Radiotherapy for Localized Prostate Cancer:Anatomy / Planning

Dose Escalation / Dose FractionationCompeting Treatment Modalities

Patrick Kupelian, M.D.Professor and Vice Chair

University of California Los AngelesDepartment of Radiation Oncology

pkupelian@mednet.ucla.edu

February 2013

Disclosures

Research grants / Honoraria / Advisory Board / Royalties:

AccuraySiemens MedicalVarian MedicalViewray Inc.VisionTree

Outline

Anatomy: Prostate MRIPelvic LN - CT

Treatment options:SurveillanceSurgeryRadiotherapy

Radiotherapy PlanningImportance of Dose EscalationHypofractionation - SBRT

Prognosticators

Stage, PSA and Gleason scoreNumber of cores positive (proxy for disease volume)

Low risk: <T2A, Gleason <6, PSA <10 - (Single focus GS 7?)

Intermediate: Heterogeneous group

High risk: T3 or GS >8 or PSA >20Two factors: Stage >T2B, GS 7, PSA between 10 and 20 - (Single focus GS 8, low PSA?)

Prostate Anatomy: CT vs US vs MR

• CT: Widely available, cannot delineate full anatomy

• Ultrasound: Not routinely available for EBRT. Cannot distinguish benign from malignant tissue

• MRI: Not routinely available. Higher level detail. Multiparametric imaging allows additional detail.

?

?

Courtesy D. Margolis, UCLA, 2013

Basic Prostate Anatomy:Cross-Sectional Imaging

• Lengthwise (sagittal) cross-section:• Peripheral Zone (~70% of prostate cancer)• Central Zone (5-8% of prostate cancer)• Transitional Zone (~20% of prostate cancer) • Anterior Fibro-Muscular

Stroma (devoid of

glandular components)• Seminal Vesicle• Urethra and Bladder

Courtesy D. Margolis, UCLA, 2013

Basic Prostate Anatomy: Multiple Levels

• Peripheral Zone• Central Gland• Transitional Zone• Anterior Fibromuscular

Stroma• Urethra

Courtesy D. Margolis, UCLA, 2013

Prostate anatomy: Additional Views

• Sagittal image through the prostate: B: bladder, SV: seminal vesicles, FS: fibromuscular stroma, P: prostate

• Coronal Oblique image through the prostate: SV: seminal vesicles, P: prostate.

B

FS

P

SVRectal

Probe

SVSV

P

Membranous Urethra

Courtesy D. Margolis, UCLA, 2013

Criteria for Prostate Cancer on T2-Weighted MRI

• Round, ovoid, or irregular dark

regions on T2WI without

corresponding hemorrhage on T1WI

• Irregular shape, disruption, or

bowing of capsule (blue arrow)

• Penetration or disruption of the dark

band with invasion of neurovascular

bundle or seminal vesicle (orange

arrow)

• Obliteration of the rectoprostatic

angle (preserved, green arrow)

Courtesy D. Margolis, UCLA, 2013

Pelvic Nodal Consensus CTV ContoursRTOG CONSENSUS GUIDELINES

Colleen A F Lawton MDMedical College of Wisconsin

• Treatment of Presacral LNs (subaortic only)• 7 mm margin around iliac vessels, carving out bowel,

bladder and bone• Commence contouring at distal common iliac vessels at

L5/S1 interspace• Stop external iliac contours at top of femoral heads

(boney landmark for Ing. ligament)• Stop contours of obturator LNs at top of symphsis pubis

25/93

32

32/93

58

58/93

61

61/93

63

63/93

Localized Prostate Cancer:Competing Treatment Modalities

Surveillance (No Dose option)

Radiotherapy: - High dose EBRT- Hypofractionation (incuding SBRT)- Brachytherapy

Surgery: - Radical Retropubic- Laparoscopic / Robotic

CryosurgeryHIFU

No DosePIVOT TRIAL

Radical Prostatectomy vs Observationfor Localized Prostate Cancer: Toxicity

EXTERNAL BEAM RT COMPARISON WITH OTHER MODALITIES

Importance of DosePSA failure by Treatment modality

Kupelian, Potters et al. IJROBP 2004;58:25-33.

Effectiveness of High Dose RT

Intermediate risk prostate Ca: Clinical stage of T2b or T2cBiopsy Gleason score (bGS) 7, orPretreatment PSA between 10 and 20 ng/mL.

Treatment arms: RRP vs Lap RP vs EBRT vs PIN=979, median follow-up 65 monthsTreated between 1996 and 2005Minimum of 2 years of follow-upAt least 4 follow-up PSA levels

Vassil et al. Urology 76, 2010

Effectiveness

Lap RP EBRT

Vassil et al. Urology 76, 2010

Localized Prostate Cancer – Radiotherapy Today

Patient outcome improvements

Improved Cure Rates: Dose escalationDoses in the 75-85 Gy range

Decreased toxicityGrade 3 toxicities < 5%

ConvenienceHypofractionation / SBRT / Brachytherapy

BENEFIT FROM DOSE ESCALATION

Questions

Who benefits?

Magnitude of benefit?

Literature Review;Series reported up to 2008External beam RT, at least 2 dose groupsNo brachytherapyNo hypofractionation>200 patients

Data adapted from Diez et al. IJROBP 2010

Studies:5 retrospective4 randomized

BENEFIT FROM DOSE ESCALATION

BENEFIT - LOW RISK

Diez et al. IJROBP 2010

Diez et al. IJROBP 2010

BENEFIT - INTERMEDIATE-HIGH RISK

919 Stage T1-T3N0M0 - RT alone - treated between 1986 and 2000

RT dose N Median Dose Median FU (mos)All patients 919 97 <72 Gy 552 68 Gy 112 >72 <82 Gy 215 78 Gy 94>82 Gy 152 83 Gy 65

LOCAL FAILURE - DOSE GROUPS

Kupelian et al. IJROBP. 71, 6–22, 2008

DISTANT FAILURE - DOSE GROUPS

Kupelian et al. IJROBP. 71, 6–22, 2008

Dose Escalation for Localized Prostate Ca

Benefit of dose escalation is seen in all risk groups

The slope of the dose response curve is relatively shallow, as demonstrated by data from randomized studies

Need large dose increases to see differences in outcomes.

RT dose has an impact on clinical outcomes, most importantly distant metastasis rates.

PATIENT-REPORTED TOXICITY

Patient Reported Quality of Life

Quality of life and satisfaction with outcome among prostate-cancer survivors.Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.

1201 patients, 625 spouses or partners

Prostatectomy / Brachytherapy / External-beam RT

No deaths occurred.Rare serious adverse events.

Symptoms exacerbated by obesity, a large prostate size, a high PSA, and older age.

Patient Reported Toxicity

Quality of life and satisfaction with outcome among prostate-cancer survivors.Sanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.

“Each prostate-cancer treatment was associated with a distinct pattern of change in quality-of-life domains related to urinary, sexual, bowel, and

hormonal function“.

Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.

Urinary Scores

Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.

Bowel Scores

Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.

Vitality-Hormonal Scores

Patient Reported Quality of LifeSanda et al, N Engl J Med. 2008 Mar 20;358(12):1250-61.

Sexual Scores

TECHNIQUE

TREATMENT PLANNING

Anatomy:Target:CTV: Low risk: Prostate only

Intermediate risk: Prostate + SV (proximal 1 cm) High risk: Prostate + SV +/- Pelvic Lymph nodes

 (Postoperative Prostate Bed: RTOG guidelines) PTV: CTV+ 5 mm (except 3 mm posteriorly) – Daily Guidance OARs / Critical Structure Definitions:Rectum: Extends 1 cm sup + inf to PTVBladder: Entire organFemurs: To level of ischial tuberositiesLarge/Small Bowel: within the primary beam aperturePenile bulb: Entire organ

Planning:Target Goals: PTV: 95% of PTV volume to get 95-110% of Rx dose.  IMRT fractionated (81 Gy in 45 fractions):OAR Dose Constraints: Rectum V50 < 50%

V80 < 20%V90 < 10%V100 < 5%

Bladder V50 < 40%V100 < 1.1%

Femurs V40 < 5%

Small Bowel V50 < 1%

External Beam Radiotherapy for Localized Prostate Cancer

DOSE ESCALATIONMETHODS

ESCALATION OF TOTAL DOSES

ESCALATION OF FRACTION SIZES

Conventional Hypofractionation

CONVENTIONAL FRACTIONATIONversus

HYPOFRACTIONATION versus

STEREOTACTIC BODY RADIOSURGERY (SBRT)

1 45

SBRT

5

Number of fractions

Fraction Size

>7 Gy 1.8-2.0 Gy

~35

ConventionalHypofractionation

Biological Rationale

Ablative?? N o r m a l t i s s u e s p a r i n g

Total Dose

~35-50 Gy ~75-85 Gy~50-75 Gy

bR

FS

0

.2

.4

.6

.8

1

0 12 24 36 48 60 72 84Months

Low Risk

Intermediate Risk

High Risk

68%85%95%

p<0.010

.2

.4

.6

.8

1

0 12 24 36 48 60 72 84

bR

FS

Months

Low Risk

Intermediate Risk

High Risk

72%83%94%

p<0.01

Biochemical Relapse Free Survival By Risk Group

ASTRO definition Phoenix definition

THE CLEVELAND CLINIC EXPERIENCE: FIRST 770 PATIENTS

Kupelian et al., IJROBP, 68(5):1424-30, 2007

Median follow-up: 45 months

Toxicity (RTOG scores)

Kupelian et al., IJROBP, 68(5):1424-30, 2007

HYPOFRACTIONATION TRIALS

LOW AND LOW / INTERMEDIATE RISK

HYPOFRACTIONATION PROTOCOLS: Phase III trials

MDACC (Pollack/Kuban): IMRT / Daily localization (Transabdominal US)N=204. Median follow-up 5.8 years

75.6 at 1.8 Gy vs 72.0 at 2.4 Gy 5 yr bRFS 94% 97%Late Gr <3 GI tox 5% 10% p=0.06

Late Gr <3 GU tox 15% 15% p=0.43

Kuban et al, IJROBP 78, S58 2010, Skinner et al, ASTRO 2012

Fox Chase (Pollack): IMRT / Daily localization (Transabdominal US)Median follow-up 55 mos

76.0 at 2.0 Gy vs 70.2 at 2.7 Gy No difference in biochemical failuresSlightly higher late GU effects with hypofracationation.Pre-RT urinary status: Important predictor of GU toxicity

Ontario Clinical Oncology Group (OCOG) : PROFIT – Prostate Fractionated Irradiation TrialN=120460.0 at 3.0 Gy vs 78.0 at 2.0 GyDaily localization

HYPOFRACTIONATION TRIALS

CHHiP Trial: N=30261st randomization: Dose: 60 Gy at 3 Gy vs 74 Gy at 2 Gy per fx2nd randomization: Image Guidance vs No Image Guidance3rd randomization: Margins

RTOG 04-15: N=1067 low risk patients70.0 at 2.5 Gy vs 73.8 at 1.8 GyIMRT or CRT / Daily localizationClosed Fall 2009

HYPOFRACTIONATION FOR HIGH RISK?

62 Gy/20 fractions / 5 weeks(3.1 Gy per fraction)

vs80 Gy/40 fractions / 8 weeks

(2 Gy per fraction)9 months ADTN=168

High-Risk:bGS of 8–10iPSA >20, or two of the following:iPSA 11–20, T>2c, GS=7

Arcangeli et al, IJROBP 78, 11-18, 2010

Italian Hypofractionation Randomized study for High Risk Cases

HYPOFRACTIONATED RT BETTER?

2.0 Gy x 40

3.1 Gy x 20

HYPOFRACTIONATION AND NODAL RT:Simultaneous prostate vs LN fraction size differences

Pervez et al. IJROBP. 76: 57-64, 2010

PROSTATE SBRT: 5 fractions or lessFaster, Better, Cheaper

SBRT for Prostate Cancer

Multiple reports, single arm studies: excellent control.Med follow-up still < 5 years

• Madsen IJROBP 2007• Fuller IJROBP 2008• King IJROBP 2009• King IJROBP 2011• Friedland TCRT 2009• Katz BMC Urol 2010• Wiegner IJROBP 2010• Bolzicco TCRT 2010

• Aluwini J Endourol 2010• Freeman RO 2010• Townsend AJCO 2011• Kang Tumori 2011• Jabbari IJROBP 2011• Mantz IJROBP 2011• Boike JCO 2011

Efficacy of SBRT

• Katz et al. ASTRO 2012Multi-institutional pooled data; 8 institutions35-40 Gy in 4-5 fractions1101 patients, ~ 3 yr median FU (6-72 mos)335 cases with a >4 years follow-up (median 53 mos)

Risk groups:Low: 639 59%Intermediate: 326 30%High: 124 11% Any androgen deprivation:No: 872 86%Yes: 146 14%

Dose groups:35 Gy: 385 35%36.25 Gy: 589 53%38-40 Gy: 127 12%

Katz et al. ASTRO 2012

0

.2

.4

.6

.8

1

Cum

. S

urv

ival

0 10 20 30 40 50 60 70 80Time

Censor Times (LO)

Cum. Survival (LO)

Censor Times (INT)

Cum. Survival (INT)

Censor Times (HI)

Cum. Survival (HI)

Kaplan-Meier Cum. Survival Plot for True_Fail_TCensor Variable: True_FailGrouping Variable: Risk_G_dAmico

LowIntermediate

High

335 cases with >4 years of follow-up (median 53 months) 5-year bRFS rates: Low risk: 97%

Intermediate-risk: 89%

1101 SBRT cases

Stereotactic Body Radiotherapy forIntermediate-risk Organ-confined Prostate Cancer:

Interim Toxicity and Quality of Life Outcomes from a Multi-Institutional StudyRobert Meier, MD

Swedish Cancer Institute, Seattle WA

Beth Israel Deaconess Medical Center, Boston, MA

Central Baptist Hospital, Lexington, KY

St. Joseph Mercy Hospital System, Ypsilanti, MI

Community Cancer Center, Normal, IL

Capital Health System, Trenton, NJ

Northwest Community Hospital, Arlington Heights, IL

Jupiter Medical Center, Jupiter, FL

Meier et al., ASTRO 2012

Toxicity and Quality of Life

Treatment Planning• Prostate prescribed 8 Gy x 5 = 40 Gy

• Prostate + proximal 2 cm seminal vesicles + 3-5 mm:7.25 Gy x 5 = 36.25 Gy

Meier et al., ASTRO 2012

• 129 patients 2007- 2010, 21 centers• Follow up 2 – 4½ yrs Median 36 months

AUA Score after SBRT

0 6 12 18 24 30 360

2

4

6

8

10

12

14

16

Months After Treatment

Mea

n A

UA

Sco

reSimilar to an implant

Multi-institutional prospective study PATIENT REPORTED OUTCOMES

Meier et al., ASTRO 2012

Late Urinary Toxicity: Gr 2+

Meier et al., ASTRO 2012

Late Bowel Toxicity: Gr 2+

Meier et al., ASTRO 2012

Planning SBRT (5 FRACTIONS):Target Goals: PTV: 95% of PTV volume to get 95-110% of Rx dose.  SBRT: (8 Gy x 5)OAR Dose Constraints: Rectum V50 (20 Gy) < 50%

V80 (32 Gy) < 20%V90 (36 Gy) < 10%V100 (40 Gy) < 5%

Bladder V50 (20 Gy) < 40%V100 (40 Gy) < 1.1%

Femurs V40 (16 Gy) < 5%

Small Bowel V50 (20 Gy) < 1%

CONCLUSIONS

Hypofractionated approaches (including SBRT) have favorable toxicity and efficacy profiles with the available follow-up.

Late rectal toxicity with hypofractionated RT is minimal. Urinary toxicity is marginally more prominent: Avoid patients with poor pre-radiation urinary function (similar to implants).

Even if only equivalent to standard fractionated RT with respect to efficacy, hypofractionation should be adopted due to convenience and cost advantages.

Hypofractionation better for high risk cancers?

Phase I studies are still needed: Approaches with novel doses, margins, dose sculpting and timing of delivery should be investigated.

Radiotherapy for Localized Prostate Cancer:

Dose EscalationDose Fractionation

Patrick Kupelian, M.D.Professor and Vice Chair

University of California Los AngelesDepartment of Radiation Oncology

pkupelian@mednet.ucla.edu

February 2013