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CYBERKNIFE SBRT FOR THE TREATMENT OF PROSTATE CANCER: 5 VS. 44 FRACTIONSTHE PHILADELPHIA CYBERKNIFE CENTER
EXPERIENCE
Olusola Obayomi-Davies M.D.Philadelphia CyberKnife Center
September 26th, 2017
Disclosure & Disclaimer
• An honorarium is provided by Accuray for this presentation
• The views expressed in this presentation are those of the presenters and do not necessarily reflect the views or policies of Accuray Incorporated or its subsidiaries. No official endorsement by Accuray Incorporated or any of its subsidiaries of any vendor, products or services contained in this presentation is intended or should be inferred.
Background-Localized Prostate Cancer• Estimated 160,000 men will be affected in
2017– 27,000 deaths– #1 cancer diagnosis in men– #3 cause of cancer related mortality
• Typically detected by PSA screening– USPSTF D-Recommendation (2012)– C Recommendation 2017 (55-69)
Cancer Facts & Figures ACS 2017Screening for Prostate Cancer: U.S. Preventive Services Task ForceRecommendation Statement, 2012, 2017.
Treatment Options-Localized Prostate Cancer
• Surgery-Prostatectomy• Radiation Therapy
– IMRT Conventional Fractionation (40-48)– IMRT Moderate Hypofractionation (20-28)– Proton Therapy – Brachytherapy
• HDR or LDR
– CyberKnife SBRT (5 treatments)
N Engl J Med 2016;375:1415-24
• 1643 men (50-69) randomized to AS, Surgery or Radiation therapy between 1999-2009.
• Primary outcome: Prostate cancer specific mortality at 10 years
The New England Journal of MedicineOctober 13, 2016 Vol. 375 No. 15
10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer
F.C. Hamdy, J.L. Donovan, J.A. Lane, M. Mason, C. Metcalfe, P. Holding, M. Davis, T.J. Peters, E.L. Turner
N Engl J Med 2016;375:1415-24
The New England Journal of MedicineOctober 13, 2016 Vol. 375 No. 15
10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer
F.C. Hamdy, J.L. Donovan, J.A. Lane, M. Mason, C. Metcalfe, P. Holding, M. Davis, T.J. Peters, E.L. Turner
IMRT-Localized Prostate Cancer• Daily radiation therapy for 8-9
weeks (40-48)• Hypofractionated regimen
(20-38) fractions• Rectal and Bladder sparing• Significant dose escalation
from 3D-CRT• Popular, high penetration in
radiation oncology community• Effective
Sveistrup et al. Radiation Oncology 2014, 9:44
External Beam Radiation5yr BDFSLow 95%Inter. 82%High 62%
• 1988-2004, 2047 patients 3D or IMRT (1996)• 66-86.4 Gy in 33-48 fractions.
Zelefsky, Int. J. Radiation Oncology Biol. Phys., Vol. 71, No. 4, pp. 1028–1033, 2008
IMRT-81 Gy
• 1996-2000, 561 patients• 81 Gy • Low rates of rectal and urinary toxicity
Zelefsky, J. Urology Vol. 176, 1415-1419, October 2006
8yr BRFSFavorable 85%Intermediate 76%Unfavorable 72%
IMRT-For Localized Prostate Cancer: Concerns
• Radiation Dose: Is 80-86 Gy high enough? – Further dose escalation required?
• Normal Structures: – Bowel, Bladder
• Opportunity cost:– 8-9 weeks of daily therapy
• Other:– Prostate motion, rectal and bladder filling
CyberKnife® SBRT-Rationale
• Radiobiology: Low αβ ratio of prostate cancer– Favors larger fractionation schemes
• Normal Structure sparing– Rectum, Bladder, Penile bulb
• Opportunity cost: 5 days versus 8-9 weeks of treatment
• Technology: Prostate motion management
CyberKnife® Prostate SBRT Rationale: αβ ratio
(2 Gy x 37 fx)bNED (5 year) 75%
SBRT (7.25 Gy x 5 fx)bNED (5 year), 94%
Fowler, Acta Oncol, 2005
CyberKnife® SBRT: αβ ratio
Wallace, Radiation Biology 2014
Prostate Motion: Where is the target?
Kupelian et al, IJROBP, 2007
CyberKnife® SBRT For Localized Prostate Cancer: Overview
• Robotic Radiosurgery Platform
• Deliver high dose radiation in 5 treatments– ≥8 weeks of daily radiation
equivalent
• Sparing of normal Structures from high dose radiation– 3-5mm margins
• Live target tracking with gold fiducials
CyberKnife.com, accessed 7/2017
CyberKnife® SBRT For Localized Prostate Cancer
Chen L. et al Rad. Onc., 2013
CyberKnife® SBRT-Concerns
• Long term data maturing
• Few prospective comparisons to more established techniques
• Concerns about late bladder and GU toxicity
• Healthcare Costs: Shrinking healthcare $$
Published Prostate SBRT Series
• 515 patients between 2006-2010 treated with CyberKnife® SBRT, 35-36.25 Gy, daily.
• NCCN Risk Stratification– Low risk-324– Intermediate risk-153– High Risk-38
• Median Follow-up 84 months
Predicting Biochemical Disease-Free Survival after Prostate Stereotactic Body Radiotherapy: Risk-Stratification and
Patterns of FailureAlan Katz, Silvia C. Formenti and Josephine Kang
Katz A, (2016) Front. Oncol. 6:168
Predicting Biochemical Disease-Free Survival after Prostate Stereotactic Body Radiotherapy: Risk-Stratification and
Patterns of FailureAlan Katz, Silvia C. Formenti and Josephine Kang
Prostate SBRT: Quality of Life
• Urinary quality of life
• Bowel quality of life
• Sexual Function
Prostate SBRT QOL: GI/GU Toxicity
Meier, R. Front. Oncol, 2015
Prostate SBRT QOL: GI/GU Toxicity
Meier, R. Front. Oncol, 2015
Prostate SBRT QOL: GU/ED
Meier, R. Front. Oncol, 2015
• 97 Hormone naive men (aged 48-82)• Adequate erectile function pre-treatment
– Firm enough for penetration
• 35-36.25 Gy in 5 fractions• Minimum 24 month follow-up• Assessments: SHIM, EPIC and
Medication/Device Questionaires
Obayomi-Davies et al. Radiation Oncology 2013, 8:256
Potency preservation following stereotactic body radiation therapy for prostate cancer
Olusola Obayomi-Davies, Leonard N Chen, Aditi Bhagat, Henry C Wright, Sunghae Uhm, Joy S Kim, Thomas M Yung, Siyuan Lei, Gerald P Batipps, John Pahira, Kevin G McGeagh, Brian T Collins, Keith Kowalczyk, Gaurav Bandi, Deepak Kumar, Simeng Suy, Anatoly Dritschilo, John H Lynch, Sean P Collins
Obayomi-Davies et al. Radiation Oncology 2013, 8:256
Potency preservation following stereotactic body radiation therapy for prostate cancer
Olusola Obayomi-Davies, Leonard N Chen, Aditi Bhagat, Henry C Wright, Sunghae Uhm, Joy S Kim, et al.
The Philadelphia CyberKnife Experience
• First CyberKnife®
System facility in Philadelphia region
• Opened in 2006• Pioneers
– Luther Brady/Jack Fowler
– Rachelle Lanciano– John Lamond
• 100 consecutive patients with NCCN intermediate or highrisk prostate cancer treated with definitive SBRT wereidentified.
• Patients with <2 years biochemical follow-up were excluded(n=26).
• Biochemical failure was defined as prostate-specific antigen(PSA) rise > 2ng/ml above nadir (Phoenix definition)
• Analyses performed using the Kaplan Meier method, withdifferences compared using log-rank test.
Stereotactic Body Radiation Therapy for Treatment of Intermediate-and High-Risk Prostate CancerMark Dziemianowicz MD, Rachelle Lanciano MD, Olusola Obayomi-Davies MD, Steven Arrigo MD, John Lamond, MD, Jun Yang PhD, Jing Feng MS, Michael Mooreville MD, Bruce Garber MD, Michael Good, Luther Brady MD.Philadelphia CyberKnife, Havertown, PA
• Risk classification: Zumsteg et al. criteria for favorable intermediate-risk (FIR) and unfavorable intermediate risk (UIR) disease– FIR: NCCN intermediate risk with a single NCCN intermediate
risk factor(cT2b-c, PSA 10-20 or Gleason score 7), Gleason < 3+4, and <50% of biopsy cores positive for cancer
– UIR: NCCN intermediate risk with ≥2 intermediate risk factors (cT2b-c, PSA 10-20 or Gleason score 7), primary Gleason pattern 4, or >50% biopsy cores positive for cancer
– High risk (HR) patients classified per NCCN guidelines
Zumsteg et al. Eur Urol Dec;64(6):895-902
Stereotactic Body Radiation Therapy for Treatment of Intermediate-and High-Risk Prostate CancerMark Dziemianowicz MD, Rachelle Lanciano MD, Olusola Obayomi-Davies MD, Steven Arrigo MD, John Lamond, MD, Jun Yang PhD, Jing Feng MS, Michael Mooreville MD, Bruce Garber MD, Michael Good, Luther Brady MD.Philadelphia CyberKnife, Havertown, PA
Philadelphia CyberKnife: Treatment Planning• All patients received
CyberKnife® SBRT
• Dose: 35-37.5 Gy/5 fractions
• CTV: Defined as prostate plus seminal vesicles
• PTV: 5mm, 3mm posteriorly– (Now 3mm superiorly)
Philadelphia CyberKnife: Results
Philadelphia CyberKnife: Results
5yr bRFSFIR-100%, p=0.007UIR-83.3%, p=0.07HR-92.3%
5yr OSFIR-96.2%, p=0.08UIR-71.4%, p=0.52HR-89.5%
• 5-year bRFS: 89.7%• 5 failures: 3 distant, 2 biochemical only
• 5-year OS: 87.3%• 7 deaths: none caused by prostate cancer
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8
PSA
bRFS
Time (years)Number at risk
74 51 40 27 13 8
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8
Ove
rall
Surv
ival
Time (years)
Philadelphia CyberKnife: Results
00.10.20.30.40.50.60.70.80.9
1
0 1 2 3 4 5 6 7 8
PSA
bRFS
Time (years)
4+3
≤3+4
≥4+4
Log-rank p=0.0195-year bRFS< 3+4 100%4+3 75%> 4+4 80%
Philadelphia CyberKnife: Results
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8
PSA
bRFS
Time (years)
ADT
NoADT
Number at riskADT 24 18 16 12 4 2 No ADT 50 33 24 15 9 6
Log-rank p=0.403
5-year BRFSADT 100%No ADT 83.4%
Patients receiving ADT n (%)FIR 13 (37.1%)UIR 3 (17.6%)HR 8 (36.4%)
Philadelphia CyberKnife: ToxicityN=74 %
Late GU ToxicityGrade 1 10 14%Grade 2 19 26%Grade 3 1 1%Grade 4 0 0%
Late GI ToxicityGrade 1 2 3%Grade 2 0 0%Grade 3 0 0%Grade 4 0 0%
Late Erectile DysfunctionGrade 1 15 20%Grade 2 24 32%Grade 3 8 11%
Front. Oncol., 23 August 2016
The Comparison of Stereotactic Body Radiation Therapy and Intensity-Modulated Radiation Therapy for Prostate
Cancer by NCCN Risk GroupsAnthony Ricco,1 Genevieve Manahan,1,2 Rachelle Lanciano,1,2,* Alexandra Hanlon,3 Jun Yang,1,2 Stephen Arrigo,1John Lamond,1,2 Jing Feng,1 Michael Mooreville,1 Bruce Garber,1 and Luther Brady1,2
1Philadelphia Cyberknife, Delaware County Memorial Hospital, Havertown, PA, USA 2Drexel University College of Medicine, Philadelphia, PA, USA 3University of Pennsylvania, Philadelphia, PA, USA
Philadelphia CyberKnife Experience• Between 2007 and 2012, 270 consecutive men were treated for
organ confined prostate cancer with either IMRT (n=120) or SBRT (n=150)
• Charts were abstracted for pretreatment and treatment factors as well as outcome and toxicity
• NCCN Risk Group Guidelines V. 2.2015 were used to stratify patients into Very Low, Low, Intermediate, High and Very High risk groups.
• Dose: – IMRT: 75.6-78 Gy in 39-42 fractions– SBRT: 36.25-37.5 Gy in 5 fractions
Philadelphia CyberKnife Experience• Late toxicity was graded by RTOG grading system at last
follow up
• Nadir +2 considered Biochemical failure
• Statistical analysis included Fisher’s Exact Test and Two-Sample Independent T-Test for comparison of pretreatment factor distribution between IMRT and SBRT, Kaplan Meier for comparison of curves
• Propensity Score matched comparison
Philadelphia CyberKnife Experience
6-year FFBF 91.9% for SBRT88.9% for IMRT
Philadelphia CyberKnife Experience
Ricco et al, Front. Oncol. August 2017
• Propensity score matched (PSM) analysis with the National Cancer Database (NCDB) for the comparison of stereotactic body radiation therapy (SBRT) and intensity modulated radiation therapy (IMRT) for organ confined prostate cancer
• Men with localized prostate cancer treated with IMRT to a dose ≥72 Gy and ≥35 Gy for SBRT to the prostate only
• Men treated with previous surgery, brachytherapy, or proton therapy were excluded.
• Matching was performed to eliminate confounding variables via PSM. Simple 1–1 nearest neighbor matching resulted in a matched sample of 5,430 (2,715 in each group).
Propensity Score Matched Comparison of Intensity Modulated Radiation Therapy vs Stereotactic Body Radiation Therapy for
Localized Prostate Cancer: A Survival Analysis form the National Cancer Database
Anthony Ricco, Alexandra Hanlon and Rachelle Lanciano
Philadelphia CyberKnife: NCBD
Ricco et al, Front. Oncol. August 2017
Philadelphia CyberKnife: NCBD
Ricco et al, Front. Oncol. August 2017
Philadelphia CyberKnife: NCDB
Ricco et al, Front. Oncol. August 2017
Philadelphia CyberKnife: NCDB
Ricco et al, Front. Oncol. August 2017
Philadelphia CyberKnife: NCDB
Ricco et al, Front. Oncol. August 2017
Ongoing Trials
CyberKnife® SBRT for Localized Prostate Cancer: Summary
• Excellent outcomes from published data– Similar to existing techniques
• Short duration– Opportunity cost
• Dose escalation compared to conventional fractionation
• Low toxicity profile with excellent QOL outcomes• Lower health care costs
Conclusion
• CyberKnife® Prostate SBRT offers an excellent radiation therapy alternative to existing techniques.
• The increased convenience, cost-effectiveness and unique radiobiology of prostate cancer offer advantages compared to existing treatment platforms.
• Clinical outcomes are at least equivalent compared to existing techniques.