Predicting <br />Clinical and Biochemical Endpoints Before External Radiotherapy<br />Brett Cox, M.D.<br />Assistant Atten...
Dose Response in Prostate Cancer<br />Fowler JF, et al.  IJROBP 2003;56:1093-1104<br />
EBRT Dose: Randomized Trials of Escalation<br />
MSKCC Dose Escalation Experience:Long Term Follow-up <br />2047 patients with T1-T3 prostate cancer<br />1988 - 2004<br />...
Stage, Gleason Score, PSA<br />< 10 vs. > 10 ng/ml<br />< 6 vs. 7-10<br />< T2c vs. > T2c<br />Risk group dependence of do...
Risk Group<br />ASTRO<br />bRFS5<br />99%<br />79%<br />72%<br />Nadir+2<br />bRFS5<br />98%<br />85%<br />70%<br />Cahlon...
MSKCC Nomogram<br />Zelefsky MJ et al.   Pretreatment Nomogram Predicting Ten-Year Biochemical Outcome of 3D-CRT and IMRT ...
Risk Groups & Nomograms are Incomplete: <br />Other Clinical Factors are Predictive<br />
Percent Positive Biopsies<br />Michigan > 75 Gy <br />Mayo Intermediate Risk < 71 Gy<br />Harvard Intermediate Risk ~ 70 G...
Perineural Invasion<br />Beard C et al.  Perineural Invasion Associated with Increased Cancer-Specific Mortality After Ext...
PSA Kinetics<br />Pretreatment PSA Velocity and Risk of Death From Prostate Cancer Following External Beam Radiotherapy.  ...
Radiation Technique: IMRT<br />Zelefsky MJ et al. High Dose Radiation Delivered by IMRT Improves the Outcome of Localized ...
Radiation Technique: IGRTInter- and Intrafraction Motion Management<br />Rectal distension at simulation predicts for incr...
Interval From Diagnosis to Start of EBRT & Treatment Delays<br />Nguyen PL et al.  The Impact of a Delay in Initiating Rad...
Why Hypofractionate ? <br />Prostate Cancer is Radiobiologically Different<br />Series		Method		a/b<br />Brenner & Hall (1...
 Reduced to same level of late effects
Reduce overall treatment length</li></ul>	↑ Access to care<br />	↑ Proportion of patients choosing radiation, <br />	↑ Eff...
What if a/b is that low?<br />Potential advantages of Hypofractionation<br />
Predictors of Clinical and Biochemical Endpoints Before External Radiotherapy<br />Radiation Dose<br />Stage<br />Gleason ...
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NY Prostate Cancer Conference - B.W. Cox - Session 4: Predicting clinical and biochemical endpoints before external radiotherapy

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  • Start with things weighted with academic importance…So it is clear that dose escalation improves clinical outcomes, both in terms of biochemical control and in terms of harder clinical endpoints including distant metastases free survival rates, the latter being from retrospective data for this institution (high risk group DMFS from Zelefsky) from this institution. So the answer should be simple – we should just keep increasing the dose, right?
  • Add other nomograms have been published – D’Amico 1999, etc.
  • For example, for intermediate risk disease, other clinical predictors of patient outcome You need to consider other pre-treatment, clinical-based factors after assigning a traditional risk group to recommend the best treatment for your patients!Example of intermeidate risk – actually a heterogeneous group, shows that other clincial factors are important and need to be used in the deciison making process, especially for the wide range of different types of intermediate risk disease. You need to consider other pre-treatment, clinical-based factors after assigning a traditional risk group to recommend the best treatment for your patients!
  • D’ Amico – greater than 50 % PPB has worse prognosis IN INTERMEDIATE RISK PATIENTS. Top figure is normal risk group stratification slide. Wong - &gt; 33% PPB is predictive in intermediate risk patients. More info about wong: EBRT was less than or equal to 71 Gy, had PPB but not PNI on MVA, on UVA PNI was also a risk factor. Again, for “localized” prostate cancer…\\2011/Quian – This paper included people with &gt; 75 Gy radiotherapy, making this more relevant to the modern dose-escalated era of treatment, all differences were significant except for OS with a p value of 0.055, so marginally close.
  • Calculated through PSA kinetics and ultrasound calculations – PSA density type readings. Authors conclusion: the volume of prostate cancer Vca and the resulting volume fraction of cancer both added significantly to PSA in their ability to predicts for early post-radiation PSA failure. These new parameters may be used to select patients for more appropriate therapy. -----------------------------MSKCC – volume of index lesion on pre-treatment MRI is predictive of PSA relapse free time in months.
  • Both papers relatively low dose of 70ish Gy. Ted Deweese is last author from hopkinsPNI in 7 % low, 18 % intermediate, 30 highPresence on PNI associated with lower bRFS and prostate cancer specific survivalEssentially good for all risk groupsMedian dose 70.5 GyHarvard paper shows about the same thing. Again, conflicting papers exist here, but provocative info and worth including in treatment info.
  • For patients beyond low risk, the findings of SVI results in a higher PSA failure rate after EBRT monotherapy, which strongly suggests the present of locally advanced and/or micrometastatic disease – provides the basis for extra treatment (hormones was the conclusion of the paper. 250 patientsNo hormonesClinically localized prostate cancer “beyond low risk patients”erMRI SVI was significant predictor of time to PSA failureECE in absence of SVI was not found to predict for PSA failure, unlike surgical series reported by D’Amico in 2000This may lead us to people who need more therapy – addition of brachy, hormones, wider fields, dose escalation…For example, for intermediate risk disease, other clinical predictors of patient outcome Example of intermeidate risk – actually a heterogeneous group, shows that other clincial factors are important and need to be used in the deciison making process, especially for the wide range of different types of intermediate risk disease. You need to consider other pre-treatment, clinical-based factors after assigning a traditional risk group to recommend the best treatment for your patients!-------------------------------------
  • Bottom line – rapid rise is badPSA rise of &gt; 2 ng/ml during the year prior to diagnosis may suggest RP alone could be inadequateMay want to stage then more aggressively than normal. If elect RT, may need to consider adding hormonal therapyObservation should be discouraged. ? Even add hormones to low risk patients?????---------------------------------------------Michigan group/Howard SandlerIntroduction: To determine if pretreatment PSA doubling time (PSA-DT) can predict post-radiation therapy(RT) PSA trajectories for localized prostate cancer.Materials and methods: Three hundred and seventy-five prostate cancer patients treated with externalbeam RT without androgen deprivation therapy (ADT) were identified with an adequate number ofPSA values. We utilized a linear mixed model (LMM) analysis to model longitudinal PSA data sets afterdefinitive treatment. Post-treatment PSA trajectories were allowed to depend on the pre-RT PSA-DT,pre-RT PSA (iPSA), Gleason score (GS), and T-stage.Results: Pre-RT PSA-DT had a borderline impact on predicting the rate of PSA rise after nadir (p = 0.08).For a typical low risk patient (T1, GS 6 6, iPSA 10), the predicted PSA-DT post-nadir was 21% shorterfor pre-RT PSA-DT &lt; 24 month compared to pre-RT PSA-DT &gt; 24 month (19 month vs. 24 month). Additionalsignificant predictors of post-RT PSA rate of rise included GS (p &lt; 0.0001), iPSA (p &lt; 0.0001), andT-stage (p = 0.02).Conclusions: We observed a trend between rapidly rising pre-RT PSA and the post-RT post-nadir PSA rise.This effect appeared to be independent of iPSA, GS, or T-stage. The results presented suggest that pretreatmentPSA-DT may help predict post-RT PSA trajectories. 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 90
  • Helps improve the therapeutic ratio!Get graph from Zelefsky et al JU 166:876-881, 2001 – shows rectal toxicity as a function of dose and technique, shouw 81 Gy IMRT has much lower toxicity that 3D CRT and equivalent toxicity to 64.8 – 70.2 Gy 3D CRT, y axis is precent grade 2 or greater rectal tox, x axis is months39% received ADT for a large gland for three months before radiation, stopped at end of radiation therapyNote that IMRT did have shorter follow up, but seems to follow the curve to date for 64-70.2 GY
  • Harvard Studyprostate carcinoma;delay;radiation therapy;prostate-specific antigen outcomeAbstractBACKGROUNDTo determine whether a delay in initiating external beam radiation therapy (RT) following diagnosis could impact prostate-specific antigen (PSA) outcome for patients with localized prostate cancer, 460 patients, who received 3D conformal RT to a median dose of 70.4 Gy for clinically localized prostate cancer between 1992 and 2001, were studied.METHODSThe primary endpoint was PSA failure (American Society for Therapeutic Radiology and Oncology definition). Estimates of PSA control were made using the Kaplan–Meier method. Delay was defined as the time between diagnosis and the start of RT. Risk groups were defined based on known predictors of PSA outcome, namely, baseline PSA level, clinical T-category, Gleason score, and percentage of biopsy cores positive for tumor. Cox multivariate regression analysis was used to determine the ability of treatment delay to predict time to PSA failure after adjusting for the other known predictors.RESULTSTreatment delay independently predicted time to PSA failure following diagnosis for high-risk (Adjusted Hazard Ratio = 1.08 per month; P = 0.029) but not low-risk patients (P = 0.31). Patients with high-risk disease (n = 240) had 5-year estimates of PSA failure-free survival of 55% versus 39% (Plog-rank = 0.014) for those with delay &lt; 2.5 months versus ≥ 2.5 months respectively. The median delay was 2.5 months.CONCLUSIONSTreatment delay adversely affected PSA outcome for high-risk patients but not for low-risk patients following RT. Cancer 2005. © 2005 American Cancer Society.-------------------------------Purpose: The protraction of external beam radiotherapy (RT) time is detrimental in several disease sites. In prostatecancer, the overall treatment time can be considerable, as can the potential for treatment breaks.We evaluatedthe effect of elapsed treatment time on outcome after RT for prostate cancer.Methods and Materials: Between April 1989 and November 2004, 1,796 men with prostate cancer were treatedwith RT alone. The nontreatment day ratio (NTDR) was defined as the number of nontreatment days dividedby the total elapsed days of RT. This ratio was used to account for the relationship between treatment durationand total RT dose. Men were stratified into low risk (n = 789), intermediate risk (n = 798), and high risk(n = 209) using a single-factor model.Results: The 10-year freedom from biochemical failure (FFBF) rate was 68% for a NTDR &lt;33% vs. 58% forNTDR $33% (p = 0.02; BF was defined as a prostate-specific antigen nadir + 2 ng/mL). In the low-risk group,the 10-year FFBF rate was 82% for NTDR &lt;33% vs. 57% for NTDR $33% (p = 0.0019). The NTDR was independentlypredictive for FFBF (p = 0.03), in addition to T stage (p = 0.005) and initial prostate-specific antigen level(p &lt; 0.0001) on multivariate analysis, including Gleason score and radiation dose. The NTDR was not a significantpredictor of FFBF when examined in the intermediate-risk group, high-risk group, or all risk groups combined.Conclusions: A proportionally longer treatment duration was identified as an adverse factor in low-risk patients.Treatment breaks resulting in a NTDR of $33% (e.g., four or more breaks during a 40-fraction treatment,5 d/wk) should be avoided. 2008 Elsevier Inc.
  • Use of hypofractionated treatment schedules should result in tumor control and late effects at least as good (or better) than external beam radiotherapy aloneEarly reactions may be less with hypofractionation.If tumor control shows a high α/β and late effects a low α/β, then hypofractionation will spare tumor more than late effectsIf early effects shows a high α/β and tumor control a low α/β, then hypofractionation will spare early effects more than the tumorMany centers are exploring fractionation schemes like this.
  • NY Prostate Cancer Conference - B.W. Cox - Session 4: Predicting clinical and biochemical endpoints before external radiotherapy

    1. 1. Predicting <br />Clinical and Biochemical Endpoints Before External Radiotherapy<br />Brett Cox, M.D.<br />Assistant Attending<br />Department of Radiation Oncology<br />Memorial Sloan-Kettering Cancer Center<br />
    2. 2. Dose Response in Prostate Cancer<br />Fowler JF, et al. IJROBP 2003;56:1093-1104<br />
    3. 3. EBRT Dose: Randomized Trials of Escalation<br />
    4. 4. MSKCC Dose Escalation Experience:Long Term Follow-up <br />2047 patients with T1-T3 prostate cancer<br />1988 - 2004<br />3D-CRT or IMRT<br />66 Gy-86.4 Gy<br />Median Age 69 years (range 45-86)<br />Median follow-up: 6.6 years (range: 3-18 yrs)<br />PSA RFS<br />Intermediate and High<br />DMFS<br />Intermediate and High<br />Zelefsky MZ, et al. Long-Term Results of Conformal Radiotherapy for Prostate Cancer: Impact of Dose Escalation on Biochemical Tumor Control and Distant Metastases-Free Survival Outcomes. IJORBP 2008; 71(4): 1028-1033<br />
    5. 5. Stage, Gleason Score, PSA<br />< 10 vs. > 10 ng/ml<br />< 6 vs. 7-10<br />< T2c vs. > T2c<br />Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer. Levegrün S, Jackson A, Zelefsky MJ, Venkatraman ES, Skwarchuk MW, Schlegel W, Fuks Z, Leibel SA, Ling CC. Radiother Oncol. 2002; 63: 11-26<br />
    6. 6. Risk Group<br />ASTRO<br />bRFS5<br />99%<br />79%<br />72%<br />Nadir+2<br />bRFS5<br />98%<br />85%<br />70%<br />Cahlon O et al. Ultra High Dose (86.4 Gy) IMRT for Localized Prostate Cancer: Toxicity and Biochemical Outcomes. IJORBP 2008; 71(2): 330-337<br />Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer. Levegrün S, et al. Radiother Oncol. 2002; 63: 11-26<br />MD Anderson Dose Escalation Trial: Kuban D et al. IJROBP 2008;70(1): 67-74<br />
    7. 7. MSKCC Nomogram<br />Zelefsky MJ et al. Pretreatment Nomogram Predicting Ten-Year Biochemical Outcome of 3D-CRT and IMRT in prostate cancer. Journal of Urology 70: 283-287.<br />
    8. 8. Risk Groups & Nomograms are Incomplete: <br />Other Clinical Factors are Predictive<br />
    9. 9. Percent Positive Biopsies<br />Michigan > 75 Gy <br />Mayo Intermediate Risk < 71 Gy<br />Harvard Intermediate Risk ~ 70 Gy<br />D’Amico A et al. The clinical utility of the PPB in Predicting Biochemical Outcome Following EBRT for Patients with Clinically Localized Prostate Cancer. IJROBP 2002; 49(3): 679 – 684.<br />Wong WW et al. Association of PPB and PNI with biochemical outcomes after EBRT. IJROBP; 60(1) 24-9. <br />Qian Y et al. The Percent Positive Biopsy Cores Improves Prediction of Prostate Cancer-Specific Death in Patients Treated with Dose-Escalated Radiotherapy. IJROBP; in press 2011<br /><ul><li>)</li></li></ul><li>Prostate Cancer Volume<br />VCa = Cancer-specific PSA/PSA in serum per cm3 of cancer<br />Fuchsjageret al. Predicting Post-External Beam Radiation Therapy PSA Relapse of Prostate Cancer Using Pretreatment MRI. IJORBP 2010; 78(3): 743-750.<br />Vca fx = Vca ultrasound prostate gland volume<br />D’Amicoet al. Prostate Cancer Volume Adds Significantly to PSA in the Prediction of Early Biochemical Failure After EBRT. IJORBP 1996; 35(2): 273-279.<br />
    10. 10. Perineural Invasion<br />Beard C et al. Perineural Invasion Associated with Increased Cancer-Specific Mortality After External Beam Radiation Therapy for Men with Low and Intermediate Risk Prostate Cancer. IJROBP 2006 60(2): 403-407.<br />Perineural Invasion Affects Biochemical Recurrence Free survival in Patients with Prostate Cancer Treated with Definitive EBRT. Hsiang-Hsuan M et al. Journal of Urology ; 70(1) 111-116.<br /><ul><li>)</li></li></ul><li>Radiographic T3 disease<br />250 patients<br />No hormones<br />Clinically localized prostate cancer “beyond low risk patients”<br />erMRI SVI was significant predictor of time to PSA failure<br />ECE in absence of SVI was not found to predict for PSA failure<br />Fuchsjageret al. Predicting Post-External Beam Radiation Therapy PSA Relapse of Prostate Cancer Using Pretreatment MRI. IJORBP 2010; 78(3): 743-750.<br />Nguyen PL et al. Quantifying the impact of seminal vesicle invasion identified using endorectal magnetic resonance imaging on PSA outcome after radiation therapy for patients with clinically localized prostate cancer. IJORBP 2004; 59(2): 400-5.<br />
    11. 11. PSA Kinetics<br />Pretreatment PSA Velocity and Risk of Death From Prostate Cancer Following External Beam Radiotherapy. D’Amico A et al. JAMA 2005; 294(4): 440-7.<br />Soto et al. Pretreatment PSA Velocity and Risk of Death From Prostate Cancer Following External Beam Radiotherapy. D’Amico A et al. JAMA 2005; 294(4): 440-7.<br />
    12. 12. Radiation Technique: IMRT<br />Zelefsky MJ et al. High Dose Radiation Delivered by IMRT Improves the Outcome of Localized Prostate Cancer. Journal of Urology 2001; 16: 876-881.<br />
    13. 13. Radiation Technique: IGRTInter- and Intrafraction Motion Management<br />Rectal distension at simulation predicts for increased biochemical & local failure when a daily repositioning technique isn’t used <br />Kupelian PA et al. Impact of Image Guidance on Outcomes After External Beam Radiotherapy for Localized Prostate Cancer. IJROBP 2008; 70(4): 1146-50.<br />de Crevoisier R et al. Increased Biochemical and Local Failure Rates in patients with distended rectum on the planning CT for prostate cancer radiotherapy. IJROBP 2005; 62: 965-73.<br />
    14. 14. Interval From Diagnosis to Start of EBRT & Treatment Delays<br />Nguyen PL et al. The Impact of a Delay in Initiating Radiation Therapy on Prostate-Specific Antigen Outcome for Patients with Clinically Localized Prostate Cancer. IJROBP 2005; 62: 965-73.<br />DAmbrosio et al. Does Treatment Duration Affect Outcome After Radiotherapy for Prostate Cancer. IJROBP 2008; 72: 1402-1407.<br />
    15. 15. Why Hypofractionate ? <br />Prostate Cancer is Radiobiologically Different<br />Series Method a/b<br />Brenner & Hall (1999) LDR / EBRT data 1.5<br />King & Fowler (2001) LDR / EBRT model 1.8 - 2.0<br />Fowler et al. (2001) LDR / EBRT data 1.49<br />Brenner et al. (2002) HDR data 1.2<br />Dasu (2007) Meta-analysis 1.85<br /><ul><li> Escalate dose radiobiologically</li></ul> ↑ Biologically effective dose = ↑ Tumor control<br /><ul><li> Reduce acute effects
    16. 16. Reduced to same level of late effects
    17. 17. Reduce overall treatment length</li></ul> ↑ Access to care<br /> ↑ Proportion of patients choosing radiation, <br /> ↑ Efficient use of medical resources<br /><ul><li> Facilitated by modern IGRT techniques</li></ul>↓ Margins<br /> ↓ Less normal tissue volume and dose<br />Dasu A “Is the a/b value for prostate tumors low enough to be safely used in clinical trials?” Clinical Oncology 2002; 19: 289-301<br />
    18. 18. What if a/b is that low?<br />Potential advantages of Hypofractionation<br />
    19. 19. Predictors of Clinical and Biochemical Endpoints Before External Radiotherapy<br />Radiation Dose<br />Stage<br />Gleason Score<br />PSA Kinetics<br />Risk Groups & Nomograms<br />Predictors of locally advanced or bulky disease:<br />Percent positive biopsies<br />Prostate cancer volume<br />PNI<br />rT3 disease<br />Radiation Technique: 3D-CRT vs. IMRT vs. IGRT<br />Inter- & Intrafraction Motion Management<br />Expediency of Delivery of EBRT<br />Fractionation Schedules<br />Molecular & Genetic Factors<br />Fields (WPRT vs. PORT)<br />Brachytherapy<br />Androgen Deprivation Therapy<br />

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