cyberknife sbrt for the treatment of ......cyberknife sbrt for the treatment of prostate cancer: 5...

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.