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NY Prostate Cancer Conference - B.W. Cox - Session 4: Predicting clinical and biochemical endpoints before external radiotherapy
1. Predicting Clinical and Biochemical Endpoints Before External Radiotherapy Brett Cox, M.D. Assistant Attending Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center
2. Dose Response in Prostate Cancer Fowler JF, et al. IJROBP 2003;56:1093-1104
4. MSKCC Dose Escalation Experience:Long Term Follow-up 2047 patients with T1-T3 prostate cancer 1988 - 2004 3D-CRT or IMRT 66 Gy-86.4 Gy Median Age 69 years (range 45-86) Median follow-up: 6.6 years (range: 3-18 yrs) PSA RFS Intermediate and High DMFS Intermediate and High 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
5. Stage, Gleason Score, PSA < 10 vs. > 10 ng/ml < 6 vs. 7-10 < T2c vs. > T2c 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
6. Risk Group ASTRO bRFS5 99% 79% 72% Nadir+2 bRFS5 98% 85% 70% 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 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 MD Anderson Dose Escalation Trial: Kuban D et al. IJROBP 2008;70(1): 67-74
7. MSKCC Nomogram 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.
8. Risk Groups & Nomograms are Incomplete: Other Clinical Factors are Predictive
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11. PSA Kinetics 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. 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.
12. Radiation Technique: IMRT Zelefsky MJ et al. High Dose Radiation Delivered by IMRT Improves the Outcome of Localized Prostate Cancer. Journal of Urology 2001; 16: 876-881.
13. Radiation Technique: IGRTInter- and Intrafraction Motion Management Rectal distension at simulation predicts for increased biochemical & local failure when a daily repositioning technique isn’t used Kupelian PA et al. Impact of Image Guidance on Outcomes After External Beam Radiotherapy for Localized Prostate Cancer. IJROBP 2008; 70(4): 1146-50. 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.
14. Interval From Diagnosis to Start of EBRT & Treatment Delays 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. DAmbrosio et al. Does Treatment Duration Affect Outcome After Radiotherapy for Prostate Cancer. IJROBP 2008; 72: 1402-1407.
18. What if a/b is that low? Potential advantages of Hypofractionation
19. Predictors of Clinical and Biochemical Endpoints Before External Radiotherapy Radiation Dose Stage Gleason Score PSA Kinetics Risk Groups & Nomograms Predictors of locally advanced or bulky disease: Percent positive biopsies Prostate cancer volume PNI rT3 disease Radiation Technique: 3D-CRT vs. IMRT vs. IGRT Inter- & Intrafraction Motion Management Expediency of Delivery of EBRT Fractionation Schedules Molecular & Genetic Factors Fields (WPRT vs. PORT) Brachytherapy Androgen Deprivation Therapy
Editor's Notes
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 - > 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 > 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 > 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 < 24 month compared to pre-RT PSA-DT > 24 month (19 month vs. 24 month). Additionalsignificant predictors of post-RT PSA rate of rise included GS (p < 0.0001), iPSA (p < 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
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.