intermediate & high riskEmphasized on the role of radiation dose escalationProstate Cancer Recurrence Risk Definitions

Very low riskT1cGleason score 6PSA < 10 ng/mlFewer than three prostate biopsy cores positive, 50% cancer in each corePSA density < 0.15 ng/ml/gLow riskT1-T2aGleason score 6PSA < 10 ng/mlIntermediate riskT2b-T2c or Gleason score 7 or PSA 10-20 ng/mlHigh riskT3a or Gleason score 8-10 or PSA > 20ng/mlVery high risk (locally advanced)T3b-T4

Brachytherapy Two methods:HDR ( >10Gy/hr) with Ir for interstitial temporary brachytherapyLDR ( grade 2 gastrointestinal toxicityDose EscalationMD Anderson dose escalation trial also reported significant DFS after follow up of 9 yrs for both intermediate risk (p=0.03) and high risk (p=0.05)Biochemical recurrence free survival found to be higher if brachytherapy used for dose escalation after EBRT (46-50Gy)Dose EscalationFor older patient with life expectancy 5-10 yrsLow risk or intermediate risk with PSA < 10 - dose of 70-72 Gy sufficientIntermediate risk or high risk - dose of 76-78 Gy recommended EBRT dose Prophylactic dose to pelvic LN is 1.8 Gy/fr to 45 Gy. Involved LN 54-56 Gy Prophylactic dose to seminal vesicle -54 Gy. Involved SV gets full doseDose to Prostate: 74-78 Gy. Minimum central axis dose is 78 GyP/O cases- prostate bed treated to 64-66 Gy but may be boosted higher for residual diseaseBrachytherapy doseLDR:Monotherapy I-125 = 144 Gy, Pd-103 = 125 GyAfter 40-50 Gy EBRT: I-125= 110 Gy, Pd 103= 90 GyHDR:Monotherapy = 9.5 Gy b.i.d.x 2 days or 10.5 Gy x 3 frAfter EBRT = 9.5 Gy x 2 fr IGRT MethodsMajor problem is Inner organ movement varying day to day or even in few secondsEspecially rectal wall movements- prostate displacement can be 2 cm in AP directionOptions- Cone beam CT, USG and fiducial markers + MV/kV portal imagingMajor issue- dose to organs at risk i.e. 3-6 cGy x 40 fr = 120-240 cGy with Cone beam CTUltrasound imaging (US) systemAvoids additional X-ray exposureLess margins required 4/4/4 mm v/s 9/15/10 mm ( van Herk formula)Problems inadequate image quality or a prostate displacement through pressure applied by probeAbout 20% images poor quality

Newer SystemsRemote automatic transperineal scanning approach. Calypso prostate Beacon transponder (tracks the target using radiofrequency waves, offering real time tracking)

IGRT MethodsIntrafraction alignment allows further reduction of safety marginsReduces dose to bladder and rectum and thus normal tissue complication probabilityBut the effects were insignificant over large number of fraction (> 10-15 fr), may be important for hypofractionationCombination of Androgen Deprivation Therapy (ADT)Many large phase III randomized studies like EORTC 22863, RTOG 85-31, RTOG 86-10 has shown EBRT + ADT superior to ADT alone Longer duration ADT better than shorter durationInclude T1 T4 tumorsADT duration 3 months to 3 years or until progressionMaximum benefit to intermediate and high risk Neoadjuvant ADT- decreases PSA level quickly and smaller prostate volume for irradiationNo reduction in toxicity

Future directionsParticle Beam RadiotherapyNeutrons, protons and heavy charged particles like carbon ionsBetter depth dose distribution and more favorable radiobiologic properties of high LET and RBE( photon 1.1-1.2, fast neutrons 3-5, charged particles 2-4)Spread out Bragg peakDose- Gray equivalent (GyE) equal to physical dose multiplied by RBENeutron BeamTwo randomized trials- RTOG 77-04 ( mixed beam) and Neutron Therapy Collaborative Working Group 85-23 ( pure Neutron beam) Significant improvement in locoregional control Only mixed beam trial has shown significant survival benefit ( 46 vs 29% after 10 yrs)Increased morbidity in centers without MLCProton BeamRandomized trial for dose escalation with proton vs conventional photonLocally advanced prostate cancer -> 50.4 Gy photon -> 25.2 GyE proton boost or 16.8 Gy photon boostPatients with poorly diff tumor had better control with protonHigh complication rate with proton ( 32vs 12% rectal bleeding; 19 vs 8% urethral stricture)SEER- Medicare linked data (2000-2009)- high GI complications with protonCarbon ion RadiotherapyNo clinical trial data of carbon vs photon at presentLargest experience from Chiba , Japan175 patients treated and followed up for 4 yrsHigh biochemical recurrence free survival rate of nearly 90%Only 2% grade 2 toxicity, no grade 3 toxicityHypofractionation ConceptsFraction dose > 2 GyTwo reasons- low / ratio and new advanced radiation techniques improving conformality of high radiation dose to target tissueCurrent Phase III studies indicate similar biochemical outcomes & toxicity Phase I & II studies of extreme hypofractionation (6-10 Gy/fr up to total of 36-50 Gy) Simultaneous Integrated BoostFocusing dose escalation on actual tumor has potential to increase tumor control and less toxicityRecurrence in prostate cancer usually originate at the site of primary tumorIn a clinical trial no increase in acute toxicity, mean long term urinary and bladder QOL scores did not decrease significantly. Long term results awaitedMRI with spectroscopyT2 weighted, diffusion weighted and contrast enhanced sequences are recommendedMRS indicates metabolism within the tissueCholine, creatinine and citrate are usedHigh choline peaks correlate to higher ratio of cellular membranes per volume and higher turnover of phospholipid membranesPETProvides a method to study metabolic activity of tumors in vivoPET/CT hybrid reduces image fusion mismatches significantlyStudies comparing PET results with histological specimens reported specificity and PPV between 80 to 90%Application of Spacer Used between prostate and rectum to generate a distance for dose fall offAllows safer hypofractionation and reirradiation Hydrogel is injected under transrectal USG guidance between Denonvilliers fascia and anterior rectal wallApplication of Spacer Early data from large multicentre trial:Clinically significant reduction in rectal dose was deemed to be reduction in V70 by 25% and achieved in 95% patientsRepeated scans showed no degradation of spacer during treatment and 6 month follow up imaging showed no residual gelQOL improved compared to non spacer treatment using 3DCRT or IMRT even though prescription dose was higher in spacer groupConclusion An optimal standard EBRT to reach favorable tumor control rates with only limited toxicity currently includes IMRT and IGRT techniques with total dose of >76-78 Gy in conventional fractionation.Option of combination with ADT need to be chosen for each individual patientProstate brachytherapy can be applied as monotherapy or as a boost to EBRT Five year viewProtons and carbon ions are available only at few centers and to few patients. Current Clinical data do not support proton over IMRT but carbon ion is promising experimental optionHypofractionation are increasingly used. Treatment duration shortened substantially, increasing patient convenience

Five year viewProgress in molecular imaging along with radiotherapy conformality and accuracy allows dose escalation to intraprostatic lesionSIB concept is a dose escalation to macroscopic tumor with best possible normal tissue protectionHydrogel spacer allow a distance of 1 cm ensuring exclusion of rectal wall from PTV and thus high isodoses.Thank you